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.
5. 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
6.
7. 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.
8. Assessment of the visual pathway from
cornea to V1
Can be affected by
Optic degradation
Defocus
Retinal pathology
9.
10. 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”
11. Optic nerve demyelination
Delayed P100
Often without significant amplitude reduction
Delay typically persists following visual
recovery
14. 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
15. 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
16. 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
17. 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
18. 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
19.
20. 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
21. 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
22.
23. 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
24. DA 0.01 DA 11.0 LA 30Hz LA 3.0 15° PERG 30° PERG
RE
6/12
LE
6/18
b- b- P50
b-
N
a- a- N95
25. 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
27. Determines generalised retinal involvement
Only detect abnormalities if >30-40% of the
retina is affected
= will miss localised macular dysfunction
33. 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
34. 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.
35. 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
36. All unilateral optic neuritis cases 1998-2010
ISCEV standard VEP, PERG, ERG
> 3 weeks from presentation
46 patients, 63% female, 59% RRMS
37. 34 year old man
Sub-acute vision loss in right eye to 6/24
EDD performed after 4 months from presentation
38. 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
39. 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
40. 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
41. Allows simultaneous
assessment of the
cone system function
over discrete macular
and paramacular areas
Hexagonal array
Covers 55-600 field
42. 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
43.
44. 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
45. 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.
46. Commonly causes VEP delays
Fundus changes will be minimal
mfERG are valuable in diagnosis
Okuno (2007) Clin Exp Ophthal
Miyake (1996) Ophthalmol
47.
48. 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
49. 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
51. 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
52. Normal VEP amplitudes
Loss of N95 component of large field pattern
ERG, indicating retinal ganglion cell loss
Conclusion – optic neuropathy
63. Symmetrical
Central focal visual field loss
Very subtle macular changes on fundoscopy
Ring enhancement (Bulls eye spectrum)
Central macular dysfunction on EDD
64. 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
66. 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
83. 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
88. 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
96. Amplitude recovery
No Yes
5 25
Latency delay
Yes No
100% 16 9
Latency recovery
No Yes 0%
5 11
76% 19% = Diagnosis of MS
97. 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
98. 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
Notas do Editor
WHAT: Here are a list of ISCEV recognised methods for performing VEP.The current standard presents basic responses elicited by three commonly used stimulus conditions using a single, midline recording channel with an occipital, active electrode. The ISCEV standard is that at least one of these techniques should be included in every clinical VEP recording session so that all laboratories will have a common core of information that can be shared or compared
Peaks are designated as negative and positive in numerical order to differentiate them from pVEPN2 and P2 are the most robust componentsN2 = 90msecP2 = 120 msAmplitude is the height between the two
preferred technique for most clinical purposes. The results of pattern reversal stimuli are less variable in waveform and timing than the results elicited by other stimuli.The pattern reversal stimulus consists of black and white checks that change phase (i.e., black to white and white to black) abruptly and repeatedly at a specified number of reversals per second.
Right:Rod specific ERG is normal, but bright flash a-wave amplitude is borderline, delay in cone flicker, pERG is subnormal to small field but normal to larger field. Delayed pVEP 124ms.Left: rod specific ERG is undetectable, mildly subnormal bright flash a-wave, but profoundly electronegative with reduction in the b:a ratio, completely lacking in oscillatory potentials. No cone function. PERG undetectable to small or large stimulus.Conclusion – RIGHT = severe central macular dysfunction with evidence of a more generalised retinal dysfunction involving the cone system, VEP changes are consequent on findings at macular level.LEFT = different pattern of abnormality, ERG is profoundly electronegative indicating post-receptoral disease, though reduction in a wave amplitude indicates some photoreceptor involvement. There is no cone system function.“I wonder if this may be autoimmune”
21 year old women with right visual field loss – pEVP from the right eye is reduced without delay, the PERG p50 reduction is consistant with macular dysfunction and explains the pVEP abnormality. Full field ERG shows no evidence of generalised retinal involvement. Right eye mfERG is consistant with macular dysfunction that extends from the right fovea over the area that encompasses the right optic disc, consistant with a diagnosis of AIBBS. Left eye is normal.
To perform a mVEP ...... describe action in video
Comparison with the inbuilt database allowing for deviation calculations on each segment – giving a topographical map, with more detail than the previously used sectoral analysis.
Other than the advantages of cooperation, learning and performance, the mfVEP provides information on neurological function with amplitude and latency details not available with the HVF. So then why not perform a conventional ffVEP? And how comparable are the traditional full field VEP and the multifocal technique?A direct comparison study was performed on 25 patients following their first episode of acute unilateral ON. The average time from onset to testing was 8 months. Full-field VEP (FF VEP) was performed according to ISCEV standard using ESPION with frontal-occipital electrode placement.
For both tests amplitude and latency of affected eye were statistically different from non-affected eye. The asymmetry of amplitude and latency between two eyes was also very similar for both tests and there was good correlation between ff and mf VEP for both amplitude and latency.
We can explain those missed cases as the clinical usefulness of full-field VEP is limited by the fact that it provides a summed response of all neuronal elements stimulated, which is greatly dominated by the macular region due to its cortical overrepresentation. However the mfVEP responses from peripheral areas are recorded independently from the central field. The relative size of field tested is shown here….
This example of a patient with optic neuritis, in whom no ffVEP could be detected in the affected eye. However the mfVEP reveals an inferior centrocecal scotoma, with preserved signals superiorly and peripherally.
This example of a patient with a traumatic optic neuropathy – the normal ffVEP misses the superior defect seen clearly on the multifocal test. The mfVEP shows advantages over both HVF testing and conventional VEP, providing the combination of both tests in one diagnostic tool.
By following the amplitude changes in the multifocal VEP we may be getting a glimpse of these pathological processes at work. In this patient presenting with acute optic neuritis the scans clockwise from top right show the amplitude deviation plot at 1 week, 2 weeks, 3 weeks and 1 month. Amplitude recovery in this case can most likely be attributed to recovery from inflammatory conduction block.Garry Miller – art exhibition entitled Optic Nerve
This set of scans follows a different patient also with optic neuritis with amplitude asymmetry deviation plots at 1 month, 3 months, 6 months and 12 months. This longer term amplitude recovery could represent restored conduction due to remyelination, or a remodeling of conduction channels along the axon or perhaps there is some neuro-plasticity in the V1 cortex.Either way, the technique can provide us with a means to track changes.
This patient was diagnosed with multiple sclerosis at the time of presentation with acute optic neuritis. Over sequential testing there was a gradual decline in amplitude values, indicating long term axonal loss. This pattern could be explained several ways. This patient may have subclinical inflammation, or a failure of remyelination with gradual axonal death from a loss of trophic support. Or there could be primary axonal loss as part of the disease process, perhaps representing a primary progressive form of Multiple Sclerosis.
Another example showing improvement in amplitude deviation plots over the first month, with a subclinical worsening over the following year. It is not yet clear whether the progression of functional deficits in MS is primarily the result of an increasing load of demyelination, or axon loss, or a combination of the two processes. However, given the increasing recognition that myelin sheaths play a role in protecting axons from degeneration, the success or failure of remyelination does have functional consequences. So it is important to look at the latency patterns.
Latency analysis has been improved since the first published studies from our group when reproducibility between tests for individual segments was not sufficient to allow for progression analysis. Any analysis following optic neuritis patients had to rely on quadrant averaging of latency values, which meant losing many of the benefits of multifocal testing. The new latency analysis program examines all 4 recorded channels for each segment – selecting the channel which shows the largest deviation between positive and negative peaks for either eye. Using that channel for both eyes the latency is measured to the second large deviation, be it either positive or negative, as this has been shown to be the most stable.This method has been shown to be reproducable and allows for progression analysis of individual segments.
Comparison with the inbuilt database allowing for deviation calculations on each segment – giving a topographical map, with more detail than the previously used sectoral analysis.
Latency recovery is seen here over the course of one year following acute optic neuritis. Recovery on many of our cases starts at the periphery with central areas recovering last.An understanding of the failure of remyelination in Multiple Sclerosis depends upon the elucidation of cellular events underlying successful remyelination, but whatever the exact mechanism, we can monitor the changes over time with latency analysis.
This case demonstrates that the lesion does not have to be within the optic nerve. This 30 year old patient presented with altered vision. Humphrey visual field testing was normal. mfVEP testing here demonstrates a right field defect respecting the vertical midline for both amplitude and latency, constituting a right homonymous hemianopia. MRI confirmed a lesion in the optic radiation with the morphology of a demyelinated plaque.
It is hard to draw any pathological conclusions from isolated examination of amplitudes. Amplitudes depend on the integrity of the of the myelin sheath, but it is now understood that MS also involves axonal damage and death. Thus the structural integrity of the axons also needs to be measured. Death of retinal ganglion cells with loss of the retinal nerve fibre layer … can be measured on OCT. In order to investigate topographical relationship between amplitude of mfVEP and retinal nerve fibre layer thickness following acute optic neuritis (ON) 50 patients were enrolled, on average 13 months post diagnosis. RNFL thickness and mfVEP amplitude were measured for upper, temporal and lower retinal sectors and corresponding areas of the visual field in affected and fellow eyes of ON patients and control eyes. Inter-eye asymmetry coefficients for both RNFL thickness and mfVEP amplitude were calculated for each zone and corresponding coefficients were correlated between each other. Conclusions: We demonstrated strong associations between structural and functional measures of optic nerve integrity. Amplitude and latency changes of the mfVEP observed in clinically normal fellow eyes may indicate the presence of subclinical inflammation in CNS. The significant correlation of the mfVEP latency with RNFL thickness in optic neuritis eyes suggests a role for demyelination in promoting axonal loss.RNFL thickness and mfVEP amplitude were measured for upper, temporal and lower retinal sectors and corresponding areas of the visual field in affected and fellow eyes of ON patients and control eyes were compared.
This patient with predominantly superior loss, shows inferior amplitude loss on mfVEP
This graph shows the relation between the assymetry co-efficients for RNFL thickness (horizontal) and amplitude (vertical). Overall results showed that there was highly significant reduction of RNFL thickness and mean mfVEP amplitude in the affected eye. Largest reduction of RNFL thickness was noticed in temporal sector and of mfVEP amplitude- in corresponding central part of the visual field. RNFL thickness correlated well with amplitude of the mfVEP.When inter-eye asymmetries were used, as shown in the graph, the correlation had an r value of 0.92.There was moderate, but significant negative correlation between RNFL thickness and mfVEP latency in ON eyes which became more apparent when inter-eye asymmetries, rather then absolute values were used (r=-0.66, p<0.001). RNFL thickness assymetry coefficient on the horizontal axis, and latency assymetry coefficient along the vertical axis.We demonstrated strong associations between structural and functional measures of optic nerve integrity. The association of RNFL defects with latency delay may support the concept that demyelination with loss of trophic support plays an important role in axonal loss.
While MRI is proven to be a very sensitive tool in confirming diagnosis of multiple sclerosis (MS) conventional T2 images do not correlate well with disability. It was suggested that new MRI techniques such as Magnetisation Transfer Ratio (MTR) which is a measure of the exchange of protons between free water and macromolecules in membranes may provide more specific measure of de/remyelination and axonal loss.However this relationship remains uncertain.The aim of our study was to assess the functional significance of MTR in optic neuritis by using established measures of axonal loss and myelination - RNFL thickness, amplitude and latency of Multifocal Visual Evoked Potential MRIwas performed on a Philips 3-T imager
In this example the patient has full axonal recovery, persistant latency delay and normal RNFL thickness. The MTR scores are equal.
In comparison to this patient with significant axon loss with thinning seen on OCT but normal latency. Note there is significant asymmetry in MTR scores.
There was consistent asymmetry in MTR between affected and fellow eyes in all patients with axonal loss with the affected eye demonstrating considerably smaller values. None of the patients with extensive demyelination alone demonstrated significant MTR asymmetry (0.001+/-0.019). There was also no asymmetry in ”full recovery” group (-0.004+/-0.017).Results of this pilot study suggest that demyelination is not always reflected in the MTR but that axonal loss does have a relationship with MTR score.
Long term studies tracking mfVEP changes over time have also been carried out using the new latency analysis protocols.30 patients with first episode ON and MRI lesions consistant with MS but not fulfuilling criteria for diagnosis, were followed with serial mfVEP. 44% of whom went on to develop clinically definite MS in the 12 months of the study period.
The remaining 19% did not recover amplitude at all, over the one year study period.
When examining latency recovery over the time there was a clear separation of patients between those in whom latency recovered versus those who did not. This graph shows the percentage recovery over time. This confirms our original results showing the dichotomy of latency recovery at the 6 month mark in those with a high risk of MS. However this study continued to follow the patients over a full year, with a widening of the differences.
Over the one year period this flow graph shows the factors that were most predictive of progression to MS - indicated as the percentage in red. The greatest risk was for those with no amplitude recovery, followed by those with amplitude recovery but no latency recovery. The lowest risk was in those with no latency delay – perhaps indicating a pure inflammatory post-infectious optic neuritis.There is a caveat in broadly applying these results to patients with a single episode of optic neuritis, as that these results will not apply to those who are subsequently diagnosed as having neuromyelitis optica or chronic relapsing intermittant optic neuropathy.