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A Review of Mild Traumatic Brain Injury Diagnostics: Current Perspectives, Limitations, and Emerging Technology [Military Medicine](Military Medicine Via Acquire Media NewsEdge) ABSTRACT Mild traumatic brain injury (mTBI) or concussion is a common battlefield and in-garrison injury caused by transmission of mechanical forces to the head. The energy transferred in such events can cause structural and/or functional changes in the brain that manifest as focal neurological, cognitive, or behavioral dysfunction. Current diagnostic criteria for mTBI are highly limited, variable, and based on subjective self-report. The subjective nature of the symptoms, both in quantity and quality, together with their large overlap in other physical and behavioral maladies, limit the clinician's ability to accurately diagnose, treat, and make prognostic decisions after such injuries. These diagnostic challenges are magnified in an operational environment as well. The Department of Defense has invested significant resources into improving the diagnostic tools and accuracy for mTBI. This focus has been to supplement the clinician's examination with technology that is better able to objectify brain dysfunction after mTBI. Through this review, we discuss the current state of three promising technologies-soluble protein biomarkers, advanced neuroimaging, and quantitative electroencephalography-that are of particular interest within military medicine. INTRODUCTION There are 1.7 million individuals who seek medical care for traumatic brain injury (TBI) each year, and TBI is responsible for about 50,000 deaths annually.1 The majority of all TBI- 75%-are classified as mild traumatic brain injury (mTBI).2 Numbers within the Department of Defense (DoD) correlate with this national trend, 76.8% of all TBI being classified as mild.3 Most criteria use the term "concussion" and "mTBI" interchangeably. For the purposes of this article we apply these terms synonymously. The actual incidence of mTBI has been estimated to be over 1.6 million cases per year.4 Approxi- mately 20% of Veterans of Operation Enduring Freedom/ Operation Iraqi Freedom have a clinical diagnosis of mTBI.5 Unfortunately, diagnostic criteria for mTBI/concussion remain problematic with criteria based on subjective patient reporting of the injury and symptoms from the injury. Diag- nostic criteria for TBI from the World Health Organization, Centers for Disease Control, DoD, and American Academy of Neurology are summarized in Table I. All offer little objective precision to guide clinicians in accurately diagnos- ing and further characterizing the nature of mTBI. Current diagnostic standards for TBI are limited, especially in mTBI, for several reasons. No single definition is uniformly accepted across disciplines of neurology, neurosurgery, neuro- psychology, and rehabilitation medicine.6 Moreover, current criteria do not involve any reflection of clinical outcomes. Characterizing the degree of injury (mild, moderate, and severe) is based on clinical self-report, with arbitrary time constraints for length of loss of consciousness (LOC) or post- traumatic amnesia. The use of supplemental neuroimaging for diagnosis of mTBI also varies between criteria. Some clinical settings and research protocols use the Glasgow Coma Scale (GCS) and the length of lost consciousness or post-traumatic amnesia exclusively, irrespective of neuroimaging findings, to characterize the nature and severity of TBI.7 Severity rating criteria used in the DoD are shown in Table II. It is clear that using the brain-injured patient's self report after injury to define the diagnosis of mTBI would often lead to inaccurate conclusions. Common symptoms reported after mTBI include headache, nausea, problems with balance and vision, dizziness, fatigue, drowsiness, sensitivity to light or noise, and sleep disturbance. Common cognitive symptoms include impairment of attention and concentration, memory, and processing speed. Reported behavioral symptoms can include anxiety, irritability, aggression, and depression. Although these symptoms resolve within about 10 days in most patients,8 they can last well beyond this time point in over 25% of cases.9-11 Moreover, the symptoms commonly seen shortly after concussion are highly nonspecific, and can be seen in many other illnesses. The diagnostic challenge inherent to the vagueness of the symptoms is compounded by the fact that the clinician relies on the concussed patient, who has neurometabolic brain dysfunction, to report an accu- rate history and symptoms. Reports from witnesses of a trau- matic event should be sought to appropriately evaluate for LOC, post-traumatic amnesia, and the presence of confusion. In the military environment, patients may ignore, hide, or exaggerate their symptoms. These circumstances surrounding the injury, including the so-called "fog of war" may make it difficult for individuals to recognize they have been con- cussed, particularly in blast-related concussion. These are just some of the pitfalls and challenges facing clinicians and service members to accurately diagnosis mTBI. Clinicians need better methods and tools to accurately diagnose, characterize, and treat mTBI, especially in a battle- field environment. Improved diagnostics can also guide return to work/play decisions, evacuation needs, and serve as prognostic indicators. Such tools aim to characterize the nature of physiological dysfunction, that is, they are biologi- cal markers of neuronal dysfunction. Several current technol- ogies are currently being investigated and show significant promise for better diagnosing and characterizing mTBI. Such work also has significant implications to help us understand the diagnosis, recovery, and prognosis in moderate and severe TBI as well. The three technologies to be covered in this review will be protein biomarkers, advanced neuroimaging, and quantitative electroencephalography (qEEG). We chose to review these particular technologies based on our opinion of their potential for use in military settings or because of recent DoDattention and investment into the technology. METHODS A search of the PubMed database was conducted using the terms "biomarker," "diffusion tensor imaging (DTI)," "spec- troscopy," "susceptibility-weighted imaging (SWI)," "EEG" or "qEEG," and "concussion" or "mTBI" to identify articles of interest. Further articles of interest were selected from the references of these works. Articles already familiar to the authors were also included in this review. This review was limited to specific technologies as discussed above. Soluble Biomarkers Soluble molecules detectable in blood, saliva, or urine may offer the most promise for a fast, reliable, and easily used tool to aid in the diagnosis and characterization of severity of TBI. Such molecules should be obtained in a quick and noninvasive way. The majority of molecules investigated to date in the diagnosis of mTBI are proteins detectable in the blood, hence the terms "protein biomarkers" and "serum biomarkers" used throughout the literature. However, as some of these molecules are not proteins found in blood, but rather other body fluids, the term "soluble biomarkers" may be preferred. To aid in the diagnosis of mTBI, useful soluble bio- markers are molecules that are absent in the peripheral tissue unless the brain tissue has been injured. The ideal biomarker is likely a small molecule that can escape the blood-brain barrier (BBB), allowing rapid measurement in the serum or other body fluid. It should also be measurable for a reason- able period after the injury.12 Further, the protein should not be elevated when other tissues are injured, allowing specific- ity for brain dysfunction over other soft-tissue trauma. The most ideal biomarker will have a level that corresponds to the degree of brain injury as well. Many candidate biomarkers have been investigated over the past decade. Table III sum- marizes the variability of potential biomarkers currently iden- tified from animal and human trials as potential biomarkers for TBI.13 We review the most promising and most studied serum biomarkers to date. S100B The most extensively studied serum biomarker in TBI is S100B. This protein is found in astrocytes within the central nervous system (CNS).14 S100B aids in cell homeostasis and prevents neuronal death by increasing cellular calcium con- centrations.15 S100B also acts as a neurotrophic factor, pro- moting neurite outgrowth and astrocytic proliferation.16 Because S100B does not cross the intact BBB, concern has been raised that alterations in S100B may be more reflective of disruption of this barrier rather than a marker of actual brain injury.17 Recent work has also shown that S100B is present in some extracerebral cell types, such as chondrocytes and adipocytes, raising concern that its presence in serum may reflect polytrauma rather than a CNS injury.18 S100B levels have demonstrated a relatively high sensitiv- ity (as high as 98.2%)19 but low specificity (30%-31%) for mTBI. It has the benefit of conferring a high negative predic- tive value -that is, if the S100B level is not elevated after an injury, the individual tested likely did not sustain a concussion. This finding has prompted a guideline issued by the American College of Emergency Physicians that recommends that com- puted tomography (CT) of the head is optional if serum S100B concentrations remain less than 0.1 ng/mL within the first 4 hours of injury.20 The low specificity of S100B eleva- tion, however, has prevented its use in distinguishing individ- uals with TBI from those with other injuries.21 Neuron-Specific Enolase (NSE) NSE is a family of glycolytic proteins of different isoforms. The gamma-gamma homodimer isoform is highly enriched in the brain, but is present in multiple other cell types. Serum levels of NSE increase after TBI and the degree of increase corresponds to the degree of injury and may serve as a marker of both mortality and poor outcome.22,23 Increased levels of NSE are detectable within 6 hours after injury.17 Although NSE levels do reliably elevate after severe TBI, the increase is much less in mTBI.24,25 This limits the sensitivity of the marker, and NSE levels do not correspond with the magni- tude of injury after mTBI. Although the relative specificity of the test has been confirmed in mTBI,24 concerns remain about the potential for elevation because of other medical conditions-NSE has been proposed as a marker for ischemic stroke, small cell lung cancer, neuroendocrine tumors, blad- der cancer, and neuroblastoma. Protein Breakdown Products The breakdown of proteins via the actions of intracellular proteases such as calpain and caspase is thought to be a key feature of TBI pathology. Levels of the breakdown products (BDP) of a-II spectrin, a structural protein, and Tau have been shown to correlate with injury severity in animal models. However, in human subjects, although the levels of spectrin-BDP rise in severe and moderate TBI, and cleaved- Tau levels elevate after severe TBI, there is no correspond- ing elevation in either of these protein products observed after mTBI.26-29 Glial Fibrillary Acidic Protein (GFAP) GFAP is a monomeric protein produced by astrocytes. GFAP levels appear to be elevated in multiple disorders affecting brain tissue, including neurodegenerative disease,30,31 stroke,32 and moderate and severe TBI.33-35 More recently, in 2012, Papa et al reported on 97 patients with mTBI as defined by a GCS of 13 to 15. In this group, elevated levels of GFAP-BDP were able to differentiate between mTBI patients with a GCS of 15 and uninjured controls with an area under the curve (AUC) of 0.88. GFAP-BDP were also predictive of both having intracranial lesions on CT and the need for neurosur- gical intervention.36 These findings have been supported by recent results from the TRACK-TBI study reported by Okonkwo et al.37 Ubiquitin Carboxy-Terminal Hydrolase (UCHL1) UCHL1 is a protease that hydrolyzes the C-terminal bond between ubiquitin and small adducts or unfolded polypep- tides38 and makes up about 1% to 2% of total soluble protein in the brain. Mutations in UCHL1 may be associated with Parkinson's disease and other neurodegenerative disor- ders.38,39 UCHL1 has previously been shown to be elevated in patients with severe TBI.40 Papa et al tested for serum levels of UCHL1 within 1 hour of injury and found that they not only differentiated mTBI patients from uninjured con- trols, but more specifically patients with a GCS of 15 from uninjured controls. Like their study with GFAP-BDP, they demonstrated that the levels of UCHL1 also were predictive of abnormalities on CT in TBI patients.41 In children with mTBI, unlike adults, there was no difference detected in serum UCHL1 levels.42 Myelin Basic Protein (MBP) MBP is the predominant protein product of myelin produced by oligodendrocytes. MBP elevates after shearing injury to brain white matter and may remain elevated for as long as 2 weeks.43 Interestingly, MBP elevation itself may promote disruption of the BBB,44 facilitating both its own entry and perhaps that of other CNS proteins into the systemic circula- tion. Although serum MBP levels have been shown to corre- late with worse outcome in pediatric TBI,45 no studies to date have reported its detection in mTBI. MicroRNAs (miRNA) miRNA are regulatory RNAs that do not code for pro- tein products themselves, but are responsible for post- transcriptional regulation of protein expression. Patterns of miRNA expression have shown promise in detecting and perhaps understanding the pathologic mechanisms in multi- ple brain diseases.46,47 Combinations of brain-injury-specific miRNA subtypes have demonstrated very high diagnostic accuracy-at or near 100% specificity and sensitivity-in severe TBI.48 These same patterns, however, were not seen in individuals who sustained mTBI.49 As others have pointed out,17 this finding of different responses highlights the potential limitations of using biomarkers present in severe TBI to diagnose mTBI. Serum Biomarker Summary Multiple individual soluble biomarkers currently show promise in assisting in the diagnosis of mTBI, correlating with the degree of injury as measured by neuroimaging. Given the limitations in each individual serum biomarker for mTBI, it is likely that no single biomarker will have the sufficient sensitivity and specificity to be sufficient for the diagnosis of mTBI. However, a combination of biomarkers may be generated to improve diagnostic accuracy. This "bio- marker signature" may further be able to predict clinical phenotype, injury severity, and prognosis. Few studies have been done to evaluate biomarker combinations in TBI over- all, and within mTBI, soluble biomarker data have been combined with clinical data to predict outcome at 1 and 6 weeks post injury.50 Other data recently reported from the TRACK-TBI study demonstrate that the combination of measurements of GFAP-BDP and UCH-L1 has higher sensi- tivity and specificity than either individual marker alone in the diagnosis of TBI (with an AUC of 0.94 for the combined tests).51 Overall, serum biomarkers appear to show promise for future use in aiding in the clinical diagnosis of TBI, and are being actively investigated. Ongoing work is examining the relative efficacy between the serum biomarkers individ- ually and in combination. Advanced Neuroimaging Conventional neuroimaging (i.e., CT and magnetic resonance imaging) does not adequately reveal abnormalities in mTBI. The DoD criteria for mTBI require an absence of abnormality on conventional neuroimaging.2,7,52 More advanced neuro- imaging techniques, aimed at detecting more subtle changes involved in mTBI, have been intensively researched in the past decade. Although multiple advanced neuroimaging techniques are being pursued (i.e., functional MRI, magneto- encephalography, single photon emission computed tomog- raphy, positron emission tomography, and perfusion-based imaging), this section will focus on advances in diffusion tensor imaging, SWI, and magnetic resonance spectroscopy (MRS).53 These three modalities were chosen for review because at this time, they appear to have the greatest potential for widespread use and have received a significant amount of attention within the DoD. The recent Defense and Veterans Brain Injury Center guideline on Neuroimaging following mTBI does provide guidance on the use of positron emission tomography and single photon emission computed tomogra- phy in the subacute and chronic phases of mTBI.54 Diffusion Tensor Imaging (DTI) Traumatic axonal injury (TAI) occurs from the application of traversing mechanical forces. TAI occurs without frank tissue disruption. In experimental models of TBI, TAI pathology develops slowly, peaks within 24 hours, and can progress up to 1 year post-injury.55,56 When TAI is diffuse, it is known as diffuse axonal injury. It has been proposed that TAI may be a significant if not the primary cause of brain dysfunction after mTBI. DTI is an emerging MRI technique that measures the directional coher- ence of water diffusion in vivo. Disruptions in axonal integ- rity may be detected by DTI. Among the studies of DTI in TBI, there has been great variability in study design and measurement approaches, limiting the comparison of data between studies.57 Using DTI, brain structure can be studied either regionally or on a whole-brain level, with regional analyses making up the majority of published studies.57 Regional analysis may be accomplished using region-of-interest analysis or tractography. Although the majority of studies have shown postconcussive changes in both whole-brain and regional analysis of DTI, this is an exception.58 Studies investigating outcome measures related to DTI changes in mTBI have used heterogeneous metrics. When summed together, the various reports have examined all domains of cognition (i.e., attention, executive function, mem- ory, motor, processing speed, visuospatial, and I.Q.). Some, but not all, of the behavioral measures tested have demon- strated a correlation with the degree of DTI abnormality.58 Along with heterogeneity among outcome measure between studies of DTI in mTBI, other limitations remain in our current knowledge. The marked heterogeneity in the method of data analysis (i.e., whole-brain versus regional analyses; region-of-interest versus tractography) limits com- parisons between studies and hinders any meta-analysis. Fur- ther, the current analyses generally identify areas of common injury. Although certain brain areas may be more susceptible to white matter damage from mTBI, the area affected in any given patient will vary according to individual factors and according to the mechanism of injury. In addition to address- ing the concerns above, further work on DTI in mTBI will need to focus on correlations between imaging abnormalities and outcomes. Susceptibility-Weighted Imaging (SWI) The presence of micro hemorrhage within the brain can be seen pathologically and is common with traumatic axonal disruption after TBI. Axonal disruption may also be inferred by the presence of micro hemorrhage on gradient echo or SWI. The small deposits of hemosiderin in the injured areas cause a low signal on the generated image. High-resolution SWI is the most sensitive of these sequences for detecting micro hemorrhage, with 3-Tesla MRI being more sensitive than imaging with 1.5-Tesla machines.59 The number and volume of SWI lesions has been shown to correlate with clinical outcomes 6 months post injury.60 SWI is typically obtained in conjunction with routine MRI studies and requires only a few minutes to complete. Magnetic Resonance Spectroscopy (MRS) MRS uses standard clinical magnetic resonance scanners to measure brain metabolism. Proton analysis is most com- monly used. MRS has the benefit of not using ionizing radiation. Assessment of various metabolites may be done of specific regions or of global measurements. The neuronal marker N-acetylaspartate (NAA) has been thought to dem- onstrate changes reflecting energy use after mTBI. Other metabolites commonly studied include creatine, choline, glutamate, and glutamine. Decrease in NAA levels is the most common and persistent finding seen after closed-head injury, and is found in both gray and white matter.61 The decrease in NAA recovers by 30 days post injury, with the NAA recovery lagging behind clinical recovery in injured athletes.62 Outcome studies using MRS have not been done in the setting of mTBI63 and, similar to DTI, there is great hetero- geneity in methodology between different studies using the technique. Both the sensitivity and the specificity of MRS in mTBI remain to be determined.63 There also remains a ques- tion which metabolites are best to be used and whether they should be reported as absolute values or as ratios.63 Neuroimaging Summary The clinical application of advanced neuroimaging tech- niques is, at the current state, hampered by the high burden of time, costly equipment, and technical expertise required to obtain, process, and interpret the imaging data. Of the methods reviewed, SWI adds the least expense in terms of finances, technical expertise, and time. This method, thus, is already done routinely in many emergency centers. QUANTITATIVE EEG (QEEG) For several decades, transient, nonspecific changes in stan- dard EEG signal have been recognized in acutely concussed individuals.64,65,66 qEEG makes use of the data acquired from standard EEG. qEEG uses software algorithms to quantify and assess trends in the EEG data acquired. Spectral analysis and coherence have been of particular interest in the evalua- tion of mTBI. Spectral analysis is used to determine how much of an EEG rhythm over a given period is of a particular frequency. Coherence measurements correlate the EEG fre- quency between two channels to assess how similar or "coher- ent" the underlying brain activity is. This coherence has been proposed to be a measure of the neural network connectivity. In 2012, Haneef et al reviewed the experience of qEEG in mTBI.67 There remains much disagreement regarding the role of qEEG in mTBI diagnosis and prognosis. Although qEEG does show changes in some individuals after mTBI, the findings are not specific for TBI. For example, other medical conditions, drug effects, and neuropsychiatric condi- tions (such as anxiety) can show similar anomalies on qEEG. A normal EEG also does not exclude the diagnosis of mTBI. Moreover, the abnormalities on EEG and qEEG change over time, and can be very transient (minutes to hours) based on time since injury. Finally, nonexperts can misinterpret EEG and qEEG signal, leading to erroneous conclusions. Despite decades of researching using the technique, there is currently little evidence to support the role of EEG and qEEG in the diagnosis of mTBI. Still, we have seen continued attention within the DoD focused on the use of this technique. Indeed, an online database search identified eight currently funded studies investigating EEG in TBI68 and the technique was highlighted in a recent DoD news article.69 Improvements in the specificity and reliability of the technique are needed before qEEG plays a reliable role in the diagnosis of mTBI. SUMMARY The accurate diagnosis of mTBI remains an important chal- lenge to military physicians in both battlefield and garrison environments. In the past decade, several technologies have emerged that show promise to improving sensitivity and specificity for the diagnosis. Ideally, these diagnostic tests would enable better objective measurement of the neuro- metabolic function after mTBI. They could enable medical providers to improve identification of soldiers with concussion, guide therapy, and make better and more objective return to duty decisions. Appropriate biomarkers should guide progno- sis and serve as a quantitative measure of the effects of potential therapies. The use of these technologies on the battlefield is also an important consideration. How much "technology" is necessary? Can it be easily deployed and readily used in a military environment? Can the test be easily interpreted? These are fundamental questions that are crucial for military medical providers. The DoD has taken an active role in pursuing research in applicable biological markers for diagnosis of mTBI. These have included soluble serum bio- markers, advanced neuroimaging, and qEEG. Many of these tests, particularly neuroimaging and soluble serum bio- markers, have begun to show promise in being adjuncts to the diagnosis of mTBI. In addition to validating currently available information about mTBI biomarkers, future work should examine how various biomarker techniques may be combined to even better improve diagnosis, guide treatment, inform prognosis, and serve as a marker of response to treat- ment. At the current time, these technologies remain largely investigational or confined to use in tertiary care medical centers. Currently, the diagnosis of mTBI remains a clinical diagnosis, based on an accurate clinical history with supple- mental history from witnesses. We are hopeful that the signif- icant funding and attention given in recent years to TBI diagnostics, both within and without the DoD, will soon result in reproducible and easily deployable objective measures. REFERENCES 1. 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The views expressed in this presentation are those of the author and do not necessarily reflect the official policy or position of the Department of the Navy, Department of the Army, Department of Defense, or the U. S. Government. doi: 10.7205/MILMED-D-13-00435 (c) 2014 Association of Military Surgeons of the United States |