- Email: [email protected]
Defining Cure
C H A P T E R
4 Defining Cure Martin Slade, PhD1 and Michael E. Hoffer, MD2 1
Medicine and Public Health, Yale University, New Haven, CT, United States 2Department of Otolaryngology and Neurological Surgery, University of Miami, Miller School of Medicine, Miami, FL, United States
Merriam-Webster defines cure as “a complete or permanent solution or remedy.”1 In practice, the notion of cure is much less tangible. For some diseases, cure is fairly straightforward and is used only when the disease is absent and has not recurred for a sufficient period of time. This is particularly true in oncology where cancer cures are well defined and the period of time necessary to be free from disease has been established. However, for most diseases, being free of symptoms can be considered being cured and this is where the notion of cure becomes more difficult to establish. This is particularly true when the disorder is poorly understood or the pathophysiology difficult to monitor in an exact fashion. Consider a migraine patient who is free of migraine headaches for the past 5 years. The individual might consider themselves cured, but it is difficult to say that the migraines are actually cured since tracking the pathologies of migraines and establishing that the particular pathology no longer exists is difficult to establish given current medical science. It might be more accurate to refer to this individual as controlled, but in modern usage many individuals use the term controlled to refer to conditions that are being managed with some type of therapeutic option. Consider, as well, a variety of musculoskeletal injuries. A broken bone can be mended and after the cast is removed and therapy is conducted the individual who suffered the break may be free from any symptoms, but is that broken bone truly “cured.” Even plain film X-rays will show evidence of the old fracture throughout the person’s lifetime. In addition to being difficult to define, the notion of “cure” is temporal and related only to the current time because almost every disease entity once cured can be “uncured.” Consider the three examples above; the cancer can recur, the migraines can begin again, and the once-broken bone can become a source of arthritis or a weak spot for a future facture. Even the most simple of cures where a bacterial infection is eradicated with antibiotics can leave the affected area of the body at risk for future infections and complications many years later.
Neurosensory Disorders in Mild Traumatic Brain Injury DOI: https://doi.org/10.1016/B978-0-12-812344-7.00004-2
49
Copyright © 2019 Elsevier Inc. All rights reserved.
50
4. DEFINING CURE
So, if the notion of cure is difficult to fully describe and temporal in nature, applying such a concept to mild traumatic brain injury is an even more difficult challenge. Mild traumatic brain injury is a heterogeneous disorder that can be associated with a variety of sequelae. Describing resolution of these sequelae may be difficult to achieve but very possible. The individual may report no more headaches or dizziness and objective tests of vestibular function may largely normalize. However, symptom resolution alone is not entirely indicative or even necessary for a cure. In one scenario the symptoms may be relieved, but the injury to the brain itself may still persist.2 In another scenario an individual could, theoretically, have a persistence of symptoms from a pathology that arose due to the brain injury or associated with the injury itself, but the brain itself may be totally healed.3 An individual might, for instance, have a neck injury at the same time as a head injury and have a persistent headache due to the neck injury even after the brain has “entirely” healed. The cure of mTBI involves brain healing which has been difficult to achieve or document. Most of the work in the area to date has been aimed at reducing or treating injury sequelae rather than addressing the primary pathophysiology of the disorder. Current strategies and developments in this area will be examined in this book. However, there have been a variety of strategies that have been utilized to address the issue of brain healing by reducing the volume or degree of injury in the first place. Some of these strategies have also been advocated to treat the sequelae of mTBI. Pharmaceutical countermeasures designed to limit the area of damage have included medicines with antioxidant, antiinflammatory, and antiapoptotic properties.4 6 Other strategies to induce brain repair include limiting the volume of injury and inducing repair through blood flow and gene changes utilizing hypothermia or factors that directly affect nitric oxide metabolism.7 10 Many investigators have begun to capitalize on successful trials in spinal cord injury and have examined stem cells use as a method for repopulating lost neurons.11 This area of research holds tremendous promise and likely will be one of the most important advances in head injury treatment in the next several years. Finally, hyperbaric oxygen has been tried with mixed results.12 Whether or not mTBI can be truly cured, the most important question is when is it safe and appropriate for an individual to return to work, school, or play. For some individuals this may be simply based on symptoms and the ability to tolerate and perform job duties while symptom-free. But for other individuals, especially those engaged in activities like sports or the military, where the possibility of another injury is very real, determining when it is safe for that individual to return to work or play is a much more challenging issue. The impact of subsequent concussions has been a challenge for investigators. This is in part due to nomenclature of the so called “Second Impact Syndrome.”13 This nosology issue aside, there is solid scientific evidence demonstrating that the physiologic changes seen in initial injury are intensified and longer lasting with subsequent injury.14,15 This work, as well as observations from the field, has resulted in most individuals concluding that subsequent impacts are potentially more harmful than a single impact.16 The exact consequences are probably related to a great number of variables including the intensity and type of the impacts, the amount of time between the impacts, and the number of previous impacts. There is clearly a great deal of work to do in this area.
I. DEFINING MILD TBI
REFERENCES
51
Almost as important as defining when an individual is clear to return to work is providing accurate prognostic estimates. This step is a critical component of caring for individuals with this disorder. Unfortunately, due to the heterogeneity of the disorder, the variable effects of the disorder on different individuals, a host of social issues, and the variability in medical care, predicting when a patient will be suitable to return to activities is very difficult. Tests designed to diagnose the disorder often do not have prognostic value17,18 or have a variety of variables which can place a patient into a response category, but do not provide even remotely accurate prediction of response time.19,20 Work is underway in our laboratory to examine novel test findings in the early and subacute periods to provide prognostic information to individuals, their work, their school, or their team. Clearly there is a great deal of work to be done in evaluating the elements of cure in mTBI. Basic science work must continue to examine biomarkers, imaging, and functional tests that can truly determine when symptoms have resolved and when the brain has healed. Studies have to be done to evaluate the impact of subsequent concussions in the context of frequency, type, and force. Work must continue on developing tests and evaluations that not only provide information on when it is safe to return to work or play, but can estimate that day in advance. As health care advances we believe that the term “cure” will be made more clear and enabling learning how to best apply a range of test and treatment options that are specific to the affected individual and to the injury they experienced. It is incumbent on science and medicine to take the steps necessary to make this a reality.
References 1. https://www.merriam-webster.com/dictionary/cure. 2. Kamins J, Bigler E, Covassin T, Henry L, Kemp S, Leddy JJ, et al. What is the physiological time to recovery after concussion? A systematic review. Br J Sports Med 2017;51(12):935 40. Available from: https://doi.org/ 10.1136/bjsports-2016-097464. Epub 2017 Apr 28. Review. PubMed PMID: 28455363. 3. Kennedy E, Quinn D, Tumilty S, Chapple CM. Clinical characteristics and outcomes of treatment of the cervical spine in patients with persistent post-concussion symptoms: a retrospective analysis. Musculoskelet Sci Pract 2017;29:91 8. Available from: https://doi.org/10.1016/j.msksp.2017.03.002. Epub 2017 Mar 14. PubMed PMID: 28347935. 4. Hoffer ME, Balaban C, Slade MD, Tsao JW, Hoffer B. Amelioration of acute sequelae of blast induced mild traumatic brain injury by N-acetyl cysteine: a double-blind, placebo controlled study. PLoS One 2013;8(1): e54163. Available from: https://doi.org/10.1371/journal.pone.0054163. 5. Eakin K, Baratz-Goldstein R, Pick CG, Zindel O, Balaban CD, Hoffer ME, et al. Efficacy of N-acetyl cysteine in traumatic brain injury. PLoS One 2014;9(4):e90617. Available from: https://doi.org/10.1371/journal. pone.0090617. 6. Mei Z, Qiu J, Alcon S, Hashim J, Rotenberg A, Sun Y, et al. Memantine improves outcomes after repetitive traumatic brain injury. Behav Brain Res 2017. pii: S0166-4328(17)30621-6. doi: 10.1016/j.bbr.2017.04.017. [Epub ahead of print] PubMed PMID: 28412305. 7. Dietrich WD, Alonso O, Busto R, Globus MY, Ginsberg MD. Post-traumatic brain hypothermia reduces histopathological damage following concussive brain injury in the rat. Acta Neuropathol 1994;87(3):250 8 PubMed PMID: 8009957. 8. Koizumi H, Fujisawa H, Ito H, Maekawa T, Di X, Bullock R. Effects of mild hypothermia on cerebral blood flow-independent changes in cortical extracellular levels of amino acids following contusion trauma in the rat. Brain Res 1997;747(2):304 12 PubMed PMID: 9046006.
I. DEFINING MILD TBI
52
4. DEFINING CURE
9. Matsushita M, Yonemori F, Furukawa N, Ohta A, Toide K, Uchida I, et al. Effects of the novel thyrotropinreleasing hormone analogue Na-((1S,2R)-2-methyl-4-oxocyclopentylcarbonyl)-L-histidyl-L-prol ina mide monohydrate on the central nervous system in mice and rats. Arzneimittelforschung 1993;43(8):813 17 PubMed PMID: 8216433. 10. Khan M, Khan H, Singh I, Singh AK. Hypoxia inducible factor-1 alpha stabilization for regenerative therapy in traumatic brain injury. Neural Regen Res 2017;12(5):696 701. Available from: https://doi.org/10.4103/16735374.206632. Review. PubMed PMID: 28616019; PubMed Central PMCID: PMC5461600. 11. Torper O, Go¨tz M. Brain repair from intrinsic cell sources: turning reactive glia into neurons. Prog Brain Res 2017;230:69 97. Available from: https://doi.org/10.1016/bs.pbr.2016.12.010. Epub 2017 Feb 7. PubMed PMID: 28552236. 12. Figueroa XA, Wright JK. Hyperbaric oxygen: B-level evidence in mild traumatic brain injury clinical trials. Neurology 2016;87(13):1400 6. Available from: https://doi.org/10.1212/WNL.0000000000003146. Epub2016 Aug 31. Review. PubMed PMID: 27581219. 13. Stovitz SD, Weseman JD, Hooks MC, Schmidt RJ, Koffel JB, Patricios JS. What definition is used to describe second impact syndrome in sports? A systematic and critical review. Curr Sports Med Rep 2017;16(1):50 5. Available from: https://doi.org/10.1249/JSR.0000000000000326. Review. PubMed PMID: 28067742. 14. Mountney A, Boutte´ AM, Cartagena CM, Flerlage WF, Johnson WD, Rho C, et al. Functional and molecular correlates after single and repeated rat closed-head concussion: indices of vulnerability after brain injury. J Neurotrauma 2017. Available from: https://doi.org/10.1089/neu.2016.4679 [Epub ahead of print] PubMed PMID: 28326890. 15. Fidan E, Lewis J, Kline AE, Garman RH, Alexander H, Cheng JP, et al. Repetitive mild traumatic brain injury in the developing brain: effects on long-term functional outcome and neuropathology. J Neurotrauma 2016;33 (7):641 51. Available from: https://doi.org/10.1089/neu.2015.3958. Epub 2015 Dec 1. PubMed PMID: 26214116; PubMed Central PMCID: PMC4827290. 16. Guskiewicz KM, Broglio SP. Acute sports-related traumatic brain injury and repetitive concussion. Handb Clin Neurol 2015;127:157 72. Available from: https://doi.org/10.1016/B978-0-444-52892-6.00010-6. Review. PubMed PMID: 25702215. 17. Sufrinko AM, Marchetti GF, Cohen PE, Elbin RJ, Re V, Kontos AP. Using acute performance on a comprehensive neurocognitive, vestibular, and ocular motor assessment battery to predict recovery duration after sportrelated concussions. Am J Sports Med 2017;45(5):1187 94. Available from: https://doi.org/10.1177/ 0363546516685061. Epub 2017 Feb 13. PubMed PMID: 28192036. 18. Peters ME, Rao V, Bechtold KT, Roy D, Sair HI, Leoutsakos JM, et al. Head injury serum markers for assessing response to trauma: design of the HeadSMART study. Brain Inj 2017;31(3):370 8. Available from: https://doi.org/10.1080/02699052.2016.1231344. Epub 2017 Jan 31. PubMed PMID: 28140672. 19. Anzalone AJ, Blueitt D, Case T, McGuffin T, Pollard K, Garrison JC, et al. A positive vestibular/ocular motor screening (VOMS) is associated with increased recovery time after sports-related concussion in youth and adolescent athletes. Am J Sports Med 2017;45(2):474 9. Available from: https://doi.org/10.1177/ 0363546516668624. Epub 2016 Oct 28. PubMed PMID: 27789472. 20. Schwed AC, Boggs MM, Watanabe D, Plurad DS, Putnam BA, Kim DY. Admission variables associated with a favorable outcome after mild traumatic brain injury. Am Surg 2016;82(10):898 902 PubMed PMID: 27779969.
I. DEFINING MILD TBI
4 Defining Cure Martin Slade, PhD1 and Michael E. Hoffer, MD2 1
Medicine and Public Health, Yale University, New Haven, CT, United States 2Department of Otolaryngology and Neurological Surgery, University of Miami, Miller School of Medicine, Miami, FL, United States
Merriam-Webster defines cure as “a complete or permanent solution or remedy.”1 In practice, the notion of cure is much less tangible. For some diseases, cure is fairly straightforward and is used only when the disease is absent and has not recurred for a sufficient period of time. This is particularly true in oncology where cancer cures are well defined and the period of time necessary to be free from disease has been established. However, for most diseases, being free of symptoms can be considered being cured and this is where the notion of cure becomes more difficult to establish. This is particularly true when the disorder is poorly understood or the pathophysiology difficult to monitor in an exact fashion. Consider a migraine patient who is free of migraine headaches for the past 5 years. The individual might consider themselves cured, but it is difficult to say that the migraines are actually cured since tracking the pathologies of migraines and establishing that the particular pathology no longer exists is difficult to establish given current medical science. It might be more accurate to refer to this individual as controlled, but in modern usage many individuals use the term controlled to refer to conditions that are being managed with some type of therapeutic option. Consider, as well, a variety of musculoskeletal injuries. A broken bone can be mended and after the cast is removed and therapy is conducted the individual who suffered the break may be free from any symptoms, but is that broken bone truly “cured.” Even plain film X-rays will show evidence of the old fracture throughout the person’s lifetime. In addition to being difficult to define, the notion of “cure” is temporal and related only to the current time because almost every disease entity once cured can be “uncured.” Consider the three examples above; the cancer can recur, the migraines can begin again, and the once-broken bone can become a source of arthritis or a weak spot for a future facture. Even the most simple of cures where a bacterial infection is eradicated with antibiotics can leave the affected area of the body at risk for future infections and complications many years later.
Neurosensory Disorders in Mild Traumatic Brain Injury DOI: https://doi.org/10.1016/B978-0-12-812344-7.00004-2
49
Copyright © 2019 Elsevier Inc. All rights reserved.
50
4. DEFINING CURE
So, if the notion of cure is difficult to fully describe and temporal in nature, applying such a concept to mild traumatic brain injury is an even more difficult challenge. Mild traumatic brain injury is a heterogeneous disorder that can be associated with a variety of sequelae. Describing resolution of these sequelae may be difficult to achieve but very possible. The individual may report no more headaches or dizziness and objective tests of vestibular function may largely normalize. However, symptom resolution alone is not entirely indicative or even necessary for a cure. In one scenario the symptoms may be relieved, but the injury to the brain itself may still persist.2 In another scenario an individual could, theoretically, have a persistence of symptoms from a pathology that arose due to the brain injury or associated with the injury itself, but the brain itself may be totally healed.3 An individual might, for instance, have a neck injury at the same time as a head injury and have a persistent headache due to the neck injury even after the brain has “entirely” healed. The cure of mTBI involves brain healing which has been difficult to achieve or document. Most of the work in the area to date has been aimed at reducing or treating injury sequelae rather than addressing the primary pathophysiology of the disorder. Current strategies and developments in this area will be examined in this book. However, there have been a variety of strategies that have been utilized to address the issue of brain healing by reducing the volume or degree of injury in the first place. Some of these strategies have also been advocated to treat the sequelae of mTBI. Pharmaceutical countermeasures designed to limit the area of damage have included medicines with antioxidant, antiinflammatory, and antiapoptotic properties.4 6 Other strategies to induce brain repair include limiting the volume of injury and inducing repair through blood flow and gene changes utilizing hypothermia or factors that directly affect nitric oxide metabolism.7 10 Many investigators have begun to capitalize on successful trials in spinal cord injury and have examined stem cells use as a method for repopulating lost neurons.11 This area of research holds tremendous promise and likely will be one of the most important advances in head injury treatment in the next several years. Finally, hyperbaric oxygen has been tried with mixed results.12 Whether or not mTBI can be truly cured, the most important question is when is it safe and appropriate for an individual to return to work, school, or play. For some individuals this may be simply based on symptoms and the ability to tolerate and perform job duties while symptom-free. But for other individuals, especially those engaged in activities like sports or the military, where the possibility of another injury is very real, determining when it is safe for that individual to return to work or play is a much more challenging issue. The impact of subsequent concussions has been a challenge for investigators. This is in part due to nomenclature of the so called “Second Impact Syndrome.”13 This nosology issue aside, there is solid scientific evidence demonstrating that the physiologic changes seen in initial injury are intensified and longer lasting with subsequent injury.14,15 This work, as well as observations from the field, has resulted in most individuals concluding that subsequent impacts are potentially more harmful than a single impact.16 The exact consequences are probably related to a great number of variables including the intensity and type of the impacts, the amount of time between the impacts, and the number of previous impacts. There is clearly a great deal of work to do in this area.
I. DEFINING MILD TBI
REFERENCES
51
Almost as important as defining when an individual is clear to return to work is providing accurate prognostic estimates. This step is a critical component of caring for individuals with this disorder. Unfortunately, due to the heterogeneity of the disorder, the variable effects of the disorder on different individuals, a host of social issues, and the variability in medical care, predicting when a patient will be suitable to return to activities is very difficult. Tests designed to diagnose the disorder often do not have prognostic value17,18 or have a variety of variables which can place a patient into a response category, but do not provide even remotely accurate prediction of response time.19,20 Work is underway in our laboratory to examine novel test findings in the early and subacute periods to provide prognostic information to individuals, their work, their school, or their team. Clearly there is a great deal of work to be done in evaluating the elements of cure in mTBI. Basic science work must continue to examine biomarkers, imaging, and functional tests that can truly determine when symptoms have resolved and when the brain has healed. Studies have to be done to evaluate the impact of subsequent concussions in the context of frequency, type, and force. Work must continue on developing tests and evaluations that not only provide information on when it is safe to return to work or play, but can estimate that day in advance. As health care advances we believe that the term “cure” will be made more clear and enabling learning how to best apply a range of test and treatment options that are specific to the affected individual and to the injury they experienced. It is incumbent on science and medicine to take the steps necessary to make this a reality.
References 1. https://www.merriam-webster.com/dictionary/cure. 2. Kamins J, Bigler E, Covassin T, Henry L, Kemp S, Leddy JJ, et al. What is the physiological time to recovery after concussion? A systematic review. Br J Sports Med 2017;51(12):935 40. Available from: https://doi.org/ 10.1136/bjsports-2016-097464. Epub 2017 Apr 28. Review. PubMed PMID: 28455363. 3. Kennedy E, Quinn D, Tumilty S, Chapple CM. Clinical characteristics and outcomes of treatment of the cervical spine in patients with persistent post-concussion symptoms: a retrospective analysis. Musculoskelet Sci Pract 2017;29:91 8. Available from: https://doi.org/10.1016/j.msksp.2017.03.002. Epub 2017 Mar 14. PubMed PMID: 28347935. 4. Hoffer ME, Balaban C, Slade MD, Tsao JW, Hoffer B. Amelioration of acute sequelae of blast induced mild traumatic brain injury by N-acetyl cysteine: a double-blind, placebo controlled study. PLoS One 2013;8(1): e54163. Available from: https://doi.org/10.1371/journal.pone.0054163. 5. Eakin K, Baratz-Goldstein R, Pick CG, Zindel O, Balaban CD, Hoffer ME, et al. Efficacy of N-acetyl cysteine in traumatic brain injury. PLoS One 2014;9(4):e90617. Available from: https://doi.org/10.1371/journal. pone.0090617. 6. Mei Z, Qiu J, Alcon S, Hashim J, Rotenberg A, Sun Y, et al. Memantine improves outcomes after repetitive traumatic brain injury. Behav Brain Res 2017. pii: S0166-4328(17)30621-6. doi: 10.1016/j.bbr.2017.04.017. [Epub ahead of print] PubMed PMID: 28412305. 7. Dietrich WD, Alonso O, Busto R, Globus MY, Ginsberg MD. Post-traumatic brain hypothermia reduces histopathological damage following concussive brain injury in the rat. Acta Neuropathol 1994;87(3):250 8 PubMed PMID: 8009957. 8. Koizumi H, Fujisawa H, Ito H, Maekawa T, Di X, Bullock R. Effects of mild hypothermia on cerebral blood flow-independent changes in cortical extracellular levels of amino acids following contusion trauma in the rat. Brain Res 1997;747(2):304 12 PubMed PMID: 9046006.
I. DEFINING MILD TBI
52
4. DEFINING CURE
9. Matsushita M, Yonemori F, Furukawa N, Ohta A, Toide K, Uchida I, et al. Effects of the novel thyrotropinreleasing hormone analogue Na-((1S,2R)-2-methyl-4-oxocyclopentylcarbonyl)-L-histidyl-L-prol ina mide monohydrate on the central nervous system in mice and rats. Arzneimittelforschung 1993;43(8):813 17 PubMed PMID: 8216433. 10. Khan M, Khan H, Singh I, Singh AK. Hypoxia inducible factor-1 alpha stabilization for regenerative therapy in traumatic brain injury. Neural Regen Res 2017;12(5):696 701. Available from: https://doi.org/10.4103/16735374.206632. Review. PubMed PMID: 28616019; PubMed Central PMCID: PMC5461600. 11. Torper O, Go¨tz M. Brain repair from intrinsic cell sources: turning reactive glia into neurons. Prog Brain Res 2017;230:69 97. Available from: https://doi.org/10.1016/bs.pbr.2016.12.010. Epub 2017 Feb 7. PubMed PMID: 28552236. 12. Figueroa XA, Wright JK. Hyperbaric oxygen: B-level evidence in mild traumatic brain injury clinical trials. Neurology 2016;87(13):1400 6. Available from: https://doi.org/10.1212/WNL.0000000000003146. Epub2016 Aug 31. Review. PubMed PMID: 27581219. 13. Stovitz SD, Weseman JD, Hooks MC, Schmidt RJ, Koffel JB, Patricios JS. What definition is used to describe second impact syndrome in sports? A systematic and critical review. Curr Sports Med Rep 2017;16(1):50 5. Available from: https://doi.org/10.1249/JSR.0000000000000326. Review. PubMed PMID: 28067742. 14. Mountney A, Boutte´ AM, Cartagena CM, Flerlage WF, Johnson WD, Rho C, et al. Functional and molecular correlates after single and repeated rat closed-head concussion: indices of vulnerability after brain injury. J Neurotrauma 2017. Available from: https://doi.org/10.1089/neu.2016.4679 [Epub ahead of print] PubMed PMID: 28326890. 15. Fidan E, Lewis J, Kline AE, Garman RH, Alexander H, Cheng JP, et al. Repetitive mild traumatic brain injury in the developing brain: effects on long-term functional outcome and neuropathology. J Neurotrauma 2016;33 (7):641 51. Available from: https://doi.org/10.1089/neu.2015.3958. Epub 2015 Dec 1. PubMed PMID: 26214116; PubMed Central PMCID: PMC4827290. 16. Guskiewicz KM, Broglio SP. Acute sports-related traumatic brain injury and repetitive concussion. Handb Clin Neurol 2015;127:157 72. Available from: https://doi.org/10.1016/B978-0-444-52892-6.00010-6. Review. PubMed PMID: 25702215. 17. Sufrinko AM, Marchetti GF, Cohen PE, Elbin RJ, Re V, Kontos AP. Using acute performance on a comprehensive neurocognitive, vestibular, and ocular motor assessment battery to predict recovery duration after sportrelated concussions. Am J Sports Med 2017;45(5):1187 94. Available from: https://doi.org/10.1177/ 0363546516685061. Epub 2017 Feb 13. PubMed PMID: 28192036. 18. Peters ME, Rao V, Bechtold KT, Roy D, Sair HI, Leoutsakos JM, et al. Head injury serum markers for assessing response to trauma: design of the HeadSMART study. Brain Inj 2017;31(3):370 8. Available from: https://doi.org/10.1080/02699052.2016.1231344. Epub 2017 Jan 31. PubMed PMID: 28140672. 19. Anzalone AJ, Blueitt D, Case T, McGuffin T, Pollard K, Garrison JC, et al. A positive vestibular/ocular motor screening (VOMS) is associated with increased recovery time after sports-related concussion in youth and adolescent athletes. Am J Sports Med 2017;45(2):474 9. Available from: https://doi.org/10.1177/ 0363546516668624. Epub 2016 Oct 28. PubMed PMID: 27789472. 20. Schwed AC, Boggs MM, Watanabe D, Plurad DS, Putnam BA, Kim DY. Admission variables associated with a favorable outcome after mild traumatic brain injury. Am Surg 2016;82(10):898 902 PubMed PMID: 27779969.
I. DEFINING MILD TBI