electrophysiological assessment of optic neuritis: is there still a role
DESCRIPTION
Visual evoked potentials were once in the diagnostic criteria for Multiple Sclerosis, but have been left off the most recent criteria. However, there are newer techniques available which are still invaluable in the diagnosis of optic neuritis and its common mimics.TRANSCRIPT
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Electrophysiological assessment of optic neuritis: is there still a role?
Dr Clare Fraser
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VEP typesThere are more than you think
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Flash Pattern reversal Pattern onset/offset
Steady state Sweep Motion Chromatic Binocular Stereo-elicited Multichannel Hemifield Multifocal Multi-frequency LED goggle
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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
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Flash VEP
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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.
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Pattern reversal VEP
Assessment of the visual pathway from cornea to V1
Can be affected by Optic degradation Defocus Retinal pathology
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pVEP
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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”
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Early studies
Optic nerve demyelination Delayed P100 Often without significant amplitude
reduction Delay typically persists following
visual recovery
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pVEP
P100 Latency delay Optic nerve disease
Optic neuritis Compression
Macular dysfunction Parkinsons disease Migraineurs
= NOT pathognomonic of optic neuritis
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VEP in diagnosis of MSGradually being forgotten
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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
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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
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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
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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
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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
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Case 1
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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
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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
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MRI
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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
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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
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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
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ERG typesAlso more than you might think
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Full field ERG
Determines generalised retinal involvement
Only detect abnormalities if >30-40% of the retina is affected
= will miss localised macular dysfunction
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Origin of ERG
Muller cellsON bipolar cells
Amacrine cells
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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
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Flicker
Rods respond up to 10-15Hz flicker Cones respond up to 70Hz flicker = 30Hz specific for cone function
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Pattern electroretinogram
Objective measure of the macular response
Uses reversing checkerboard Corneal electrode Field size 15 and 30 degrees
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pERG
Retinal ganglion cell origin
Driven by macular photoreceptors
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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
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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.
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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
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Moorfields study
All unilateral optic neuritis cases 1998-2010
ISCEV standard VEP, PERG, ERG > 3 weeks from presentation 46 patients, 63% female, 59% RRMS
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Example
34 year old man Sub-acute vision loss in right eye to 6/24EDD performed after 4 months from presentation
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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
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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
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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
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Multifocal ERG
Allows simultaneous assessment of the cone system function over discrete macular and paramacular areas
Hexagonal array Covers 55-600 field
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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
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Case 2
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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
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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.
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Occult macular disease
Commonly causes VEP delays Fundus changes will be minimal mfERG are valuable in diagnosis
Okuno (2007) Clin Exp OphthalMiyake (1996) Ophthalmol
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Neuromyelitis optica
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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
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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
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Case 3Even when you thought you had done it all right
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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
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Results from elsewhere
Normal VEP amplitudes Loss of N95 component of large field
pattern ERG, indicating retinal ganglion cell loss
Conclusion – optic neuropathy
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Tests done
Autoantibodies, serum ACE, B12, folate
Lebers mutation, NMO antibody Immunoglobulins, electrophoresis Lead, arsenic, mercury
= all negative
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Management
No improvement after bilateral cataract extraction
No improvement with a course of steroids
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Examination NHNN
Right 3/60 Ishihara: test plate
only
Anterior segment normal
Left 6/36 (variable) Test plate +2/17
Anterior segment normal
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Goldman fields
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Fundus photos
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Pattern VEP
Right eye- Amplitude
3.7uV- Latency 95
ms
Left eye- Amplitude 3.8
uV- Latency 98ms
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Flash VEP
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ERG
DA 0.01
DA 11.0
LA 30Hz
LA 3.0
b-
a-
b-
a-
b-
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Pattern ERG
P50
N95
15 degree
30 degree
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Autofluorescence
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Summary
Symmetrical Central focal visual field loss
Very subtle macular changes on fundoscopy
Ring enhancement (Bulls eye spectrum)
Central macular dysfunction on EDD
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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
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ISCEV recommendationsInternational Society for Clinical Electrophysiology of Vision
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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
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Multifocal VEP
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Results page
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Grey scale results output
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Full field vs. multifocal
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-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
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pVEP versus mfVEP
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pVEP versus mfVEP
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Recovery from inflammation
1 week
2 weeks
3 weeks
4 weeks
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Amplitude recovery over 1 year
1 month
3 months
6 months
12 months
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Long term axonal loss1 month
3 months
6 months
12 months
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Recovery and loss of amplitude
1 month
6 months
12 months
1 week
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Latency
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Latency delay
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Latency recovery
1 month
6 months
12 months
1 week
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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
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Optic radiation lesion
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OCT and mfVEP correlation
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Superior RNFL loss
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RNFL vs. mfVEP
AmplitudeR=0.92
LatencyR=-0.66
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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
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Magnetisation transfer ratio
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MTR: 0.47 0.45
Amp:
Lat:
OCT:
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MTR: 0.41 0.06
Amp:
OCT:
Lat:
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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
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Tracking progress
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Amplitude
RECOVERY 81% NON RECOVERY 19%
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Latency – percentage recovery
69%
Months since optic neuritis
31%
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Amplitude recoveryNo Yes5 25
Latency delayYes No16 9
0% No Yes
5 11
76% 19%
Latency recovery
100%
= Diagnosis of MS
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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
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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
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Sydney Eye Hospital