neuro-ophthalmology of concussion-lvm-2018 meeting/dr. messner... · pulled from competition when...

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Leonard V. Messner, OD, FAAO

Professor & Vice President for Patient Care Services – Illinois college of Optometry

Executive Director – Illinois Eye Institute

The Neuro-ophthalmology of

Concussion:

Clinical Spectrum and

Complications

Financial Disclosure

• ISPB research grant – VICTORS study

• AAO FDR research support – SENSA

study

• Carl Zeiss Meditec• King Devick Technologies

Key Points

• Frontal vulnerability & metabolic dysfunction

of white mater tracts

• Signs /symptoms of concussion

• Complications

• Visual dysfunction and testing protocols

• Search for biomarkers

• Return to play/learn

“During the past 7 years the practice

has been too prevalent of allowing

players to continue playing after a

concussion. Again this year this is

true. Sports demanding personal

contact should be avoided after a

concussion.”

1937 – Proceedings of the 17th Annual Football

Coaches Association

“The Concussion Epidemic”

• Increased NFL interest inconcussion / chronic traumatic encephalopathy

• School sports/youthconcussions drawingnational attention

• Historical lack of evidence-based clinical protocols

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State concussion bill closer to realityHouse panel agrees on plan to protect kids

L'l See More

You th sports leagues

have grown into a $5

billion industry wit h

virtual ly no regulaton.

Kids suffer injuries at an

alarming rate, and some

organizers are abusing

both children and league

funds. In t he f ive-day

series "Utt leleagues, big

costs," The Dispat ch

explores where youth

sports have taken wrong

turns in recent years.

By Jim Siegel

The Columbus Dispatch - Wednesday June 13, 2012 7:59 AM

Abill designed to educate coaches and ensure that young Ohio athletes are

pulled from competition when they show concussion-like symptoms passed

a House committee yesterday after 1 0 revisions and several

months of debate.

There has been general agreement that more needs to be done to protect

youths from the dangers of concussions, but legislators have struggled to

balance issues regarding liability and who is responsible for allowing a

player to return to action. Some members still expressed reservations

yesterday.

9 7

VIDEO

Weather hard to c./1through thJs

fog

POLmcs SPORTS BUSINESS SCIENCE/TECH LOCAL

Super Bowl Confetti Made Entirely From Shredded

Concussion StudiesPHOTO FINISH Sports·NFL Football • Super Bowi • ISSUE 50•04 · Feb 2, 2014

pathology slide courtesy of Ann McKee, MD

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Concussion

• Concussion is a form of mild traumatic brain injury (TBI) owing to structural, metabolic and functional changes involving white mater tracts of the central nervous system in the absence of macroscopic findings

Giza CC, et al. Neurology 2013

Concussion (cont.)

• Functional rather than structural injury

• Axonal predilection – Diffuse axonal injury

• Loss of consciousness in less than 10%

Johnson VE, et al. Exp Neurol 2012

Epidemiology

• 300,000 to 4 million per year

• Nearly 85% of concussions may go undiagnosed

• Multiple studies suggest rate on rise

• Boys’ High school football followed by girls' soccer

• Girls have a higher rate of concussion

CDC Report 2007JAMA 2010

High School Concussions (per 100,000

• Football: Between 60 and 76

• Girl's soccer: Between 33 and 35

• Boys' lacrosse: Between 30 and 46• Girls' lacrosse: Between 20 and 31• Boys' soccer: Between 17 and 19• Boys' wrestling: Between 17 and 23• Girls' basketball: Between 16 and 18• Softball: Between 11 and 16• Boys' basketball: Between 11 and 21• Girls' field hockey: Between 10 and 24• Cheerleading: 11• Girls' volleyball: Between 5 and 8• Boys' baseball: Between 4 and 6

Halstead M, et al. Pediatrics 2010

Meehan WP. Et al. Am J Sports Med 2011

Incidence of Concussion During Practice & Games in Youth, High School and Collegiate

American Football Players

• Prospective analysis of self-reported concussions 2012-2013

• High school & college concussion incidence:

o Practice: 58%

o Game: 42%

Dompier TP, et al. JAMA Pediatrics 2015

Concussion in Youth Sports

• Children are more susceptible to head injury than adults and require a longerperiod of recovery than adults

Kirkwood MJ, et al. Pediatrics 2006

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Age of First Exposure to Football and Later-Life Cognitive Impairment in Former NFL Players

(DETECT study)

• Analysis of cognitive function among 42 former NFL players based-on age of first exposure (AFE) to tackle football

o AFE <12 years associated with greater later-life cognitive impairment vs. AFE >12 years

o Repetitive head trauma during critical period of brain development may lead to later-life cognitive impairment

Stamm JM, et al. Neurology 2015

Age of First Exposure to American Football

and Long-term Neuropsychiatric and

Cognitive Outcomes

• Analysis of behavior, mood and cognition among 214 former amateur and professional football players based-on age of first exposure (AFE) to tackle football

o AFE <12 years associated with 2X greater odds risk of abnormal performance on all evaluative measures

o Most noteworthy were abnormal outcomes related to neuropsychiatric and executive function performance

Alosco ML, et al. Translational Psychiatry 2017

TBI in Elderly & Increased Risk of

Dementia

• Longitudinal study of

TBI in older adults

• TBI associated with

increased risk of

dementia at earlier age

• Further increased risk

with APOE e4 allele

Luukinen et al. Eur J Neurology 2005

Long-Term Sequelae of TBI & Role of

“Cognitive Reserve”

Bigler & Stern Handb Clin Neurology 2015

WWI

• Advent of trench warefare and continuous shelling

• 10% overall fatalities due to shrapnel/indirect trauma

• Term “shell shock” used to describe psychiatric findings Battle of Ypres - 1917

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Major Frederick Mott• British neuropathologist

who proposed studying

brains of deceased WWI

soldiers

• Questioned link between

“shell shock” and

organic brain disease

• In 1917, British Army

bans further use of

term “shell shock”

WWII

• Finnish psychiatrist Dr. Harry Federley

adopts term LMF (Lacks Moral Fibre) for

combat-related neuroses

• German psychiatrist Dr. Rudolph

Brickenstein: “…that if a soldier did break

down and could not continue fighting, it

was a leadership problem, not one for

medical personnel or psychiatrists.

Breakdown (he said) usually took the form

of unwillingness to fight or cowardice.”

Combat-Related TBI

• Most deployed soldiers report one or moreblast injuries

• TBI proposed as “signature injury” of modern combat

• Limited data on prevalence

• Potential link to post-traumatic stressdisorder (PTSD)

mTBI in Soldiers Returning from Iraq

• Survey of 2525 Army soldiers 3-4 months after return from deployment

– 4.9% reported injury with LOC

• 43.9% with PTSD

– 10.3% injury with altered mental status

• 27.3% with PTSD

Hoge CW et al. N Engl J Med 2008

PTSD & Post-TraumaticHeadache

• Retrospective analysis of 270 soldiers withpost-traumatic headache

• 105 (39%) met criteria for PTSD

Rosenthal JF, et al. Headache 2013

Challenges in Recognition and

Management of Concussion

1. Wide variety of symptoms or delayed onset –easily “missed” by coaches, medical staff

2. Denial of symptoms (“I feel fine”)

– Metabolically-mediated euphoria (McKee 2010)

3. Many diagnostic/management protocols not evidence-based

4. Traditional neurological / radiological studies (CT, MRI, EEG) normal with mTBI

– Metabolic vs. structural changes

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“Structure vs. Function”

• Concussion is a metabolic rather than astructural abnormalityo Detectable abnormalities { decreased N-

acetylaspartate (NAA)} on MR spectroscopy

Vagnozzi R, et al. Brain 2010

Biomechanics of Concussion…”Brain in a Box”

• Direct injury to brain at point ofcontact (coup)

• Injury opposite the point of impact (contrecoup)

• Rotational forces withshearing/stretching of axons

• “wash-over” effect (blast injuries)

Maruta J, et al. Ann NY Acad Sci 2010

Linear Acceleration

Rotational Acceleration

Dynamic Response Characteristics of Concussion

• Magnitude of linear acceleration

• Magnitude of rotational acceleration

• Direction of impact

• Duration of event

Hoshizaki B. AAN SCC 2015

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Hoshizaki B. AAN SCC 2015

Pathophysiology ofConcussion

from “Head Games: The Film” 2012

“Frontal Vulnerability”

AnteriorCorona Radiata

(Dorso-lateral Prefrontal Cortex)

Corpus

Callosum (genu)

Diffuse Axonal Injury (DAI)

• Rapid axonal stretching

• Axoplasmic stasis with focal axonal swelling (“axonal varicosities” / “axonal bulbs”)

• Ionic imbalance (Ca++ and K+)

• Accumulation of candidate proteins – amyloid precursor protein (APP)

• Microtubular disarrangement

• Dispersal of tau

Johnson VE, et al. Exp Neurol 2012

Neuropathology of Concussion

• Biochemical changes

• Structural changes

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Normal Neuronal Transmission

• Glutamate is the

primary excitatory

amino acid /

neurostransmitter

• Release and binding of

glutamate to NMDA

receptors → opening of

Ca++ channels →

increased intracellular

Ca++

(NMDA)

Normal Neuronal Transmission (cont.)

• Excess glutamate is

taken-up into glia

(astrocytes)

• 16:1 intracellular /

extracellular glutamte

glutamate

Concussion (Diffuse Axonal Injury)

• Reverse glutamate transport with excessive accumulation at synapse

• Repetitive / excessive depolarization & ionic imbalance

– Increased intracellular Ca++

– Increased extracellular K+

Giza & Hovda J Athl Train 2001

glutamate

Neurometabolic Cascade

• Increased:– Intracellular Ca++

– Extracellular K+

• Attempt to restore neuronal membrane potential via NA+/K+ pump

• Increased ATP demand triggering jump in glucose metabolism – “reparative hyperglycolysis"


Neurometabolic Cascade (cont.)

• “Reparative

hyperglycolysis”

required in the setting

of reduced cerebral

blood flow (rCBF)

• Disparity between

energy demand and

rCBF → energy crisis


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• Following short period

of cellular

hypermetabolism, brain

goes into period of

prolonged metabolic

depression


Excess Ca++ →

mitochondrial

dysfunction &

reduction in N-Acetyl Aspartate (NAA)


Vagnozzi, et al. Neurosurgery2008

Vagnozzi, et al, Brain 2010

Longhi ,et al. Neurosug2005

Energy NAA ATP

6 hrs

15 hrs

35%

46%

57%

45%

1H-MRS Decrease in NAA / ATP s/p Concussion

Cerebral NAA levels are decreased for

weeks after concussion

Energy

Neuronal

function

With (1H-MRS)NAA cerebral levels were decreased for

weeks after concussion

AFTER

the concussion-related clinical symptoms were resolved

Normalization to control values occurred

30 days post injury

Vagnozzi et al, Neurosurg 2008

Window of Vulnerability

Window of Vulnerability in Animal Models

• Mouse model of control vs single vs. multiple closed-head injury (CHI)

• 2nd CHI within 3-5 days of initial impact showed significant cognitive impairment vs control/single CHI

• Greater axonal injury if 2nd CHI within 3 days of initial impact

• 2nd CHI after 7 days → no difference in cognitive function vs. single CHI

Longhi et al. Neurosurgery 2005

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The Evils of Excessive Intracellular

Ca++• Ca++ sequestration into

mitochondria → impaired oxidative metabolism / ATP synthesis → energy failure

• Calpain-mediated proteolysis / phosphorylaIon of tau → neurofilament collapse & breakdown of microtubules

• Perivascular accumulation of neurofibrillary tau tangles (NFTTs)

Concussion Signs & Symptoms

• Physical: Headache, vision changes, dizziness

• Cognitive: memory impairment,concentration

• Emotional: irritability, sadness, depression

• Sleep disorders: hypersomnia, hyposomnia

Post-Traumatic Headache / Post-

Traumatic Migraine

Biochemical Changes in the Brain with TBI &

Migraine

Increase in:

• Release of excitatory amino

acids (glutamate)

• Cellular depolarization

• Intracellular Ca++

• Extracellular K+

• Serotonin (5-HT)

• Endogenous opioids

Decrease in:

• Glucose metabolism

• ATP production

• rCBF

• Mg++

Packard & Ham Headache 1997

Complications of Concussion

• Second-impact syndrome (SIS)

• Postconcussion syndrome (PCS)

• Chronic traumatic encephalopathy (CTE)

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Second-Impact Syndrome

• Sustaining a second concussion before“recovery” from first concussion

• Majority in pediatric/adolescent populations (< 20 yrs.)

• Loss of cerebral autoregulation with enhancement of cerebrovascular congestion

– Diffuse cerebral edema / transtentorial herniation

– 90% mortality (within minutes to days!)

Cantu RC, et al. Phys Sportsmed 1995Weinstein E, et al. J Neurosurg Pediatr 2013

Postconcussion Syndrome

• 2-5% of all concussions

• Increased risk with LOC & PTA

• > 1 month(s) duration of three or more of the thefollowing:– Fatigue– Disordered sleep– Irritability / aggressiveness– Anxiety / depression– Personality changes / apathy– Impaired attention / memory

– Impaired eye tracking

Diagnostic and Statistical Manual of Mental Disorders. Fourth EditionHeitger MH et al. Brain 2009

Crosby progressing slowly; return not setTuesday, January 25, 2011

By Dave Molinari, Pittsburgh Post-Gazette

Vs. Capitals January 1, 2011

Vs. Lightning January 6, 2011

Chronic Traumatic Encephalopathy

(CTE)

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Lexington Herald Leader 1989

Historical Perspective of CTE

• Martland – “Punch drunk”

– JAMA 1928

• Millspaugh – “Dementia pugilistica”

– US Naval Medical Bulletin 1937

• Critchley – “Medical aspects of boxing particularly from a neurological standpoint”

– Psychological Bulletin 1957

• Corsellis – neuropathology of CTE among boxers

– Psychological Medicine 1973

Mike Webster (1952-2002)

• 16 years in NFL

• Significant history of depression and memory loss prior to death

• Died in 2002 (age 50)

• Autopsy of brain by BennetOmalu MD (Pgh Medical Examiner)

• Pathology slides reviewed by Steven DeKorsky MD (Univ. Pittsburgh) with diagnosis of CTE

• Controversy as to relationship with NFL career / repetitive head trauma

Neuropathology of CTE

• Atrophy of cerebral hemispheres, temporal lobe, mammillary bodies & brainstem

• Ventricular dilatation

• Fenestration of septum pelucium

• Marked accumulation of tau-

immunoreactive astrocytes

McKee AC, et al. J Neuropathol Exp Neurol 2009

Pathophysiology of CTE

• Repetitive head trauma

• Up-regulation of amyloid precurserproteins (APP)

• Aβ synthesis

• Phosphorylation of Tau

• Microtubular disarrangement

• Perivascular liberation of Tau involving base of cortical sulci

DeKorskey S. AAN SCC 2015

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Mlcrotubutes

MicrotubuleSubunilsFallApart

Disintegrating

Microt u bTangled Clumpsol TauProteins

DisintegratingMlcrotubules

Koroshetz W. AAN SCC 2015

McKee AC, et al. J Neuropathol Exp Neurol 2009

APOE4 Allele

• APOE facilitates normal sequestration of cholesterol and Aβ

• APOE4 allele results in faulty accumulation of Aβ and hyperlipidemia

• 40-50% prevalence of APOE4 with AD (vs. 14% normal population)

• Allele frequency is 2X as high in African American as in Caucasian populations

DeKorskey S. AAN SCC 2015

APOE 4 & CTE

• Increased chronic neurologic deficits in boxers

with APOE4 (Jordan BD, et al. JAMA 1997)

• APOE4 identified within early cohort of

biopsy-proven CTE (Omalu BI, et al.

Neurosurgery 2011)

Prominent NFL Players with CTE

• Mike Webster

• Andre Waters

• Junior Seau

• Dave Duerson

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100

Dave DuersonMr. Duerson’s Clinical History

• Long-standing complaints of headaches since NFL and onward.

• Over the ~5 years prior to death, he had worsening short-term memory difficulties, as well as problems with language and “vision”

• Increasingly out of control:– Short fuse– Hot tempered– Physically abusive– Verbally abusive

Comparison with other former NFL players

Slide courtesy of Ann McKee, MD

• Co-Captain of 2010Penn Football Team

• Began playing football at 9years old

• Committed suicide April 26, 2010, at the age of 21

• No history of concussion• No history of mental illness• Mentioned doing poorly in

two classes to his parents the day before hanging himself in his off-campus apartment

Owen Thomas


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18 y/o male with CTE


Stage 1: headache and loss of attention and

concentration

Stage 2: depression, explosivity

and short-term memory loss

Stage 3: loss of executive

dysfunction and cognitiveimpairment

Stage 4: dementia, word-finding

difficulty and aggression

McKee AC, et al. Brain 2012

Clinical “Spectrum” of CTE

• Boston University study of 36 male subjects with histopathologicallydocumented CTE

• Retrospective interviews with next-of-kin

– 61% Behavioral/mood disturbances (younger

• age)

– 31% Cognitive impairment/dementia (olderage)

Stern RA, et al. Neurology 2013

New Sideline Tests

Slide courtesy of Laura Balcer, MD

Concussion Tests: 2 Types• Testing for diagnosis:

King-Devick (K-D) test, Standardized Assessment of Concussion (SAC),SCAT5, MACE, Concussion Recognition Tool (CRT5)

• Testing for management: ImPACT, other computerized testing

Initial Assessment: SCAT3

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SCAT 3 for Sideline Testing

• System checklist• Testing for cognitive function = SAC• Testing for balance = BESS or timed

tandem gait

• Does not include testing for visual/visual-motor function!

SCAT 5

• Enhancement of SCAT 3:

– Expansion of word recall from 5 to 10 words (minimize “ceiling effect” of SCAT 3)

– No less than 10 min. administration requirement (by physician or appropriately trained healthcare personnel)

– Requisite testing at normal heart rate

– Rapid Neurological Screen (cervical exam, reading ability, balance/gait, visual tracking & finger-nose coordination)

Echemendia RJ et al. Br J Sports Med 2017

Anatomy of Concussion

• Cerebral cortex, brainstem and cerebellum

• All pathways involved with concussion

• All pathways involved with vision/visual-motor function

• Photophobia

• Accommodative dysfunction

• Vergence dysfunction

– Convergence insufficiency

• Versional dysfunction

– Saccadic dysfunction

Vision & Visual-motor Dysfunction in

Concussion

Binocular

Vision

Disorders

Photophobia

• Light sensitivity during sub-acute phase (7-19 days) with recovery x 6 months

• Chronic / persistent photophobia with post concussion syndrome

• Disturbance of cortico-thalamic pathways with meningeal irritation (post-traumatic migraine?)

• Value of light-filtering lenses?

Vos PE, et al. Eur J Neurol 2002Bohnen N, et al. J Neurol 1991Digre KB, et al. J Neuroophthalmol 2012

• Two-fold (0.3 log units) increase in binocular contrast sensitivity (Pelli-Robson letter CS chart) for TBI patients wearing Corning photochromic filters (CPF) as compared to no filters and healthy control subjects

• 39% improvement in reading rate among TBI/CPF group as compared to no filters and healthy controls

Jackowski MM, et al. Neurorehabilitation 1996

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• Case study of two

adolescents with post-

concussion syndrome

• Improvement of

photosensitivity &

headaches with computer

gaming glassesLynch JM, et al. J Athl Train 2015

Thin-Film Optical Notch Filter Spectacle

Coatings for the Treatment of Migraine and

Photophobia

• Migraine-related photophobia linked to stimulation of intrinsically photosensitive retinal ganglion cells (IPRGCs)

• Bi-phasic spectral sensitivity (480nm & 620nm)

Hoggan RN, et al. J Clin Neurosciences 2016

• Accommodative disorders

• Convergence insufficiency

• Saccadic dysfunction

Binocular Vision Disorders

• Cross-sectional study of 100 subjects post

concussion (mean age = 14.5 yrs)

• 69% with one or more binocular vision problems

– Accommodative disorders (51%)

– Convergence insufficiency (49%)

– Saccadic dysfunction (29%)

Master CL, et al. Clin Pediatr 2016

Highest prevalence

If within 1 month

Of concussion

• Accommodative amplitudes

• Accommodative facility

Accommodative DysfunctionAccomodative Amplitude Testing:

Donders Push-Up Method

• 20/20 letter stimulus

• Target moved closer to

subject (1-2cm/s) until

sustained blur reported

• Endpoint conversion to

dioptric value

• Test performed OD, OS

& OU

Photo courtesy of Valarie Kattouf, OD

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Accommodative Dysfunction with TBI

• Alvarez et al. 2012: 24%

• Ciuffreda et al. 2007: 41%

• Stelmack et al. 2009: 47%

• General population: 6-9%

Alvarez TL, et al. Optom Vis Sci 2013Ciuffreda KJ, et al. Optometry 2007Stelmack JA, et al. Optometry 2009Porcar E, et al. Optom Vis Sci 1997Hokoda SC, et al. J Am Optom Assoc 1985

• Convergence Insufficiency

Vergence Disorders

• Convergence insufficiency is the inability to maintain binocular function (keeping the two eyes working together) while working at a near distance

• Dysfunction of midbrain reticular formation

• Typically, one eye will turn outward (intermittent exotropia) when focusing on a word or object at near

• Near point of convergence (NPC) > 10 cm from nose is considered suspicious for convergence insufficiency

Convergence Insufficiency

American Association for Pediatric Ophthalmology & Strabismus - 2015

Testing for Convergence Insufficiency:

Evaluation of the Near Point of

Convergence (NPC)• 20/30 visual target

brought in toward patient’s nose

• Objective observance of outward (exo) deviation of one eye

• Subjective report of diplopia

• Endpoint recorded in target distance from nose (cm)

Photo courtesy of Valarie Kattouf, OD

• Diplopia while reading

• Headaches/eye strain while reading

• Avoidance of near-point tasks (computer

work, reading, etc.)

• Blurred vision while reading

• Closing one eye to relieve near-point

symptoms

Symptoms of Convergence

InsufficiencyConvergence Insufficiency with TBI

• Alvarez et al. 2012: 23%

• Ciuffreda et al. 2007: 42%

• Brahm et al. 2009: 46%

• General population: 4-6%

Alvarez TL, et al. Optom Vis Sci 2013Ciuffreda KJ, et al. Optometry 2007Brahm KD, et al. Optom Vis Sci 2009

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Effect of Sub-concussive Impacts from Soccer on NPC

• Soccer balls projected from JUGS machine

• 10 headers @ 25 mph over 10 minutes (ave. 23 g)

• Comparison of baseline vs. post-header

• Recession in post-header NPC

Tierney RT, et al. AAN Sports Concussion Conference 2014

Concussion Recovery as a Function of NPC

• Prospective analysis of concussion symptoms and NPC among 28 collegiate athletes with sports-related concussion

• Shortened (improved) NPC with resolution of symptoms

Figler R, et al. AAN Sports Concussion Conference 2014

• Analysis of 78 athletes s/p sports-related concussion (ave. 6 days)

• Assessment of NPC, neurocognitive function (ImPACT) & symptoms score (PCSS)

• 42% of concussed athletes had CI

• Athletes with CI had worse neurocognitive impairment and higher symptom scores than did those with normal NPC

Pearce KL, et al. Am J Sports Med 2015

• Saccades

• Pursuits

Versional Dysfunction

Brain Areas Responsible for Saccadic

Function

• Frontal eye fields

• Dorsolateral prefrontal

cortex

• Supplementary motor

area

• Posterior parietal cortex

• Parietal eye fields

• Superior colliculus

Fukushima K, et al. Front Syst Neurosci 2013

DeSouza JFX, et al. J Neurophysiol 2003

Pierrot-Deseilligny C, et al. Curr Opin Neurol 2004

Types of Saccades

• Voluntary - FEF

• Predictive - DLPFC, FEF

• Memory - DLPFC, FEF

• Reflex - Parietal

• Antisaccade - DLPFC, FEF-direct eyes away from a target

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Challenges to Brain

• Saccades must be fast (300-500 deg/sec, up to

900-100 deg/sec) and brief (100-200 msec)

• Saccades must be accurate

• Saccade-generating “burst neurons” in the

brainstem must discharge vigorously

• Prone to malfunction in concussion!

Slide courtesy of Janet Rucker, MD

• Prospective analysis of 36 PCS subjects vs. healthy controls

• PCS associated with worsening of anti-saccades, self-paced saccades, memory-guided sequences & smooth pursuits

• Eye movement dysfunction showed higher

correlation with symptom load as compared to neuro-psych testing

• Biological substrate for concussion-related

symptoms

Rapid Number Naming

(King Devick Test)

Requires intact saccades

Total time to read three test cards (< 1 minute)

Baseline compared to post-event retest

High levels of test-retest reliability were observed (intraclass correlation

coefficient 0.97 [95% confidence interval 0.90-1.0])

Test Card 1 Test Card 2 Test Card 3

Evaluation of a Diagnostic Test Marker

• Phase 1 - The test makes sense as a marker

• Phase 2 - Can distinguish obvious cases from controls (high risk athletes)

• Phase 3 - can distinguish less typical instances (other athletes)

• Phase 4 - large scale studies

• Phase 5 - used in clinical trials (e.g. OCT & low contrast acuity in MS)

JAMA 259:1699;1988

Evaluation of a Diagnostic Test Marker

• Phase 1 - The test makes sense as a marker

• Phase 2 - Can distinguish obvious cases from controls (high risk athletes)

• Phase 3 - can distinguish less typical instances (other athletes)

• Phase 4 - large scale studies

• Phase 5 - used in clinical trials (e.g. OCT & low contrast acuity in MS)

JAMA 259:1699;1988

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• Postfight K-D scores (n = 39 participants) were significantly higher (worse) for those with head trauma during the match (59.1 ± 7.4 vs 41.0 ± 6.7 seconds, p < 0.0001, Wilcoxon rank sum test)

• Those with loss of consciousness showed the greatest worsening from prefight to postfight. Worse postfight K-D scores (r(s) = -0.79, p = 0.0001) and greater worsening of scores (r(s) = 0.90, p < 0.0001) correlated well with postfight MACE scores

• Worsening of K-D scores by ≥5 seconds was a distinguishing characteristic noted only among participants with head trauma

• High levels of test-retest reliability were observed (intraclasscorrelation coefficient 0.97 [95% confidence interval 0.90-1.0])

K-D Scores Worse after Trauma in Boxers and

MMA Fighters

Neurology 2011;76:1456-1462.

Pre-season testing (219 athletes)

Post-season

King-Devick Test:

Penn Collegiate Athlete Study

0

Group 1: Concussion during season (n=13)

Group 2: No concussion (n=206)

Testing on sidelines at time of concussion (n=10):

All except one had worse scores vs. baseline by an average of 5.9 seconds (range 0 to 28 seconds)

J Neurol Sci 2011;309:34-39.

K-D Scores Worsen from Baseline after

Concussion… but Not Exercise!

Galetta KM et al. J Neurol Sci 2011.

K-D

sc

ore

(s

ec

)

Basketball Scrimmage

Concussion

KD in Amateur Rugby

• Premier Rugby Team followed for a season

• Post-match KD testing of all players

• 22 concussions overall

• 5 were diagnosed at the time of the event

• Players were routinely tested post-match- 17

unrecognized concussions were diagnosed this way (77%)

• Undetected concussion 3 to 4 times more than detected!

J Neurol Sci 2013

Combining Vision & Balance Testing for

Sideline Assessment of Concussion

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• University of Florida study of K-D test, SAC &

BESS in the sideline assessment of concussion

• N=217 athletes (men’s football, women’s

soccer, and women’s lacrosse with 30

concussions

Marinides Z, et al. Neurology Clin Prac 2014

Results

• 52% of concussions detected with SAC

• 79% of concussion detected with K-D test

• 80% of concussion detected with BESS

• 95% of concussions detected with

combination of K-D & BESS


combination of K-D, SAC & BESS


University of Florida Comparative Analysis of Vision,

Cognition & Balance

Marinides Z, et al. Neurology Clinical Practice 2014

Results

• 52% of concussions detected with SAC

• 79% of concussion detected with K-D test

• 80% of concussion detected with BESS


combination of K-D & BESS


What About Youth Sports?

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• Study of sideline testing for concussion among

youth (n=243; mean age 11 ± 3 yrs.)) and

collegiate (n=89; mean age 20 ± 1 yr.)

• Individual and combined analysis of K-D test,

SAC and timed tandem gait for suspected

concussion (n=12)

Galetta KM. et al. J Neuroophthalmol 2015

Results

• 68% probability of identifying concussed athletes by SAC

• 87% probability of identifying concussed athletes by timed tandem gait

• 92% probability of identifying concussed athletes by K-D test

• 98% probability of identifying concussed athletes by combination of K-D & timed tandem gait

Galetta KM. et al. J Neuroophthalmol 2015

NY Area Youth Hockey League:

K-D is a Useful Test in Kids

Galetta KM, et al., J Neuro-Ophthalmol 2015

• N=1,419 athletes from 15 published studies

• De-identified participant-specific data for pooled analyses; meta-analyses using fixed-effects model techniques

• Pooled sensitivity 86% (96/112 concussed had worsening), specificity 90% (181/202 controls had no worsening of K-D)

• Relative risk of concussion if any worsening of K-D score from baseline = 4.92 (5x risk!)

Galetta KM, et al. Future Medicine-Concussion 2015

The Search for SurrogateBiomarkers

• PET scans of retired NFL players reveals FDDNP signals in areas of presumed Tau deposition (Small GW, et al. Am J Geriatr

Psychiatry 2013)

• FDDNP PET scans on 5 retired NFL players with

history of mood & cognitive dysfunction

• Comparison of PET signals with age-matched

norms

• FDDNP signals higher in NFL players

(subcortical regions and amygdala)

Small GW, et al. Am J Geritr Psychiatry 2013

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FDDNP Binding (NFL v. Control)

Small GW, et al. Am J Geriatr Psychiatry 2013

Comparison OF FDDNP – PET Findings

in retired NFL Players vs. AD

NFL Players (n = 14)

• High signal lesions within

amygdala and subcortical

regions responsible for

learning, mood, emotions &

behavior

AD (n = 24)

• High signal lesions within

medial temporal lobe with

minimal to no involvement

of subcortical regions

(cognitive behavior)Barrio JR, et al. PNAS 2015

• Study of 78 former NFL players & 16 health age-matched controls

• The NFL group had higher exosomal tau than the control group (p <

0.0001)

• Exosomal tau discriminated between the groups, with 82% sensitivity,

100% specificity, 100% positive predictive value, and 53% negative

predictive value

• Within the NFL group, higher exosomal tau was associated with worse

performance on tests of memory (p = 0.0126) and psychomotor speed (p =

0.0093)

SternRA, et al. J Alzheimer’s Disease 2016

The Search for Ocular Surrogate

Biomarkers

• Retinal deposition of hyperphosphorylated tau (McKee A. personal communication 2012)

• Potential for OCT and other visual tests as surrogate biomarkers of CTE

• Multi-center study of 46 collision sport athletes as

compared to age-matched healthy controls

– Illinois Eye Institute/Illinois College of Optometry

– NYU Langone Medical Center/Department of Neurology

• Comparison of OCT, low contrast acuity, rapid

number naming & quality of life among

boxers/retired NFL players vs. age-matched controls

Leong D, et al. J Neuro-ophthalmol 2017

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25

Results

• N=150 (46 Athletes, 104 Controls)

Boxing (n=14)

Football (n=29)

Ice Hockey (n=3)

Controls

(n=104, 208 eyes)

Athletes

(n=46, 92 eyes)

Age, years, mean (SD) 43.9 ± 1.3 46.1 ± 12.2

Male (%) 61.5 97.8

Race (%)

Caucasian 66.4 63.0

African Amer. 28.9 37.0


Results: Visual Pathway Structure

Controls

(n=104,

208 eyes)

Athletes

Boxing

Athletes

(n=14, 28

eyes)

Football

Athletes

(n= 29, 58

eyes)

Average RNFL thickness,

µm, mean ± SD 94.3 ± 0.983.5 ± 2.8

p < 0.001 93.0 ± 1.9

Average GCC thickness,

µm, mean ± SD81.6 ± 0.5

76.7 ± 2.1

p = 0.0281.2 ± 1.2


Visual Function: Low Contrast Acuity

Controls

(n=104,

208 eyes)

Athletes

Boxing

Athletes

(n=14,

28 eyes)

Football

Athletes

(n= 29,

58 eyes)

Binocular 2.5%,mean (letters/70)

38.6 ± 0.531.7 ± 2.1

p = 0.00236.6 ± 1.0

Binocular 1.25%, mean (letters/70)

29.8 ± 0.6 26.4 ± 2.0 29.8 ± 0.8

Monocular 2.5%, mean (letters/70)

30.8 ± 0.624.4 ± 2.0

p = 0.003 29.2 ± 1.1

Monocular 1.25%, mean (letters/70)

21.2 ± 0.816.3 ± 2.0

p = 0.0321.1 ± 1.2


Visual Function: K-D and Quality of Life

Controls

(n=104,

208 eyes)

Athletes

Boxing

Athletes

(n=14,

28 eyes)

Football

Athletes

(n= 29,

58 eyes)

NEI-VFQ-25, mean (score/100)

93.3 ± 0.6 91.5 ± 1.689.0 ± 1.9

p = 0.04

10-Item Supplement, mean (score/100)

93.1 ± 0.785.5 ± 3.4

p = 0.031

84.9 ± 2.3

p = 0.001

King-Devick Test, sec, mean ± SD

40.0 ± 0.6 42.4 ± 2.137.5 ± 0.9

p = 0.02


VICTORS Conclusions

• RNFL, GCC and visual loss are present among contact sport athletes,

particularly boxers

• Reductions in visual function and quality of life among athlete groups

• Similar to patterns observed in MS, Alzheimer’s and Parkinson’s diseases

• Visual dysfunction and structural changes associated with TBI exposure can

be detected in vivo

• Unique opportunity to identify at-risk athletes for neuroprotection trials


Blood-Based Biomarkers for

Concussion

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Experimental Candidates

• Spectrin N-terminal fragment (SNTF)

• Glial Fibrillary Acid Protein (GFAP)

• Aldolace C (ALDOC)

• CSF Astrocytic Phosphoprotein 15 (PEA 15)

• Brain Lipid Binding Protein (BLBP)

Challenges with Blood-Based

Biomarkers

• Insufficient specificity for concussion (may be

present in health brains)

• Variable sensitivity among current candidate

markers (lack of discriminatory ability to

diagnose mild TBI)

• Lack of acute presence after injury

• Lack of standardization for testing protocols

Wanner IB SCC 2015

• Elevated plasma tau 6 hours s/p concussion = prolonged return to play

• Saliva miRNA associated with prolonged

concussion recovery in children

Hicks S, et al. Pediatric Academic Societies Meeting 2017

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27

What about return to play?

McAvoy AAN SCC 2015

Risks of Premature Return to Play

• Risk of second impact syndrome• Repeat impact before normalization

of brain function (“window of vulnerability”)

• Chronic headaches• Depression• Long-term cognitive deficits• Post-traumatic encephalopathy

(CTE)

• 2013 NCAA survey of 789 athletic trainers

and 111 team physicians (530 institutions)

• 64.4% pressure from athletes

• 53.7% pressure from coaches

• Greater pressure if female clinicians or if

under supervisory purview of athletic

department

Graduated Return to Play Protocol

AAN Clinical Practice Reference Sheet for Clinicians, 2011.

Rehabilitation Stage Functional Exercise at Each

Stage of Rehabilitation

(1) No activity Complete physical, cognitive rest

(2) Light aerobic exercise Walking, swimming, stationary bike

(3) Sport-specific exercise Running drills in soccer, skating drills in hockey, etc.

(4) Noncontact drills More complex training drills, may start resistance training

(5) Full-contact practice With medical clearance, participate in normal training activities

(6) Return to play Normal game play

Return to Learn

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Return to Learn

• Return to learn must precede return to play

• Return to school when symptoms are tolerable for 30-45 min (usually within 2-4 days of concussion)

• Schools/teacher should make adjustments to incorporate 5-10 min. of rest/hour

Halstead ME, et al. Pediatrics 2013

• 88 individuals (age 11-22 years) with ED presentation for

acute concussion

• Initial neurocognitive and balance assessments with daily

record of post-concussive symptoms

• Randomized to strict rest (5 days) vs. 1-2 days rest followed by

step-wise return to activity

• No difference between groups re. NC/balance outcomes

• Increased symptoms among strict rest group

Thomas DG, et al. Pediatrics 2015

Leddy JJ, et al. Physical Medicine and Rehab Clinics 2016

Role of Vision Therapy in Concussion

Management

• Scientific basis for therapeutic value

• Addition to traditional vestibular and cognitive

rehab

• For who and when and how to intervene (?)

Key Points

• Frontal vulnerability & metabolic dysfunction

of white mater tracts

• Signs /symptoms of concussion

• Complications

• Visual dysfunction and testing protocols

• Search for biomarkers

• Return to play/learn

There’s No Such Thing as a

Tough Brain

NFL Hall of Fame-Class of 1997Mike Haynes, far left Mike Webster (1952-2002); far right

neuro-ophthalmology of concussion-lvm-2018 meeting/dr. messner... · pulled from competition when...

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