Neuro-ophthalmology of Concussion-LVM-2018 · • TBI proposed as “signature injury” of modern...
Transcript of Neuro-ophthalmology of Concussion-LVM-2018 · • TBI proposed as “signature injury” of modern...
6/4/2018
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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 (speakers bureau)
• King Devick Technologies (scientific advisory
board)
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.
Illinois Dave Duerson Act
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
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
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”
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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
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
“Structure vs. Function”
• Concussion is a metabolic rather than astructural abnormalityo Detectable abnormalities { decreased N-
acetylaspartate (NAA)} on MR spectroscopy
o Abnormal fractional anisotropy (FA) on diffusion tensor imaging (DTI)
Vagnozzi R, et al. Brain 2010Chong CD. 5th Annual NYU Concussion Symposium 2018
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
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Dynamic Response Characteristics of Concussion
• Magnitude of linear acceleration
• Magnitude of rotational acceleration
• Direction of impact
• Duration of event
Hoshizaki B. AAN SCC 2015
Hoshizaki B. AAN SCC 2015
Pathophysiology ofConcussion
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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
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)
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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"
Giza & Hovda J Athl Train 2001
Neurometabolic Cascade (cont.)
• “Reparative
hyperglycolysis”
required in the setting
of reduced cerebral
blood flow (rCBF)
• Disparity between
energy demand and
rCBF → energy crisis
Giza & Hovda J Athl Train 2001
Neurometabolic Cascade (cont.)
• Following short period
of cellular
hypermetabolism, brain
goes into period of
prolonged metabolic
depression
Giza & Hovda J Athl Train 2001
Excess Ca++ →
mitochondrial
dysfunction &
reduction in N-Acetyl
Aspartate (NAA)
Neurometabolic Cascade (cont.)
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Vagnozzi, et al. Neurosurgery 2008
Vagnozzi, et al, Brain 2010
Longhi ,et al. Neurosug 2005
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
The Evils of Excessive Intracellular
Ca++• Ca++ sequestration into
mitochondria → impaired oxidative metabolism / ATP synthesis → energy failure
• Calpain-mediated proteolysis / phosphorylaJon 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
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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)
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
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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)
Lexington Herald Leader 1989
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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
Mlcrotubutes
MicrotubuleSubunilsFallApart
Disintegrating
Microt u bTangled Clumpsol TauProteins
DisintegratingMlcrotubules
Koroshetz W. AAN SCC 2015
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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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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
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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
Slide courtesy of Ann McKee, MD
18 y/o male with CTE
Slide courtesy of Ann McKee, MD
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
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“Two Presentations 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
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
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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
• 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
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• 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 DysfunctionAccommodative 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 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
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
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• 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
• 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])
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K-D Scores Worse after Trauma in Boxers and
MMA Fighters
Neurology 2011;76:1456-1462.
• 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
Combining Vision & Balance Testing for
Sideline Assessment of Concussion
• 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
University of Florida Comparative Analysis of Vision,
Cognition & Balance
Marinides Z, et al. Neurology Clinical Practice 2014
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The Search for SurrogateBiomarkers
• 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
• Retired NFL player: High signal lesions within amygdala and subcortical regions responsible for learning, mood, emotions & behavior
• AD patients: High signal lesions within medial temporal lobe with minimal to no involvement of subcortical regions (cognitive behavior)
Barrio JR, et al. PNAS 2015
• Postmortem analysis of former NFL player with initially positive FDDNP-PET
• Antemortem confirmation of CTE associated with original FDDNP-PET foci
• FDDNP-PET as an indicator of CTE in a live individual???
Omalu B, et al. Neurosurgery 2017
• 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)
Stern RA, 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
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• 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
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
Leong D, et al. J Neuro-ophthalmol 2017
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
Leong D, et al. J Neuro-ophthalmol 2017
Blood-Based Biomarkers for
Concussion
Experimental Candidates
• Ubiquitin Carboxyl-terminal Hydrolase-L1
(UCH-L1)
• Glial Fibrillary Acid Protein (GFAP)
• Spectrin N-terminal fragment (SNTF)
• Aldolace C (ALDOC)
• CSF Astrocytic Phosphoprotein 15 (PEA 15)
• Brain Lipid Binding Protein (BLBP)
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Experimental Candidates
• Ubiquitin Carboxyl-terminal Hydrolase-L1
(UCH-L1)
• Glial Fibrillary Acid Protein (GFAP)
• Spectrin N-terminal fragment (SNTF)
• Aldolace C (ALDOC)
• CSF Astrocytic Phosphoprotein 15 (PEA 15)
• Brain Lipid Binding Protein (BLBP)
Return to PlayBerlin Concussion Consensus
Statement - 2017
“After a brief period of rest during the acute
phase (24-48 hours) after injury, patients can be
encouraged to become gradually and
progressively more active…The exact amount
and duration of rest is not yet well-defined in
the literature and requires further study.”
McAvoy AAN SCC 2015
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
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Risk Factors for Prolonged Recovery
• Prior history of psychiatric illness (anxiety)
• Female gender
• High school age
• Loss of consciousness
• Post-concussion amnesia
• Prior history of ADHD
• Prior history of migraine
Wethe J. 5th Annual NYU Concussion Symposium 2018
• 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
Return to Learn 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
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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 (?)
– Persistent symptoms after 4 weeks (pre-teen)
– Persistent symptoms after 2 weeks
(adolescent/adult)
Master C. 5th Annual NYU Concussion Symposium 2018
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