found in translation · found in translation: new treatment approaches for pediatric traumatic...
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Found in Translation: New Treatment Approaches for Pediatric Traumatic Brain Injury
Christopher C. Giza, M.D. Pediatric Neurology and Neurosurgery Children’s Discovery &
Innovation Institute Los Angeles, CA
May 28, 2015 20+5min
Credit where credit deserved!
Basic Scientists David Hovda, Ph.D. Me Fernando Gomez-Pinilla, Ph.D. Grace Griesbach, Ph.D. Neil Harris, Ph.D. Mayumi Prins, Ph.D. Raman Sankar, M.D., Ph.D. Rick Staba, Ph.D.
Students Lauren Fraund Isaac Gadinsky Phoebe Hua Briana Meyer Akash Patel Sonal Singh
Graduate Students Daya Alexander Chaitali Biswas, Ph.D. Andrew Segal
Lab Assistants Yan Cai, M.S. Sima Ghavim
Residents/Fellows Anish Patel, M.D. Raj Rajaraman, M.D.
Nurse Practitioners Sue Yudovin Kristina Murata
Clinical Investigators Robert Asarnow, Ph.D. Talin Babikian, Ph.D. Meeryo Choe, M.D. John DiFiori, M.D. Jason Lerner, M.D. Andy Madikians, M.D. Joyce Matsumoto, M.D. David McArthur, Ph.D., M.P.H.
www.birc.ucla.edu [email protected] Twitter: @griz1
Medical Students Daisuke Furukawa Kyla Sherwood
Post-docs Emily Dennis, Ph.D. Tiffany Greco, Ph.D. Lisa Moran, Ph.D. Aylin Reid, M.D., Ph.D.
Funded by: NS27544, HD061504, NCAA, Dept of Defense, Joseph Drown Foundation, UCLA
BIRC, UCLA Steve Tisch BrainSPORT Consultant: Alcobra, NHLPA, Pearson TLC
Research Assistants Jesse Fischer Alma Martinez Max Zeiger
Program Manager Constance Johnson
What’s Important? 1. Why Pediatric TBI?
2.Monitoring the Injured Brain a) In the ICU b) On the playing field
3.Activating the Injured Brain a) After severe TBI b) After concussion
4.Conclusions
TBI is the #1 cause of death and disability in kids and teenagers!!
Faul M, et al., TBI in the United States, CDC report 2010
What’s Important? 1. Why Pediatric TBI?
2.Monitoring the Injured Brain a) In the ICU b) On the playing field
3.Activating the Injured Brain a) After severe TBI b) After concussion
4.Conclusions
Post-TBI seizures
Reid A, et al; Epilepsia submitted 2015
47% of rats showed seizure activity after TBI.
1: L Frontal 2: L Frontal 3: R Frontal 5: L Ant Parietal 6: L Ant Parietal 7: Lesion core 8: Lesion care 9: L Parietal 10: L Parietal 11: L Ant Hippo 12: L Ant Hippo 13: L Post Hippo 14: L Post Hippo 15: R Parietal 16: R Parietal
0
5
10
15
20
≥ 5 secs ≥ 10 secs
Aver
age
Num
ber o
f Sei
zure
s in
1 H
our
Defined Seizure Duration
Rats with More Severe Injury Have More Frequent Seizures
MildModerateSevere
More severe injury caused more frequent seizures
Subclinical szs (14 pts, 16%)
Early post-traumatic seizures (EPTS)
53 pts 34 pts
Subclinical szs only
(6 pts, 7%)
39% with EPTS Risk factors for seizure: • younger age • bleeding • abusive head trauma
EPTS occur pretty frequently after pediatric TBI and can be associated with worse outcomes.
Arndt D, Lerner J et al., Epilepsia 2013
Metabolism Memory Metabolism
Memory
Metabolism Memory
Metabolism Memory
Prins ML, et al., J Neurotrauma 2013
Repeat concussion and metabolic vulnerability
2nd TBI BEFORE recovery from 1st TBI Single TBI
day1 day2 day3 day4 day5 day6 day7 day8
3 1 3
1
2nd TBI AFTER recovery from 1st TBI
3 1
Glu
cose
met
abol
ism
2nd concussion before full recovery results in worse brain metabolism & memory
Diagnosing Concussions • There is NO SINGLE test to
diagnose concussion
Executive Committee Hack (DoD), Hainline (NCAA), Koroshetz (NIH)
Administrative Coordinating Center:
Indiana U School of Medicine McAllister (coPI)
Advanced Research Coordinating Center:
Medical College of Wisconsin McCrea (coPI)
Longitudinal Clinical Study Coordinating Center:
U of Michigan Broglio (coPI)
Longitudinal Clinical Study Core (CSC)
Advanced Research Core (ARC)
U Nebraska (BIG10) Molfese
U Michigan (BIG10) Eckner
Washington (PAC12) Chrisman
U North Carolina (ACC)
Guskiewicz & Mihalik
U Pittsburgh (ACC)
Kontos & Collins
U Georgia (SEC)
Schmidt
U Florida (SEC)
Clugston
U Oklahoma (BIG12)
Anderson
UCLA (PAC12)
Giza & DiFiori
Consortium Operating Committee
Anderson, Broglio (co-Chair), Clugston, Duma, Giza, Guskiewicz, McAllister (co-Chair), McCrea (co-Chair), McGinty, Molfese, Putukian
Senior Scientific Advisory Panel Crainiceanu, Iverson,
Jordan, Kelly, Marshall, Saykin, Smith, Talavage,
Wallace
U Wisconsin (BIG10) Brooks
Princeton (Ivy)
Putukian
Concussion Research Initiative
US Military Academy
(Independent) Svoboda & Kelly
US Air Force Academy
(Mountain West) McGinty & Campbell
US Coast Guard Academy
(New England) Doria
US Naval Academy
(Independent) Pyne & Tsao
Virginia Tech (ACC)
Duma & Rowson
NCAA-DOD Grand Alliance CARE Consortium
U Delaware (Colonial) Buckley & Kaminski
Humboldt State (California Collegiate)
Ortega
Azusa Pacific (Pacific West)
Hoy
U Rochester (University) Bazarian
California Lutheran (Southern California)
Davis
Concussion Exposure: Sports
Helmet-based systems
Add video here
Imaging Chronic Concussions?
Barrio J., et al., PNAS 2015
FDDNP-PET is a marker for amyloid and tau protein; in retired NFL players it may be a marker for chronic brain damage.
What’s Important? 1. Why Pediatric TBI?
2.Monitoring the Injured Brain a) In the ICU b) On the playing field
3.Activating the Injured Brain a) After moderate-severe TBI b) After concussion
4.Conclusions
Pediatric TBI: Glutamate-NMDA receptor dysfunction
PID1 Sham FPI FPI
PID2 Sham FPI
PID4 Sham FPI
PID7 Sham
Hippocampus: Ipsilateral NR2A
-60 -40 -20
0 20 40
1 2 3 4 5 6 7 Post-injury day
% o
f Sha
m
*
Giza, Santa Maria & Hovda, J. Neurotrauma 2006
NR2A protein (IQ gene) is selectively reduced after developmental TBI.
* *
ANOVA, Overall effect of injury, p<0.05
*
Glutamate neurotransmission drives the (BOLD) signal seen on fMRI
Bonvento,G. et.al., TINS, 2002
Post-TBI Impaired Activation: Translational Imaging
Con
trols
TB
I
Children with TBI show less network activation during memory
Prins, et al., in Ped TBI, Anderson & Yeates, eds 2010; Cazalis et al., Front Neurol 2011
Con
trol
TBI
100% 75 50 25 0
Immature rats with TBI show less hippocampal activation and more memory impairment
Santa Maria N.S., et al., in revision 2015
D-Cycloserine (DCS) Treatment: Reverses TBI Dysfunction
-30
-20
-10
0
10
20
30
%ch
ange
from
S-S
al
S-Sal S-high DCS FP-Sal
FP-low DCS
FP-high DCS
ANOVA, Overall injury effect (p<.01)
Overall drug effect (p<.05)
Hippocampal NR2A
Santa Maria N.S., et al, J Neurotrauma abst 2007; in revision 2015
Treatment with DCS restores normal NR2A (IQ gene) levels in rats
D-cycloserine
• NMDAR co-agonist • Binds at glycine site • FDA approved agent • Good bioavailability • Penetrates BBB
Clinical Trial: Cognitive Tx + DCS
D-cycloserine PI: Asarnow, NINDS R21 grant, 2014-2016
Post-concussive Impaired Activation
Griesbach, et. al. Neurosci 2004
In Normals, ↑ Running, ↑ BDNF
Following TBI, Early ↑ Running
↔ BDNF Also… Worse cognition
Following TBI, Delayed ↑ Running
↑ BDNF Better cognition
Exercise immediately post-injury worsens outcome; but delayed exercise helps.
Exercise as Treatment? SubSymptom Threshold Exercise Training
Leddy JJ, et al., Clin J Sport Med 2010
N=12 refractory PCS patients (6 athletes, 6 non-athletes)
All subjects exercised near HR max w/o symptom exacerbation. No adverse reactions or drop-outs
• Symptoms improved • Athletes improved more rapidly • Heart rate & blood pressure at
maximal exercise improved
The Future of Pediatric TBI? 1. Monitoring the injured brain in the ICU will allow more
rapid intervention for seizures & secondary brain injury.
2. Baseline testing the brain will allow better diagnosis & treatment of sports concussion.
3. Combinations of pharmacological and behavioral therapies can be synergistic in enhancing TBI outcome.
4. Properly timed exercise / activity may be therapeutic for achieving optimal concussion outcomes in athletes.
UCLA Steve Tisch BrainSPORT Sports concussion clinic
12th and Wilshire, Santa Monica 200 Medical Plaza, Westwood
OPENING in 2015… Wasserman Building, Westwood
Email: [email protected]
Website: Google “UCLA BrainSPORT”
Baseline assessments
Comprehensive care
Safe return to play
Education & Research