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