Single Isolated Concussion Part II: Diagnosis, Recovery Assessment, and Treatment

This article is a continuation of one published in the previous issue of Practical Neurology, which focused on definitions, classification, and prognosis of a single isolated concussion, or mild traumatic brain injury (mTBI). Here in part II, diagnosis, treatment, and recovery assessment are addressed. The focus of this article is a single mTBI occurring in a patient without a history of previous mTBI.

Diagnosis

Diagnosis of mTBI is clinical, and the diagnostic criteria are:

1. Any immediate alteration in the level of consciousness of <30 minutes
2. Posttraumatic amnesia lasting from minutes to a few hours but <24 hours
3. Normal structural imaging studies (CT scan or MRI)
4. A nonfocal neurologic examination

If all 4 are present, the patient meets the criteria for having mTBI.

Recovery Assessment

There are many assessment tools to help physicians monitor a patient’s recovery from mTBI that aid the physician in following the patient’s somatic, behavioral, and cognitive complaints during the recovery period. Examples include symptoms scales, (eg, the standardized assessment of concussion [SAC] and the sport concussion assessment tool-5 [SCAT-5]), balance tests, computerized neurocognitive tests, and formal neuropsychological testing. It is of note that these are not validated as diagnostic tools but rather are tools for assessing recovery from the initial injury. If these scales show that patients have symptoms lasting longer than expected based on a typical natural history of recovery within approximately 1 to 3 months, suspicion of postconcussion syndrome (PCS) or a neurocognitive disorder (NCD) due to a traumatic brain injury (TBI) may arise.

Symptom Scales
The most commonly used mTBI symptoms questionnaire is the Rivermead Post-Concussion Symptoms Questionnaire,¹ a 16-item self-report during the first 24 hours following an mTBI and comparing status in that period to status prior to injury. Symptoms are reported by severity on a scale from 0 to 4: not experienced, no more of a problem, mild problem, moderate problem, and severe problem.

A second commonly used assessment tool is the graded symptom checklist (GCS), another self-report measure of mTBI symptoms derived from the Head Injury Scale.² The Post-Concussion Symptom Inventory³ and the Post-Concussion Symptoms Scale⁴ are 2 other mTBI symptoms scales used primarily in school-age children and adolescents.

The SAC was formulated at the request of the American Academy of Neurology (AAN). It is a standardized protocol used to evaluate athletes within minutes of having sustained an mTBI.⁵ The SAC evaluates cognition: orientation, immediate memory, concentration, and delayed recall. The total possible score is 30, and in a control population without mTBI, the mean score was 26.6. The test assesses a patient’s orientation, immediate and delayed memory, concentration (ie, ability to repeat 3 to 6 numbers in reverse sequence and recite the months of the year in reverse), neurologic assessment (ie, consciousness, amnesia, strength, sensation, and coordination), and optional exertional maneuvers when indicated. The reliability, sensitivity, and specificity of the SAC as a measure of cognitive function during the initial 1 to 2 days following mTBI has been validated^6,7; however, another study found that it was only valid in the first 6 hours after recovery.⁸

The SCAT-5 ⁹ is intended for the use of health care professionals trained in assessing and managing sports-related mTBIs in children age >13 years. The SCAT-5 was not designed to be used in isolation or to make or exclude the diagnosis of mTBI. It consists of a symptom checklist; immediate and delayed word recall and reverse order number list recall; and a rapid neurologic screening examination that includes evaluation of the cervical spine, speech, ability to read, balance, gait, visual tracking, and finger-to-nose coordination. The SCAT-5 mandates a written clearance by a health care professional prior to returning to play or sport.

Balance Tests
The ability to maintain postural stability has been evaluated as an objective measure of mTBI recovery. Balance requires multiple sensory inputs and outputs to the muscles. A clinical, practical, and cost-effective method, the Balance Error Scoring System (BESS), has been developed as a standardized, quick sideline measurement of postural stability.¹⁰ The patient holds 3 different stances (double leg, single leg, tandem) on a firm surface and a medium-density foam pad, each for 20 seconds, with hands on hips and eyes closed. Errors are counted and summed to a maximum error score of 10 per trial.

Computerized Neurocognitive Tests
Several proprietary tests have been developed to monitor concussed individuals. Computerized neuropsychological test batteries are objective methods for testing large groups, are generally brief, and can be used in follow-up for tracking recovery. In these populations, the test can be administered at baseline so that in the case of injury, there is a standard to which postinjury results can be compared. The proposed advantages over traditional neuropsychological testing include ease of administration and alternate test forms to reduce the possibility of practice effects. The most commonly encountered computerized neurocognitive tests include Immediate Post Concussion Assessment and Cognitive Testing (ImPACT),¹¹ CogState/Axon,¹² CNS Vital Signs,¹³ and Automated Neuropsychological Assessment Metrics (ANAM).¹⁴ To date, all current evidence- and consensus-based sports mTBI recommendations advise against using a single computerized neurocognitive test to diagnose or manage mTBI and recommend that these tests be used in conjunction with other evaluation modalities to make management decisions. Factors limiting the use of computerized neurocognitive tests include premorbid learning disabilities that are not discernable on computerized testing, underreporting of prior mTBIs, language issues, administration of testing in a suboptimal environment (including an unsupervised condition), and potential inappropriateness of the test for the age of the injured individual.¹⁵

Neuropsychological Testing
Neuropsychological testing provides a scientifically validated and objective method to evaluate certain brain functions. It is important to understand the purpose behind a neuropsychological evaluation: what it may and may not reveal about an individual. A neuropsychological profile will demonstrate the presence of cognitive and behavioral strengths and weaknesses but is unable to identify what caused a problem. As there is no neuropsychological profile that precisely correlates to a specific area of brain and no specific area of the brain that precisely correlates to a neuropsychological function, neuropsychological studies cannot localize the findings to a specific area of the brain or to a specific injury. As reported by the Therapeutics and Technology Assessment Subcommittee of the AAN, “Neuropsychological assessment is not intended to provide a diagnosis or to indicate the precise localization of a focal brain lesion.”¹⁶

A neuropsychological evaluation is the only mTBI assessment tool to include validity testing, which is subject to responder biases. This is of particular note because there is an inverse relationship between financial incentives and the pace of recovery from closed head trauma.^17-21 The 2016 Consensus Statement on Concussion in Sport reported, “It must be emphasized, however, that NP (neuropsychological) testing should not be the sole basis of management decisions. Rather, it provides an aid to the clinical-management process in conjunction with a range of assessments of different clinical domains and investigative results.”²²

Treatment

Physical and/or Cognitive Rest
There is controversy regarding whether physical and/or cognitive rest is beneficial in patients recovering from an mTBI.The conference recommended complete cognitive and physical rest until recovery. Although physical and cognitive rest is often recommended,^23-25 several recent systematic reviews and meta-analyses of controlled randomized studies have concluded it may have no benefit and may even be detrimental.^26-30

Education and Cognitive or Psychologic Rehabilitation
Meta-analysis has shown patient education (eg, an informational booklet and follow-up phone call) to be efficacious in reducing mTBI symptomatology.^31-33 Anticipatory guidance with reassurance and education has been shown to be effective as a preventive measure against the development of prolonged mTBI symptomatology.²⁴

Some meta-analyses of controlled studies provides little evidence to support active psychological treatment for patients with mTBIs, although patient education is beneficial if initiated in the early period following injury.^34-36 In contrast, other meta-analyses suggest that there is some positive effect of cognitive behavioral therapy for adults who sustained an mTBI, whereas education, information, or assurance may not be as beneficial as previously thought.^37,38

Medication
There is no approved pharmacologic intervention for the treatment of postconcussive symptomatology, and the 2016 Consensus Statement on Concussion in Sport concluded there was limited evidence supporting the use of pharmacotherapy.²² Off-label use of medications approved for the treatment of Alzheimer’s dementia, attention-deficit/hyperactivity disorders, generalized anxiety disorders, depressive disorders, and dysthymia for treating patients with mTBI is based primarily on anecdotal evidence and/or personal opinion. Meta-analyses have shown that there is insufficient evidence to determine whether pharmacological treatment is effective or that there is no effective pharmacologic treatment that speeds recovery from an mTBI.^39-41

Treating the symptomatology following an mTBI is analogous to treating the symptomatology following a flu-like illness. Antipyretics to reduce temperature, antihistamines to combat nasal and conjunctival discharge, decongestants and/or nasal spray to relieve a stuffy nose, analgesics to relieve the aches and pains, and sleeping pills to facilitate rest may alleviate some of the flu-related symptomatology but have no effect on the duration of the illness. The side effects of polypharmacy may be worse than the illness itself. Not only does polypharmacy produce frequent and substantial side effects, it also acts as a nocebo.

To date, multiple meta-analytical studies and systematic reviews have failed to identify a significant benefit of bed rest, cognitive rest, cognitive rehabilitation, or medications in the treatment of concussed individuals. As with most illnesses, there appears to be a benefit to patient education.⁴²

Postconcussion Syndrome
Following mTBI, individuals often complain of a mixture of somatic, behavioral, and cognitive difficulties. In the past, such patients have been given the diagnosis of PCS. A syndrome is defined as a group of symptoms that collectively indicate or characterize a disease, psychological disorder, or other abnormal condition. In 1992, the 10th revision of the International Classification of Diseases (ICD-10) proposed diagnostic criteria for a PCS as shown in the Table.⁴³

Neuroimaging findings are often cited as evidence that prolonged symptomatology following mTBI results from brain damage. To date, SPECT, PET, and functional MRI studies have yielded conflicting results, as many of the neuroimaging findings are not specific to head injury and have been identified in individuals with other neurologic conditions.^44-56 There is no proven relationship between neuroimaging findings and subjective⁵⁷ or objective postconcussion findings.^58,59 Finally, most studies do not utilize a control population, and there is no consensus opinion or definition of mTBI across studies.⁶⁰

Psychogenic contribution to PCS is suggested by many empiric clinical observations. The symptom complex of PCS is similar to the somatization found with various psychiatric diagnoses, such as anxiety disorders, depressive and bipolar disorders, somatization disorders, and posttraumatic stress disorders. In addition, anxiety and depression can produce both subjective complaints and objective cognitive deficits that are similar to those identified in PCS and that improve with antidepressant treatment.^61,62 Several studies have shown that both psychiatric predispositions (poor coping skills, limited social support, and negative perceptions) and psychiatric comorbidity (depression, anxiety, panic attacks, and posttraumatic stress disorder) are more prevalent in patients with PCS compared with general population controls or head-injured individuals who do not develop a PCS.^63-73 The 2016 Consensus Statement on Concussion in Sport reported, “There is a growing body of literature that psychological factors play a significant role in symptom recovery and contribute to the persistence of symptoms in some cases.”²²

Other factors that appear to play a role in the pathogenesis of PCS symptomatology include misattribution, litigation, and chronic pain. The very low, even absent, rate of postconcussion symptomatology in certain countries and in children suggests a prominent role for misattribution in the pathogenesis of PCS. Patients without a history of head trauma often expect PCS symptomatology following a concussion and their physicians may mistakenly attribute their complaints to the head injury when they are actually unrelated.⁷⁴ Pending litigation also contributes to the presence and duration of PCS symptomatology.⁷⁵ Furthermore, failure of patients to recover after their claims are settled does not invalidate this observation, as a financial settlement may serve to reinforce the illness behavior. Patients with chronic pain have cognitive, behavioral, and somatic symptoms at a rate similar to a brain-injured cohort.^76,77 Other possible influences on the pathogenesis of PCS include advanced age, preinjury unemployment, low educational level, substance abuse, misinterpretation of normal variation in neuropsychological test results, secondary gain, and nocebo expectations.⁷⁸

The popularity of PCS as a diagnostic entity stems from a review by Alexander,⁷⁹ who reported, “at one year after injury approximately 15% of patients with mTBI still have disabling symptoms.” Of the references cited for this claim,^80,81 1 study gathered data for only 1 month. In the other, of the 19 symptomatic individuals identified as having disabling symptoms after 1 year, 42% were involved in litigation, and 50% endorsed a symptom at 1 year that was not present at 6 weeks. The incidence of symptoms reported was lower than that reported in normal cohorts.

Persistent Symptoms
According to the 2016 Consensus Statement on Concussion in Sport, persistent symptoms is the preferred term to identify mTBI symptomatology that persists beyond the expected recovery time frame of 10 to 14 days in adults and 4 weeks in children.²² Persistent symptoms reflects the nonspecific posttraumatic symptoms that may be linked to coexisting or confounding factors and do not necessarily reflect ongoing physiologic injury to the brain.

Patients who had mTBI may develop signs and symptoms of anxiety and/or depression due to an anticipated prolonged work absence, job security, having to repeat a grade or semester at school, or loss of income with inability to pay the rent. Such complaints may be unrelated to physiologic brain injury.

Neurocognitive Disorder Due to a Traumatic Brain Injury
Since the 1990s, there have been significant advances in understanding the pathophysiology of mTBIs and thus complaints following. In 2015, the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), published by the American Psychiatric Association, provided a much-needed update.⁸² The DSM-5 no longer contains a specific entry for a PCS, but instead uses the term neurocognitive disorder (NCD) due to traumatic brain injury (TBI) to describe patients with cognitive complaints following a TBI. According to the DSM-5, an NCD due to TBI can be further classified as major or mild, depending on whether the cognitive difficulties interfere with activities of daily living. Of note, this diagnosis cannot be made after a concussion, but only after a more severe TBI.

When postconcussive symptoms continue longer than expected, an alternative explanation must be considered. The recovery timetable following a concussion as well as the frequency in which concussive complaints are identified in normal control populations, psychological diagnoses, and nonconcussive injuries (sprains and strains) reinforce the necessity of a search for an alternative explanation.

Conclusion

When an individual sustains a single isolated mTBI, whether at home, in the athletic arena, at the job site, or because of a motor vehicle accident, a physician can confidently advise the patient, spouse, family, attorney, or any other interested party that the somatic, behavioral, and cognitive complaints resolve in approximately 3 months. During the recovery phase, various assessment tools assist the physician in monitoring the patient’s recovery. To date, multiple meta-analytic studies and systematic reviews have failed to identify a statistically significant benefit to bed rest, cognitive rest, cognitive rehabilitation, or medications in the treatment of patients after an mTBI. Only patient education with anticipatory guidance has been shown to hasten recovery and reduces the incidence of prolonged postconcussion complaints.

PCS describes the presence of subjective complaints during a patient’s recovery period. As multiple prospective and controlled studies with baseline evaluations have demonstrated, concussion symptomatology dissipates in approximately 3 months, its use represents a temporary phenomenon. It is analogous to giving a label (eg, post-flu syndrome) to a patient who demonstrates symptoms (cough, sore throat) during her or his approximately 2-week recovery from a flu-like illness. A neurocognitive disorder due to a TBI reflects a permanent condition in which the cognitive deficits following a TBI persist. When encountering a patient who has sustained a single and isolated mTBI, whose complaints have persisted for substantially longer than expected based on the natural history of the diagnosis, an alternative explanation for the symptom complex must be explored.

1. King NS, Crawford S, Wenden FJ, et al. The Rivermead Post-Concussion Symptoms Questionnaire: a measure of symptoms commonly experienced after head injury and its reliability. J Neurol. 1995;242:587-592.

2. Janusz JA, Sady MD, Gioia GA. Postconcussion symptom assessment. In: Kirkwood MW, Yeates KO, eds. In: Mild Traumatic Brain Injury in Children and Adolescents: From Basic Science to Clinical Management. New York: Guilford Press; 2012:241-263.

3. Schneider J, Gioia G. Psychometric properties of the Post-Concussion Symptom Inventory (PCSI) in school age children. Neurorehabilitation. 2007;10:91-99.

4. Lovell MR, Collins MW. Neuropsychological assessment of the college football player. Head Trauma Rehabil. 1998;13:9-11.

5. McCrea M. Standardized mental status testing on the sideline after sport-related concussion. Journal Athl Train. 2001;36:274-279.

6. McCrea M, Guskiewicz KM, Marshall SW, Kelly J. Acute effects and recovery time following concussion in collegiate football players: the NCAA Concussion Study. JAMA. 2003;290:2556-2563.

7. McCrea M. Standardized mental status assessment of sports concussion. Clin J Sport Med. 2001;11:176-181.

8. Kennedy CH, Porter Evans J, Chee S, et al. Return to combat duty after concussive blast injury. Arch Clin Neuropsychol. 2012;27:817-827.

9. Echemendia RJ, Meeuwisse W, McCrory P, et al. The Sport Concussion Assessment Tool 5th Edition (SCAT5): background and rationale. Br Sports Med. 2017;51:848-850.

10. Guskiewicz KM. Postural stability assessment following concussion: one piece of the puzzle. Clin J Sport Med. 2001;11:182-189.

11. Immediate Post-Concussion Assessment Cognitive Testing [computer program]. Version 6.0. Pittsburgh: NeuroHealth Systems; 2006.

12. Louey AG, Cromer JA, Schembri AJ, et al. Detecting cognitive impairment after concussion: sensitivity of change from baseline and normative data methods using the CogSport/Axon cognitive test battery. Arch Clin Neuropsychol. 2014;29:432-441.

13. Gualtieri CT, Johnson LG. Reliability and validity of a computerized neurocognitive test battery, CNS Vital Signs. Arch Clin Neuropsychol. 2006;21:623-643.

14. Levinson DM, Reeves DL. Monitoring recovery from traumatic brain injury using automated neuropsychological assessment metrics (ANAM V1.0). Arch Clin Neuropsychol. 1997;12:155-166.

15. Kuhn AW, Solomon GS. Supervision and computerized neurocognitive baseline test performance in high school athletes: an initial investigation. J Athl Train. 2014;49:800-805.

16. Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Assessment: neuropsychological testing of adults: considerations for neurologists. Neurology. 1996;47:592-599.

17. Binder LM, Rohling ML. Money matters: a meta-analytic review of the effects of financial incentives on recovery after closed head trauma. Am J Psychiatry. 1996;153:7-10.

18. Larrabee GL. Exaggerated MMPI-2 symptom report in personal injury litigants with malingered neurocognitive deficit. Arch Clin Neuropsychol. 2003;18:673-686.

19. Ardolf BR, Denney RL, Houston CL. Base rates of negative response bias and malingered neurocognitive dysfunction among criminal defendants referred for neuropsychological evaluation. Clin Neuropsychol. 2007;21:899-916.

20. Chafetz MD. Malingering on the social security disability consultative exam: predictors and base rates. Clin Neuropsychol. 2008;22:529-546.

21. Greve KW, Bianchini KJ, Stickle TR, et al. Effects of a community toxic release on the psychological status of children. Child Psychiatry Hum Dev. 2007;37:307-323.

22. McCrory P, Meeuwisse W, Dvorak J, et al. Consensus Statement on Concussion in Sport: the 5th International Conference on Concussion in Sport held in Berlin, October 2016. Br J Sports Med. 2017;51:838-847.

23. McCrory P, Meeuwisse W, Johnston K, et al. Consensus Statement on Concussion in Sport: the 3rd International Conference on Concussion in Sport held in Zurich, November 2008. Br J Sports Med. 2009;43:76-84.

24. Giza CC, Kutcher JS, Ashwal S, et al. Summary of evidence-based guideline update: evaluation and management of concussion in sports: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2013;80:2250-2257.

25. Baugh CM, Kroshus E, Daneshvar DH, et al. Concussion management in United States college sports: compliance with National Collegiate Athletic Association Concussion Policy and areas for improvement. Am J Sports Med. 2014;43:47-56.

26. Relander M, Troupp H, Af Bjorkesten G. Controlled trial of treatment for cerebral concussion. Br Med J. 1972;30:777-779.

27. de Kruijk JR, Leffers P, Meerhoff S, et al. Effectiveness of bed rest after mild traumatic brain injury: a randomized trial of no versus six days of bed rest. J Neurol Neurosurg Psychiatry. 2002;73:167-172.

28. af Geijerstam JL, Oredsson S, Britton M. Medical outcome after immediate computed tomography or admission for observation in patients with mild traumatic head injury: a randomized controlled trial. BMJ. 2006;333:465-471.

29. Gibson S, Nigrovic LE, O’Brien M, Mehann III WP. The effect of recommending cognitive rest on recovery from sport-related concussion. Brain Inj. 2013;27:839-842.

30. Thomas DG, Apps JN, Hoffmann RG, et al. Benefits of strict rest after acute concussion: a randomized controlled trial. Pediatrics. 2015;135:213-223.

31. Borg J, Holm L, Peloso PM, et al. Non-surgical intervention and cost for mild traumatic brain injury: results of the WHO Collaborating Taskforce on Mild Traumatic Brain Injury. J Rehabil Med. 2004;43:76-83.

32. Comper P, Bisschop SM, Carnide M, Tricco A. A systematic review of treatments for mild traumatic brain injury. Brain Inj. 2005;19:863-880.

33. Gravel J, D’Angelo A, Carrière B, et al. Interventions provided in the acute phase for mild traumatic brain injury. Systematic Reviews. 2013;2:1-12.

34. Snell DA, Surgenor LI, Hay-Smith EJ, Siegert RJ. A systematic review of psychological treatments for mild traumatic brain injury: an update on evidence. J Clin Exp Neuropsychol. 2009;31:20-38.

35. Rohling ML, Faust ME, Beverly B, Demakis G. Effectiveness of cognitive rehabilitation following acquired brain injury: a meta-analytic reexamination of Cicerone et al.’s (2000 and 2005) systematic reviews. Neuropsychology. 2009;23:20-39.

36. Al SA, Sanford D, Carson AJ. Psychological approaches to treatment of postconcussion syndrome: a systematic review. J Neurology Neurosurg Psychiatry. 2010;81:1128-1134.

37. Institute of Medicine. Cognitive rehabilitation therapy for traumatic brain injury: elevating the evidence. IOM Report Brief. Bethesda: Institute of Medicine; 2011.

38. Kumar KS, Samuelkamaleshkumar S, Viswanathan A, Macaden AS. Cognitive rehabilitation for adults with traumatic brain injury to improve occupational outcomes. Cochrane Database Syst Rev. 2017;6:CD007935.

39. Chew E, Zafonte RD. Pharmacological management of neurobehavioral disorders following traumatic brain injury: a state-of-the-art review. J Rehabil Res Dev. 2009;46:851-879.

40. Wade DT, King NS, Wenden FJ, et al. Does routine follow up after head injury help? A randomized controlled study. J Neurol Neurosurg Psychiatry. 1997;62:478-484.

41. Dougall D, Poole N, Agrawal N. Pharmacotherapy for chronic cognitive impairment in traumatic brain injury. Cochrane Database Syst Rev. 2015;12:CD009221.

42. The ICD-10 Classification of Mental and Behavioral Disorders: Clinical Descriptions and Diagnostic Guidelines. Geneva: World Health Organization; 1992.

43. Beauchamp K, Mutlak K, Smith WR, Stahel P. Pharmacology of traumatic brain injury: where is the “golden bullet”? Mol Med. 2008;14:731-740.

44. Byrnes KR, Wilson CM, Brabazon F, et al. FDG-PET imaging in mild traumatic brain injury: a critical review. Front Neuroenergetics. 2013;5:13.

45. Davalos DB, Bennett TL. A review of the use of single-photon emission computerized tomography as a diagnostic tool in mild traumatic brain injury. Appl Neuropsychol. 2002;9:92-105.

46. Mirza M, Titus A, Erdogan F, Köseoğlu E. Interictal SPECT with Tc-99m HMPAO studies and migraine patients. Acta Neurol Belg. 1998;98:190-194.

47. Nakabeppu Y, Nakjo M, Gushiken T, et al. Decreased perfusion of the bilateral laminae in patients with chronic pain detected by Tc-99m-ECD SPECT with statistical parametric mapping. Ann Nucl Med. 2001;15:459-463.

48. Mountz JM, Bradley LA, Modell JG, et al. Fibromyalgia in women: abnormalities of regional cerebral blood flow in the laminas and the caudate nucleus are associated with low pain threshold levels. Arthritis Rheum. 1995;38:926-938.

49. Smith MT, Perlis ML, Chengzai VU, et al. Neuroimaging of NREM sleep in primary insomnia: a Tc-99-HMPAO single photon emission computed tomography study. Sleep. 2002;25:325-335.

50. Shirakawa SI, Takeuchi N, Uchimura N, et al. Study of image findings in rapid eye movement sleep behavior disorder. Psychiatry Clin Neurosci. 2002;56:291-292.

51. Asenbaum S, Zeithofer J, Saletu B, et al. Technetiom-99m-HM-PAO SPECT imaging cerebral blood flow during REM sleep in narcoleptics. J Nucl Med. 1995;36:1150-1155.

52. Holman BL, Carvalho PA, Mendelson J, Johnson KA. Brain perfusion is abnormal in cocaine-dependent polydrug users: a study using technetium-99m-HMPAO and ASPECT. J Nucl Med. 1991;32:1206-1210.

53. Wood SW. Regional cerebral blood flow imaging with SPECT in psychiatric disease: focus on schizophrenia, anxiety disorders, and substance abuse. J Clin Psychiatry. 1992;543(suppl):20-25.

54. Wortzel HS, Filley CM, Anderson CA, et al. Forensic applications of cerebral single-photon emission computed tomography in mild traumatic brain injury. J Am Aca Psychiatry Law. 2008;36:310-322.

55. Hoehn-Sarci R, Pearlson GD, Harris GJ, et al. Effects of fluoxetine on regional cerebral blood flow in obsessive-compulsive patients. Am J Psychiatry. 1991;148:1243-1245.

56. Machlin SR, Harris GJ, Pearlson GD, et al. Elevated medial-frontal cerebral blood flow in obsessive-compulsive patients: a SPECT study. Am J Psychiatry. 1991;148:1240-1242.

57. Shin SS, Bales WJ, Dixon CE, Huang M. Structural imaging of mild traumatic brain injury may not be enough: overview of functional and metabolic imaging of mild traumatic brain injury. Brain Imaging Behav. 2017;11:691-710.

58. Belanger HG, Vanderplog RD, Curtiss G, Warden DL. Recent neuroimaging techniques in mild traumatic brain injury. J Neuropsychiatry Clin Neurosci. 2007;19:5-20.

59. Anderson K, Taber K, Hurley R. Functional imaging. In: Silver J, McAllister T, Yudofsky S, eds. Traumatic Brain Imaging. Arlington, VA: American Psychiatric Association Publishing; 2005:107-133.

60. Amyot F, Archiniegas DB, Brazaitis MP, Stocker D. A review of the effectiveness of neuroimaging modalities in the detection of traumatic brain injury. J Neurotrauma. 2015;32:1693-1721.

61. Brand N, Jolles J. Information processing in anxiety and depression. Psychol Med. 1987;17:145-153.

62. Nicholson K, Martelli MF, Zasler ND. Does pain confound interpretation of neuropsychological test results? Neurorehabilitation. 2001;16:225-230.

63. McCauly SR, Boake C, Pedroza C, et al. Postconcussional disorder: are the DSC-IV criteria an improvement over the ICD-10? J Nerv Ment Dis. 2005;193:540-550.

64. McCauley SR, Boake C, Levin HS, et al. Postconcussional disorder following mild to moderate brain injury: anxiety, depression and social support as risk factors and comorbidities. J Clin Exp Neuropsychol. 2001;23:792-808.

65. Oppenheimer DR. Microscopic lesions in the brain following head injury. J Neurol Neurosurg Psychiatry. 1968;31:299-306.

66. Blumbergs PC, Scott G, Manavis J, McLean AJ. Staining of amyloid precursor protein to study axonal damage in mild head injury. Lancet. 1994;344:1055-1056.

67. Mayer AR, Ling J, Mannell MV, et al. A prospective diffusion tensor imaging study in mild traumatic brain injury. Neurology. 2010;74:643-650.

68. Wilde EA, McCauley SR, Hunter JV, et al. Diffusion tensor imaging of acute mild traumatic brain injury in adolescents. Neurology. 2008;70:948-955.

69. Aoki Y, Inokuchi R, Gunshin M, et al. Diffusion tensor imaging studies of mild traumatic brain injury: a meta-analysis. J Neurol Neurosurg Psychiatry. 2012;83:870-876.

70. McAllister TW, Sparling MB, Flashman LA, Saykin AJ. Neuroimaging findings in mild traumatic brain injury. J Clin ExpNeuropsychol. 2001;23:775-791.

71. Hughes DG, Jackson A, Mason DL, et al. Abnormalities on magnetic resonance imaging seen acutely following mild traumatic brain injury: correlation with neuropsychological tests and delayed recovery. Neuroradiology. 2004;46:550-558.

72. Kant R, Smith-Seemiller L, Isaac G, Duffy J. Tc-HMPAO SPECT in persistent post-concussion syndrome after mild head injury: comparison with MRI/CT. Brain Inj. 1997;11:115-124.

73. Korn A, Golan H, Melamed I, Friedman A. Focal cortical dysfunction and blood-brain barrier disruption in patients with postconcussion syndrome. J Clin Neurophysiol. 2005;22:1-9.

74. Cantu RC. Posttraumatic retrograde and anterograde amnesia: pathophysiology and implications in grading and safe return to play. J Athl Train. 2001;36:244-248.

75. Ponsford J, Willmott C, Rothwell A, et al. Factors influencing outcome following mild traumatic brain injuries in adults. J Int Neuropsychol Soc. 200;6:568-579.

76. Iverson GL, McCracken LM. “Postconcussive” symptoms in persons with chronic pain. Brain Inj. 1997;11:783-790.

77. Smith-Seemiller L, Fow NR, Kant R, Franzen MD. Presence of post-concussion syndrome symptoms in patients with chronic pain vs mild traumatic brain injury. Brain Inj. 2003;17:199-206.

78. Barsky AJ. The iatrogenic potential of physician’s words. JAMA. 2017;318(24):2425-24261.

79. Alexander MP. Mild traumatic brain injury: pathophysiology, natural history, and clinical management. Neurology. 1995;45:1253-1260.

80. Rutherford WH, Merritt JD, McDonald JR. Symptoms at one year following concussion from minor head injuries. Injury. 1979;10:225-230.

81. McLean AJ, Temkin NR, Dikmen S, Wyler AR. The behavioral sequelae of head injuries. J Clin Neuropsychol. 1983;5:361-376.

82. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA: American Psychiatric Association; 2013.

Gerald S. Steiman, MD

Steiman Neurology Group

Columbus, OH