Mild Traumatic Brain Injuries were previously undiagnosable, and therefore treatment uncertain, and damages speculative

 

Authors:  Robert Bitonte, Bianca Tribuzio, Kim Hecht,  and Donald J. DeSanto


 

Introduction

 

Every year, an estimated 1.5 million individuals sustain a traumatic brain injury (TBI), and approximately 75% of these are classified as a mild TBI [1,2]. The American Congress of Rehabilitation Medicine defines a mild traumatic brain injury as a patient “who has had a traumatically induced physiological disruption of brain function, as manifested by at least one of the following:

  1. any period of loss of consciousness;
  2. any loss of memory for events immediately before or after the accident;
  3. any alteration in mental state at the time of the accident (eg, feeling dazed, disoriented, or confused); and
  4. focal neurological deficit(s) that may or may not be transient;

but where the severity of the injury does not exceed the following:

  • loss of consciousness approximately 30 minutes or less;
  • after 30 minutes, an initial Glasgow Coma Scale (GCS) of 13-15; and
  • post-traumatic amnesia (PTA) not greater than 24 hours.”[3]

Mild TBI has been termed a “silent epidemic,” [4] because many patients do not have visible physical signs.  Rather, many patients possess disabling cognitive, psychological, and/or behavioral impairments and employment disabilities that are often unnoticed or misdiagnosed.  Individuals seeking medical attention generally receive a standard history and physical exam. Further imaging such as a head Computerized Tomography (CT) or possibly Magnetic Resonance Imaging (MRI) will usually be obtained if the patient has loss of consciousness, posttraumatic amnesia, focal neurological deficits, physical signs of a skull fracture, or was involved in a dangerous mechanism of injury, or are older than the age of 65 [5]. The current diagnostic tests are neither sensitive nor specific enough to identify individuals who have sustained a mild TBI [6-8]. Individuals therefore may not be receiving the proper diagnosis, and without a diagnosis, it is difficult to provide precise and appropriate clinical management.  Accurate diagnosis would also be of immense assistance in distinguishing those that truly suffer from mild TBI sequelae as opposed to those with malingering symptoms [9].

Emerging research in imaging tests and serum biomarkers appear to assist with a more accurate diagnosis of mild TBI [6-8]. These imaging tests are better at identifying microstructural damage like diffuse axonal injury (DAI) and small hemorrhages that occurs in mild TBI [10]. The biomarkers are specific proteins released after injury [11]; which include: S100B, Neuron Specific Enolase (NSE), and Cleaved-Tau Protein (CTP) [8]. S100B has the most promising research at this time and could be a potential screening tool with its increased sensitivity for identifying mild TBI [5,12]. 

Considering the number of individuals that sustain a mild TBI, and the cost of lost productivity associated with this problem, it is important to establish a diagnosis of mild TBI in order to appropriately treat those most affected by the injury.  We propose individuals that are medically evaluated for mild TBI receive a standard history and physical exam combined with newer imaging tests, along with serum biomarkers to provide a precise and timely diagnosis of mild TBI. These measures will help ensure appropriate treatment to be initiated and payors be identified.

 

Imaging

 

The current difficulty in the definitive diagnosis of mild TBI can be partly attributed to the fact that when patients are evaluated with imaging tests, it is done with CT or MRI, which are mainly aimed at identifying macroscopic lesions.  However, these conventional imaging tests are limited in their capacity to assess microscopic white matter injury associated with DAI. DAI is caused by acceleration and deceleration forces or rotation forces acting on the head, leading to shearing of the brain tissue [13].  Only a small percentage of patients with mild TBI demonstrate visible pathology such as fractures, contusions, and hemorrhages on head CT. In a review study that examined 4000 patients, 5-10% of mild TBI patients with a GCS score of 15 had an abnormal head CT [7]. In a similar study by Harad et al. only 20-30% of patients with initial GCS score of 13 had an abnormal head CT. [14].Standard MRI has improved detection of small hemorrhages, herniation, midline shift and brain edema compared to the use of CT for screening of these problems [10].  Despite these improvements over CT, standard MRI is not suited to identify diffuse axonal injury. Furthermore,abnormal findings onCT and MRI do not correlate with decreased neuropsychological outcomes acutely at 1 month or at one year follow up [15]. These findings suggest conventional head CT and MRI are unable to accurately diagnose or prognosticate recovery in mild TBI patients.

Fortunately, newer imaging tests and their incorporated software provide improved detection and localization of injured tissues or altered function associated with mild TBI.  However, these new tests are mainly employed for research at this time.  Susceptibility Weighted Imaging (SWI) has improved localization of hemorrhage [16].  Magnetic resonance spectroscopy (MRS) uses metabolite measurements associated with brain injury to determine dysfunctional regions [16].  Functional MRI has been used for localization of altered cortical activation while performing certain tasks [16]. Diffusion Weight imaging (DWI), Diffusion Tensor Imaging (DTI) and Diffusion Kurtosis Imaging (DKI) provide improved edema and axonal injury detection [17]. DKI is a newer imaging modality that is superior to DTI in examining tissue complexity. DTI measures tissue organization through measurements of random translation of water molecules of Gaussian or bell curve distribution. DTI measures diffusivity under the assumption of unimpeded water diffusion in a homogenous environment [17]. Biological tissues display increased heterogeneity of microstructure; which is taken into account by various measurements in DKI [18].DKI has the potential for increased precision with the diagnosis of mild TBI compared to DTI, but at this time there are few studies of its use in the evaluation of mild TBI.  This paper will mainly focus on DTI and SWI because they have a significant data supporting the diagnosis of mild TBI.  Other imaging tests are discussed as supportive evidence of specific areas in the brain that are affected by mild TBI and correlated with deficits in various cognitive domains.

 

Diffusion Tensor Imaging (DTI)

 

DTI studies have become the preferred imaging modality to evaluate DAI associated with TBI in mild TBI research.  DTI has four times improved sensitivity over CT for detecting non-hemorrhagic DAI and can evaluate for other intracranial pathology as it twice as sensitive as CT for detecting contusion [15]. DTI permits the evaluation of white matter, nerve fibers and can assess myelin sheaths and nerve cell membranes [19]. DWI and DTI detect changes in diffusion between different groups of H2O molecules, while DTI has the additional capability of assessing the direction of the water diffusion [20]. Compared to most imaging tests, DTI can identify microscopic tissue damage and examine white matter tracts. The parameters assessed in DTI are: fractional anisotropy (FA), apparent diffusion coefficient (ADC), and mean diffusivity (MD).  DTI uses FA as an index of local coherence of fibers [21].  Normally, water molecules in white matter tracts align along the direction of the tract and move faster along an axon, and are therefore termed anisotropic. Decreased structural integrity of brain tissue leads to increased random motion of water molecules in all directions or otherwise described as a reduction in FA [17]. FA is measured on a scale from 0 to 1. In areas of highly restricted diffusion, such as corpus callosum, the FA is high.  The FA is moderate in the gray matter because it moderately restricted to the diffusion of fluids through the tissue. The FA approaches 0 in areas of low restriction such as cerebral spinal fluid [19]. ADC is the average of the diffusion of water measured in 3 planes x,y,z [22].  Mean diffusivity is similar to ADC as it measures average diffusion [22]. 

 

Diffusion Tensor Imaging in the Evaluation of Mild TBI at the Acute, Subacute, and Chronic stages

DTI studies have shown that even one mild TBI can show damage to the white matter tracts in the acute, sub-acute and chronic phases post-injury.  These studies will be discussed below, with the main areas significantly correlated with mild TBI being the: internal capsule, corpus callosum and subcortical white matter; although other areas have also been shown to be impaired by mild TBI.

 

Acute and Subacute Changes in mild TBI

Contrasting findings have been reported on DTI studies with some studies reporting increased FA while others report decreased FA in areas affected by mild TBI.  To study the acute phase of injury, Bazarian et al. [23] compared mild TBI patients to matched orthopedic patients that did not sustain head injuries within 72 hours of injury.  They demonstrated that the mild TBI group had significantly increased FA in the posterior corpus callosum as compared to orthopedic controls. Mayer et al. [24] also found at less than 3 weeks post-injury, mild TBI participants had increased FA in the corpus callosum and various left hemispheric tracts, with normalization of FA after 3-5 months.  In contrast to these two studies [23, 24], Arfanakis et al. [25] found decreased FA predominantly in the internal capsule and corpus callosum of mild TBI participants sustaining an injury within 24 hours with a tendency towards normalization of FA in 2 of the 5 patients at 30 days. Rutgers et al. [26] examined those with mild, moderate, and severe TBI and found that at less than 3 months, patients with mild TBI had lower FA and significantly higher ADC in the genu of the corpus callosum compared with control subjects [26].  At 3 months post-injury, no significant difference was found between the groups. Although FA was different, the areas affected by mild TBI were similar between the studies. The differing FA values may represent different pathophysiological processes. Increased FA may represent axonal swelling or cytotoxic edema, while decreased FA may represent axonal degradation and discontinuity with water between the spaces Mayer et al. [24]. In the future, serial DTI studies may provide a way to monitor the resolution of various deficits in mild TBI patients.

 

Chronic Changes in mild TBI

DTI studies have documented persistent chronic changes in the white matter following one mild TBI episode. DTI studies performed after 3 months continue to reveal pathology in areas similar to those found in the acute and sub-acute phases of mild TBI.  In a study that examined military personnel that sustained blast injuries resulting in mild TBI, participants were examined within 90 days of injuries with follow up after 6-12 months [27].  The investigators found mild TBI patients had decreased relative anisotropy in the middle cerebellar peduncles, cingulum bundles and right orbito-frontal cortex with persistent changes on follow up [27].  A study of civilian participants by Inglese et al. [17] found increased MD and lower FA in corpus callosum, centrum semiovale also known as the cerebral white matter, and internal capsule significant changes in the mild TBI group that was evaluated an average of 4.05 days and 5.7 years post-injury compared to healthy controls.  Lipton et al. [28] examined those with continued post-concussive symptoms including: “difficulty with attention, concentration, memory and poor job performance”.  Mild TBI participants had significantly decreased FA in the corpus callosum, subcortical white matter, and internal capsules bilaterally compared to the control group [28].  Kraus et al. [29] found decreased fractional anisotropy in the corticospinal tract, sagittal stratum and superior longitudinal fasciculus of individuals with chronic mild TBI.  These findings show long-term alterations in white matter can be found even years post-injury. The areas most commonly affected are the cerebral lobar white matter and the corpus callosum and internal capsule. Military personnel that sustained blast injuries were different than civilian populations in that they were more affected in the cerebellar peduncles and not the corpus callosum or internal capsule.

Rutgers et al. [30] wanted to further investigate sites that had a predilection for injury in 21 mild TBI participants that were on average 5.5 months post-injury at subacute (<3 months) and chronic (> 3 months) stages of injury compared to controls. They observed significantly reduced FA in cerebral lobar white matter, corpus callosum, and cingulum [30].  Of all the regions with deficits, changes in the cerebral lobar white matter were seen in 61.8% of mild TBI and most prominently in the frontal lobe of 42% of patients [30]. The cingulum or corpus collosum is affected in 23.6% of the individuals with mild TBI. Finally, the internal capsule, mesencephalon, brain stem and cerebellum had changes in 5.7% to 2.1% of the mild TBI participants [30].  Rutgers et al. [30] also utilized fiber tracking and found discontinuity of the white fiber tracts such as supratentorial projection fiber bundles and corpus callosum fibers. 19.3% of mild TBI participants had discontinuity of the fronto-temporo-occipital fiber bundles[30].   These findings also support chronic visible changes demonstrated in the same areas as the subacute and acute stage of mild TBI.

 

Mild TBI patients assessed with neuropsychological testing and structural correlates established on DTI

 

The studies in the previous section utilized DTI in the evaluation of areas affected by mild TBI.  Other studies have gone further to corroborate areas of altered function seen on advanced imaging with deficits in cognitive function seen on neuropsychological testing [18, 31-36]. The correlation between neuropsychological testing and advanced imaging has improved the precision with which various cognitive deficits can be diagnosed [18, 31-36].

Neuropsychological evaluations are important in assessing how mild TBIs have affected cognitive function.  The domains examined are: attention, speech and language, memory or orientation, visual-spatial or constructional ability, executive function, affect and mood, and thought processing.  Research utilizing DTI has improved the recognition of specific areas associated with cognitive processes in normal and abnormal populations.  Sasson et al. [31] studied the variance in cognitive domains as assessed by computerized neuropsychological testing and examined different regions with diffusion tensor imaging in a healthy population consisting of a large array of ages. DTI parameters measured demonstrated an association of executive function with the frontal white matter and the superior longitudinal fasciculus. Information processing corresponded with the cingulum, corona radiata, inferior longitudinal fasciculus, parietal white matter, and thalamus [31].  Memorywas localized to changes in the temporal, frontal, cingulate and parahippocampal regions [31].  Similarly, mild TBI assessed with neuropsychological testing in conjunction with DTI as well other advanced diagnostic imaging tests, have found some similar correspondences. Evidence of correlation between neuropsychological testing and regions of altered function demonstrated on advanced diagnostic imaging in patients following mild TBI are: frontal cortex [32], corpus callosum [34, 35], uncinate fasciculus [33-35], superior longitudinal fasciculus [34], anterior corona radiata, thalamus [18,36]and cerebellum [39]. Establishing structure-function associations may be used to predict persistent cognitive deficits as well as distinguish malingerers from those with legitimate impairments.

 

Frontal Cortex/Dorsolateral Prefrontal Cortex (DLPFC)

Using DTI, Rutgers et al. determined that 42% of patients sustaining a mild TBI were identified to have altered white matter changes in the frontal lobe [30]. Lipton et al. [28] found individuals with mild TBI exhibited impaired performance in neuropsychological tests of executive functions correlated with decreased fractional anisotropy in the DLPFC at 2 weeks post injury.  In the McAllister et al. [32] study, many patients with mild TBI complained of poor memory, inability to concentrate and thinking slower.  These complaints are descriptions of impairment in working memory [32]. McAllister and his colleagues [32] utilized fMRI to examine healthy controls vs. mild TBI patients 1 month following injury.  They found mild TBI patients had decreased overall activation of the frontal cortex compared to controls in performing the attention/vigilance task and then the memory task [32].  They also had increased activation of right parietal and DLPFC compared to controls when they performed the second memory task compared to the first memory task [32].  These findings offer evidence that impairment seen on neuropsychological tests of executive function and memory can also be demonstrated in mild TBI populations.  

 

Corpus Callosum

Rutgers et al. [30] found that 26% of mild TBI participants had decreased FA in the corpus callosum. The corpus callosum connects with various regions in the brain as well as directly connects the two hemispheres of the brain. The genu of the corpus callosum connects to the frontal cortex, while the body and splenium connect to the temporal, parietal and occipital portion [19]. The extent to which the corpus callosum is damaged appears to correlate with total IQ.   Matsushita et al. [19] examined 9 adults with mild TBI and 11 subjects with moderate TBI 0-20 days post TBI (average 3.5 days) and compared them to 27 matched healthy controls. Significantly decreased FA in the genu, stem and splenium of the corpus callosum was seen in moderate TBI group compared to controls, while the mild TBI group was only different from the control group with decreased fractional anisotropy in the splenium of the corpus callosum [19]. 11 of the 20 TBI participants underwent neuropsychological testing with a mean of 560 days post-injury and a positive correlation was noted between FA in splenium of the corpus callosum and total IQ [19].

 

Uncinate Fasciculus, Superior Longitudinal Fasciculus, and Anterior Corona Radiata

The uncinate fasciculus is a white matter tract that connects the orbitofrontal cortex to the temporal pole [33].  Its proposed function has been related to emotion and memory, although recent research reveals that it is involved in language, and specifically naming deficits [33].  The superior longitudinal fasciculushas a role in “visual awareness, maintenance of attention, initiation of complex motor behavior, phonemic and articulatory aspects of language, and lexical decision making” Geary et al. [34] found mild TBI subjects with deficits in uncinate fasciculus and superior longitudinal fasciculus correlated with impairment in verbal learning.  Niogi et al. [35] founddecreases in FA values in anterior corona radiata was correlated with deficits in attention while deficits in the uncinate fasciculus correlated with deficits in memory and attention.

 

Thalamus

The thalamus acts as a relay station as it has reciprocal projections to the entire cerebral cortex and is involved in processing and transmitting cognitive, sensory and motor function information [18,36, 37].The role of the thalamus is related to attention, concentration, and processing speed [18,36, 37].Little et al. [36] found that thalamic changes accounted for variance in executive function, attention and memory.  Grossman et al. [18] utilized DKI to compare healthy controls to individuals that had sustained a mild TBI within one year. They found mild TBI patients had deficits in attention and processing speed as well as executive functions that correlated with white matter changes in the thalamus [18].

 

Cerebellum

The cerebellum appears to be affected in 5.7% to 2.1% of participants in the Rutgers et al. study [30] of a civilian population, but may have higher incidence in military personnel sustaining a mild TBI [27].  The cerebellum has a role in cognitional and perception as it projects to prefrontal cortex [38].  It also has circuits to the temporal, posterior parietal, and limbic cortices [38]. Alteration in pathways to frontal cortex lead to decreased working memory [38,39].

Hattori et al. [39] recruited mild TBI individuals from a treatment-seeking population that presented with cognitive fatigue as major limiting factor in returning to work despite near normal neuropsychological testing.  Healthy controls were compared to subjects who had sustained mild TBI at 6 least months prior to the study with average of 28.6 months post-injury [39]. 6 of 15 subjects were involved in litigation, but none had disability claims [39].  They utilized Single-Photon Emission of Computerized Tomography (SPECT) to measure active areas of the brain during a test for attentional processing entitled Paced Auditory Serial Addition Test (PASAT) [39]. SPECT evaluates brain function through the detection of radiotracers that light up in areas associated with increased blood flow [20]. Subjects with mild TBI had significantly lower PASAT scores than controls in the first of four sessions performed [39]. Another interesting finding in the study was that mild TBI subjects had greater activation seen in DLPFC, which corresponds with working memory and executive function [39]. Differing regions of activation may represent compensation for deficits in the frontocerebellar circuit [39]. Additionally, increased activation in the cerebellar cortex correlated with PASAT performance in the healthy control group [39]. These findings suggest the use of neuropsychological testing in combination with advanced imaging has improved correlation of area of cognitive deficits with regions/white matter tracts altered by the mild TBI.

 

Susceptibility Weighted Imaging (SWI)

 

SWI has enhanced recognition of microhemorrhages that may not be picked up on CT, T1 or T2 weighted MRIs, or GRE MRI at this time [10]. SWI detects blood at the level of iron and blood products [10].  In one study that utilized SWI in mild TBI patients, the locations of microhemorrhages were related to patient complaints [40].  Visual complaints correlated with microhemorrhages in occipital regions whereas hearing deficits correlated with temporal hemorrhages [40].  The microhemorrhages were not detected in 76% of patients on conventional MRI in this study [40].  Tong et al. [41] examined children and adolescents who suffered mild to severe TBIs and found a significant inverse relationship between the GCS, and the number and size of hemorrhagic DAI lesions seen on SWI. Participants who suffered a mild TBI had the lowest quantity and smallest volume of hemorrhagic lesions while those with severe TBI (lower GCS) had the highest quantity and largest volume of hemorrhagic lesions [41]. Finally, the authors noted a direct relationship between degree of disability and number and size of hemorrhagic lesions found on 6 and 12-month follow-up, suggesting worse prognosis in those with greater number and size of hemorrhagic lesions [41].

 

Biomarkers

 

There are emerging advances in the use of biomarkers for the diagnosis of mild TBI [8].  These new advances in biomarkers show that neurons and supporting cells are damaged during head trauma. This damage leads to the release of specific proteins into the cerebrospinal fluids [11]. Furthermore, if the blood brain barrier is affected, these proteins may be released and found in the peripheral circulation [42]. Many proteins are released after brain injuries.   New research is attempting to measure the serum or cerebrospinal fluid concentration of biomarkers released after brain injury [8]. This is an attempt to correlate outcomes and sequelae of symptoms following a mild TBI.  This will assist with a more accurate diagnosis of mild TBI.  The biomarkers with the most hopeful research are the following: S100B, Neuron-Specific Enolase (NSE), and cleaved tau protein (CTP) [8,43].

 

S100B

In the current discussions and studies surrounding biomarkers, S100 B is viewed as the most promising marker for diagnosing mild TBI [8,44-47]. S100B is a protein released from astrocytes. It is found in brain tissue and may be measured in the cerebrospinal fluid and serum following an injury. However, S100B is not specific to brain injury [8,48]. Studies have also shown elevated levels of S100B in bone fractures, thoracic contusions without fractures, burns, and minor traumas [48]. It is released into the CSF and serum and has been detected as early as 30 minutes after a brain injury. The half-life is approximately 97 minutes [49]. S100B is very sensitive for mild TBI, however not very specific. In one study designed to evaluate if S100B was a predictor of CT findings after mild brain injury, S100B was found to have a high sensitivity of 0.95 and low specificity of 0.31 when measured within 12 hours of initial injury [50]. In an additional study where S100B was used as a predictor of findings of CT within 3 hours, the sensitivity was improved. It was found to be 0.99 and specificity found to be .30 [12]. This high sensitivity has prompted a number of studies to evaluate if it could be used as a screening tool and possibly decrease the need for obtaining a head CT on all individuals who sustain a minor head injury [12, 50, 51].

A prospective multicenter study by Biberthaler et al. [12] specifically studied if S100B measurements could affect the need for an initial head CT. Every patient had serum S100B measured an average of 60 minutes within trauma and had a head CT to determine if they had any intracranial pathology relevant to head trauma.  They found that patients with positive head CT findings had the highest S100B concentrations with a GCS of 13, less with a GCS of 14, and lowest S100B concentrations with GCS of 15. They also found that patients with negative head CT had S100B concentrations equally low as the concentration in GCS of 15.  The researchers discovered that in defining the cutoff level for S100B at 0.10 ug/L, they were able to have 99% sensitivity for ruling out intra-cerebral lesions.  However, S100B only had a specificity of 30%. The authors believed this could be improved if they were using an MRI for imaging instead of CT because of the MRI’s ability to detect smaller lesions.   And finally, the researchers determined that screening with S100B levels in patients sustaining mild brain injuries, might allow for a decrease in 30% of head CTs. [12] This reallocation of resources might be best for the appropriate uses of newer imaging when indicated.

Elevated S100B levels following mild TBI are associated with a number of unfavorable outcomes.  According to a review by Lomas and Dunning [52], these elevated S100B levels could be used as a predictor for poorer long-term outcomes. Stranjalis et al. [53] found that patients with mild head injury and elevated S100B had worse short-term outcome measured by decreased return to work. These patients with an increased S100B had a failure to return to work rate of 37% compared to 4.9% in patients who had did not have an elevated S100B levels. In another study, elevated S100B levels were associated with neuropsychological abnormalities [54]. Waterloo et al. [54] defined patients with minor head injury as having the following: positive loss of consciousness secondary to a head injury, a GCS of 14 or 15, no focal neurological deficits, and no abnormal intracranial pathology found on CT. The researchers performed neuropsychological testing on patients with and without elevated S100B. Although elevated S100B levels in patients with minor head injury did not affect cognition, the researchers did find differences in sequential reaction time and selective attention.  Specifically, the patients with increased S100B levels appeared to have decreased attention and limitations in speed of processing information [54].

Although S100B appears to have the most promising research related to mild TBI, the studies have not been whollyconsistent. Many studies use variable serum cut off levels and have not reached a consensus on the accuracy of the data. However, S100B has been proven to have a strong association with severe TBI, but mild TBI is still in the incipient phase of research [55].  Another reason S100B does not have consistent research data is that many studies have shown extra-cranial injuries from the trauma could be associated with the elevated S100B [48,56]. One way to correct for this extra-cranial release has been proposed by Bazarian et al. [44].  They studied the use of a correction factor—creatine kinase (CK)—with the extra-cranial release of S100B. The researchers measured S100B and CK levels in 96 mild TBI patients. They compared the S100B corrected with CK and the uncorrected S100B levels to test their ability to predict initial head CT, headache present at three months, and symptoms associated with post-concussive syndrome at three months. The corrected S100B had a statistically significant improvement in the ability to predict headache at three months.  However, there was no significance of correlation with initial head CT or three month post-concussive syndrome. The study concluded that S100B itself was poorly predictive of outcome, but that CK is valid as a correction factor of S100B [44]. Possibly, this research will encourage additional studies of S100B using CK as a correction factor.

 

Neuron Specific Enolase (NSE)

NSE is a protein found in the glycolytic pathways of neurons and neuroendocrine cells. It is another common biomarker that has been studied in its relationship to brain injury [5, 8]. It can be detected as early as six hours from injury and has a half-life of 24 hours. It has been found to be associated with poor short-termand long-term outcomes from brain injury [45]. De krujik et al. [57] found that elevated NSE following a mild TBI was associated with an increase in headaches and dizziness six months after initial injury. 

Unlike S100B, NSE has been found to have high specificity in relation to certain aspects of brain injury. One recent prospective study in particular studied the correlation between NSE, severity of brain injury as measured by the Glasgow Coma Scale (GCS), and prognosis as measured by the Glasgow Outcome Score (GOS). Although there was no significance in mild brain injury in particular; they did find that NSE of all patients studied including: mild, moderate, and severe brain injury, was 87% sensitive and 82.1% specific for predicting a poor neurological outcome according to the GOS [58]. However, this is inconsistent when predicting intracranial lesions in pediatric patients following brain injury, NSE has a 77% sensitivity and 52% specificity [45].

 

Cleaved-Tau Protein (CTP)

CTP is a breakdown product of microtubule-associated tau protein. This protein is associated with axons in brain tissue [8]. In a rat-model study by Gabbita et al. [59], CTP was found to be elevated after TBI. The increase was found to be severity dependent, with severe TBI having more of an increase than mild TBI. The researchers also found that the levels were significantly elevated within six hours and peaked within 168 hours. The researchers felt CTP was a potential marker of brain injury in the rat-model and it would be beneficial to see if the same applies to humans [59].

However, a recent pilot study was performed by Bazarian et al. [60] to evaluate if there was a relationship between elevated CTP levels and S100B levels and symptoms associated with mild TBI at 3 months. Unfortunately, the researchers did not find significant a relationship between neither CTP nor S100B and symptoms associated with these patients who sustained a mild TBI at three months.

Using serum biomarkers as a tool for diagnosing mild TBI is still evolving.  Begaz et al. [46] performed a review of prospective cohort studies of the relationship between serum biomarkers S100 proteins, NSE, CTP and mild TBI. They found that none of the biomarkers had a consistently reliable correlation with persistent symptoms, known as post-concussion syndrome, following mild TBI. However, they did feel it was necessary to combine a number of clinical factors along with the biomarkers to predict the development of post-concussion syndrome after sustaining a mild TBI [46].

S100B has the most research supporting it as a diagnostic marker for mild TBI [5,8,46].  Although studies have shown there is an elevation in S100B after a person has sustained a mild TBI, it is inconsistently correlated with neuropsychological testing [54,61]. The most consistent research has shown the positive correlation between S100B predicting head CT outcomes. This may possibly decrease the number and expense of CT scans in the future  [1,52].\

Using S100B as a screening tool for performing a head CT is a level C recommendation in the “Clinical Policy: Neuroimaging and Decisionmaking in Adult Mild Traumatic Brain Injury In the Acute Setting” in 2008.  The recommendation states, “In mild TBI patients without significant extra-cranial injuries and a serum S-100B level less than 0.1 g/L measured within 4 hours of injury, consideration can be given to not performing a CT” [5]. However, they did note that the Food and Drug Administration has not yet approved S100B [5].  The clinical policy does believe there is a potential for biomarkers, to be utilized for the detection of abnormal head CT [5] but continued research is still needed.  Some have suggested the possibility of combining these biomarkers in a panel with a history and a physical examination. [5,46]. Others have suggested this along with a correction factor of CK for extra-cranial sources [44].  Combining the panel and correcting for extra-cranial sources, along with a history and physical exam, health care providers will be able to diagnose mild TBI more precisely and accurately and allow the appropriate allocation of resources for diagnostic studies.

 

Long Term Sequalae of Mild TBI

 

Unfavorable Outcome

Individuals who sustain a mild TBI may encounter a number of complications including emotional, physical, and cognitive symptoms [1, 62, 63, 64]. Patients who sustain mild TBI exhibit functional disability such as difficulty with finding or sustaining jobs, individual relationships, and the ability to return to school [63,64]. Vanderploeg et al. [63] found that individuals with mild TBI had increased self-reporting depression, post-concussive symptoms, disability, underemployment, low income, and marital problems.  Individuals who sustained mild TBIs were also found to have “unfavorable short-term outcomes” [65]. These include failure to return to work or activities.  These unfavorable outcomes have even been correlated with elevated S100B levels. Although there is some discourse surrounding symptoms following a mild TBI, post concussive symptoms, and post concussive syndrome, researchers believe having this positive correlation between elevated S100B and mild TBI and “unfavorable short term outcome” would assist with supporting true post-concussive symptoms [65]. As Deutsch et al. [64] point out, an individual’s sense of self is tied to his/her type of work. Returning to work is a crucial component of the patient’s rehabilitation. In general, the more severe the injury, the more likely patients will have poor return to work outcome [66]. Return to work outcome is also related to non-modifiable risk factors such as age, marital status and pre-injury educational level. These factors—elder [67], unmarried, and less education [68] —negatively influence a patient’s return to work outcome.

Improved prognostication and being able to determine those who might be more susceptible to poorer outcome would more efficiently allocate resources to appropriate individuals to improve their recovery.  The standard imaging studies in mild TBI patients generally do not distinguish between individuals who will have favorable outcomes compared to those with unfavorable outcomes.   Messe et al. [69] compared imaging of mild TBI patients with good outcomes, imaging of mild TBI patients with poor outcomes, and imaging of mild TBI with healthy controls.  Patients with mild TBI who had poor outcomes had a significantly increased mean diffusivity on DTI compared to the good outcome group [69]. Changes on DTI that may be predictive of poor outcome would be useful in the establishment of appropriate follow-up and rehabilitative care.

With brain injuries in general, the combination of the loss of income and the cost of disability has been estimated to cost society $56 billion a year [70].  Mild TBI are estimated to account for over a quarter of this at $16.7 billion [70]. However, many believe this number underestimates the number of mild TBIs due to diagnosis in the emergency department and released, treatment in a non-hospital setting, undiagnosed patients who never received any treatment. [2,70].

 

Persistence of Symptoms

It has been estimated that 80 to 90% of patients who sustain mild TBI fully recover from their injury within three months [9].  When followed with serial imaging, the recovery correlates with the normalization of FA in various injured areas seen on DTI [24, 25, 26]. This leaves 10 to 20% of patients who sustain mild TBIs who continue to have persistent symptoms and may have what is referred to as post-concussive syndrome (PCS) [62, 71, 72] or “post-concussive disorder” [9].  The ICD-10 characterizes post-concussive syndrome as one that occurs after a head injury with loss of consciousness with symptoms in 3 or more categories that begin no later than 4 weeks post injury. The categories are as follows: “(1) headache, dizziness, malaise, fatigue, noise intolerance (2) irritability, depression, anxiety, emotional lability (3) subjective concentration, memory, or intellectual difficulties without neuropsychological evidence of marked impairment (4) insomnia (5) reduced alcohol tolerance (6) preoccupation with the above symptoms and fear of brain damage with hypochondriacal concern and adoption of sick role” [73]. 

The DSM-IV criteria for PCS are similar to ICD-10 with a requirement of head trauma with concussion as manifested by loss of consciousness, post-traumatic amnesia, and, less commonly, onset of seizures.  Neuropsychological testing would demonstrate difficulty with attention or memory.  Patients need to have three or more symptoms that last at least three months and begin shortly after the injury or worsening of previous symptoms. Diagnosis also requires disturbance in social and occupational functioning [72].

Carroll et al. [71] have summarized that patients exhibit deficits in regards to cognitive, emotional, and physical effects from mild traumatic brain injury, but the majority of these patients recover within 3 to 12 months.  They report that many symptoms continue to persist, but if this is the case, then there are a number of contributing factors such as psychosocial stressors, co-morbid conditions, and situational [71].  Long-term sequelae of mild TBI has been controversial as the symptoms tend to be vague and can be found in non-TBI populations.  Furthermore, individuals involved in litigation or have pre-existing social or psychological issues generally report increased symptoms or deficits [74-76]. Through meta-analyses, it has also been found that patients with mild, uncomplicated TBI can recover and reach normal cognitive function within one to three months [77]. However, there is confusion over the use of the term “postconcussive syndrome”. It can be used to describe any combination of symptoms following mild TBI and has been documented to be present in individuals following trauma [78], including college students and individuals with depression or chronic pain [79].  These studies demonstrate a lack of consensus among chronic symptoms or the resolution of mild TBI symptoms.

 

Treatment

 

It is difficult to identify continued deficits and, in turn, the treatment of mild TBI. Although there has been consistent evidence for deficits and treatment of moderate and severe TBI, mild TBI lacks consistent evidence. For instance, there is sufficient evidence to show that there is a relationship between patients with a moderate or severe brain injury and impaired social functioning, unprovoked seizures, dementia, Parkinson’s Disease, endocrine deficiencies [62]; however, the committee consisting of Bazarian et al. did find that “there is limited/suggestive evidence of an association between sustaining a mild TBI resulting in loss of consciousness or amnesia” [62] in relation to seizures following a brain injury, parkinsonism, “ocular/visual motor deterioration” [62].   This committee also found that “there is sufficient evidence of an association between sustaining a TBI and development of post-concussive symptoms (such as memory problems, dizziness, and irritability).”[62] They believed this applied to patients who sustained all severities, from mild to severe, of brain injuries [62].

Although there is not a standardized treatment for mild TBI, a number of interventions have been shown to be helpful. Ruff [9] has found that cognitive therapy tailored to the individual patient, education of available resources, and recognition of symptoms can assist recovery.  The Clinical Practice Guideline: Occupational and Physical Therapy for Mild Traumatic Brain Injury [80] recommends a number of interventions physical and occupational therapists can provide in relation to temporomandibular disorders, attention, balance dysfunction, vestibular dysfunction, and several other deficits.  It is likely best to continue to treat these patients utilizing a team approach with an early recognition of symptoms, prevention of further immediate injury, education of symptoms and prevention, cognitive, physical, occupational, and if necessary, vocational therapy, neuropsychological testing, necessary medications, and continued monitoring by specialists.  In terms of rehabilitation and facilitating the patients’ return to work, the importance of continued cognitive therapy and behavioral re-evaluation to understand the changing needs of the patient is stressed [9, 66].  Treatment is critical, because the lack of treatment can lead to decreased productivity [70] and increased healthcare costs.

 

Conclusion

 

A growing number of individuals are sustaining mild TBI each year. Many of these patients are not receiving the appropriate evaluation and diagnosis [2, 81]. The current tests do not provide a true objective diagnosis and may not identify individuals who have sustained a mild TBI [2, 81]. This current standard of diagnosis, which only utilizes imaging such as CT or MRI to rule out acute brain injury, is not sufficient to make a precise diagnosis of mild TBI.  Bazarian suggested this is similar to addressing a patient with acute cardiac symptoms with only a Chest X-Ray and EKG [82].  A Chest X-Ray and EKG alone do not provide enough data to make a precise and timely diagnosis. Other tests such as: echocardiograms, angiograms; and blood biomarkers such as: troponin, CK-MB, and LDH are also utilized to make a specific diagnosis in relation to cardiac disease [82]. Without sufficient evidence to support a diagnosis, treatment of mild TBI will likely be found to be speculative, as was the case in Scognamillo v. Herrick, (2003) 106 Cal. App. 4th 1139.

It is vital these individuals who sustain a mild head injury receive a diagnosis. Without determining a precise diagnosis, patients may not receive medically necessary treatment.  In most jurisdictions, including California, all health plans are required to provide medically necessary care. This includes care for diagnosis, as well as treatment. [83, 84].  It would be hard to argue that medically necessary care for headache, dizziness, cognitive deficits in mild head trauma [1,62] differ markedly from the same symptoms caused by migraine or tension headaches alone. However, there is emerging research in innovative technology and biomarkers that may assist with an objective, precise, and timely diagnosis of mild TBI [8, 10, 16, 81, 82]. Using new diagnostic tests discussed, it would be possible to identify patients who would have a poorer outcome after sustaining a mild TBI [69]. Treatment for these patients would emphasize closer observation. Continued monitoring and constant reevaluation of these patients is vital to address the changing needs of the patient in regards to treatment and rehabilitation [9].  We advocate that individuals who present onstandard history and physical exam as possibly having a mild TBI be evaluated with DTI imaging and biomarkers as these diagnostic tests will assist with the precision and timeliness of diagnosing mild TBI.

The precision and timeliness of an accurate diagnosis is critical not only if the patient will require medically necessary treatment to return to being a vital functioning member of society, but it will also establish the responsible party for such treatment. The diagnostic tests recommended have the ability of establishing the causal link between injury, the responsible person, and the damages sustained. In the past, an individual having a mild TBI could not establish the causation required to impose liability or fault on the person or entity properly to bear the responsibility for the medically necessary treatment required.

The tests advocated in this article can now provide what in the past was not possible, which is (1) precision and timeliness of an accurate diagnosis, and (2) a legal basis for establishing causation between the act or omission causing injury and the medically necessary care to treat the injuries proximately resulting therefrom. Precision and timeliness of an accurate diagnosis is critical and necessary to establish a responsible party and if the patient will require medically necessary treatment to return to being a vital and functioning member of society.   

 

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Robert Bitonte, MD, JD. rbitonte@aol.com 213-680-3007. Fax: 213-680-1030

Bianca Tribuzio, DO. University of California, Los Angeles.  biancatribuzio@gmail.com.  213-680-3007. Fax: 213-680-1030

Kim Hecht, DO.drkimhecht@gmail.com  213-680-3007. Fax: 213-680-1030

Donald J. DeSanto, JD. DeSanto Law Firm, Van Nuys, CA dondesanto@desantolaw.com. 330-519-8782. Fax: 330-702-8800

 

 

Corresponding author: Bianca Tribuzio

234 S. Figueroa St. #1941

Los Angeles, CA, USA 90012

Email: Biancatribuzio@gmail.com 

213-680-3007. Fax: 213-680-1030

 

 

 

Acknowledgement

We would like to acknowledge, with deep gratitude, Dr. Jerome Tobis for his continued support, encouragement, and gentle criticism during the development and research for this paper.

 

Disclaimer

The authors declare that they have no competing financial, personal, or professional interests.

 

Editor’s note: The views and opinions expressed in the articles contained in the International Neuro-Trauma Letter are those of the authors and contributors alone and do not necessarily reflect the views, policy or position of the International Brain Injury Association or all members of the NTL Editorial Board. The NTL is provided solely as an informational resource and the inclusion of any particular article does not establish or imply IBIA’s endorsement of its contents.