TBI – The Scope of the Problem - Rehabilitation Research Center

CereScan Corp. 2014
Update on the Role of Brain SPECT
Imaging in the Evaluation and
Treatment of TBI
S. Gregory Hipskind, MD, PhD
Chief Medical Advisor, CereScan Corp
Confidential
Traumatic Brain Injury
 Approximately 1.7 million mild traumatic
brain injuries occur every year
 20% of mTBI’s have persistent or chronic
effects leaving 340,000 new chronic
mTBI patients per year
 1.365 million ER visits and 275,000
annual TBI hospitalizations per year
 Current traumatic brain injury population
(ages 5+) in the last decade is
approximately 3.4 million. By 2020 the
number will be approximately 15.1 million
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Traumatic Brain Injury Perspective
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Mild Traumatic Brain Injury (MTBI) Defined
The 9/03 CDC report to Congress:
“An occurrence of an injury to the head resulting from blunt trauma or
acceleration or deceleration forces with one or more of the following
conditions attributable to the head injury during the surveillance.”
1. Any period of observed or self-reported transient confusion, disorientation or impaired consciousness
under 30 minutes.
2. Any period of observed or self-reported dysfunction of memory (amnesia) around the time of injury
lasting less than 24hrs.
3. Observed signs of other neurological or neuropsychological dysfunction such as:
a. Seizure acutely following head injury.
b. In infants and young children irritability, lethargy or vomiting following head injury, or
c. Symptoms among older children and adults such as headache, dizziness, irritability, fatigue
or poor concentration when identified soon after injury.
Ref: American Congress of Rehabilitation Medicine, 1993
World Health Organization, 2009
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Pathobiology of Traumatic Brain Injury: 1
Primary Injuries – “Visible”:
•
•
•
•
•
•
•
Skull Fractures
Subdural/Epidural Hematomas
Brain Contusions
Diffuse Axonal Injury
Coup/Contracoup Injuries
Complicated vs. Non-Complicated: Not Predictive of
Outcome so No Longer Used
GCS in Mild: 13-15, Often CT Negative (>80% of time) in
acute setting
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Brain Injury as a Disease Process
• Recent advances in cellular mechanisms
involved in traumatic brain injury suggests
that TBI is a complex disease process that
unfolds over time.
• No longer viewed as an isolated “event.”
• The old forensic adage “worst is first” no
longer applies.
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Pathobiology of Traumatic Brain Injury: 2
Secondary Injuries – “Invisible”:
develop over hours, days, weeks and longer.
1)
2)
3)
4)
Fundamentally involve compromise of the neurovascular unit
NVU (also known as the Blood-Brain Barrier).
Result in a neurometabolic cascade of increased excitatory amino
acids (glutamate, aspartate), decreased CBF, swelling, alterations
in K+/CA++ pumping mechanisms.
Loss of integrity of the NVU leading to leakage of fluid (edema)
and release of cytokines and other reactive oxygen species (ROS)
which initiate the neuroinflammatory response which increases
over hours, days and weeks.
Tau Protein Build-Up: Chronic Tau Encephalopathy (CTE).
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Traumatic Brain Injury / Neurometabolic Cascade
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Calcium, Mitochondria & The Neurometabolic Cascade
Bigler, E. D., & Maxwell, W. L. (2012). Neuropathology of mild
traumatic brain injury: relationship to neuroimaging findings.
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The Mother Mitochondria
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Basic Neuron & Organelles
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Stages of Axonal Injury
Bigler, E. D., & Maxwell, W. L. (2012). Neuropathology of mild
traumatic brain injury: relationship to neuroimaging findings.
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Microtubules & Neurofilament Injury
Bigler, E. D., & Maxwell, W. L. (2012). Neuropathology of mild
traumatic brain injury: relationship to neuroimaging findings.
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A Case of Death & mTBI: Axonal Pathology
Bigler, E. D., & Maxwell, W. L.
(2012). Neuropathology of mild
traumatic brain injury: relationship
to neuroimaging findings.
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Pathobiology of Traumatic Brain Injury: 3 – Vascular Injury
Bigler, E. D., & Maxwell, W. L. (2012). Neuropathology of mild
traumatic brain injury: relationship to neuroimaging findings.
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Neurometabolic Summary
Bigler, E. D., & Maxwell, W. L. (2012). Neuropathology of mild
traumatic brain injury: relationship to neuroimaging findings.
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Real World Relevance of Football Research
In car crash
tests at 25 mph
dummies hit
windshields at
100g
Source: Endeavors, Spring 2008, Vol. XXIV, No. 3, May 14, 2008
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Acceleration/Deceleration Forces
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Concussion Equals Mild Traumatic Brain Injury (AAN)
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Cortical & Subcortical Locations and Pattern of TBI Neuropathology
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Even Psychiatrists Believe!
Stein, M., & McAllister, T. (2009). Exploring the convergence of posttraumatic stress disorder
and mild traumatic brain injury. American Journal of Psychiatry, 166(7), 768-776.
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Post Concussion Syndrome Defined
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TBI Timeline
PCS
PPCS
Interventions:
-Lifestyle
-Cog. Rehab
-Medication
-HBOT
-NIR
10% Persist
# of Symptoms
90%
Resolve
3 mo
6 mo
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12 mo
24 mo
(Maximal Natural
Spontaneous Healing)
Medical Consequences of Traumatic Brain Injury
* 90% of victims experience cognitive function effects, including:
- Memory loss
- Impaired judgment
- Difficulty concentrating and completing tasks
- Difficulty communicating
* 61% have decreased neurophysical ability, such as:
- Seizures
- Loss of smell, taste or vision
- Speech impairments
- Headaches
- Fatigue
- Loss of balance
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Cognitive Reserve
Bigler, E. D. (2013). Traumatic brain injury, neuroimaging, and neurodegeneration. Frontiers in human neuroscience, 7.
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Compound Effect
Odds Ratio
3.5
3.4x
2.8x
3x 3
2.5
2x 2
1.5x
1.5
1x 1
0.5
0
1 Previous
2 Previous
1
2
3 Previous
3
Previous Concussions
Previous Previous
Source: Guskiewicz et al., JAMA 290:2549, 2003
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Rates of Dementia
1.9%
2 .0 0 %
1.8 0 %
1.6 0 %
1.4 0 %
1.2 0 %
1.0 0 %
0 .8 0 %
0 .6 0 %
0 .4 0 %
0.01%
0 .2 0 %
0 .0 0 %
National Average
30-49 Year Old Retired Players
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Brain Injury Can Cause Psychiatric Illness
The Story of
Phineas Gage
(1848)
Phineas Gage was once a
shrewd, energetic railroad
foreman…
Until one day an iron tamping bar
shot completely through the front
of his head.
Gage miraculously recovers. All
his functions are intact..
But he was “no longer Gage.” He
became fitful, irreverent, willful,
pertinaciously obstinate,
capricious, and vacillating.
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Psychiatric Consequences of TBI
* 77.5% suffer from psychosocial difficulties including:
- Depression and mood changes
- Anxiousness
- Impulsiveness
- Self-centered behavior
Jorge 2004:
A study of 91 patients with TBI revealed the incidence of depression was 33% [p<0.05
relative to controls] during the first year after TBI.…Depressed patients had a 76.7%
incidence of comorbid anxiety and a 56.7% incidence of aggressive behavior.
Fann 2004:
Study of 939 patients with TBI revealed prevalence of any psychiatric illness in the first
year was 49%. Adjusted relative risk for any psychiatric illness in the 6 months following
moderate to severe TBI was 4.0 [and 2.8 following mild TBI] in subjects without past history
of psychiatric illness.
* “Fast Facts” from ThinkFirst, National Injury Prevention Foundation
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Concussions and Depression in Retired Football Players
16.5%
18
16
14
11%
12
% Depressed
5 or
more
10
8
5.5%
6
4
2
3 or
more
at
least 1
0
Number of Concussions
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Visualizing the “Invisible Injury”:
Brain Imaging Techniques
Anatomic
Functional
X-Rays
SPECT
CT
PET
MRI
fMRI
DTI
MRS
MEG
QEEG
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Imaging Concussions and TBI – How Do We See It?
 CT superior in demonstrating
fractures and hemorrhage
 MRI superior in demonstrating
contusion, white matter lesions,
and diffuse axonal injury
 SPECT superior in demonstrating
lesions or areas of dysfunction
that can closely correlate with
symptoms
 fMRI cannot visualize base of
brain well
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How is SPECT different from MRI & CT?
• SPECT tracks brain blood flow or “activity”
• MRI & CT are anatomical studies
MRI
CT
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Surface View SPECT
Correlation Between Cerebral Metabolism vs. Perfusion:
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SPECT Is Widely Accepted For Traumatic Brain Injury
•
Society of Nuclear Medicine Brain Injury Council-1996
• Use of SPECT in the management of patients with moderate to severe head trauma is
now well recognized.
• Society of Nuclear Medicine-1999 Procedure Guidelines
• TBI is a common indication for use of SPECT
• European Association of Nuclear Medicine-2002 Procedure Guideline
• SPECT has prognostic value. All forms of TBI are considered to be common
indications for its use.
• Center for Disease Control – 2003 Report to Congress
• SPECT has diagnostic use in mild traumatic brain injury.
• American College of Radiology-2012 Practice Guidelines
• Symptomatic TBI, especially in the absence of CT and/or MRI findings is considered
to be a clinical indication for use of SPECT.
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SPECT – Predictor of Outcome
Author
Year
No. of
Pts
Johnson
1993
29
Jacobs
1994
67
Read
1995
27
Jacobs
1996
136
Jobst
1997
200
Sensitivity
(Initial/12 Mo.)
Specificity
91%
59%
95%
92.6%
54%
100%
89%
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Positive
Predictive
Value
Negative
Predictive
Value
Initial
12
Mo.
86%
91%
-
-
-
59%
95%
97%
-
92.6%
-
-
85%
44%
100%
100%
80%
89%
-
-
Advanced SPECT vs Standard SPECT
Advanced
Standar
d
TBI Found
► Old Software and Camera
► Lack of “Read” Experience by Radiologists
► No Normative Database & Single Scan Protocol
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Advanced SPECT vs Other Specialists (SPECT)
Advanced
Remedial
► Single Scan Eliminates Valuable Information
► No Normative Database Comparison
► Outdated Software-Doesn’t Provide Statistical Information
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CereScan Multi-Modality Technology: SPECT
Siemens e.cam®
Signature Series
Dual Detector, Variable
Angle configured for
brain imaging
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Normal
Worse
Vertex
Underside
The Best of Both Worlds: SPECT Fused With MRI
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Detecting White Matter Pathology: Diffusion Tensor Imaging (DTI)
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Molecular PET – Tau Imaging: A Whole New Ballgame
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THE INVISIBLE BRAIN INJURY PROJECT
An elegant design to address all of the primary issues
concerning:
Identification, Treatment, & Reintegration
• Neuropsychogical Testing
• Health Survey
• Enhanced Functional Brain
Imaging
Identification &
Measurement
Broad Therapy
Design
• NIR LED Light Therapy
• Exercise
• Ongoing Psychological
Monitoring
• Daily Journal
Documentation
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• Post Treatment
Neuropsychogical Testing
• Weekly Review & QC
• Post-treatment
Neuroimaging
• Data Analysis & Conclusions
Clinical
Outcomes
SO WHAT IS THE TREATMENT?
The treatment is near infrared (NIR) light
• We believe the evidence is very supportive that NIR increases ATP
production via an effect of nitric oxide on mitochondrial cytochrome
oxidase.
• Second we believe that in the brain, nitric oxide released from
hemoglobin during NIR treatments (1) causes vasodilation and, with
repeated treatments, angiogenesis (2).
• Are we alone in proposing and observing this?
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NIR Therapy: a non-invasive, non-drug therapy
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Accelerated Tissue Healing: How does it work?
– The 1998 Nobel Prize in Physiology or Medicine was jointly
awarded to Robert F. Furchgott, Louis J. Ignarro and Ferid
Murad “for their discoveries concerning nitric oxide as a
signaling molecule in the cardiovascular system”.
• Nitric Oxide release
– Increases blood flow (vasodilation)
– Enhances lymphatic drainage
– Tissue repair signaling molecule
• Direct stimulation of cell healing processes
– Maximizes cell proliferation and remodeling
phases of tissue repair
– Direct anti-inflammatory effect
– Demonstrated effects on neuronal growth
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Nitric Oxide
Clinical Use of Near-Infrared Phototherapy
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Cellular Mechanisms of Near-Infrared Light
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Location and Severity of Brain Injury
First soldier – Pre-treatment Neuroimaging
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Standard deviation
Wounded Warrior Healing Process
12–Week Focused
NIR Therapy
Experiencing Concussive Event
 Exercise Therapy
 Cognitive Behavioral
Therapy (CBT)
 No Self-Medicating with
Alcohol or Drugs
 Neuropsychological Testing
Clinical data provided by:
Victoria Howatt, LCSW, PhD(ABD)
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Functional SPECT Baseline
Facilitating Targeted Treatment
Standard deviation
U.S. Service Members
Functional SPECT Follow-up
+ Statistical Analysis
To Quantify Improvement
Improvements in Patient’s Behavioral & Cognitive
Functioning Validated by SPECT Imaging
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Preliminary Results (Subject 1)
Images: Pre v. Post NIR Treatment
Six Weeks
Treatment
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Preliminary Results (Subject 1)
Images: Pre v. Post NIR Treatment
Six Weeks
Treatment
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Preliminary Results (Subject 2)
Images: Pre v. Post NIR Treatment
Six Weeks
Treatment
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Preliminary Results (Subject 1)
Preliminary Results (Subject 1)
Quantitative Analysis: Pre v. Post NIR
0.75
Pre/Post Treatment Standard Deviation from Normal
0.5
0.25
0
Mean Standard Deviation
-0.25
-0.5
-0.75
-1
-1.25
-1.5
-1.75
-2
-2.25
-2.5
-2.75
-3
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
Pre-Treatment -2.571 -2.084 -2.622 -2.326 -1.055 -1.047 -0.69 0.0168-0.685 -0.337 -0.924 -0.366 -0.079 -0.363 -1.461 -1.109 -0.842 -0.888 -0.693 -0.243 -0.1490.2124-1.644 -1.457 -2.697
Post-Treatment -1.4 -0.765 -2.075 -1.785 -0.497 -0.128 0.026 0.38180.13580.3963-0.0560.50730.39360.2503-0.945 -0.725 -0.236 -0.565 -0.1370.19770.41560.4791 -1.49 -1.362 -2.315
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Self-Symptom Reporting
Frequency of Symptoms
Intensity of Symptoms
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10 Week Case Study: SPECT Imaging Results
Pre Therapy Perfusion
Post Therapy Perfusion
Diet: Plant-based, organic; no gluten, dairy, refined sugar, alcohol, caffeine
Lifestyle: 6 days/week cardiovascular exercise (45+ min), meditation, yoga
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The Future Of Brain Diagnostics
Comprehensive Neuroimaging and Brain Health Centers:
•Advanced Quantitative SPECT
•PET/CT
•MRI/fMRI/MRS
•EEG
•Molecular Imaging (Tau)
•Diffusion Tensor Imaging
•MR Spectroscopy
•Disease specific treatments:
HBOT, NIR, PEMF
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The Future Of Neuroscience
Great spirits have
always
encountered
violent opposition
from mediocre
minds.
- Albert Einstein
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CereScan Corp. 2014
Thank You!
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