Mild Traumatic Brain Injury

Grant L. Iverson, Ph.D.

Professor, Department of Physical Medicine and Rehabilitation,

Harvard Medical School;

Director, MassGeneral Hospital for Children™ Sport Concussion Program; &

Associate Director of the Traumatic Brain Injury Program,

Home Base, Red Sox Foundation and Massachusetts General Hospital

Trondheim, Norway

May 4, 2017

Funding Disclosure • US Department of Defense (grants)

• Canadian Institute of Health Research (grants)

• Lundbeck Canada (grant)

• AstraZeneca Canada (grant)

• ImPACT Applications, Inc. (unrestricted philanthropic support)

• CNS Vital Signs

• Psychological Assessment Resources, Inc.

• Tampere University Hospital

• Alcohol Beverage Medical Research Council

• Rehabilitation Research and Development (RR&D) Service of the US Department of Veterans Affairs

• Defense and Veterans Brain Injury Center (former independent contractor; HJF/GD)

• Mooney-Reed Charitable Foundation (unrestricted philanthropic support)

• INTRuST Posttraumatic Stress Disorder and Traumatic Brain Injury Clinical Consortium funded by the Department of Defense Psychological Health/Traumatic Brain Injury Research Program (X81XWH-07-CC-CSDoD)

• Football Players Health Study, Harvard University (NFLPA Funding)

Other Disclosures

• Speaker honorariums and travel expenses for

conferences and meetings

• Independent practice in forensic

neuropsychology, including athletes

Traumatic brain injuries occur on a broad

continuum of severity, from very mild injuries to

catastrophic injuries resulting in death or severe

disability.

Continuum of TBI Severity

Approximately 90% of all injuries

Very mild/transient Uncomplicated mild Complicated mild Moderate Severe Catastrophic

Moderate-Severe TBI

• Can result in:

– widespread damage to the structure and function of

the brain

– permanent changes in physical functioning,

cognition, emotional functioning, behavior, and

personality

– permanent disability from work

• Outcome is variable, however, ranging from very good

to very poor.

Susceptibility Weighted Imaging

(SWI)

• SWI exploits differences in magnetic

susceptibility between tissues, and is sensitive

to microhemorrhages.

• SWI is very sensitive to bleeding in the

GM/WM boundaries, making it is possible to

see very small lesions.

Why is White Matter

Vulnerable?

1. Anatomy

2. Physics & Forces

Mild Traumatic Brain Injuries

are Not Created Equally

Spectrum of MTBI

Extremely Mild Structural Damage

(Transient) (Permanent)

Continuum of Pathophysiology

Minor Major Neurometablic & Neurometabolic Pathoanatomical

(e.g., Contusion)

Rate of Day-of-Injury CT

Abnormalities

• Incidence of intracranial abnormalities in MTBI

in Emergency Department studies

–5% to 40% across studies

– It increases with lowering of GCS: 15, 14, 13

• MRI reveals a greater rate

First

Author

Year

Number

Scanned

GCS

Scores

%

Abnormal

Livingston 1991 111 14-15 14

Stein 1992 1,538 13-15 17.2

Jeret 1993 702 15 9.4

Moran 1994 96 13-15 8.3

Borczuk 1995 1,448 13-15 8.2

Iverson 2000 912 13-15 15.8 Thiruppathy 2000 912 13-15 15.8

Stiell 2005 2,171 13-15 12.1

Stiell 2005 1,822 15 8.0

Ono 2007 1,064 14-15 4.7

Saboori 2007 682 15 6.7

Emergency Department Cohort

• Tampere University Hospital, Tampere, Finland

• August 2010-July 2012

• 3,023 patients presenting to ED and underwent

head CT

• 2,766 mild head trauma

• Average Age: 56.4, 50% are between 34 and 77

• Isokuortti et al. (under review)

Tampere ED Mild Head Trauma Cohort

Rates of Complicated MTBI Isokuortti et al. (under review)

10,1

40,7

52

0

10

20

30

40

50

60

GCS=15 GCS=14 GCS=13

Percentage Abnormal Stratified by GCS

Acute (red) and Pre-Existing Lesions (black) Stratified by

Age Group in Suspected or Confirmed MTBI (N=2,766)

4.9%

3.0% 9.9%

7.3% 12.2% 11.4% 22.2%

20.1% 18.6% 17.7%

1.2 %

4.2 %

11.5 %

23.5 %

29.3 % 32.2 %

48.7 %

56.9 %

66.0 %

78.9 %

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

20-29 30-39 40-49 50-54 55-59 60-64 65-69 70-74 75-79 80+

Acute intracranial lesion Pre-existing intracranial abnormality

Are intracranial abnormalities

related to clinical outcomes?

See Panenka et al. (2015) for a

Review (Table 1)

Cognitive Outcomes

• Those with intracranial abnormalities performed more poorly on neuropsychological testing (Table 1, 11 of 19 studies—58%)

• In several of these studies the relationship is modest (small to medium effect sizes)

• Usually on a small number of the cognitive tests

Functional Outcomes

• In 4 of 13 studies, complicated MTBI patients had greater problems as measured by the

– Glasgow Outcome Scale,

– Functional Independence Measure,

– Global Adaptive Functioning Scale,

– return to work.

• Most studies, however, have not found a significant difference in functional outcomes.

Symptom Reporting

• Paradoxically some studies in the literature

suggest that complicated MTBI patients report

fewer symptoms.

• The most consistent finding is that these two

groups are not different on symptom reporting

(9 of the 13 studies).

To date, macroscopic structural injuries are

not strongly related to clinical outcomes in

MTBI studies

More refined imaging studies might show stronger associations

Personality and psychosocial factors can be vey important

Continuum of

Biological & Psychological

Vulnerability

Extremely Hardy/Resilient Extremely Vulnerable

There is no simple, reasonably

explanatory model for good or poor

outcome

Biopsychosocial Model

• Pre-Injury – Genetics

– Personality

– Resilience/hardiness

– Vulnerability

– Mental Health

– Prior brain injuries

• Post-Injury – Traumatic axonal injury

– Neurophysiological / neurometabolic disturbance

– Social psychological factors (expectations, good-old-days bias)

– Depression, anxiety, traumatic stress

– Chronic bodily pain and/or headaches

Post-

Concussion

-Like

Symptoms

Personality

Characteristics or

Disorders

Biopsychosocial

Resilience/Hardiness

Biopsychosocial

Vulnerability

Pre-Existing Mental

Health Problems

Previous Brain Injuries

Narcissistic

Dependent

Histrionic

Passive-

Aggressive

ADHD

Learning Disability

Genetics Relating to

Injury Vulnerability

Depression

Anxiety

Genetic

Vulnerability

Cognitive

Diminishment

Mental Health Problems

Social

Psychological

Factors

Insomnia

Chronic Headaches

or Bodily Pain

Depression

Traumatic

Axonal Injury

Altered

Neurotransmitter

Systems

Expectations

Diagnosis Threat

Nocebo Effect

Lifestyle & Family

Dynamics Changes

Anger/Bitterness

Justification/Entitlement

Litigation Stress

Anxiety/Stress/Worry

PTSD

Biopsychosocial Model for Poor Outcome

Copyright © 2010, Grant Iverson, Ph.D.

Pre-Injury Factors

Recovery from Concussion in

Sports

By definition, a sport-related

concussion is a mild traumatic brain

injury.

By consensus, sport-related

concussions are characterized by

normal structural neuroimaging.

Is sport-related concussion a benign

injury?

Results from meta-analyses

Adverse Effects of Sport Concussion on Cognition

Pathophysiology

• Complex interwoven cellular and vascular changes

• Multilayered Neurometabolic Cascade

• Under certain circumstances, cells degenerate and die

Primary Mechanisms

• Ionic shifts

• Abnormal energy metabolism

• Diminished cerebral blood flow

• Impaired neurotransmission

Fortunately, the brain undergoes

dynamic restoration

Assessment Timeline

Sideline Post-

Game

24 Hours

First Week

Second Week

Third Week

At Risk!

Recovery Time in Athletes

Some evidence that biological recovery

might take longer than clinical recovery

in some athletes.

NCAA Football Cohort

• 1,631 players

• 94 concussions

• Balance problems resolved in 3-5 days

• Symptoms gradually resolved by 7 days

• Cognition resolved by 5-7 days

• 91% appeared recovered by 7 days

McCrea et al. (2003)

Pennsylvania High School Football

Cohort

• 2,141 players

• 3-year prospective cohort study

• 134 concussions

• Players followed until recovered

Collins, Lovell, Iverson, Ide, Maroon (2006)

Recovery Curve (N = 134)

91%

46%

Days Post Injury

Recovery Curves (N = 134)

Days Post Injury

94%

84%

Berlin Consensus

&

Reviews

Recovery from Mild Traumatic Brain Injury

in Civilians

Subjects

• Tampere University Hospital, ED, Finland

• 49 patients with MTBIs

• No history of medical, mental health, or substance

abuse problems

• All underwent MRI for clinical or research purposes:

24.5% Abnormal

• First Research Visit, SCAT2; M = 30.4 hours (SD =

27.3) and all within 5 days

One Month Outcome

• ICD-10 Postconcussional Syndrome, Mild in

Severity =

23% of the MTBI sample

12% of the Community Control sample with

remote ankle injuries

Acute Predictors of One-Month

Post-Concussion Syndrome

• Loss of Consciousness: No

• Retrograde Amnesia: No

• Post-Traumatic Amnesia: No

• Abnormal MRI: No

• High Symptom Reporting in first few days: Yes

• Acute Psychological Distress: Yes (strongest predictor)

Most people recover functionally within 3 months

following injury.

Examples of Neuropsychology Meta-Analyses

Most people return to work within 3 months.

Return to work rates are highly variable across studies

and are likely influenced by many factors separate from

the injury to the brain.

Are there Microstructural White Matter

Abnormalities?

Cannot see on standard CT or MRI

If present, are these abnormalities associated with

persistent symptoms?

Traumatic Axonal Injury

• In general, unless exposed to very serious

forces, axons do not “shear” at the point of

injury.

• Stretch causes a temporary deformation of an

axon that gradually returns to the original

orientation and morphology even though

internal damage might have been sustained

Traumatic Axonal Injury

• In summary, a single acceleration/deceleration event might result in:

– (a) no apparent change in structure or function,

– (b) functional or metabolic change,

– (c) eventual structural change in the axon, or

– (d) frank separation of the axon into proximal and distal segments.

• These outcomes are dependent on the force applied to the brain.

Diffusion Tensor Imaging (DTI)

• DTI measures both the directionality and the

magnitude of water diffusion in white matter.

• Often considered proxy measures for the microstructural integrity of white matter in the human brain.

Common Analyses

• Region of Interest

• Tract-Based Spatial Statistics

• Tractography

• Emerging: Multivariate ROIs (Atlas-Based Approach)

Review of 50 DTI Studies in MTBI (Wäljas et al., 2014)

Findings Yes No Not

Reported

Abnormal White Matter 88% 12% ---

Correlated with:

Return to Work 0% 2% 98%

Post-Concussion Symptoms 12% 6% 82%

Cognitive Functioning 54% 8% 38%

Mental Health Problems 6% 8% 86%

DTI is interesting and has advanced

knowledge in TBI.

Remember, however, white matter

abnormalities are present in many

conditions—even in healthy adults.

And many of these conditions are present before injury or sometimes in

the years after injury.

ADHD

Learning Disability/Dyslexia

Depression

Hypertension

Non-Traumatic TMJ Disorder

Migraine

Marijuana & Alcohol Abuse in

Adolescents

More Bad News for Smokers

These data suggest that smoking affects the microstructural

integrity of cerebral white matter and support previous data

that smoking is associated with impaired cognition.

CONCLUSIONS: We document lower cognitive

performance and reductions in brain structural integrity

among adolescents with Metabolic Syndrome, thus

suggesting that even relatively short-term impairments in

metabolism, in the absence of clinically manifest vascular

disease, may give rise to brain complications.

Isolated White Matter Hyperintensities

in Healthy Adults

Examining DTI in a Civilian

Biopsychosocial Outcome from

MTBI Study

Prospective Study of One Year

Outcome from Civilian MTBI

Tampere, Finland

Recruited from the Emergency Department

Imaging and Clinical Assessment at 3-4 Weeks

Clinical Assessment at 1 Year

Wäljas M, Iverson GL, Lange RT, Hakulinen U, Dastidar P, Huhtala H, Liimatainen S, Hartikainen K, Öhman J. A prospective biopsychosocial study of the persistent post-concussion symptoms following mild traumatic brain injury. J Neurotrauma. 2015 Apr 15;32(8):534-47.

Prospective Outcome Study on MTBI

(N = 126 at one month and 103 at one year) Wäljas et al. (2015)

ICD-10 Mild Post-Concussion Syndrome

• MTBI One Month: 59% MTBI One Year: 38%

• Healthy Controls: 31%

Abnormal Structural MRI and/or DTI

• Abnormal structural MRI = 12.1%

• Diffusion Tensor Imaging (DTI): Multifocal areas

of unusual white matter

– MTBI Group = 50.7%

– Healthy Controls =12.4%

Predictors of the Post-Concussion

Syndrome

• One Month: pre-injury mental health problems

and bodily injuries.

• Being symptomatic at one month was a

significant predictor of being symptomatic at

one year.

• Depression was significantly related to PCS at

both one month and one year.

• Structural MRI abnormalities and

microstructural white matter findings (DTI)

were not significantly associated with greater

post-concussion symptom reporting, and they

were not significant predictors of PCS at one-

month or one-year following injury.

Participants and Procedures

• 62 adults with MTBIs

• 31 complicated and 31 uncomplicated

• Neurocognitive testing (many tests)

• Symptom Ratings

– British Columbia Postconcussion Symptom Inventory

– Beck Depression Inventory-Second Edition

– Beck Anxiety Inventory

• DTI on a 3T MRI scanner approximately 6-8

weeks post injury.

Reduced FA in body and genu of the corpus callosum and the

left frontal corona radiata and

Increased radial diffusivity in genu of the corpus callosum

and left frontal corona radiata

No Significant Differences

• Symptoms

• Broad range of neuropsychological tests

Depression and the

Post-Concussion Syndrome

Civilians who sustain an MTBI are at substantially

increased risk for experiencing depression in the

first year following injury.

The etiology of depression is likely individualized

and multifactorial.

Post-concussion-like symptoms can be mimicked or

magnified by traumatic stress, anxiety, pain, depression,

sleep disturbance, and social psychological factors at any

point in the recovery trajectory.

Individuals who are symptomatic at 3-6 months are

at considerable risk for being symptomatic at 1-2

years post injury.

Factors Affecting Recovery Time

• General health

• Previous concussions / neurological problems

• Pre-injury mental health problems

• Mechanism of Injury: MVA vs. Sports

• Acute Psychological Distress in the first few days

• Severity of concussion symptoms in the first week

• Post-Acute co-occurring conditions (depression, PTSD,

chronic pain)

• Personality Characteristics

• Motivation

• Litigation

Conclusions

• Mild TBIs are heterogeneous.

• Most athletes appear to recover within one month and

most civilians appear to recover within three months.

• Macroscopic intracranial lesions are not strongly related

to outcome.

• Microstructural differences as measured by DTI are not

strongly related to outcome.

• A biopsychosocial model helps conceptualize good and

poor outcome in individual cases.

Next Lecture:

Treatment and Rehabilitation for Persistent

Post-Concussion Symptoms

Thank You