Electrophysiological assessment of optic neuritis: is there still a role?

Dr Clare Fraser

VEP typesThere are more than you think

Flash Pattern reversal Pattern onset/offset

Steady state Sweep Motion Chromatic Binocular Stereo-elicited Multichannel Hemifield Multifocal Multi-frequency LED goggle

Flash VEP

Less sensitive Highly variable across the population Low asymmetry = used to detect

subtle asymmetry between the eyes and hemispheres

Useful when Poor cooperation Optical factors

Flash VEP

Functional / non-organic

Demonstration of normal function in the presence of symptoms that suggest otherwise is fundamental to help avoid unnecessary investigations

Short-duration pattern-onset stimulation = reduces that ability of the patient to defocus

Graefes Arch Clin Exp Ophthalmol. 2007 Apr;245(4):502-10. Epub 2006 Nov 17.Assessment of patients with suspected non-organic visual loss using pattern appearance visual evoked potentials. McBain VA, Robson AG, Hogg CR, Holder GE.

Pattern reversal VEP

Assessment of the visual pathway from cornea to V1

Can be affected by Optic degradation Defocus Retinal pathology

pVEP

Historical context

Halliday, A.M., W. MacDonald, and J. Mushin, Delayed visual evoked response in optic neuritis. Lancet, 1972: p. 982-985.

Halliday, A.M., W. McDonald, and J. Mushin, Visual evoked response in the diagnosis of multiple sclerosis. Br Med J, 1973. 1: p. 661-664.

1976: Lawton-Smith “new fangled VEP”

Early studies

Optic nerve demyelination Delayed P100 Often without significant amplitude

reduction Delay typically persists following

visual recovery

pVEP

P100 Latency delay Optic nerve disease

Optic neuritis Compression

Macular dysfunction Parkinsons disease Migraineurs

= NOT pathognomonic of optic neuritis

VEP in diagnosis of MSGradually being forgotten

1983 – Poser criteria

Developed to reflect the advances in detection techniques including MRI, CSF analysis and VEP

“para-clinical evidence of one lesion”

Poser C, Paty D, Scheinberg et al. New diagnostic criteria for MS: guidelines for research protocols.(1983) Annals Neurol; 13(3):227-231

2001 – McDonald criteria

positive VEP evidence of optic pathway involvement was included in the criteria for a diagnosis of primary progressive MS

criteria dominated by clinical and MRI evidence of lesions

McDonald WI, Compston A, Edan G et al (2001). "Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis". Ann. Neurol. 50 (1): 121–7

2005 - revisions

Polman CH, Reingold SC, Edan G et al (2005). "Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria"". Ann. Neurol. 58 (6): 840–6

2011 - revisions

VEP is no longer included

Polman, Chris et al. (2011). Diagnostic criteria for multiple sclerosis: 2010 Revisions to the McDonald criteria. Annals of Neurology Feb; 69(2): 292-302

Future of VEP

MRI and OCT currently demonstrate structure only

VEPs provide functional information

Better positioned for use in clinical trials of newer medications that aim to preserve or return function

Niklas A, Sebraoui H, Hess E et al. (2009) Outcome measures for trials of remyelinating agents in multiple sclerosis. Mult Scler; 15(1):68-74

Case 1

Presentation

19 yo M: painless blurring of left vision 1/52 VAR 6/5 VAL 6/9 Ishihara 16/17 7/17

Left RAPD Bilateral disc pallor L>R

Follow-up

CT scan brain and orbits – normal Pattern VEP P100

Right = 112ms, 8.27uV Left = unrecordable

Diagnosed as optic neuropathy

Stable on review 4 months later

MRI

6 months later

Returns with bilateral reduction in vision• VAR 6/9 VAL 6/36 PH 6/9• Ishihara 17/17

0/17 PVEP: right eye = delay 124ms, left eye =

unrecordable

Full electrodiagnostic panel

RE6/12

N

LE6/18

P50

N95a-

b-b-

a-

b-

DA 0.01 DA 11.0 LA 30Hz LA 3.0 30° PERG

15° PERG

Teaching point

VEP is sensitive in detecting optic nerve dysfunction

VEP abnormalities are not specific for optic nerve disease and can reflect dysfunction anterior to the optic nerve

ERG typesAlso more than you might think

Full field ERG

Determines generalised retinal involvement

Only detect abnormalities if >30-40% of the retina is affected

= will miss localised macular dysfunction

Origin of ERG

Muller cellsON bipolar cells

Amacrine cells

Full field ERG

A-wave = photoreceptors Reduced in RP

B-wave = inner retinal layers Decreased in retinoschisis, CRVO,CRAO

CSNB Oscillatory potentials = amacrine

cells Attenuated in CRVO, CRAO, CSR, CSNB

Flicker

Rods respond up to 10-15Hz flicker Cones respond up to 70Hz flicker = 30Hz specific for cone function

Pattern electroretinogram

Objective measure of the macular response

Uses reversing checkerboard Corneal electrode Field size 15 and 30 degrees

pERG

Retinal ganglion cell origin

Driven by macular photoreceptors

pERG in optic neuritis

382 eyes with optic nerve demyelination 30% had abnormal N95:P50 ratio Acute ON transient reduction P50

suggesting macular involvement Degree of initial P50 reduction was

related to final visual outcome = prognostic value

Holder GE (2001) Pattern electroretinography (PERG) and an integrated approach to visual pathway diagnosis. Prog Retin Eye Res 20:531-561

Further evidence of macular involvement

Focal macular ERG a- and b- waves are attenuated at onset of

ON and recover by 6 months Authors concluded that the inflammation

extends at least to the inner nuclear layers

Nakamura H, Miyamoto K, Yokota S, Ogino K, Yoshimura N (2011) Focal macular photopic negative response in patients with optic neuritis. Eye (Lond) 25:358-364.

ERG in optic neuritis

69 cases of optic neuropathy (neuritis) “enhanced ERGs” in 42% = >600uV

▪ Auerbach 1969

Of “supra-normal” ERG cases 22% had optic nerve pathology

▪ Feinsod 1971

Reduced b-wave amplitudes in ON with and without MS (not ISCEV standards)

▪ Fotiou 1989, 1999

Retinal vascular changes in MS▪ Lightman 1987

Moorfields study

All unilateral optic neuritis cases 1998-2010

ISCEV standard VEP, PERG, ERG > 3 weeks from presentation 46 patients, 63% female, 59% RRMS

Example

34 year old man Sub-acute vision loss in right eye to 6/24EDD performed after 4 months from presentation

Results - ERG

No pts had >30% ERG intraocular asymmetry

Only 3/46 pts had bright flash ERG b-wave amplitude of 600-630uV = not supra normal in our laboratory

No difference between those with and without MS

Results -pERG

pERG N95 amplitude significantly lower in clinically affected eyes

pERG P50 mild abnormalities in 9/46 No pERG P50 abnormalities in fellow

eyes

No difference in patients with and without MS

Study conclusions

ISCEV standard ERG data from eyes with optic neuritis did not significantly differ from: the uninvolved eye normal values for our laboratory between MS and non-MS patients

No patients had “supra-normal” ERG

Fraser CL, Holder G. (2011).Electroretinogram findings in unilateral optic neuritis. Doc Ophthal; 123(3):173-8

Multifocal ERG

Allows simultaneous assessment of the cone system function over discrete macular and paramacular areas

Hexagonal array Covers 55-600 field

mfERG in MS

OCT imaging in a subset of MS patients showed significant thinning of the inner and outer nuclear retinal layers, more extensive than expected from retrograde degeneration secondary to ON

Confirmed with mfERG abnormalities ? Primary retinal pathology associated

with rapid progression and higher MS-severity scores

Saidha S, Syc S, Ibrahim M et al. (2011) Primary retinal pathology in MS as detected by OCT. Brain; 134: 518-533

Case 2

Referred with optic neuritis

21 year old woman with right visual field loss, no pain

Diagnosed as optic neuritis in A&E Right eye: reduced without delay, PERG p50

reduction is consistent with macular dysfunction. Full field ERG normal

Big blind spot syndrome

Right eye: mfERG is consistent with macular dysfunction that extends from the right fovea over the area that encompasses the right optic disc, consistent with a diagnosis of AIBBS.

Left eye: normal.

Occult macular disease

Commonly causes VEP delays Fundus changes will be minimal mfERG are valuable in diagnosis

Okuno (2007) Clin Exp OphthalMiyake (1996) Ophthalmol

Neuromyelitis optica

Neuromyelitis optica

AQP4 is found on inner membrane of Muller cells (responsible for ERG b-wave)

Focal arteriolar narrowing recorded in NMO▪ Benfenati, Neuroscience 2010

OCT shows more severe retinal damage after optic neuritis in NMO patients

▪ Ratchford, Neurology 2002

? Is there any difference in the electrophysiology

NMO

Study VEP, OCT + visual fields mean RNFL thickness significantly reduced OCT correlated with HVF OCT correlated weakly with acuity and VEP

latency▪ De Seze J, Arch Neurol 2008

Comparison of AQP4+ versus MS lacked P100 component 65% vs 24% Lower frequency of delayed P100 6% vs 33%

▪ Wanatabe A et al. J Neurol Sci 2009

Case 3Even when you thought you had done it all right

History

6 year history of slowly progressive changes over one year, then stable since

Initially thought it was peripheral vision

Sensitive to bright lights Difficulty seeing faces Difficulty reading Can’t see stars at night

Results from elsewhere

Normal VEP amplitudes Loss of N95 component of large field

pattern ERG, indicating retinal ganglion cell loss

Conclusion – optic neuropathy

Tests done

Autoantibodies, serum ACE, B12, folate

Lebers mutation, NMO antibody Immunoglobulins, electrophoresis Lead, arsenic, mercury

= all negative

Management

No improvement after bilateral cataract extraction

No improvement with a course of steroids

Examination NHNN

Right 3/60 Ishihara: test plate

only

Anterior segment normal

Left 6/36 (variable) Test plate +2/17

Anterior segment normal

Goldman fields

Fundus photos

Pattern VEP

Right eye- Amplitude

3.7uV- Latency 95

ms

Left eye- Amplitude 3.8

uV- Latency 98ms

Flash VEP

ERG

DA 0.01

DA 11.0

LA 30Hz

LA 3.0

b-

a-

b-

a-

b-

Pattern ERG

P50

N95

15 degree

30 degree

Autofluorescence

Summary

Symmetrical Central focal visual field loss

Very subtle macular changes on fundoscopy

Ring enhancement (Bulls eye spectrum)

Central macular dysfunction on EDD

Teaching points

Focal central scotoma – not optic nerve

VEP alone cannot differentiate macular and optic nerve lesions

Pattern and focal ERG are a largely independent measure of macular function

Schmeisser, E. Occult maculopathy detected by focal ERG. Doc Ophthal 103: 211-218: 2001

ISCEV recommendationsInternational Society for Clinical Electrophysiology of Vision

Appropriate use

Retrobulbar Neuritis Pattern VEP Pattern ERG + Standard ERG

Active Retrobulbar Neuritis Electrophysiological tests of little

diagnostic value but they may be of value in studies evaluating therapy

Unexplained Visual Loss Pattern VEP, Standardised ERG, Pattern

ERG

Multifocal VEP

Results page

Grey scale results output

Full field vs. multifocal

-0.2

-0.1

0.0

0.1

0.2

0.3

0.4

0.5

0.6

-0.1 0.0 0.1 0.2 0.3 0.4 0.5 0.6

MF amplitude asymmetry coefficient

FF

am

pli

tud

e as

ymm

etry

co

effi

cien

t

-5

5

15

25

35

45

0 10 20 30 40 50

MF latency asymmetry ms

FF

lat

ency

asy

mm

etry

ms

Amplitude and latency

pVEP versus mfVEP

pVEP versus mfVEP

Recovery from inflammation

1 week

2 weeks

3 weeks

4 weeks

Amplitude recovery over 1 year

1 month

3 months

6 months

12 months

Long term axonal loss1 month

3 months

6 months

12 months

Recovery and loss of amplitude

1 month

6 months

12 months

1 week

Latency

Latency delay

Latency recovery

1 month

6 months

12 months

1 week

mfVEP latency

Not specific for demyelination (as with pVEP)

Delays reported in: Glaucoma Retinal disease

Hood D, Chen Y, Yang B et al.(2006) The role of mfVEP latency in understanding optic nerve and retinal disease. Trans Am Ophthalmol Soc;104:71-77

Optic radiation lesion

OCT and mfVEP correlation

Superior RNFL loss

RNFL vs. mfVEP

AmplitudeR=0.92

LatencyR=-0.66

Longitudinal study

25 patients with ON and MRI evidence of demyelination

OCT and mfVEP at 6 and 12 months Despite ongoing thinning RNFL there was

an increase in mfVEP amplitudes Independent of latency changes ? Evidence of increased post-synaptic

activity in striate cortex supporting the concept of cortical reorganisation

Klistorner A, Arvind H, Garrick R et al. (2010) Interrelationship of optical coherence tomography and multifocal visual-evoked potentials after optic neuritis. IOVS; 51(5):2770-2777

Magnetisation transfer ratio

MTR: 0.47 0.45

Amp:

Lat:

OCT:

MTR: 0.41 0.06

Amp:

OCT:

Lat:

Early findings

-0.03

-0.02

-0.01

0.00

0.01

0.02

0.03

0.04

0.05

0.06

0.07

"Axonal loss" "Demyelination" Full Recovery

MT

R a

sy

mm

etr

y

Tracking progress

Amplitude

RECOVERY 81% NON RECOVERY 19%

Latency – percentage recovery

69%

Months since optic neuritis

31%

Amplitude recoveryNo Yes5 25

Latency delayYes No16 9

0% No Yes

5 11

76% 19%

Latency recovery

100%

= Diagnosis of MS

Conclusion

Structural information from OCT and MRI cannot replace the functional assessment of ocular electrodiagnostics

mfVEP is an interesting research tool in understanding ON and MS

Conclusion

VEP alone cannot differentiate macular and optic nerve lesions VEP should not be interpreted without an

ERG

Measures of macular function Pattern ERG = mass response of macular

retinal ganglion cells Multi-focal ERG = assessment of cone

system over discrete macular areas

Sydney Eye Hospital