Pathophysiology ofConcussions

November 9, 2013

Jon Schultz, MDUMKC Sports Medicine Kansas City, Missouri

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

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

“DINGS” MATTER

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

MECHANISM OF INJURY

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

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

Giza and DiFioriPathophysiology of Sports-Related Concussion: An Update on Basic Science and Translational Research Jan • Feb 2011 SPORTS HEALTH

Lateral fluid percussion for inducing a concussion in the lab

concussion video.htm

Ionic and metabolic dysfunction

Cerebral microdialysis measured elevated levels of glutamate and potassium in head-injured patients in the ICU. J Neurosurg.1998;89:507-518, 971-982.

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 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Chefer V, Thompson A, Zapata A and Shippenberg T

Overview of Brain Microdialysis

Curr Protoc Neurosci. 2009 April

Schematic representation of MD catheter in brain tissue.

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 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Matthew F. Grady, MD, et al, Pediatric Annals, September 2012 - Volume 41 · Issue 9

Na+ influx

pH↑↓

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.

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 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

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;16:135-148, J Neurosurg. 1997;86:241-251.

• Profound glucose metabolic depression was seen after mild TBI, to the same degree as severe TBI. J Neurotrauma. 2000;17:389-401.

• Metabolic recovery generally takes weeks to months after moderate to severe TBI. J Head Trauma Rehabil. 2001;16:135-148.

Pathophysiology of concussion“neurometabolic cascade”

Neurotramsmitter release due to massive depolarization of neurons and axonal stretch inury

Ionic disrup

tion

Energy supply and demand mismatch

Decreased

cerebral blood

flow

Increased inflammation and axonal swelling

Neurotransmission disruption

Giza and DiFioriPathophysiology of Sports-Related Concussion: An Update on Basic Science and Translational Research Jan • Feb 2011 SPORTS HEALTH

So now what do we do???

Good legs

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;157:349-358. Brain Res. 1998;783:286-292. J Neurosci. 1996;16:4776-4786.

Motorcortex

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;561:106-119.

Voluntary exercise

If the animal runs within 1 week of a mild injury, BDNF levels do not increase and cognitive performance suffers. Neuroscience. 2004;125:129-139.

BDNF = brain-derived neurotrophic factor

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;561:106-119.

• 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. 2005;56:364-374.

Does this apply to humans?

It appears so…

95 student-athletes (80 males, 15 females: age = 15.88 +/- 1.35 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;43:265-274.

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 associatedwith recurrent concussion in collegiate football players: the NCAAconcussion study. JAMA. 2003;290:2549-2555

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

Apo E4

Tauprotein

Amyloid β

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. 2009

RETURN TO PLAY ISSUESA 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.