NANOS 2018
Using the visual system to study neurologic
diseases
GREGORY P. VAN STAVERN, M.D.
PROFESSOR, DEPARTMENT OF OPHTHALMOLOGY AND VISUAL SCIENCES AND NEUROLOGY
DIRECTOR, VISUAL ELECTROPHYSIOLOGY SERVICES
WASHINGTON UNIVERSITY IN ST. LOUIS
Disclosures
I have no relevant financial disclosures
Goals
Rationale for using visual system to
study neurodegenerative diseases
Reviewing available tools
Discussing applications in several
neurodegenerative diseases
The Cookie Thief Picture is highly sensitive to
the presence of simultagnosia
1. True
2. False
Evidence of Alzheimer’s disease can be detected
before the onset of cognitive dysfunction
1. True
2. False
Model of an Ideal System
Pervasive
Accessible
Tools to assess structure-function
relationships
Assessment methods minimally
invasive and inexpensive
Visual system
Large amount of brain devoted to vision
Functional changes may not occur in parallel with structural changes-need a system where both can be quantified
Retinotopic organization
Fewer synapses and less modulation than other systems
Redundancyneuroplasticity
Tools readily available to ophthalmologists and neurologists
Disability and Vision
Visual dysfunction contributes significantly to reduced QOL in neurologic disease
Often under-recognized and under-measured in neurodegenerative disease
Multiple Sclerosis:
EDSS underestimates visual disability
AD:
Prominent visual-spatial dysfunction
Impaired reading and driving
Most dementia scales (MMSE, CDR) do not directly address impact of visual disability
Balcer LJ. J Neuro Ophth 2014
Heesen C et al. Mult Scl 2008
Vision and Neurologic Disease
Quantifiable metrics of visual function might be
valuable surrogate markers
Detectable early in disease stage
Monitoring and tracking progression of disease
Assess efficacy of neuroprotective strategies
May capture “hidden” aspects of disability
Some diseases ideally suited for visual structure-
function metrics
Tools of the trade
Structural:
Ophthalmoscopy
Optical coherence tomography (OCT)
MRI (conventional, DTI, etc)
Functional:
Psychophysical
Visual acuity (high and low contrast)
Perimetry
Color perception
Visual electrophysiology
OCT angiography
Psychophysical tests
(functional markers)
Visual acuity (high and
low contrast)
Contrast sensitivity
Color discrimination
Perimetry (automated or
kinetic)
VFQ-25 QOL Surveys
Optical Coherence
Tomography
• Generates high resolution images measuring echo time delay of reflected light
• Interference data from multiple rapid scans used to generate color-coded map of retina
Retinal nerve fiber layer= axons
Macular volume= ganglion cells (neurons)
Outer retina= photoreceptors (neurons)
Resolution ~1 u
Visual Electrophysiology
Captures functional changes in visual
system
Quantifiable metrics
More objective assessment
May allow more precise structure-function
correlations
Relatively accessible and inexpensive
Test Advantages Disadvantages
Pattern VEP Widely available Reliant upon cooperation,fixation, refractionMacular dominated response
Non-localizing
Photopic negative
response
RGC functionLess reliant upon fixation
Measuring baselineEye movement artifact
Full field ERG Objective assessment of rod and
cone function
Isolates inner and outer retinal
function
Less dependent upon fixation
and cooperation
Widely available
No topographic informationMore time consuming than
other EP tests
Multi-focal ERG Assesses localized retinal dysfunctionCorrelation with field loss
Dependent upon cooperation and fixationNot widely available
Pattern ERG Information about macular and RGC functionEasy to perform
Dependent upon cooperation
and fixation
Not widely available
Requires good VA
OCT Angiography
Novel technique using motion subtraction
technology to analyze retinal and optic nerve
blood flow
Visualizes capillary-level circulation at each level
of retina
No dye/contrast required
Powerful tool to assess blood flow to retina and
optic nerve
Sequential Imaging to Detect Motion
RetinalAngiography– VesselDensity
Retinal angiography scan combines data from repeated B-scans in the
horizontal and vertical planes over the macula and then uses a Split Spectrum
Amplitude Decorrelation Angiography (SSADA) algorithm to determine
tissue locations with active flow indicating underlying large and small blood
vessels.
Optic nerve angiography scan combines data from repeated B-scans
in the horizontal and vertical planes over the optic nerve and then
uses a Split Spectrum Amplitude Decorrelation Angiography
(SSADA) algorithm to determine tissue locations with active flow
indicating underlying large and small blood vessels.
King-Devick Test
•Rapid number naming test
•Captures saccades, attention
and language
•Requires integration of
brainstem, cerebellum, and
cortex
•Can be administered in 1-2
minutes with minimal training
•Applications in TBI, MS, and
other neurologic diseasesVentura RE et al. Ocular motor assessment in Concussion. J Neurol Sci 2016;361:79-86
Galetta KM et al. The King-Devick test and sports related concussion. J Neurol Sci 2011;309:34-39
Neurodegenerative disease and
Vision
Alzheimer’s disease
Parkinson’s disease
Multiple Sclerosis
Isolated optic neuritis
Axonal loss in anterior visual pathway
Traumatic brain injury
Ocular motor dysfunction
Mitochondrial diseases
LHON
Preclinical and Symptomatic AD
Preclinical AD
~20 y
No AD Symptomatic AD
~7-10 y
Synaptic/Neuronal Integrity
↑ CSF tau
+ Amyloid
Imaging
↓ CSF Aβ42
Transition
Zone
0.5 1 2 3Cognitively Normal
Spread of tau
(PET)
accumulation
Brain atrophy
Altered task and
resting fMRI
Subtle decline in
episodic memory
and attention
↑ CSF SNAP-25
and Neurogranin
Death
CDR
Roe CC et al Amyloid imaging results from the AIBL Study of Aging.
Neurobiol Aging 2010 31:1275-83
Alzheimer’s Disease Neuroimaging Initiative (ADNI)
The Eye in Alzheimer’s Disease
AB plaques and neurofibrillarytangles present in retina
Loss of axons and RGC neurons in retinal in AD vs controls
Correlation to retinal dysfunction by visual electrophysiology
Retinal vascular abnormalities cortical AB burden
Detection of Aβ in retina using curcumin labeling
Frost S et al. Ocular biomarkers for early detection of AD. J Alz Dis2010;22:1-16
PET Biomarkers
PET Negative
SubjectsPET Positive
Subjects
n = 200.398
n = 70.288
•Association between rNFL thinning and macular
volume loss confirmed with multiple studies1
•rNFL loss begins ~2-3 months after ON, max @ ~6
mo2
•Correlates with Low Contrast VA1
•Short term progression of rNFL and LCVA in
longitudinal studies1,3
1. Sakai RE, Balcer LJ et al. Vision in MS. J Neuro-Ophthalmol 2011;31:362-3732. Henderson AP, Altmann DR et al. A serial study of retinal changes following optic
neuritis. Brain 2010;133;2592-2602
3. Talman LS, Bisker ER et al. Longitudinal study of vision and rNFL in MS. Ann Neurol 2010;67:749-760
Disease free controls All MS MS, no ON MS, +ON
MS and OCT
164 MS and 64 HC
Serial of SD-OCT with segmentation
6% MS patients had microcystic ME during follow up
Increased INL associated with increased risk of disease activity
TBI and Concussion
1.4-3.8 million sports-related TBI/year in US
Visual system frequently affected in TBI:
Acute changes in saccadic latencies, memory-guided saccades,
spatial accuracy (Heitger MH et al, Prog Brain Res 2002)
Longer term changes in saccadic accurary and gap saccade test
(Drew AS et al, Neurosci Lett 2007)
Ocular motor metrics can assessed quantitatively and qualitatively
Structure Location/Brodman
n’s area
Function
Frontal Eye
Fields
Anterior to pre-
motor cortex;
Brodmann Area 8
Initiates voluntary, non-visually guided,
contraversive saccades
Parietal Eye
Fields
Lateral bank of
interparietal
sulcus; adjacent to
Brodmann area 7a
Initiates voluntary, visually guided,
contraversive saccades
Supplementary
Eye Fields
Anterior to
supplementary
motor cortex (area
6), dorsal medial
frontal lobe
Involved in planning and learning of
saccadic movements
Dorsolateral
Prefrontal
Cortex
Dorso-lateral
frontal lobe;
Brodmann area
9,46
Involved in memory guided saccades
(saccades toward remembered objects)
Superior
Colliculus
Caudal midbrain,
posterior to
Periaqueductal
gray
Regulates excitatory and inhibitory
signals involved in generation of
saccades, and control of eye-head
movement
Paramedian
Pontine
Reticular
Formation
Paracentral pons,
anterior and
lateral to medial
longitudinal
fasciculus
Direct projections to effector
extraocular muscles to move eye
Cortical and Sub-cortical Control of Saccades
King-Devick test and TBI
Reliably distinguishes concussed from non-concussed athletes
Valid across multiple ages group and sports
Easily administered and scored with minimal training
Increases sensitivity of other sideline assessment tests (SAC
and BESS)
Meta analysis of 15 studies showed that K-D test has sensitivity
of 86% and specificity of 90% for detecting concussion
Vision and eye movements critical components of concussion
and TBI assessment
• Ventura M et al. Diagnostic tests for concussion. J Neuro Ophthalmol
2015;35:73-81
• Galetta KM et al. The King Devick test: meta analysis and systematic
review. Concussion 2015
Summary
Visual system may be an attractive model for
studying neurologic disease
Emerging evidence that structural and
functional retinal, optic nerve, and ocular motor
changes occur in wide variety of neurologic
conditions
Opportunity for collaborations between neuro-
ophthalmologists and other sub-specialty
neurologists
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