Differential Diagnosis for TBI, PTSD: a Case for Single-Photon Emission Computerized Tomography
Symptoms of persistent mild-to-moderate TBI have tremendous overlap with those of PTSD.
Traumatic brain injury (TBI) has been all over the news — and consequently on the minds of Americans. Yet, TBI is neither a new problem nor a rare malady. TBI ranges from mild TBI (concussion), moderate TBI (usually associated with a loss of consciousness at the time of injury), and severe TBI.
The Centers for Disease Control and Prevention estimated that 1.5 million Americans sustained TBI annually in 2000.1 As of 2006, the estimates had risen to 1.7 million brain injuries per year.2 These prevalence proportions will increase as military personnel return home and the problem of repeated mild TBI (mTBI) becomes more recognized in sports. Current estimates of TBI among veterans range from 9.6% to 20%,3 with an estimated total of more than 300 000 cases among military personnel since 2000.4 The current estimates of combined sports-related concussions and brain injuries in the United States are 1.6 to 3.8 million each year.5
TBI results in a wide spectrum of neurological, psychiatric, cognitive, and emotional consequences. In part, the variation is related to the severity of the injury, which is stratified based on Glascow Coma score, periods of unconsciousness, and degrees of amnesia. Furthermore, the diversity of sequalae can be related to the areas of the brain that are injured, the severity of the injury (highly variable within the classification of “mild” and “moderate”), and the evolution of the injury over time due to neuroinflammatory processes.
It is not easy to diagnose TBI. Perhaps the key complication is that the symptoms of persistent mild-to-moderate TBI have tremendous overlap with those of post-traumatic stress disorder (PTSD),6 a mental disorder that can develop after a person is exposed to 1 or more traumatic events. These overlapping symptoms include headaches, fatigue, irritability, cognitive difficulties, anxiety, sleep disturbance, memory impairment, difficulty concentrating, and emotional dysregulation. Clinically, these populations may overlap by 33% to 42%.7,8
The Congressional Research Service9 reported 103 792 servicemen and women diagnosed with PTSD from 2000 to 2012. For patients with both TBI and PTSD, the US Department of Veterans Affairs (VA) acknowledges that the patient is often diagnosed with one or the other. Note that several of the question items within the Clinician-Administered PTSD scale10 can be symptoms of TBI, such as poor concentration, memory difficulties, anhedonia, social isolation, sleep difficulties, and irritability. The VA recently concluded there was a lack of diagnostic accuracy for the dually affected veteran.11
The economic costs to society for treatment of PTSD and TBI are significant, with the Rand Corporation estimating an annual cost for TBI between $591 million and $910 million. Within the first 2 years after returning from deployment, the estimated costs associated with the treatment of PTSD and major depression for 1.6 million service members ranged between $4 billion to $6.2 billion.12
The Failure of Traditional Neuroimaging
Traditional brain imaging modalities such as magnetic resonance imaging (MRI) and computed tomography (CT) provide little evidence in cases of mild-to-moderate TBI. This is likely secondary to the fact that CT and MRI detect structural defects, which in the case of mild-to-moderate TBI are likely either not present or below the imaging resolution of MRI or CT. Both certainly have their applications in helping to diagnose traumatic brain injuries (especially severe injuries). Typically, CT remains a vital first step in the assessment of any TBI due to its superior capacity to visualize hemorrhage and skull fracture. Unfortunately, the sensitivity of CT is very low for mild-to-moderate TBI, and so the majority of CT scans in mild-to-moderate TBI are read as normal.
A significant body of literature shows that single-photon emission computerized tomography (SPECT) scans are more sensitive for mild-to-moderate TBI than CT scans. In a combined sample of more than 4,000 mild TBI cases, roughly 5% to 10% had abnormal CT scans.13-15 In a prospective study of 92 adult and pediatric patients with TBI compared with a database of 40 healthy individuals,16 SPECT and CT scans were performed within 72 hours of injury. The CT scans were abnormal in only 34% of cases. In contrast, the SPECT scans were abnormal in 63%. In all cases with positive SPECT scans, the findings were co-localized with lesions revealed on CT scan.
SPECT scans have also proven to be more sensitive for detecting mild-to-moderate TBI than anatomical MRI scans. In a study of 13 patients with moderate TBI compared with 21 screened controls, MRI was positive in only 50% of cases, whereas SPECT was positive in 100% of cases.17 In a retrospective study of 228 cases, SPECT revealed evidence of functional brain deficits in 68% of the cases, whereas CT and MRI scans were completely negative.18 The SPECT scans revealed that 46% of cases had frontal lobe hypoperfusion, 55% had basal ganglia/thalamic hypoperfusion, and 18% had temporal lobe hypoperfusion.
Currently, The Society of Nuclear Medicine19 and the European Association of Nuclear Medicine20 recognize SPECT as having diagnostic and prognostic value for TBI (both in acute concussion and long-standing injury). The American College of Radiology21 cites symptomatic TBI, especially in the absence of CT and/or MRI findings, as a clinical indication for the use of SPECT. It should be noted that the outdated 1996 TTASAAN report22 by the American Academy of Neurology, which concluded that SPECT was an experimental technique, was based on only 6 early studies. Its conclusions have been superseded by the more current literature.
The International Society of Applied Neuroimaging (of which I am currently the president) recently reviewed all of the extant literature on the use of SPECT neuroimaging in TBI.23 To summarize the state of current literature, 903 patients included in 19 longitudinal studies demonstrated Level II A evidence for the utility of SPECT to identify lesions in the clinical setting of TBI. Of the 19 longitudinal studies, 14 (77%) had neurological or neuropsychology outcome measures to which SPECT abnormalities were correlated. A total of 2,121 patients in 52 cross-sectional studies of TBI were also reviewed.
Recent In-Roads in Neuroimaging
The challenge in neuroimaging has been to have an inexpensive and reliable method of discerning TBI from the uninjured and from those with PTSD. The military has made beating this challenge a high priority. Recent research has focused on new ways to use MRI to ferret out more information from the brain. In April 2016, a group under the direction of Gerald Riedy, MD, PhD, at the National Intrepid Center of Excellence, published a paper24 on the findings in 834 military service members who had been exposed to bomb blasts (84%) or lost consciousness with their TBI (63%). Using a high-powered 3 Tesla MRI, they were able to find evidence of white matter T2 weighted hyperintensities in 51.8% of those injured. Assuming all who were exposed to blasts had a brain injury, this technique picked up between 62% and 82% of the mild-to-moderate TBI cases. These data fit with a recent postmortem histopathology study of a small number of service members who had acute or chronic blast exposure-related TBI or impact-related TBI.25 Postmortem analysis showed astroglial scarring at the grey-white matter junctions, along blood vessels, and just below the pial surface. In other words, the axons and white matter were damaged at interfaces between tissue and fluid and between tissues with different densities.
The challenge is to get this highly refined technique to work in the average MRI in the average VA, military hospital, or in the field. That hurdle has yet to be overcome, and when it is, the accuracy will likely be lower than the range of 62% to 82% achieved in the research setting.
From the functional MRI research a concept has risen of the “default mode network” (DMN), which is a grouping of structures in the brain that tend to be most synchronously active when the brain is in a resting state. More precisely, these areas are more co-active in-between tasks. For example, changes in the activity and connectivity of the DMN have been found in depression.26 Attempts to use the DMN to identify TBI have had mixed results. In a comparison of 15 patients with TBI with 12 healthy controls, Nathan and colleagues27 found there was high variability in the findings of the patients with TBI, consistent with the variability in the structures and degree of injury that is inherent to TBI. However, increased levels of linked activity were found among the elements of the DMN.
In another study, Raji and colleagues28,29 analyzed more than 20 000 SPECT scans of patients with TBI and/or PTSD compared with controls and found that quantitative analysis of the DMN allowed a high level of discrimination between the different conditions — with greater than 94% accuracy. Specifically, the DMN is hyperperfused in individuals diagnosed with PTSD and hypoperfused in patients diagnosed with TBI. This work delivered a very strong message: that SPECT can unravel a distressing conundrum for those who treat veterans. The differentiation of TBI and PTSD and the combination of both conditions has been a daunting task for military and veteran services. Indeed, this work was recognized by Discover magazine as one of the top 20 scientific findings of 2015.30
The opportunity exists to radically change the way medicine approaches TBI. The protocol that my colleagues and I elaborated on in this pair of papers28,29 can be readily applied worldwide. SPECT scanners are available in virtually every major city and most countries. The number of SPECT scanners far outnumbers 3 Tesla MRI machines. SPECT scanners also outnumber positron emission tomography (PET) scanners by 12:1 in the United States and 100:1 in Canada.31,32 The technological build-up to implement SPECT neuroimaging for TBI diagnostics would be small. Moreover, the software to perform the type of quantitative analysis used by our group is freely available. The initial step is to change the way medicine conceptualizes TBI, as even mild TBI has lasting effects on a person's life and health.33 TBI can be accurately diagnosed using neuroimaging and treated with new cutting-edge techniques.34
- Bazarian JJ, McClung J, Shah MN, Cheng YT, Flesher W, Kraus J. Mild traumatic brain injury in the United States, 1998-2000. Brain Injury. 2005;19(2):85-91.
- Faul M, Xu L, Wald M, Coronado VG. Traumatic brain injury in the united states. U.S. department of health and human services report. http://www.cdc.gov/TraumaticBrainInjury/. Accessed July 10, 2016.
- Vaishnavi S, Rao V, Fann JR. Neuropsychiatric problems after traumatic brain injury: Unraveling the silent epidemic. Psychosomatics. 2009;50:198-205.
- DoD worldwide numbers for TBI 2014. Defense and Veterans Brain Injury Center website. http://dvbic.dcoe.mil/dod-worldwide-numbers-tbi. Accessed July 10, 2016.
- Injury prevention and control: traumatic brain injury.Centers for Disease Control and Prevention website. http://www.cdc.gov/TraumaticBrainInjury/. Accessed July 9, 2016.
- Hoge CW, McGurk D, Thomas JL, Cox AL, Engel CC, Castro CA. Mild traumatic brain injury in U.S. soldiers returning from Iraq. N Engl J Med. 2008;358:453-463. doi:10.1056/NEJMoa072972
- Lew HL. Rehabilitation needs of an increasing population of patients: traumatic brain injury, polytrauma, and blast-related injuries. J Rehabil Res Dev. 2005;42(4):xiii-xvi.
- Dursa EK, Reinhard MJ, Barth SK, Schneiderman AI. Prevalence of a positive screen for PTSD among OEF/OIF and OEF/OIF-era veterans in a large population-based cohort. J Trauma Stress. 2014;27:542-549.
- The veterans health administration's treatment of PTSD and traumatic brain injury among recent combat veterans. Congressional Budget Office website. https://www.cbo.gov/sites/default/files/cbofiles/attachments/02-09-PTSD.pdf. Accessed October 13, 2016.
- Blake DD, Weathers FW, Nagy LM, Kaloupek DG, Charney DS, Keane TM. Clinician-administered PTSD scale for DSM-IV. National Center for Posttraumatic Stress Disorder. http://www.clintools.com/victims/resources/assessment/ptsd/protected/CAPSIV.pdf. Accessed July 9, 2016.
- Taylor BC, Hagel EM, Carlson KF, et al. Prevalence and costs of co-occurring traumatic brain injury with and without psychiatric disturbance and pain among Afghanistan and Iraq War veteran V.A. users. Med Care. 2012;50(4):342-346. doi:10.1097/MLR.0b013e318245a558.
- Tanielan T, Jaycox LH. Invisible wounds of war: psychological and cognitive injuries, their consequences, and services to assist recovery. Rand Center for Military Health Policy Research. http://www.rand.org/content/dam/rand/pubs/monographs/2008/RAND_MG720.pdf. Accessed October 13, 2016.
- Borczuk P. Predictors of intracranial injury in patients with mild head trauma. Ann Emerg Med. 1995;25(6):731-736.
- Miller EC, Holmes JF, Derlet RW. Utilizing clinical factors to reduce head CT scan ordering for minor head trauma patients. J Emerg Med. 1997;15(4):453-457.
- Haydel MJ, Preston CA, Mills TJ, Luber S, Blaudeau E, DeBlieux PM. Indications for computed tomography in patients with minor head injury. N Engl J Med. 2000;13;343(2):100-105.
- Gowda NK, Agrawal D, Bal C, et al. Technetium Tc-99m ethyl cysteinate dimer brain single-photon emission CT in mild traumatic brain injury: a prospective study. AJNR Am J Neuroradiol. 2006;27(2):447-451.
- Shin YB, Kim SJ, Kim IJ, et al. Voxel-based statistical analysis of cerebral blood flow using Tc-99m ECD brain SPECT in patients with traumatic brain injury: group and individual analyses. Brain Inj. 2006;20:661-667.
- Abu-Judeh HH, Parker R, Aleksic S, et al. SPECT brain perfusion findings in mild or moderate traumatic brain injury. Nucl Med Rev Cent East Eur. 2000;3(1)5-11.
- Juni JE, Waxman AD, Devous MD, et al. Procedure guideline for brain perfusion SPECT using (99m)Tc radiopharmaceuticals 3.0. J Nucl Med Technol. 2009;37(3):191-195.
- Tatsch K, Asenbaum S, Bartenstein P, et al. European Association of Nuclear Medicine procedure guidelines for brain perfusion SPET using (99m)Tc-labelled radiopharmaceuticals. Eur J Nucl Med Mol Imaging. 2002;(10):BP36-42.
- ACR-SPR practice parameter for the performance of single photon emission computed tomography (SPECT) brain perfusion and for brain death examinations. American College of Radiology. http://www.acr.org/~/media/55108DB59AFD44FDB0E5339DC73DC821.pdf. Accessed October 13, 2016.
- Assessment of brain SPECT: report of the therapeutics and technology assessment subcommittee of the American Academy of Neurology. Neurology. 1996;46(1):278-285.
- Raji CA, Tarzwell R, Pavel D, et al. Clinical utility of SPECT neuroimaging in the diagnosis and treatment of traumatic brain injury: a systematic review. PloS One. 2014;9(3):e91088.
- Riedy G, Senseney JS, Liu W, et al. Findings from structural MR imaging in military traumatic brain injury. Radiology. 2016;279(1):207-215. doi:10.1148/radiol.2015150438.
- Shively S, Horkayne-Szakaly I, Jones R, Kelly J, Armstrong R, Perl D. Characterisation of interface astroglial scarring in the human brain after blast exposure: a post-mortem case series. Lancet Neurol. 2016;15(9):944-953. doi:10.1016/s1474-4422(16)30057-6.
- Dichter GS, Gibbs D, Smoski MJ. A systematic review of relations between resting-state functional-MRI and treatment response in major depressive disorder. J Affect Disord. 2015;172:8-17.
- Nathan DE, Oakes TR, Yeh PH, et al. Exploring variations in functional connectivity of the resting state default mode network in mild traumatic brain injury. Brain Connect. 2015;5(2):102-114.
- Amen DG, Raji CA, Willeumier K, et al. Functional neuroimaging distinguishes posttraumatic stress disorder from traumatic brain injury in focused and large community datasets. PLoS One. 2015;10(7):e0129659.
- Raji CA, Willeumier K, Taylor D, et al. Functional neuroimaging with default mode network regions distinguishes PTSD from TBI in a military veteran population. Brain Imaging Behav. 2015;9(3):527-534.
- Millman C. Brain scans may lead to better diagnoses. Discover. http://discovermagazine.com/2016/janfeb/19-brain-scans-may-lead-to-better-diagnoses. Accessed July 10, 2016.
- Positron Emission Tomography in Canada 2015. Canadian Agency for Drugs and Technologies in Health. https://www.cadth.ca/positron-emission-tomography-canada-2015. Published September 29, 2015. Accessed July 11, 2016.
- Gholamrezanezhad A, Mirpour S, Mariani G. Future of nuclear medicine: SPECT versus PET. J Nucl Med. 2009;50:16N-18N.
- Prins ML, Alexander D, Giza CC, Hovda DA. Repeated mild traumatic brain injury: mechanisms of cerebral vulnerability. J Neurotrauma. 2013;30(1):30-38. doi:10.1089/neu.2012.2399.
- Henderson TA, Morries LD. SPECT perfusion imaging demonstrates improvement of traumatic brain injury with transcranial near-infrared laser phototherapy. Adv Mind Body Med. 2015 B;29(4):27-33.