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