Found in Translation: New Treatment Approaches for Pediatric - - PowerPoint PPT Presentation

▶
found in translation
SMART_READER_LITE
LIVE PREVIEW

Found in Translation: New Treatment Approaches for Pediatric - - PowerPoint PPT Presentation

Dec 05, 2023 42 likes •254 views

Found in Translation: New Treatment Approaches for Pediatric Traumatic Brain Injury Christopher C. Giza, M.D. Childrens Discovery & Pediatric Neurology and Neurosurgery Innovation Institute 20+5min Los Angeles, CA May 28, 2015

slide-1
SLIDE 1

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

slide-2
SLIDE 2

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 cgiza@mednet.ucla.edu 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

  • f 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

slide-3
SLIDE 3

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

slide-4
SLIDE 4

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

slide-5
SLIDE 5

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

slide-6
SLIDE 6

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

5 10 15 20 ≥ 5 secs ≥ 10 secs

Average Number of Seizures in 1 Hour Defined Seizure Duration

Rats with More Severe Injury Have More Frequent Seizures

Mild Moderate Severe

More severe injury caused more frequent seizures

slide-7
SLIDE 7

Subclinical szs

(14 pts, 16%)

Early post-traumatic seizures (EPTS)

53 pts 34 pts

Subclinical szs

  • nly

(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

slide-8
SLIDE 8

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

Glucose metabolism

2nd concussion before full recovery results in worse brain metabolism & memory

slide-9
SLIDE 9

Diagnosing Concussions

  • There is NO SINGLE test to

diagnose concussion

slide-10
SLIDE 10

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

slide-11
SLIDE 11

Concussion Exposure: Sports

Helmet-based systems

Add video here

slide-12
SLIDE 12

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.

slide-13
SLIDE 13

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

slide-14
SLIDE 14

Pediatric TBI:

Glutamate-NMDA receptor dysfunction

PID1 Sham FPI FPI PID2 Sham FPI PID4 Sham FPI PID7 Sham

Hippocampus: Ipsilateral NR2A

  • 60
  • 40
  • 20

20 40 1 2 3 4 5 6 7 Post-injury day % of Sham

*

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

  • n fMRI

Bonvento,G. et.al., TINS, 2002

slide-15
SLIDE 15

Post-TBI Impaired Activation: Translational Imaging

Controls TBI

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

Control TBI

100% 75 50 25

Immature rats with TBI show less hippocampal activation and more memory impairment

Santa Maria N.S., et al., in revision 2015

slide-16
SLIDE 16

D-Cycloserine (DCS) Treatment:

Reverses TBI Dysfunction

  • 30
  • 20
  • 10

10 20 30

%change from S-Sal

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
slide-17
SLIDE 17

Clinical Trial: Cognitive Tx + DCS

D-cycloserine

PI: Asarnow, NINDS R21 grant, 2014-2016

slide-18
SLIDE 18

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.

slide-19
SLIDE 19

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

slide-20
SLIDE 20

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.

slide-21
SLIDE 21

UCLA Steve Tisch BrainSPORT

Sports concussion clinic

12th and Wilshire, Santa Monica 200 Medical Plaza, Westwood OPENING in 2015… Wasserman Building, Westwood Email: concussioncare@mednet.ucla.edu Website: Google “UCLA BrainSPORT”

Baseline assessments Comprehensive care Safe return to play Education & Research