It’s Not All Fun and Games:

1. It’s Not All Fun and Games: Understanding Pediatric Sports Concussions from Pathophysiology to Clinical Care Symposium V: Child Neurology Society 39th Annual Meeting Providence, RI October 16th, 2010

2. Fri/Sat/Sun, October 15-17, 2010 Objectives • At the end of the symposium, the attendee should be able to: • describe the physiological changes associated with concussive brain injury and how they relate to clinically relevant sequelae, • properly identify and assess the child/adolescent with mild traumatic brain injury, • develop a management plan for acute concussions and for the subset of patients who develop chronic post-concussive symptoms, and • become familiar with available resources and evidence-based guidelines for concussion care.

3. Speakers / Program • Found in Translation: A Clinician’s Guide to the Pathophysiology of Concussion (Christopher C. Giza, M.D., Mattel Children’s Hospital and UCLA Brain Injury Research Center, Los Angeles, CA) • ACE Your Concussion Assessments: Tools for Concussion Assessment and Management (Gerard A. Gioia, Ph.D., Director of Pediatric Neuropsychology, Children’s National Medical Center, George Washington University, Washington, DC) • Comprehensive Clinical Care for Concussed Children: Long-term sequelae and Follow-up (Jane Gillett, M.D., F.R.C.P., Medical Director of the Acquired Brain Injury Program, Department of Medicine, McMaster University, Hamilton, Ontario) • Developing Evidence-Based Concussion Guidelines (Jeff Kutcher, M.D., Director, Michigan NeuroSport, Department of Neurology, University of Michigan) • Panel Question & Answer Email: cgiza@mednet.ucla.edu Slides / Handouts will be available on the CNS website

4. Found in Translation: A Clinician’s Guide to the Pathophysiology of Pediatric Sports Concussions Child Neurology Society 39th Annual Meeting Providence, RI October 16th, 2010 Christopher C. Giza, M.D. UCLA Brain Injury Research Center Pediatric Neurology and Neurosurgery Mattel Children’s Hospital - UCLA

5. Disclosure Grant support from: Child Neurology Foundation/Winokur Family Foundation, Department of Defense, NINDS/NIH, Thrasher Pediatric Research Foundation, Today and Tomorrow’s Children’s Fund Christopher C. Giza, M.D. UCLA Brain Injury Research Center Pediatric Neurology and Neurosurgery Mattel Children’s Hospital - UCLA

6. Important Points • What is a Concussion? • The Neurometabolic Cascade of Concussion • Pediatric Issues • Imaging the Cascade • Conclusions

7. Definition of Concussion 1997 • A trauma-induced alteration in mental status that may or may not involve loss of consciousness Practice Parameter, Quality Standards Subcommittee, American Academy of Neurology 1997

8. Definition of Concussion 2009 • A complex pathophysiological process affecting the brain induced by traumatic biomechanical forces • Due to direct blow or by an ‘impulsive’ force • Rapid symptom onset followed by spontaneous resolution • Clinical symptoms largely reflect dysfunction rather than structural damage • Results in graded set of symptoms, with or without loss of consciousness • Standard structural neuroimaging is normal McCrory P et al., Consensus Statement on Concussion in Sport, (3rd ), Br J Sport Med 2009

9. Important Points • What is a Concussion? • The Neurometabolic Cascade of Concussion • Basic Concussion Pathophysiology • Vulnerability • Impaired Neural Activation • Pediatric Issues • Imaging the Cascade • Conclusions

10. K+ K+ Glutamate Glutamate K+ K+ K+ Neurometabolic Cascade: Potassium & Glutamate Flux Katayama , et.al., J Neurosurg 1990

11. ADP ADP Glutamate Glutamate ATP ATP Glucose Neurometabolic Cascade: Hyperglycolysis and Energy Crisis K+ Pump Energy Crisis!!!

12. Ca2+ Protease activation Glutamate Glutamate Neurometabolic Cascade: Calcium, mitochondrial dysfunction and death Cell Damage/ Death!!! ATP ATP Energy Crisis!!! Mito Glucose For review, see Giza and Hovda, J Athl Training, 2001

13. Inflammation Ca2+ Axonal blebs and swelling Glutamate Impaired axonal transport Microtubule and neurofilament injury Axonal degeneration Neurometabolic Cascade: Axonal Injury Axonal swelling Myelin Damage

14. Post-concussive Vulnerability Repeat mTBIs separated by 3 days cause maximum reduction of NAA. NAA can be a biomarker for metabolic distress. Vagnozzi et al., J Nsurg 2005, 2007

15. LA Times, Sept 16, 2008 Post-concussive Vulnerability:Second Impact Syndrome HIGH SCHOOL FATALITY It's not just professional athletes who are at risk for serious head trauma. Last fall, Costa Mesa, Calif, high school football player Matthew Colby died from a head injury, 15 hours after collapsing during a game. The Orange County coroner's report lists the cause of death as "traumatic encephalopathy with brain swelling due to left subdural hemorrhage, acute and subacute, due to blunt force trauma, head." • Definition: rare syndrome of catastrophic cerebral edema occurring after experiencing two concussions in close succession • Clinical presentation: profound neurologic deterioration and collapse after second concussion • Treatment: Intensive care • Outcome: High mortality Vastag, JAMA 2002 Controversy exists: See Cantu, Clin Sports Med, 1998 vs. McCrory & Berkovic, Neurology, 1998.

16. Following TBI, Early  Running  BDNF Also… Worse cognition Following TBI, Delayed  Running  BDNF Better cognition Post-concussive Impaired Activation In Normals,  Running,  BDNF Exercise initiated in the 1st week after injury causes worse outcome. Griesbach, et. al. Neurosci 2004

17. Post-concussive Effects of Activity on Recovery N = 95 High School Concussed Athletes Scores represented by percentiles as compared to normative Data 5 Days Post-Injury Those with the highest (and lowest) levels of exertion post-concussion had worse neurocognitive scores and higher symptom scores. Activity Level Majerske C, et al., J Athl Training 2008

18. Important Points • What is a Concussion? • The Neurometabolic Cascade of Concussion • Pediatric Issues • Is Younger Better…Or Not? • Cumulative effects: When is Enough, Enough? • Age-Specific Assessments • Grade School-High School-College-Pro... • Imaging the Cascade • Conclusions

19. 1 . 6 Control/STD * 1 . 5 FP/STD Sham/EE 1 . 4 FP/EE 1 . 3 1 . 2 1 . 1 FP/EE 1 . 0 Sham/STD Sham/EE Group Dendritic reconstruction Average Smarter after EE Average after trauma and EE Ip, Giza, et.al., J Neurotrauma, 2002 Is Younger Better…or Not? Loss of Experience-Dependent Plasticity Cortical thickness Cortical thickness and dendritic arborization increase in response to Enriched Environment. Experience-dependent brain plasticity was impaired after developmental mTBI. Occipital Cortical thickness (mm) Fineman, Giza, et.al., J Neurotrauma, 2000

20. * * * * + * + * * * Is Younger Better…or NOT!Impaired learning / plasticity High school athletes took longer to recover both symptoms and cognition than college athletes. Also, HS athletes demonstrated cognitive impairment beyond the time of symptom resolution. Modified from Field M, et al., J Pediatr, 2003

21. When is Enough…Enough? Cases of tau accumulation have been seen in athletes brains. Neuropathologically confirmed CTE n=51 Mean age at of beginning sport 15.4 y ± 2.2 First symptoms noted 42.8 y ± 12.7 Common symptoms: memory loss, violent outbursts, mood disturbance, cognitive decline, eventual movement abnormalities. McKee A, et al., J Neuropathol Exp Neurol 2009

22. One Size Fits All Ages…??? Neurocognitive function changes with age McCrory P, et al., BJSM 2004

23. Genetic Predisposition? Black = coma Stripes = ataxia, migraine ½ black = migraine only = mTBI induced AMS Kors EE, et al., Ann Neurol 2001

24. Important Points • What is a Concussion? • The Neurometabolic Cascade of Concussion • Pediatric Issues • Imaging the Cascade • Conclusions

25. Human TBI: Abnormal glucose metabolism (PET) GCS 15 GCS 5 GCS 15 Glucose metabolism may show profound abnormalities in humans, even after mild TBI. Bergsneider, Hovda, et.al. 2000

26. Human mTBI: Impaired Activation (fMRI) Mild TBI patients (GCS 13-15), n=12; controls n=11 Average time of testing was 22.1 ± 10.5 days after TBI. Loss of consciousness: 1 to 30 min. Post-traumatic amnesia: 15 min to 24 hrs. % correct mTBI control 0-back 95.1 96.2 1-back 95.8 95.5 2-back 81.0 89.4 No significant differences Controls Mildly injured individuals demonstrate abnormal activation patterns during a more difficult working memory task. Mild TBIs McAllister, et al. Neurology, 1999

27. Human mTBI: Altered metabolism (MRS) Single concussion There were significant reductions of NAA/Cr for 30 days after 1 concussion and 45 days after 2 concussions. Double concussion Vagnozzi, et.al. Neurosurgery, 2008 Vagnozzi, et.al. Brain, 2010

28. Human mTBI: Abnormal axons (DTI) In adolescents with mTBI, DTI of the CC performed within 6 days showed increased FA and decreased diffusivity. These abnormalities in DTI correlated well with post-concussion symptoms. Wilde E, et.al. Neurology, 2008

29. Altered neurotrans-mission fMRI Glutamate Mito Energy Crisis Axonal injury DTI PET, MRS Neurometabolic Cascade: Now we can see it Protein Biomarkers? MRI Cell Damage/ Death Protease activation

30. Conclusions • Concussion causes neuronal dysfunction without significant acute cell death. • The concussed brain is in a state of metabolic vulnerability. • Issues particularly relevant for pediatric concussions include: • impaired neural activation and plasticity. • risk for a chronic accumulation of mild injuries. • Current guidelines and assessments are not yet validated in the developing brain. • Younger athletes may have a higher risk of sequelae due to genetic predisposition and lack of self-selection. • Biomarkers like neuroimaging (and maybe blood tests) allow us to see post-concussive physiological dysfunction in vivo in humans.

31. Beware multiple sport-related injuries! Email: cgiza@mednet.ucla.edu