Mild Traumatic Brain Injury and Postconcussion Syndrome: The New Evidence Base for Diagnosis and Treatment Michael Mc

1. Mild Traumatic Brain Injury and Postconcussion Syndrome:The New Evidence Base for Diagnosis and TreatmentMichael McCrea, PhD, ABPP-CNNeuroscience Center, Waukesha Memorial HospitalDepartment of Neurology, Medical College of Wisconsin

3. Objective: MTBI from A to Z Review and gain a clearer understanding of: MTBI on the all-Severity TBI Landscape Basic and Clinical Science of MTBI The True Natural History of MTBI Implications for Rethinking Postconcussion Syndrome

4. Unpaid Political Announcement MTBI, more than any other clinical entity, is a neuropsychological construct The contribution by neuropsychologists to MTBI research is unmatched by any other discipline Neuropsychologists are uniquely suited to evaluate and treat MTBI Neuropsychologists should not limit their role in MTBI just to neuropsych testing

5. Concussion Research Consortium (CRC)

6. Part 1: The TBI Landscape Epidemiology and impact of all-severity TBI Zeroing in on MTBI: Epi and Impact Challenges in Defining & Diagnosing MTBI Advances in MTBI research methodologies Top 10 Conclusions

7. Traumatic Brain Injury: The Big Picture Major public health problem world wide 1.4-3.0 million cases/yr in US Leading cause of death & disability: 50-100K TBI deaths/yr in U.S. 40+% of all trauma fatalities in US each year At risk: very young/very old, males, minorities, low SES, substance abusers Cost: ~ $100 billion/yr in US The Forgotten Entity

8. Significance of MTBI: �Silent Epidemic�

9. Challenges in Defining & Diagnosing MTBI Classifying TBI severity an imperfect science Varied emphasis on acute injury characteristics Limitations of traditional methods (GCS) Limited reliability, validity, predictive power of newer classification methods Numerous case and administrative definitions

11. MTBI Definitions

12. The Elusive MTBI Denominator: Research Implications

13. The Elusive MTBI Denominator: Clinical Implications

14. Injury Severity is Strongest Predictor of Recovery after moderate and severe TBI

16. MTBI is a Different Animal All Together

17. Acute MTBIResearch Limitations Lack of witness account of injury Immediate accessibility to injured patients Neuropsychological testing impractical in ER Lack of objective measures under constraints Lack of premorbid baseline measures Multitude of non-injury factors: alcohol/drugs, other injuries, litigation, others

18. MTBI Unknowns & Clinical Challenges Diagnosis: Minimum threshold for injury (i.e., was there indeed an MTBI?) Defining characteristics? Other causes for symptoms? Recovery: How long should it take to recovery after MTBI? What is the expected natural course of this injury? Prognosis: What are the acute and subacute predictors of positive and negative outcomes after MTBI? Complications: To what extent are neurologic versus psychological factors contributing to symptoms and deficits? Treatment: Given all this, what approach to treatment gives my patient the best chance for recovery? Outcome: What are the best methods to assess recovery and functional outcome after MTBI?

20. Causes of TBI

21. TBI Landscape: Main Conclusions TBI a major public health problem worldwide > 80% classified as MTBI (500/100K population) Young/old, male, minorities of low SES at risk Nothing �mild� about the total impact of MTBI What works for moderate/severe may not for MTBI Traditional MTBI research hampered by many issues New innovative approaches to prospective researchers New groundbreaking findings to date Poised to answer: What is natural history of MTBI? MTBI science extends our understanding of PCS

22. Part 2: Basic & Clinical Science of MTBI Biomechanics Neurophysiology Neuroimaging

23. How much is enough to cause brain injury?

24. Accelerometry Instrumentation

26. University of North Carolina HITS Study Methods 60 College football players equipped with HITS system Impacts recorded, analyzed for all exposures (games, practice) Analysis of impact frequency, magnitude data Correlation with clinical assessment measures Look at biomechanical risk x position, other factors

27. HITS Study Results > 27,000 impacts recorded 9 concussions observed in HITS equipped players Average magnitude of concussion impacts: 95 g 67% of concussions (6/9) > 95 g < 1 % of non-concussive impacts > 95 g Range of concussion impact 60-120 g

28. Neurophysiology of MTBI Diffuse Axonal Injury (DAI) prominent in moderate and severe TBI, not in MTBI The pathophysiology of MTBI renders neurons dysfunctional, but not destroyed

29. Serum Biomarkers of MTBI Potential diagnostic, prognostic utility? S-100 proteins, neuron specific enolase (NSE) and cleaved Tau protein (CTP) S-100 B most extensively studied S-100 B sensitivity 80-100%, specificity 40-80%; poor PPV (13-40); NPV 95-100 Risk of false positives (diagnosis, prognosis)

32. MTBI Basic & Clinical Science: Main Conclusions Major advances in biomechanics, neurophysiology, functional neuroanatomy of MTBI Suggestion of minimal BM threshold 80-100 g; informative to clinical practice Clear pathophysiology: Neurometabolic cascade with time course similar to natural clinical course CT still acute imaging of choice MRI more sensitive than CT for structural lesion �Complicated� MTBI indicates more severe gradient of injury, but not a perfect predictor of recovery, outcome Functional imaging techniques show great promise, require further study of Sensitivity, Specificity, Prognostic Value

33. Part 3: What is the true natural history of MTBI?

34. Part 3: Natural History of MTBI Acute symptoms and symptom recovery Acute cognitive effects and early recovery Neuropsychological recovery Influence of acute injury characteristics on recovery Measuring neurophysiological recovery Functional outcome after MTBI Exceptions to the rule: Longterm effects of MTBI? Top 10 Conclusions

37. In 1999, our group in collaboration with the NCAA, launched a large prospective study designed to measure the immediate effects and early recovery in symptoms, cognitive functioning, and postural stability following concussion in a large case series of collegiate athletes. We also have large-scale studies with a parallel design at the high school level. In combination, these studies provide us with a wealth of data to analyze, the results of which we�d like to share with you this afternoon. In 1999, our group in collaboration with the NCAA, launched a large prospective study designed to measure the immediate effects and early recovery in symptoms, cognitive functioning, and postural stability following concussion in a large case series of collegiate athletes. We also have large-scale studies with a parallel design at the high school level. In combination, these studies provide us with a wealth of data to analyze, the results of which we�d like to share with you this afternoon.

38. NCAA, Project Sideline & CDC Concussion Studies

39. Out methods following very closely the SLAM model created by Barth and colleagues, implementing a preseason baseline testing protocol for all athletes upon enrollment in the study. A multidimensional set of outcome measures was used to assess symptoms, cognitive functioning, and postural stability at several time points in players who sustain a concussion during the sports season, along with a tightly matched non-injured control subject. In our high school studies, we�ve also included fMRI to evaluate the neurophysiological effects and recovery after injury, which Dr. Hammeke will describe for you this afternoon. Out methods following very closely the SLAM model created by Barth and colleagues, implementing a preseason baseline testing protocol for all athletes upon enrollment in the study. A multidimensional set of outcome measures was used to assess symptoms, cognitive functioning, and postural stability at several time points in players who sustain a concussion during the sports season, along with a tightly matched non-injured control subject. In our high school studies, we�ve also included fMRI to evaluate the neurophysiological effects and recovery after injury, which Dr. Hammeke will describe for you this afternoon.

40. Immediate Symptoms

41. Day 3 Symptoms

42. Day 7 Symptoms

44. SAC Clinical Database > 750 Concussions Grade 1, 2, 3 Concussions Youth, HS, College, Pro Athletes Follow-up: minutes, days, weeks, months With & Without Previous Baseline All gradients of concussion: LOC, PTA, Neither Sensitivity/Specificity: RCI�s, GEE�s, SRB modeling Studies of non-sports MTBI

45. Complexity of Neuropsychological Testing

46. Interpreting Neuropsychological Recovery Simple Group Comparisons/RMANOVA: injured vs. control performance; confounded by baseline performance, practice effects, RTTM, other serial testing factors, mult comp�s Generalized Estimating Equations (GEE): longitudinal regression estimating mean group differences between concussion and controls adjusted for baseline score, age, education, history Standard regression based (SRB): empirical method to detect meaningful change at individual case level with correction for practice effects & regression to the mean; (Obtained-Predicted/SE prediction) larger than criterion (translated 90% CI) Clinical Decision-Making Influenced by method applied to measure recovery

50. Neuropsychological Recovery after MTBI: The Meta-Analytic Age A Quantitative Review of the Effects of Traumatic Brain Injury on Cognitive FunctioningSchretlin, David & Shapiro, Ann (International Review of Psychiatry, 2003, 15, 341-349) Factors Moderating Neuropsychological Outcomes Following MTBI: A Meta-AnalysisBelanger, Curtiss, Demery, Lebowitz, & Vanderploeg (JINS, 2005, 11, 215-227) Outcomes from Mild Traumatic Brain InjuryIverson, Grant(Current Opinion in Psychiatry, 2005, 18, 301-317)

54. Putting Tests to the Test

55. Classifying Individual Impairment SRB Model: Linear regression on control BL scores to generate formula to predict scores at T2... Regression coefficient, intercept of regression line used with BL score to predict score for each subject at T2 and subsequent time points Meaningful change: (Obtained-Predicted/SE prediction) > criterion (translated 90% CI) Empirical method to detect �true� impairment/recovery; correction for practice effects, RTTM

58. Added Value of Neuropsychological Testing Collie et al (2006): Cognitive testing in symptomatic vs. asymptomatic athletes within 11 days after concussion Symptomatic athletes (n=36): Impaired on 3 of 9 cognitive measures 2.2 days post injury Asymptomatic athletes (n=25): Impaired on 1 of 9 cognitive measures 3.5 days post injury; Improved on 2/9 Group mean change from baseline, not individual rates of impairment; no report of false positive impairment rate Schatz et al (2006): ImPACT cognitive and symptom score sensitivity 81.9%, specificity 89.4% < 72 hr post; 85% correctly classified; no report of cognitive predictor independent of symptoms Van Kampen (2006): NP testing increased sensitivity from 64% to 83% over symptoms alone; 30% false + rate

59. Evolution of Neuropsychological Testing in Sports Concussion 1997: �Development of a standardized neuropsychological test battery is recommended to detect impairment associated with concussion�  (AAN Practice Parameter) 1999: �The usefulness of neuropsychological assessment in clinical decision making should not be short-changed� (AOSSM Concussion Workshop Group) 2001: �Neuropsychological Testing is one of the cornerstones of concussion evaluation�  (CISG, Vienna Agreement Statement)

60. Evolution of Neuropsychological Testing 2004: �Neuropsychological testing should not be done while the athlete is symptomatic because it adds nothing to return-to-play decisions and may contaminate the testing process by allowing practice effects to confound results� �recommended that neuropsychological testing remain one of the cornerstones of concussion evaluation in complex concussion�is not currently regarded as important in the evaluation of simple concussion� should not be the sole basis for management decisions, either for continued time out or return to play decisions� (CISG, Prague Agreement Statement)

61. Influence of Acute Injury Characteristics on Recovery As we�re all aware, the critical importance of unconsciousness and amnesia as as indicators of acute brain injury and predictors of clinical outcome have been debated for several years. The same is observed in the sports concussion world, where concussion grading scales and injury management guidelines have placed various emphasis on LOC and PTA. One of the many advantages to the sports concussion model is that all injuries are witnessed and recorded, often by a sports medicine profession, which in this case enabled us to look at the influence of these two particular injury characteristics on acute injury severity and natural recovery course in our sample of injured athletes. As we�re all aware, the critical importance of unconsciousness and amnesia as as indicators of acute brain injury and predictors of clinical outcome have been debated for several years. The same is observed in the sports concussion world, where concussion grading scales and injury management guidelines have placed various emphasis on LOC and PTA. One of the many advantages to the sports concussion model is that all injuries are witnessed and recorded, often by a sports medicine profession, which in this case enabled us to look at the influence of these two particular injury characteristics on acute injury severity and natural recovery course in our sample of injured athletes.

62. Acute Injury Characteristics: Frequency & Influence

67. �When and how does the brain recover?

68. Functional MRI ADVANTAGES: Non-invasive Better spatial/temporal resolution than PET/SPECT No radiation exposure � multiple studies More methodologically appropriate for studying effects of treatment and rehabilitation MR technology access Low cost compared to PET

74. Encoding PhaseLeft SMA/PreSMA

75. Day 1: Encoding PhaseLeft SMA/PreSMA

77. Functional Model of MTBIMeasuring Clinically Meaningful Cerebral Change

78. Functional Outcome After MTBI Overwhelming majority of MTBI resume normal independent social, occupational, educational function within days to weeks of injury Highly variable methods on RTW research Non-injury factors associated with poor functional outcome Higher risk of depression, anxiety (12-44%), which receive insufficient attention

79. Science of MTBI Recovery Clear, sound evidence Kids: rapid recovery, no residual cognitive, behavioral, academic deficits Adults: rapid symptom, cognitive recovery; no impairments 3-12 mos Non-injury factors predict persistent symptoms

80. Exceptions to the Rule? Single, uncomplicated concussion a benign neurologic event, but�. �Complicated� MTBI Repeat Concussion: Immediate, mid-range, longterm risks Second Impact Syndrome: - Mechanism, pathology, risk Chronic effect on symptoms and cognition Longterm Effects: What happens when they get old?

82. What about chronic symptoms or functional impairments after repeat concussion?

84. 2001 Health Survey of Retired NFL Players History of concussion from participating in professional football: 61% of all respondents Ave no. concussions during pro football career: 2.1 24% of respondents sustained 3 or more concussions 12% of respondents sustained 5 or more concussions 71% reported having returned to play on the same day as their concussion (18% reported this occurrence 3+ times) 16% reported that concussions have a permanent effect on thinking/ memory skills as they get older

85. Is recurrent concussion a longterm risk for depression? 12% of retired NFL players have had or currently have a bout with clinical depression. Of those with a history of depression: 87% still suffer from depression 46% currently being medically treated �Does depression limit your activities of daily living?� 23% = NEVER 64% = SOME 12%=OFTEN

86. Concussion As Risk for Depression

88. NFL vs. Normative PAD Age Distribution

89. NATURAL HISTORY OF MTBIMAIN CONCLUSIONS Symptom recovery in days to weeks in most cases Measurable cognitive impairments w/o LOC, PTA, neuro Favorable cognitive recovery overlapping symptom recovery; no permanent impairment Neurophysiological recovery c/w clinical recovery (days to wks) AIC�s and focal lesions indicate more severe gradient, not perfectly predictive of outcome Favorable functional outcome is expected Non-injury factors best predictors of poor outcome Exceptions to the rules: Recurrent MTBI

90. Implications for Rethinking Postconcussion Syndrome

91. Part 4: Implications for Rethinking Postconcussion Syndrome Defining Postconcussion Syndrome Non-specificity of PCS Symptoms Epidemiology of PCS: Another denominator problem PCS: Neuropsychological Disorder Psychological Theories of PCS Interventional Models for PCS A practical model for clinical management of PCS Top 10 Conclusions

92. What is �PCS�? ICD-10: F07.2 (part of class of disorders with �a demonstrable etiology in cerebral disease, brain injury, or other insult leading to cerebral dysfunction�). Def: A syndrome that occurs following head trauma (usually sufficiently severe to result in loss of consciousness) and includes a number of disparate symptoms such as headache, dizziness, fatigue, irritability, difficulty in concentration and performing mental tasks, impairment of memory, insomnia, and reduced tolerance to stress, emotional excitement, or alcohol.

93. What is �PCS�? DSM-IV- proposed new category: A. History of a head trauma that has caused significant concussion (loc, pta, sz) B. Evidence from neuropsychological testing of impaired attention or memory C. Three or more occur shortly post-injury and persist for at least 3 months: Headache Dizziness Irritability Fatigue Anxiety, depression, or emotional lability Sleep disturbance Personality change Apathy

94. Non-specificity of PCS symptoms Symptoms are not specific to concussion/TBI; e.g.: Trahan et al, 2001: Pts with depression endorse significantly more PCS Sxs than pts with mTBI. Lees-Haley et al, 2001: Non-TBI personal injury claimants endorse PCS symptomatology at high rates, comparable on many symptoms to mTBI claimants (e.g., concentration impairments 63% mTBI, 65% other). Iverson & McKraken, 1997: Chronic pain pts endorse PCS Sxs at high rate (81% endorsing 3+ symptoms) Gouvier et al., 1988: High base rates of �PCS� symptoms in normal (college) population

95. Prevalence of �PCS� Symptoms

96. Reliability & Validity of PCS Criteria Boake et al (2004): agreement b/n DSM and ICD symptom criteria, poor overall agreement because few patients met criteria for cognitive deficit and clinical significanceConclusion: limited agreement b/n diagnostic systems leading to different diagnosis and treatment in the same case Boake et al. (2005): At 3 mos, higher prevalence of PCS with ICD-10 (64%) than DSM-IV (11%); 40% of non-TBI sample met ICD criteria, 7% for DSM; Conclusion: PCS symptoms are not sufficient to make the diagnosis of MTBI; linking residual symptoms to TBI is a major problem Kashluba et al (2006): ICD-10 PCS symptoms unable to accurately classify MTBI patients from NC�s at 3 months

97. What�s the incidence of �PCS�? Epidemiology? Frequent citation of influential Alexander (1995 Neurology) review article: �at one year after injury approximately 15% of [mild TBI] patients still have disabling symptoms� Articles referenced for this figure are Rutherford et al., 1978; McLean et al., 1983. This figure and these citations echoed in multiple publications, but�..

98. Original citations for the �15%� at 1 year Rutherford et al., 1979 (actually mis-cited in the Alexander article) 145 consecutive mild TBI cases admitted to hospital in Belfast. 131 followed up at one year, 19 still reporting symptoms (14.5%) 8/19 involved in lawsuits, 6/19 suspected of malingering at 6 weeks post-injury (overlap of 5) 10/19 pts reporting at least one new symptom not endorsed 6 weeks post-injury Age not related to duration of symptoms, but gender was (women more likely to be symptomatic) No controls (e.g., ortho injuries)

99. Original citations for the �15%�at 1 year McLean et al., 1983 11 pts with mild TBI (GCS 13-15) 8 pts with mod TBI (GCS 9-12) 1 pt with severe TBI (GCS=8) Controls N=52, friends of pts (non-injured) Groups compared on neurocognitive scores and symptom checklist at 3 days & 1 month post-injury. No difference in neurocognitive scores, but more symptoms in pt group at 1 month.

100. Epidemiology of PCS: Methodological Issues Ascertainment Bias? Extremely common, estimated incidence of 1.54 million concussions with LOC/year in US alone1; perhaps 12-15 times as many concussions with no LOC. Only a small percentage of these pts ever seek any form of medical treatment. A small percentage of those ever see a neuropsychologist MTBI patients enrolled in studies represent select subsample Underscores need for appropriate control groups

101. PCS: Neuropsychological Disorder Biopsychosocial basis for PCS (Iverson, Zasler, Lange) In most studies examining predictors of PCS symptomatology in TBI, injury severity is usually not predictive (sometimes relationship is found to be inverse), but non-injury variables are: Blaming of other(s) for injury, Limited social support Current levels depression/anxiety Premorbid psychiatric Hx Presence of PTSD Somatization Motivational factors (exaggeration, malingering)

102. Psychological Theories of PCS Expectation as Etiology: preformed expectations about effects of head injury, misattribute common complaints to head injury �Good Old Days� Hypothesis: EAE + consideration that people attribute all sx�s to negative event Nocebo Effect: expectations of sickness and associated emotional distress cause the sickness in question Diasthesis-Stress Model: interaction b/n physiological, psychological, motivational and iatrogenic factors

103. Efficacy of Psychological Intervention for PCS Mittenberg et al. (1996): 58 subjects with mTBI, randomly assigned to 1 of 2 groups: Treatment: given printed educational material and met once (1 hr) prior to discharge with therapist Control- normal hospital treatment and discharge instructions 6-month follow-up by blinded interviewer (no baseline Sx differences)�

104. Treatment group reported significantly shorter mean symptom duration (33 vs 51 days), fewer symptoms, and less severe symptoms Results suggest that brief, early psychological intervention can minimize �PCS� Additional studies� Efficacy of Psychological Intervention for PCS

105. Ponsford et al., (2002): 202 adults with mTBI, 79 assigned to intervention within one week of injury: Intervention consisted only of informational booklet re expected natural history of symptoms and coping strategies At 3 months post-injury, intervention group reported fewer overall symptoms and less current stress Similar findings from Minderhoud et al. (1980), Relander et al. (1972), Wade et al., (1998), Paniak et al., 2000, Ponsford et al., 2001. Efficacy of Psychological Intervention for PCS

106. WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury Results of survey of non-surgical interventions and cost for mTBI (J Rehabil Med 2004): �Evidence that early intervention can reduce long-term complaints, and that this intervention need not be intensive.�

107. Postconcussion Syndrome: Main Conclusions Sx-Based diagnosis of PCS problematic (poor reliability of criteria, nonspecificity of sx�s) PCS estimates severely inflated; true incidence ~ 1-5% Frequency of structural injury higher than PCS Science to rethink PCS: Neuropsychological Disorder Psychological bases indicates psychological and educational interventions Effective intervention will improve functional outcome and reduce disability from PCS Need to rule out motivational factors Neuropsychologists the key component

108. Warning: Commercial Re-Run MTBI, more than any other clinical entity, is a neuropsychological construct The contribution by neuropsychologists to MTBI research is unmatched by any other discipline Neuropsychologists are uniquely suited to evaluate and treat MTBI Neuropsychologists should not limit their role in MTBI just to neuropsych testing

110. Neuropsychology�s Response AAN Position Statement: Where are neuropsychology and rehabilitation psychology? Military MTBI Task Force: Inter-organizational collaboration between:- APA Division 40- APA Division 22- American Academy of Clinical Neuropsychology- National Academy of Neuropsychology Military, VA, Civilian Psychologists Position statement and call to action

111. Contact Information Michael McCrea, PhD, ABPP-CNNeuropsychology ServiceWaukesha Memorial Hospital721 American Avenue, Suite 501Waukesha Memorial HospitalWaukesha, WI 53188Office: 262-928-2156Fax: 262-928-5580Email: michael.mccrea@phci.org