2. Pathophysiology of Concussions
November 9, 2013
Jon Schultz, MD
UMKC Sports Medicine
Kansas City, Missouri

3. Learning Objectives
Appreciate the historical progression of concussion research
Recognize the impact of concussions on today’s society
Describe our current understanding of concussive pathophysiology

4. So what’s the big deal???
“Compared to the complexity of a brain, a galaxy is just an inert lump” physicist Sir Roger Penrose
“Concussion is considered to be among the most complex injuries in sport medicine to diagnose, assess, and manage” McCrory et al, Consensus Statement on Concussion in Sport, Clin J Sport Med Volume 23, Number 2, March 2013
Limited research abilities
ED visits for sports-related TBI has risen over the past 10 years
Post-concussive syndrome, malignant cerebral edema, & second impact syndrome
Worries of chronic traumatic encephalopathy and dementia in retired NFL players

5. “DINGS” MATTER 43 HS athletes with “Grade 1” concussion
AJSM, Lovell et al (2004)
43 HS athletes with “Grade 1” concussion
Neuropsych testing 36 hrs after concussion
Statistically significant differences in memory and symptoms compared to baseline
Conclusion: Old standard RTP guidelines may be too liberal

6. MECHANISM OF INJURY Rotational Linear
Rotational (angular) acceleration: diffuse shearing forces deep in brain causing axonal injury
Translational (linear) acceleration: tensile (pulling apart) and compressive forces resulting in focal brain injury
Rotational
Linear

7. Pathophysiology of concussion
“neurometabolic cascade”
Nuerotramsmitter release with massive depolarization of neurons along with axonal stretch inury
Ionic disruption
Metabolic disruption
Energy supply and demand mismatch
Decreased cerebral blood flow
Mitochondrial dysfunction
Increased inflammation and axonal swelling
Neurotransmission disruption
Window of vulnerability
Pathophysiology of Sports-Related Concussion: An Update on Basic Science and Translational Research
Giza and DiFiori
Jan • Feb 2011
SPORTS HEALTH

8. Lateral fluid percussion for inducing a concussion in the lab

9. Ionic and metabolic dysfunction
Cerebral microdialysis measured elevated levels of glutamate and potassium in head-injured patients in the ICU. J Neurosurg.1998;89: ,

10. Components of clinical MD catheter
Components of clinical MD catheter. 1, pump connector; 2, inlet tube; 3, MD catheter; 4, MD membrane; 5, outlet tube; 6, microvial holder; 7, microvial for collection of microdialysate.
Components of clinical MD catheter. 1, pump connector; 2, inlet tube; 3, MD catheter; 4, MD membrane; 5, outlet tube; 6, microvial holder; 7, microvial for collection of microdialysate.
Tisdall M M , and Smith M Br. J. Anaesth. 2006;97:18-25
© The Board of Management and Trustees of the British Journal of Anaesthesia All rights reserved. For Permissions, please

11. Chefer V, Thompson A, Zapata A and Shippenberg T
Overview of Brain Microdialysis
Curr Protoc Neurosci April

12. Schematic representation of MD catheter in brain tissue.
Schematic representation of MD catheter in brain tissue. Fluid isotonic to the brain ECF is pumped through the MD catheter at a rate of 0.3 µl min−1. Molecules at high concentration in the brain ECF equilibrate across the semi-permeable MD membrane and can be analysed in the collected perfusate (the microdialysate).
Tisdall M M , and Smith M Br. J. Anaesth. 2006;97:18-25
© The Board of Management and Trustees of the British Journal of Anaesthesia All rights reserved. For Permissions, please

13. Na+ influx
pH↑↓
Matthew F. Grady, MD, et al, Pediatric Annals, September Volume 41 · Issue 9

14. Changes in LPR in ‘at-risk’ (a) and normal (b) brain during a period of low and normal CPP. The normal range for LPR is shown by the shaded area.
Changes in LPR in ‘at-risk’ (a) and normal (b) brain during a period of low and normal CPP. The normal range for LPR is shown by the shaded area. Note the increase in LPR in the ‘at-risk’ tissue during a period of cerebral hypoperfusion with normal values measured by the catheter in normal brain.
Tisdall M M , and Smith M Br. J. Anaesth. 2006;97:18-25
© The Board of Management and Trustees of the British Journal of Anaesthesia All rights reserved. For Permissions, please

15. Human evidence
After human TBI, positron emission tomography (PET) scanning has shown a similar pattern of early hyperglycolysis followed by glucose metabolic depression. J Head Trauma Rehabil. 2001;16: , J Neurosurg. 1997;86:
Profound glucose metabolic depression was seen after mild TBI, to the same degree as severe TBI. J Neurotrauma. 2000;17:
Metabolic recovery generally takes weeks to months after moderate to severe TBI. J Head Trauma Rehabil ;16:

16. Pathophysiology of concussion
“neurometabolic cascade”
Neurotramsmitter release due to massive depolarization of neurons and axonal stretch inury
Ionic disruption
Metabolic disruption
Energy supply and demand mismatch
Decreased cerebral blood flow
Mitochondrial dysfunction
Increased inflammation and axonal swelling
Neurotransmission disruption
Window of vulnerability
Pathophysiology of Sports-Related Concussion: An Update on Basic Science and Translational Research
Giza and DiFiori
Jan • Feb 2011
SPORTS HEALTH

17. So now what do we do???

18. Motor
cortex
Forced overuse within the first week of experimental injury actually worsened the animal’s recovery, causing greater cell death in the brain and hampering neurologic recovery. Exp Neurol.1999;157: Brain Res. 1998;783: J Neurosci. 1996;16:
Good legs

19. Delay forced overuse
Delay overuse by 1 week, and neurologic recovery was more complete. But the amount of cell death was not affected. Brain Res.
1991;561:

20. Voluntary exercise
If the animal runs within 1 week of a mild injury, BDNF levels do not increase and cognitive performance suffers. Neuroscience. 2004;125:
BDNF = brain-derived neurotrophic factor

21. What we know in the rat post-injury
Period of vulnerability to premature activation = known abnormal metabolic state after experimental TBI = 7 to 10 days. Brain Res. 1991;561:
A 2nd TBI within 3 to 5 days after the first = impaired cognitive function but not when the second injury was applied at 7 days. Neurosurgery ;56:

22. Does this apply to humans?

23. It appears so…
95 student-athletes (80 males, 15 females: age = / years) with “moderate” postconcussive activity fared the best on neurocognitive testing. The higher and the lower activity levels were associated with the worst scores. J Athl Train.2008;43:

24. College football players
With a history of concussion were 3.4 times more likely to suffer a concussion that season.
6.5% of football players had a repeat injury in the same season
75% (9 of 12) had a recurrent injury within 7 days of the first injury, and 11 of 12 recurred within 10 days.
The risk for repeat injury appears to be greatest within 10 days following the initial concussion.
Guskiewicz KM, McCrea M, Marshall SW, et al. Cumulative effects associated
with recurrent concussion in collegiate football players: the NCAA
concussion study. JAMA. 2003;290:

25. Rats and CTE Molecular markers associated with dementing processes
Alzheimer disease is characterized by accumulation of tau and amyloid β (Aβ) protein
Rodents do not readily develop Aβ plaques
Apolipoprotein (Apo) E4 allele may be a genetic marker making certain individuals more susceptible to dementia

26. Tau
protein
Apo E4
Amyloid β

27. SYMPTOMS OF CONCUSSIONS
Headache
Nausea
Balance problems/dizziness
Fatigue
Drowsiness
Feeling “in a fog”
Difficulty concentrating
Difficulty remembering
Sensitivity to light
Sensitivity to noise
Blurred vision
Feeling slowed down
Randolph, et.al. Arch. Clin. Neuropsychol

28. RETURN TO PLAY ISSUES
A player with diagnosed concussion should not be allowed
to return to play on the day of injury.
Occasionally, in adult athletes,
return to play on the same day as the injury may be allowed.