THE “WHAT”, “WHO”, THE “WHAT”, “WHO”, “WHEN”, “HOW” AND “WHEN”, “HOW” AND

“WHAT COULD BE” WITH “WHAT COULD BE” WITH CONCUSSION CONCUSSION

INJURIESINJURIES

David R. Wiercisiewski, MDDavid R. Wiercisiewski, MDCarolina Neurosurgery & Spine Carolina Neurosurgery & Spine

Charlotte, NCCharlotte, NC

Financial Relationships

I have no financial relationships to disclose

DEFINITIONDEFINITION

“…“…a biomechanically induced a biomechanically induced neurological injury resulting in an alteration in neurological injury resulting in an alteration in mental status such as confusion or amnesia mental status such as confusion or amnesia which may or may not involve a loss of which may or may not involve a loss of consciousness.”consciousness.”

AAN, 1997AAN, 1997

DEFINITIONDEFINITION

““Cerebral concussion is essentially a Cerebral concussion is essentially a reversible syndrome without detectable reversible syndrome without detectable pathology.”pathology.”

Denny-Brown, 1941Denny-Brown, 1941

THE CONFLICT BETWEEN THE CONFLICT BETWEEN DEFINITION DEFINITION

ANDANDPERCEPTIONPERCEPTION

A concussion is a A concussion is a brain injurybrain injury that occurs in sports that occurs in sports

It is contrary in every way to any other type of It is contrary in every way to any other type of “sports injury”“sports injury”

Most people look at it only as a “sports injury”Most people look at it only as a “sports injury”

PREVALENCEPREVALENCE

The Center for Disease Control (CDC) The Center for Disease Control (CDC) reports that an estimated 1.8 to 3.6 million reports that an estimated 1.8 to 3.6 million concussion injuries occur in sports and concussion injuries occur in sports and recreational activities annually in the USA.recreational activities annually in the USA.

CONCUSSION RATESCONCUSSION RATES

Boys soccerBoys soccer 22.6822.68Girls soccerGirls soccer 12.9212.92Boys basketballBoys basketball 9.72 9.72Girls basketballGirls basketball 17.2117.21BaseballBaseball 11.9011.90SoftballSoftball 10.0310.03WrestlingWrestling 9.27 9.27CheerleadingCheerleading 9.26 9.26FootballFootball 31.3731.37

(per 100,000 athlete-exposures)(per 100,000 athlete-exposures)

CONCUSSION RATESCONCUSSION RATESBY GENDERBY GENDER

MalesMales 19.91 19.91

FemalesFemales 10.91 10.91

(per 100,000 athlete-(per 100,000 athlete-exposures)exposures)

OTHER FACTOIDSOTHER FACTOIDS

Game v. practiceGame v. practice

Position in game v. Position in game v. practice per sportpractice per sport

Mechanism or play that Mechanism or play that caused concussioncaused concussion

MECHANISM MECHANISM OFOF

INJURYINJURY

PATTERNS OF FORCEPATTERNS OF FORCE

RotationalRotational

LinearLinear

Impact decelerationImpact deceleration

VerticalVertical

ROTATIONAL FORCESROTATIONAL FORCES

Dynamic loading (<200 msec) Dynamic loading (<200 msec)

Caused by direct impact or indirect impulse Caused by direct impact or indirect impulse which creates increased inertial loading by which creates increased inertial loading by sudden changes in motionsudden changes in motion

Damage occurs at surface Damage occurs at surface andand at zones where at zones where there is a change in densitythere is a change in density

Increased force/shear strain = deeper Increased force/shear strain = deeper penetration of injurypenetration of injury

TRANSLATIONAL FORCESTRANSLATIONAL FORCES

Static loading (> 200 msec)Static loading (> 200 msec)

Less common cause of injuryLess common cause of injury

Site of impactSite of impact is important for focal is important for focal component of injury and clinical component of injury and clinical signs/symptoms signs/symptoms

IMPACT DECELERATIONIMPACT DECELERATION

Falls or head impact to groundFalls or head impact to ground

More common than linear/translational patternMore common than linear/translational pattern

Coup-contrecoup pattern of injuryCoup-contrecoup pattern of injury

HYPOTHESISHYPOTHESISFORFOR

CEREBRAL CONCUSSIONCEREBRAL CONCUSSION

“ “graded set of clinical graded set of clinical syndromes following head syndromes following head injury wherein the increased injury wherein the increased severity of disturbance … severity of disturbance … caused by mechanically caused by mechanically induced strains affecting the induced strains affecting the brain in a centripetal brain in a centripetal sequence of disruptive effect sequence of disruptive effect on function and structure” on function and structure”

Ommaya & Gennarelli, Brain, 1974.Ommaya & Gennarelli, Brain, 1974.

GRADESGRADESOFOF

CEREBRAL CONCUSSIONCEREBRAL CONCUSSION

I – Confusion without amnesiaI – Confusion without amnesiaII – Confusion with PTAII – Confusion with PTAIII – Confusion with PTA + RAIII – Confusion with PTA + RAIV – Coma (loss of consciousness)IV – Coma (loss of consciousness)V – Coma (PVS)V – Coma (PVS)VI – Coma leading to deathVI – Coma leading to death

Ommaya and Gennarelli, 1974.Ommaya and Gennarelli, 1974.

THE “HOW”THE “HOW”

PATHOPHYSIOLOGYPATHOPHYSIOLOGYOFOF

CONCUSSIONCONCUSSION

BASIC RESEARCHBASIC RESEARCH

Experimental models with mice and ratsExperimental models with mice and rats

Mechanism of injuryMechanism of injuryClosed-skull weight dropClosed-skull weight drop

Closed-skull controlled impact Closed-skull controlled impact

Lateral fluid percussion injury (FPI)Lateral fluid percussion injury (FPI)

OBSERVED CHANGESOBSERVED CHANGES

Molecular alterationsMolecular alterations

Ionic and neurotransmitter disturbancesIonic and neurotransmitter disturbances

Synaptic perturbationsSynaptic perturbations

Structural changesStructural changes

NEUROMETABOLIC NEUROMETABOLIC CASCADECASCADE

Disruption of neuronal cell membrane + axonal Disruption of neuronal cell membrane + axonal stretchingstretchingIndiscriminate flux of ions through previously Indiscriminate flux of ions through previously regulated ion channels and membrane defectsregulated ion channels and membrane defectsRelease of excitatory amino acidsRelease of excitatory amino acidsIncreases ionic flux furtherIncreases ionic flux furtherNa/K pump works at maximum capacity to restore Na/K pump works at maximum capacity to restore ionic balanceionic balanceEnergy stores become depleted—”metabolic crisis”Energy stores become depleted—”metabolic crisis”

IONIC FLUX IONIC FLUX

Neuronal cell membrane deformity as a result of Neuronal cell membrane deformity as a result of traumatraumaDeformity allows K+ efflux and glutamate (EAA) Deformity allows K+ efflux and glutamate (EAA) release release Glutamate binds to and activates NMDA receptors Glutamate binds to and activates NMDA receptors which causes depolarization of the neuron and also which causes depolarization of the neuron and also allows for an influx of Ca++allows for an influx of Ca++Depolarization also results in neuronal suppression Depolarization also results in neuronal suppression similar to the mechanism in migrainesimilar to the mechanism in migraine

CELLULAR RESPONSECELLULAR RESPONSE

Restore ionic balance through activation of Na/K Restore ionic balance through activation of Na/K pumpspumpsPumps require higher levels of glucose metabolism to Pumps require higher levels of glucose metabolism to restore balance due to operating at maximum capacityrestore balance due to operating at maximum capacityIntracellular energy stores are depleted which Intracellular energy stores are depleted which demands more rapid but inefficient glycolysisdemands more rapid but inefficient glycolysisMitochondrial function subsequently is diminished Mitochondrial function subsequently is diminished which leads to an increase in lactate productionwhich leads to an increase in lactate productionLactate contributes to local acidosis, increased Lactate contributes to local acidosis, increased membrane permeability and cerebral edemamembrane permeability and cerebral edema

GLUCOSE METABOLISMGLUCOSE METABOLISMMITOCHONDRIAL EFFECTSMITOCHONDRIAL EFFECTS

Initial response to injury is hyperglycolysisInitial response to injury is hyperglycolysis30 minutes after a lateral FPI there is a 30-40% 30 minutes after a lateral FPI there is a 30-40% increase in glucose metabolismincrease in glucose metabolismAt 6 hours there is a reduction to 50% of normalAt 6 hours there is a reduction to 50% of normalReduction is due to oxidative dysfunction of Reduction is due to oxidative dysfunction of mitochondria who cannot keep up with energy mitochondria who cannot keep up with energy demandsdemandsThere is also production of superoxide free radicals There is also production of superoxide free radicals which can create further intracellular injurywhich can create further intracellular injury

MORE ABOUT MITOCHONDRIAMORE ABOUT MITOCHONDRIA

Activation of the NMDA Activation of the NMDA receptor by glutamate receptor by glutamate allows for Ca++ influxallows for Ca++ influx

Ca++ accumulates in the Ca++ accumulates in the mitochondria creating the mitochondria creating the glycolytic abnormalities and glycolytic abnormalities and oxidative dysfunctionoxidative dysfunction

Mitochondria are down-Mitochondria are down-regulated after a lateral FPI regulated after a lateral FPI for at least 10 days for at least 10 days

RESULTRESULTOFOF

METABOLIC CRISISMETABOLIC CRISIS

Cerebral hypofunction or permanent damageCerebral hypofunction or permanent damage

Single mTBI = self-limited, transient changesSingle mTBI = self-limited, transient changes

Multiple mTBI = more lasting derangementMultiple mTBI = more lasting derangement

YOU MAKE THE CALLYOU MAKE THE CALL

VASCULAR RESPONSEVASCULAR RESPONSE

Triphasic response to concussion based on Triphasic response to concussion based on severe TBI modelssevere TBI models

Day 0 = Cerebral hypoperfusionDay 0 = Cerebral hypoperfusion

Day 1-3 = Cerebral hyperemiaDay 1-3 = Cerebral hyperemia

Day 4-15 = Cerebral vasospasm Day 4-15 = Cerebral vasospasm

Mild TBI is similar but to a lesser extentMild TBI is similar but to a lesser extent

AXONAL INJURYAXONAL INJURY

Axonal injury is felt to be reversible in mild Axonal injury is felt to be reversible in mild TBITBI

Decreased axonal transport noted in the Decreased axonal transport noted in the inferior and superior frontal regions as well as inferior and superior frontal regions as well as in the supracallosal regionin the supracallosal region

Correlates with changes in motor speed, Correlates with changes in motor speed, executive function and behaviorexecutive function and behavior

VULNERABILITYVULNERABILITY

Related to:Related to:Metabolic perturbationsMetabolic perturbations

Altered blood flow dynamicsAltered blood flow dynamics

Axonal injuryAxonal injury

Abnormal neural activationAbnormal neural activation

Reduced cerebral perfusionReduced cerebral perfusion

Exacerbated by:Exacerbated by:Repeated mild injuries Repeated mild injuries concussive or sub-concussive concussive or sub-concussive within window of within window of impairmentimpairment

RECOVERY TIMELINESRECOVERY TIMELINES

Study using MRS looking at altered metabolism in 13 Study using MRS looking at altered metabolism in 13 concussed adult athletes (>18 years old) at 3, 15, 22 concussed adult athletes (>18 years old) at 3, 15, 22 and 30 days post-injuryand 30 days post-injuryMetabolism reduced at 3 and 15 days and normalized Metabolism reduced at 3 and 15 days and normalized by 30 daysby 30 days3 athletes suffered a “repeat” injury in the 3-15 day 3 athletes suffered a “repeat” injury in the 3-15 day window and took 45 days to normalizewindow and took 45 days to normalizeSingle concussion group reported being symptom Single concussion group reported being symptom free at 3 days and double concussion group at 30 daysfree at 3 days and double concussion group at 30 days

Vagnozzi et al., Brain 2010Vagnozzi et al., Brain 2010

SECOND IMPACT SYNDROMESECOND IMPACT SYNDROME

Potential catastrophic outcome as a result of a repeat Potential catastrophic outcome as a result of a repeat concussion injury while recovering from the initial concussion injury while recovering from the initial injuryinjury

Cellular, metabolic, axonal and vascular disturbances Cellular, metabolic, axonal and vascular disturbances are amplifiedare amplified

Profound cerebral edema develops which may lead to Profound cerebral edema develops which may lead to coma and severe neurological disability or deathcoma and severe neurological disability or death

Primary rationale for delayed RTPPrimary rationale for delayed RTP

Is there a spectrum for Second Impact Syndrome???Is there a spectrum for Second Impact Syndrome???

LONG TERM OUTCOMESLONG TERM OUTCOMES

Genetic predispositionGenetic predispositionApo E-4 alleleApo E-4 allele

Amyloid and tau Amyloid and tau depositiondeposition

Number of concussionsNumber of concussions3 or more3 or more

Length of careerLength of careerLongevity = ExposuresLongevity = Exposures

CHRONIC TRAUMATICCHRONIC TRAUMATICENCEPHALOPATHY (CTE)ENCEPHALOPATHY (CTE)

Associated with memory disturbances, behavioral and Associated with memory disturbances, behavioral and personality changes, Parkinsonism and speech and personality changes, Parkinsonism and speech and gait abnormalitiesgait abnormalities

Neuropathologically characterized by atrophy of the Neuropathologically characterized by atrophy of the cerebral hemispheres, medial temporal lobe, cerebral hemispheres, medial temporal lobe, thalamus, mammillary bodies and brainstemthalamus, mammillary bodies and brainstem

Microscopically there is extensive tau protein Microscopically there is extensive tau protein depositiondeposition

TAU PROTEINTAU PROTEIN

Protein that invades cortical Protein that invades cortical nerve cells and disables nerve cells and disables them effectively shutting them effectively shutting them downthem down

Unlike Alzheimer’s disease Unlike Alzheimer’s disease and the neurofibrillary and the neurofibrillary tangles associated with that tangles associated with that disease, the build up of tau disease, the build up of tau protein is related to protein is related to environmental factors such environmental factors such as trauma or injury.as trauma or injury.

CHRONICCHRONIC TRAUMATICTRAUMATIC ENCEPHALOPTHYENCEPHALOPTHY

NFL Survey—NFL Survey—>50 = 5x risk>50 = 5x risk

30-49 = 19x risk30-49 = 19x risk

Comparative data from Comparative data from the Framingham heart the Framingham heart studystudy

Concept of Concept of subconcussivesubconcussive trauma trauma

Sports Legacy InstituteSports Legacy Institute

HOW CAN WE PREVENT MORE HOW CAN WE PREVENT MORE STORIES LIKESTORIES LIKEGENE ATKINS?GENE ATKINS?

THANK YOUTHANK YOU