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Axonal loss and myelin in early ON loss in postacute optic neuritis.

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ORIGINAL ARTICLE
Axonal Loss and Myelin in Early ON Loss
in Postacute Optic Neuritis
Alexander Klistorner, PhD,1 Hemamalini Arvind, MD,1 Than Nguyen, MD,2 Raymond Garrick, MD,3
Mark Paine, MD,2 Stuart Graham, PhD,1 Justin O’Day, MD,2 John Grigg, MD,1 Francis Billson, MD,1
and Con Yiannikas, MD3
Objective: To investigate the relation between retinal nerve fiber layer (RNFL) thickness and latency and amplitude of multifocal visual-evoked potentials (mfVEPs) in the postacute stage of optic neuritis in patients with early or possible multiple
sclerosis.
Method: Thirty-two patients with clinical diagnosis of unilateral optic neuritis and magnetic resonance imaging lesions typical
of demyelination and 25 control subjects underwent mfVEP and optical coherence tomography imaging.
Results: Although there was significant reduction of RNFL thickness in the affected eyes (18.7%), a considerably larger decrease
was observed for the amplitude of the mfVEPs (39.8%). Latency of the mfVEPs was also significantly delayed in optic neuritis
eyes. In fellow eyes, the amplitude of mfVEPs was significantly reduced and the latency prolonged, but RNFL thickness remained unaltered. RNFL thickness correlated highly with the mfVEP amplitude (r ⫽ 0.90). There was also strong correlation
between optical coherence tomography measure of axonal loss and mfVEP latency (r ⫽ ⫺0.66).
Interpretation: Although our findings demonstrate strong associations between structural and functional measures of optic nerve
integrity, the functional loss was more marked. This fact, together with amplitude and latency changes of the mfVEPs observed
in clinically normal fellow eyes, may indicate greater sensitivity of mfVEPs in detecting optic nerve abnormality or the presence
of widespread inflammation in the central nervous system, or both. The significant correlation of the mfVEP latency with RNFL
thickness suggests a role for demyelination in promoting axonal loss.
Ann Neurol 2008;64:325–331
Multiple sclerosis (MS) is an inflammatory and degenerative disease of the central nervous system (CNS)
with predominant involvement of white matter. Although the concept that inflammation and demyelination are major pathological substrates of neurological
deficit prevailed for a long time, it has recently become
clear that permanent neurological disability in MS is
associated with axonal loss.1 It is now believed that axonal injury is an early event in disease pathogenesis and
is not restricted to long-standing lesions.2,3
Various studies implicate the inflammatory component, together with chronic demyelination, as a principal cause of axonal transection and subsequent axonal
degeneration in MS.4,5 However, the interaction and
interdependency of inflammatory, demyelinating, and
neurodegenerative components in early disease is still
far from clear.6 Thus, recent magnetic resonance imaging (MRI) studies demonstrated “mismatch” between
measures of inflammation and neurodegeneration even
at early stages of MS (see Filippi and Rocca7 for review). Similarly, a neuropathological study8 reported
no correlation between plaque load (as a measure of
inflammatory demyelination) and axonal loss in corticospinal and sensory tracts.
Optic neuritis (ON) is a frequent initial manifestation of MS.9 In contrast with most brain lesions, the
effects of disease on the optic nerve are clinically apparent and potentially measurable, and therefore
present an opportunity to examine the processes of myelin destruction, repair, and axonal degeneration.10
It is understood that transection of axons along the
visual pathway leads to retrograde degeneration, which
ultimately reaches the retinal nerve fiber layer (RNFL)
and retinal ganglion cells. The RNFL is the only part
of the CNS where unmyelinated axons can be visualized and axonal degeneration can be quantified in
vivo.11 Therefore, RNFL thickness as measured by optical coherence tomography (OCT) has been recently
suggested as a structural marker of axonal loss in the
optic nerve.12,13
The visual-evoked potentials (VEPs), in contrast,
were developed as a means of functional assessment of
From the 1Department of Ophthalmology, Save Sight Institute,
University of Sydney, Sydney; 2Center for Eye Research, Melbourne
University, Melbourne; and 3Department of Neurology, University
of Sydney, Sydney, Australia.
Published online in Wiley InterScience (www.interscience.wiley.com).
DOI: 10.1002/ana.21474
Received Jan 11, 2008, and in revised form Jun 13. Accepted for
publication Jun 20, 2008.
Address correspondence to Dr Klistorner, PO Box 4337, Sydney,
2001, NSW, Australia. E-mail: sasha@eye.usyd.edu.au
© 2008 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
325
the integrity of the visual pathway in ON (for review
see Nuver14). The amplitude of the VEPs is believed
to reflect the number of functional optic nerve fibers,
which is determined by combination of two factors:
the severity of the inflammation (acute or chronic)
along the visual pathway and axonal degeneration.15
Therefore, diminished amplitude indicates either inflammatory conduction block or axonal atrophy, or both.
Delayed conduction of VEPs has also been found in a
high proportion of patients with ON and is thought to
reflect demyelination of the optic nerve fibres16 with the
subsequent shortening of latency thought to represent
the process of remyelination.15,17
Conventional full-field VEP is greatly dominated by
the macular response because of its cortical overrepresentation.18 In contrast, the newly developed multifocal visual-evoked potential (mfVEPs) enables simultaneous recording from multiple regions of the visual
field up to eccentricity of 20 to 30 degrees, allowing
assessment of much larger cross-sectional area of the
optic nerve.19
In this study, we examined the interrelation between
RNFL thickness and the latency and amplitude of
mfVEPs in the postacute stage of ON in patients with
early or possible MS. RNFL thickness was used as a
surrogate marker of axonal degeneration and latency of
mfVEPs as a marker of demyelination, whereas mfVEP
amplitude was used to assess combined effect of inflammation and axonal loss.
Subjects and Methods
This was a prospective, cross-sectional study. Procedures followed the tenets of the Declaration of Helsinki, and written
informed consent was obtained from all participants.
Subjects
Patients who had suffered a single clinical episode of ON
between 6 months and 3 years before the current visit and
no previous demyelinating events were recruited. ON was
diagnosed by a consultant neuro-ophthalmologist and was
based on clinical findings. Exclusion criteria were atypical
presentation, bilateral ON, recurrent ON, and a history of
any other ocular disease.
Thirty-two patients satisfied the inclusion criteria and
were enrolled in the study. At the time of the enrollment, 13
patients had a diagnosis of MS and 19 patients had ON as a
clinically isolated syndrome (CIS). All 19 patients with CIS
had brain or spinal cord demyelinating lesions detected by
MRI and were classified as high risk for development of
MS.20
Twenty-five age-matched control subjects were also examined using both mfVEP and OCT techniques. The eligibility
criteria for control subjects included 6/6 vision in both eyes
and normal ophthalmic examination. For OCT and mfVEP
group analysis, one eye of the each healthy subject was selected randomly.
Multifocal Visual-Evoked Potential Recording
and Analysis
Multifocal mfVEP testing was performed using the Accumap
(ObjectiVision Pty. Ltd, Sydney, Australia) employing standard stimulus conditions described in detail elsewhere.21 In
brief, the stimulus consisted of a cortically scaled dart-board
pattern of 58 segments (eccentricity up to 24 degrees) (Fig
1A). Each segment contained a 4 ⫻ 4 grid of black and
white checks, which reversed patterns according to a pseudorandom sequence.
The visual stimulus was generated on a 21-inch highresolution display. All recordings were performed monocularly. Four gold-cup electrodes (Grass, West Warwick, RI)
were used for bipolar recording: two electrodes 4cm either
Fig 1. (A) Multifocal, cortically scaled stimulus used in multifocal visual-evoked potential (mfVEP) recording. Each sector (area
4 ⫻ 4 checks) reversed polarity according to an individual pseudorandom sequence. (B) Example of mfVEPs recorded from the unaffected eye of patient with optic neuritis (ON). (C) mfVEPs recorded from the eye of the same patient. Amplitude and latency of
individual traces were derived as shown in insets. Note almost complete amplitude recovery but significant latency delay in affected
eye. VEP ⫽ visual-evoked potential.
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side of the inion, one electrode 2.5cm above, and one 4.5cm
below the inion in the midline. Electrical signals were recorded along four channels: as the difference between superior and inferior, left and right, and obliquely between horizontal and inferior electrodes. Visual-evoked responses were
amplified 1 ⫻ 105 times and band-pass filtered 1 to 20Hz.
“Opera™” software correlated the pattern reversal sequence with the electrical signals recorded, and a response
for each segment was obtained. The largest peak-trough amplitude within the interval of 70 to 210 milliseconds was
determined for each channel. For amplitude analysis, the
wave of maximal amplitude among the four channels was
automatically selected by the software to create a combined
topographic map (see Fig 1B).22 Latency analysis was performed as follows: there were four traces (four channels) for
each eye recorded for every individual segment. Amplitude of
the traces from all four channels of both eyes from a single
segment of the visual field was analyzed as described earlier,
and the amplitude of the largest wave was recorded. The second peak of the largest wave was automatically determined
for latency measurement by a specially designed algorithm.
The same channel and the same peak (minimum or maximum) were then used for latency analysis for that particular
segment in the other eye (see Fig 1B) (see Klistorner and
colleagues17 for details).
The signal was considered nonrecordable (and therefore
latency was not analyzed) in segments where the amplitude
of the response was less then 1.96 times the noise level (determined as standard deviation of the trace within the interval 400 –1,000 milliseconds). Averaged latency was calculated
and analyzed if at least two thirds (67%) of segments had
identifiable response.
Optical Coherence Tomography Recording
and Analysis
OCT was performed using OCT-3 scanner (Stratus, software
version 3.0; Carl ZeissMeditec, Dublin, CA). The Fast
RNFL protocol consisting of three circular scans with diameters of 3.4mm centered on the optic disc was used to acquire the data. Dilation of pupils was not required in any of
the study patients. OCT scan was considered acceptable if
signal strength score was 7 or more. Mean total RNFL thickness was assessed.
where VON is measurement in the ON affected eye, and
VFEL is measurement in the fellow eye (RNFL thickness is
measured in micrometers or mfVEP amplitude in nanovolts
or mfVEP latency in milliseconds).
Variability of intereye asymmetry was similar for mfVEP
amplitude and RNFL thickness ( p ⫽ 0.8). Standard deviation of asymmetry coefficient in the group of control subjects was 0.022 for RNFL thickness and 0.019 for mfVEP
amplitude.
Statistics
Statistical analysis was performed using SPSS 11.0 for Windows (SPSS, Chicago, IL). Mean values of RNFL thickness
and mfVEP amplitude and latency were compared between
control subjects, affected and fellow eyes of patients using
one-way analysis of variance, and Tukey test for post hoc
comparisons. Pearson’s correlation and linear regression analysis was used to examine relations between structural and
electrophysiological measures. Partial correlations were used
to control for the effect of possible confounding factors (age,
sex, and time since onset of ON). Significance was assessed
at the p ⬍ 0.05 level.
Results
Demographic data are presented in the Table.
Optic Neuritic Eyes
The mean RNFL thickness in the ON eye was reduced
by 19.2% compared with control eyes (84.5 ⫾ 15. 1 vs
104.0 ⫾ 9.2␮m; p ⬍ 0.0001) (Fig 2A). There was
significant negative correlation between age and RNFL
thickness (r ⫽ 0.33; p ⫽ 0.02). No significant association of RNFL thickness with sex or time since onset
of ON was detected ( p ⫽ 0.38 and 0.9, respectively).
Larger reduction (39.8%) was observed for the amplitude of the mfVEP (142.9 ⫾ 44.0 vs 237.3 ⫾
30.8nV in affected and control eyes, respectively; p ⬍
0.0001). Data from 26 patients, who had sufficient
amplitude for latency to be calculated, were used for
Table. Demographic Data of Optic Neuritic Patients
and Healthy Control Subjects
Characteristics
Asymmetry Analysis
As was previously reported, intersubject variability in both
OCT and mfVEPs is high23,24 and may, as a result, mask the
relation between the two measures.11 To minimize its effect,
we calculated and used between-eye asymmetry of RNFL
thickness and amplitude and latency of the mfVEPs when
associations between those measures were analyzed. Intereye
asymmetry was used earlier in studies of both mfVEP and
RNFL thickness, and proved to be more sensitive in detection of abnormality, as well as demonstrating relations between various measures compared with absolute values.11,25
Relative asymmetry coefficient was calculated as follows24:
共VON ⫺ VFEL兲/共VON ⫹ VFEL兲
n
ON Patients
Control
Subjects
32
25
Sex ratio, M:F
1:3 (8/24)
1:3 (6/19)
Mean age (SD), yr
36.7 (10.4)
35.9 (11.2)
ⱖ6/7.5
21
25
ⱕ6/9, ⱖ6/15
10
Visual acuity
⬍6/15
Time since the onset
of ON (SD)/range,
mo
1
14.7 (7.9)/6–36
ON ⫽ optic neuritis; SD ⫽ standard deviation.
Klistorner et al: Axonal Loss and Myelin in Early ON
327
Fellow Eyes
Although there was no significant difference between
RNFL thickness in fellow and control eyes (103.8 ⫾
10.8 vs 104.0 ⫾ 9.2␮m; p ⫽ 0.29) (see Fig 2A), the
mfVEPs demonstrated a considerable reduction
(23.3%) of the amplitude in clinically unaffected fellow eye (182.2 ⫾ 36.0 vs 237.3 ⫾ 30.8nV; p ⬍
0.0001) (see Fig 2B). Latency of the mfVEP response
was also significantly delayed in the fellow eye
(146.6 ⫾ 5.6 milliseconds) as compared with the control group (141.3 ⫾ 5.1 milliseconds; p ⫽ 0.003) (see
Fig 2C). Changes of both amplitude and latency of
mfVEPs in the fellow eye were, however, significantly
smaller than in the ON eyes ( p ⬍ 0.001 for both comparisons) (see Figs 2B, C).
Correlation between Retinal Nerve Fiber Layer
Thickness and Multifocal Visual-Evoked Potential
Amplitude and Latency
Linear regression analysis demonstrated strong correlation between intereye asymmetry values of the RNFL
thickness and the mfVEP amplitude (r ⫽ 0.90; p ⬍
0.0001) (Fig 3A). This was unchanged by correcting
for confounding factors. For each 0.1-unit increase of
the asymmetry coefficient of the RNFL thickness, the
amplitude asymmetry of the mfVEPs increased by 0.16
unit.
There was also strong correlation between RNFL
thickness and mfVEP latency (r ⫽ ⫺0.66; p ⬍ 0.002)
with reduction of RNFL thickness associated with
longer conduction time (see Fig 3B).
Fig 2. Average values of retinal nerve fiber layer (RNFL)
thickness (A), multifocal visual-evoked potentials (mfVEP)
amplitude (B), and mfVEP latency (C) in affected and fellow
eyes of optic neuritis (ON) patients and healthy control subjects. Asterisks indicate highly statistically significant difference
(p ⬍ 0.001).
latency analysis (see Fig 2B). There was significant prolongation of latency in ON eyes as compared with control eyes (163.9 ⫾ 11.6 vs 141.3 ⫾ 5.1 milliseconds;
p ⬍ 0.001) (see Fig 2C). No association of the mfVEP
amplitude or latency with any of the confounding factors was found.
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Discussion
To the best of our knowledge, this study is the first to
examine the relation between OCT measures of axonal
loss and multifocal electrophysiology, which provides a
congruent topographic measure of optic nerve function.
This study confirms earlier reports26 –29 that established significant reduction of the RNFL thickness in
the postacute stage of ON. The level of RNFL reduction found in this analysis (19.2%), however, is somewhat less than in some of the previously reported studies. We believe that the discrepancy in the degree of
RNFL reduction found in various studies may be because of patient selection criteria. Thus, Parisi and coworkers,30 who examined only patients with definite
MS and did not exclude patients with multiple episodes of ON, reported a reduction of around 45% in
RNFL thickness. Trip and coworkers,11 who also
found a larger reduction (30%), selectively enrolled
subjects with incomplete visual recovery and a longer
time since the episode of ON (up to 9 years). We, in
contrast, examined patients with a single, relatively recent episode of ON, regardless of visual outcome. It is
understood that more damage to axons of the optic
Fig 3. Correlation between intereye asymmetries of the mean
retinal nerve fiber layer (RNFL) thickness and multifocal
visual-evoked potential (mfVEP) amplitude (A) and latency
(B).
nerve is likely in patients with longer duration of MS
or recurrent ON.29
Parallel to OCT changes, mfVEPs also demonstrated
considerable decline of the amplitude in ON eyes. This
corroborates the finding of previous electrophysiological studies of ON, which reported 40 to 60% amplitude reduction in the postacute stage of ON.11,15,30
There have been, however, conflicting data regarding
the correlation between structural (thickness of RNFL
as determined by OCT) and functional (amplitude and
latency of VEP) measures of optic nerve integrity in
the literature. Thus, although some studies30 found significant reduction of full-field VEP amplitude in ON
eyes, they reported no correlation of the latter with
RNFL thickness. In contrast, other studies demonstrated high correlation between the two measures.31
One of the important findings of this study was the
demonstration of strong correlation between RNFL
thickness and mfVEP amplitude. The multifocal nature of mfVEPs (which allows for considerable contribution from the periphery of the visual field and,
therefore, makes two techniques more compatible) and
use of intereye asymmetry analysis may have helped
unmask the true nature of the relation.
There is previous evidence suggesting subclinical involvement of the fellow eye in clinically unilateral
ON.15,32 In fact, significant reduction of RNFL thickness in the fellow eye of MS patients has been reported
in several studies,29,30,33 implying that the optic nerve
of the fellow eye gradually loses axons because of possible subclinical inflammation or slow axonal atrophy.
Others argued, however, that although there was a
trend for thinner RNFL in fellow eye, the difference
from eyes of healthy subjects was not significant.27,34
We found no reduction of RNFL thickness in the
fellow eye. The discrepancy between our finding and
those mentioned earlier may again reflect differences in
selection criteria, particularly the time since occurrence
of the ON and nature of the disease. The high proportion of patients with CISs as opposed to an MS diagnosis in our study may have contributed to this finding. Costello and coworkers,28 who used a cohort of
patients similar to ours, found RNFL values of the fellow eye comparable with those found in this study
(100␮m). At the 2007 European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS)
meeting, data on 2-year follow-up of the same group of
patients, which demonstrated no changes in fellow eye
RNFL thickness, was reported.35 Absence of the control group in this study, however, prevented statistical
assessment of the fellow eye data. Also, Noval and coworkers31 reported no reduction of RNFL thickness in
the fellow eye at least within the first 6 months after
ON. The mfVEP, in contrast, demonstrated significant
reduction of amplitude in the fellow eye.
Prolongation of the latency is understood to be an
indicator of optic nerve demyelination.36 It is believed
that demyelination is intimately related to axonal loss
in MS.3 A number of recent studies suggested that myelin plays a vital role in providing trophic support to
axons and protecting them from inflammatory mediators and immune cells.37,38 Loss of normal axonmyelin interaction may also contribute to induction of
axonal degeneration.39 However, the relation of demyelination and axonal loss is not straightforward. Thus,
no correlation was found between plaque load and axonal density in the spinal cord, suggesting that the
inflammatory-demyelinating process does not determine the degree of axonal loss, at least in this tract.8
Some of the recent studies of the visual pathway27,30
found no correlation between speed of conduction (using latency of the full-field VEP) and RNFL thickness,
and therefore concluded that demyelination is not directly related to axonal loss.27 This study, in contrast,
established an unambiguous relation between the two
measures, with longer latency being linked to more severe axonal damage. Although OCT samples RNFL
across the whole retina, the full-field VEP used in pre-
Klistorner et al: Axonal Loss and Myelin in Early ON
329
vious studies is heavily biased toward the macular region, therefore resulting in incongruity between the
tests and, as a consequence, lack of correlation. Better
topographical correspondence of the two techniques
used in this study is more suitable for the task of comparison of the two methods. It has also been shown
earlier that latency changes in the full-field VEPs may
be more artifactual than real as it is a result of summation of multiple responses derived from different
parts of the visual field and may be susceptible to the
effect of cancellation.16 Due to the nature of multifocal
stimulation, this does not happen in mfVEP.
The association of delayed latency with RNFL reduction supports the concept that demyelination may
play an important role in promoting axonal loss. The
cross-sectional design of this study, however, does not
permit us to draw definite conclusions in this regard.
This concept needs further investigation in longitudinal studies, but it raises exciting possibilities about the
potential role of remyelination and remyelinating therapies in preventing long-term disability in MS.
This study also demonstrated a considerably larger
percentage decline of the amplitude of the mfVEPs
compared with RNFL thickness in both ON and fellow eyes, indicating that functional deficit is greater
than structural loss. OCT and mfVEP measure different but related aspects of the visual pathways, that is,
RNFL thinning versus axonal “function” or integrity
from a functional standpoint. Although this may indicate greater sensitivity of the mfVEPs to axonal loss
compared with RNFL measurement by OCT, it may
also represent loss of axonal function from channel failure on the denuded, but structurally preserved, axon in
the affected eye.40 Considering that the clinically unaffected fellow eyes also showed mfVEP changes, an alternative explanation for the larger reduction of
mfVEP amplitude (in both eyes) is ongoing inflammation in the visual pathway possibly as part of a more
diffuse, slow inflammation in the white matter.41 Histopathological and radiological changes in normalappearing white matter of the CNS, indicating diffuse
CNS inflammation, have been reported, and our findings may lend support to this concept.42,43 Although
chronic inflammation would reduce mfVEP amplitude
because of axonal dysfunction or conduction block in
some fibers, it may (if only slightly) increase RNFL
thickness caused by edema,31,44 therefore resulting in
even greater discrepancy between the two measures.
In summary, we demonstrated a strong association
between RNFL thickness and mfVEP amplitude in
ON patients with early or possible MS. The close correlation validates both techniques in ON as markers of
RNFL loss. However, the VEP losses in the fellow eye
suggest this may be the more sensitive of the two. Although the OCT may be simpler to perform, both
should be used to monitor the disease, with the VEPs
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September 2008
providing additional functional data on optic nerve recovery after an episode of ON. Latency of the mfVEPs
also showed a significant correlation with structural
measures of axonal loss (RNFL thickness) in these patients suggesting a role for demyelination in promoting
axonal damage.
Disclosure
A.K. was a consultant for ObjectiVision. All other authors report no conflicts of interest.
The study was supported by the Sydney Medical Foundation and
ORIA.
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