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1 From the Cattedra di Clinica Oculistica, Università di Roma "Tor Vergata"; 2 Fondazione per l’Oftalmologia G. B. Bietti, Rome; 3 AFaR–CRCCS, Divisione Oculistica Ospedale Fatebenefratelli, Rome; and 4 Istituto di Clinica delle Malattie Nervose e Mentali, Università di Roma "La Sapienza," and 5 IRCCS Neuromed, Pozzilli, Italy.
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Abstract |
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METHODS. Fourteen patients with a diagnosis of definite MS were examined. All had been affected by optic neuritis (MSON) with complete recovery of visual acuity (14 eyes included in study). These were compared with 14 eyes from 14 age-matched control subjects. NFL thickness was measured by optical coherence tomography (OCT). Three different measurements in each quadrant (superior, inferior, nasal, and temporal) were taken and averaged. The data in all quadrants (12 values averaged) were identified as NFL Overall, whereas the data obtained in the temporal quadrant only (3 values averaged) were identified as NFL Temporal. Retinal and visual pathway function was assessed by simultaneously recording pattern electroretinograms (PERGs) and visual evoked potentials (VEPs) using high-contrast (80%) checkerboard stimuli subtending 15 minutes and 60 minutes of the visual arc (min arc) and reversed at the rate of two reversals per second.
RESULTS. In MSON eyes there was a significant (P < 0.01) reduction in NFL thickness in both NFL Overall and NFL Temporal evaluations compared with the values observed in control eyes. PERG, (15-min arc checks) and VEP (15-min arc and 60-min arc checks), showed a significant (P < 0.01) delay in latency and reduction in amplitude. NFL Overall and NFL Temporal values were significantly correlated (P < 0.01) to the PERG P50 latency and P50 to N95 amplitude recorded with 15-min arc checks. No correlations (P > 0.01) between NFL values and the other electrophysiological data (PERG recorded with 60-min arc checks and VEP recorded with 15-min arc and 60-min arc checks) were found.
CONCLUSIONS. There is a correlation between PERG changes and NFL thickness in MS patients previously affected by optic neuritis, but there is no correlation between VEP changes and NFL thickness.
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Introduction |
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A new noninvasive technology allowing cross-sectional imaging of the eye was recently introduced by Huang et al.,20 Puliafito et al.,21 and Hee et al.22 23 This is an objective method of quantifying the nerve fiber layer (NFL) in vivo and of assessing the retinal thickness by optical coherence tomography (OCT).
In our study OCT, PERG, and VEP were performed in a group of MS patients previously affected by optic neuritis to assess whether a correlation exists between the structural (NFL thickness) and functional (PERG, VEP) findings.
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Methods |
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An ophthalmologic examination, including anterior segment biomicroscopy, visual acuity, applanation tonometry and ophthalmoscopy, was performed in all subjects tested. Inclusion criteria for the study were refractive errors, when present, within -2 and +2 spherical diopters; intraocular pressure less than 18 mm Hg in both eyes (average of two measurements); no concomitant ocular or systemic disease; and complete recovery of visual acuity (10/10) after the optic neuritis episode.
The 14 MSON eyes were compared with 14 eyes from 14 age-matched control subjects. In MS patients affected by unilateral optic neuritis (11/14), we considered the fellow eye (11 MS contralateral eye, MSCE) a further control. OCT, PERG, and VEP were assessed both in MS patients and in control subjects.
Informed consent was received from all subjects involved in the study. The research followed the tenets of the Declaration of Helsinki, and the protocol was approved by the local ethics committee .
OCT Examination
OCT, including a fiber optic delivery system coupled with a slit
biomicroscope (Humphrey, San Leandro, CA), was used. This system
provides the operator with a video camera view of the scanning probe
beam on the fundus and OCT imaging acquired in real time on a computer
monitor. After dilation with 1% tropicamide, each eye was scanned
three times using a circle size of 3.4 mm (1.7-mm radius).
Near-infrared light (84-nm wavelength) was used. Throughout scanning,
the patient kept the eyes constantly fixed on an internal target
provided by the equipment. The measurements were obtained from three
nonconsecutive scans (i.e., the patient was allowed to rest for a few
seconds before repositioning to proceed to the following scan).
The OCT software was an automated computer algorithm that identifies the anterior and posterior border of the retina, making it possible to calculate NFL and total retinal thickness by quadrant and by clock hour. Retinal thickness was determined by computer as the distance between the first reflection at the vitreoretinal interface and the anterior boundary of the second reflective layer corresponding to the retinal pigment epithelium and the choriocapillaris. NFL thickness was automatically assessed by computer assuming the correlation with the red highly reflective layer at the vitreoretinal interface.26
The average values of three different measurements per quadrant (superior, inferior, nasal, and temporal) were calculated. The overall data obtained in all quadrants (12 values averaged) were identified as NFL Overall, and the data obtained in the temporal quadrant only (3 values averaged) were identified as NFL Temporal. NFL Temporal was taken to evaluate the temporal fiber in which the papillomacular bundle fibers are included.27
Electrophysiological Examination
In accordance with procedures in previously published
studies,28
29
30
simultaneous PERG and VEP recordings were
performed using the following methods. The subjects under examination
were seated in a semidark, acoustically isolated room in front of the
display surrounded by a uniform field of luminance of 5
cd/m2. Before the experiment, each subject was
adapted to the ambient room light for 10 minutes. The pupil diameter
was approximately 5 mm. Mydriatic or miotic drugs were never used.
Stimulation was monocular after occlusion of the other eye. Visual
stimuli were checkerboard patterns (contrast 80%, mean luminance 110
cd/m2) generated on a TV monitor and reversed in
contrast at the rate of two reversals per second. Two check sizes were
used as visual stimuli: At the viewing distance of 114 cm the check
edges subtended 60 and 15 minutes of visual angle (min arc). The screen
of the monitor subtended 18° and a small red target (0.5°) was
placed in the center of the stimulus field to maintain stable fixation.
The refraction of all subjects was corrected for viewing distance.
PERG Recordings
The bioelectric signal was recorded by a small Ag-AgCl skin
electrode placed over the lower eyelid. PERGs were derived bipolarly
between the stimulated (active electrode) and the patched (reference
electrode) eye using the method previously described.31
The ground electrode was at Fpz. The interelectrode resistance was
lower than 3 k
. The signal was amplified (gain 50,000), filtered
(band-pass 1–30 Hz), and averaged with automatic rejection of
artifacts (200 events free from artifacts were averaged for every
trial) by BM 6000 (Biomedica Mangoni, Pisa, Italy). The
analysis time was 250 msec. The transient PERG response is
characterized by a number of waves with three subsequent peaks of
negative (N), positive (P), and negative polarity, respectively. In
normal subjects these peaks have the following latencies: 35, 50 and 95
msec (N35, P50, N95).
VEP Recordings
Cup-shaped Ag-AgCl electrodes were fixed with collodion in the
following positions: active electrode in Oz, reference electrode in
Fpz, and ground in the left arm. The interelectrode resistance was kept
below 3 k. The bioelectric signal was amplified (gain 20,000),
filtered (band-pass 1–100 Hz), and averaged (200 events free from
artifacts were averaged for every trial) by BM 6000. The analysis time
was 250 msec. The transient VEP response is characterized by a number
of waves with three subsequent peaks of negative, positive, and
negative polarity, respectively. In normal subjects these peaks have
the following latencies: 75, 100, and 145 msec (N75, P100, N145).
In the recording session, simultaneous PERGs and VEPs were recorded at least twice, and the resultant waveforms were superimposed to check the repeatability of the results. We accepted PERG and VEP signals with a signal-to-noise ratio higher than 2. The noise was measured by recording the bioelectric signals (200 averaged events) while the monitor was screened by a cardboard. Noise less than 0.1 µV (mean 0.086 µV) was observed in all subjects tested. For all PERGs and VEPs the peak latency and the peak amplitude of each of the averaged waves were measured directly on the display by means of a pair of cursors.
Statistics
The data are reported as mean values ± 1 SD. The differences
between control and MSON and MSCE eyes and between MSON and MSCE eyes
were statistically evaluated with one-way analysis of variance for
repeated measures. To assess whether a correlation exists between OCT
and electrophysiological parameters, linear regression analysis
(Pearson’s test) was adopted. In both statistical analyses,
P < 0.01 was considered significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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PERG and VEP Evaluation
Examples of PERG and VEP recordings from control and MSON eyes are
shown in Figure 1
.
PERGs
Using 60 min arc checks, MSON eyes showed P50 latency, N35 to P50
and P50 to N95 amplitudes with values similar to those of control eyes
and to those of MSCE eyes (P > 0.01). Using 15 min arc
checks, the P50 latency was significantly delayed compared with that in
the control eyes and MSCE eyes; N35 to P50 and P50 to N95 amplitudes
were significantly reduced compared with those in control and MSCE
eyes. No significant differences were found between MSCE and control
eyes.
VEPs
In MSON eyes, the VEP obtained in response to 60-min arc and
15-min arc checks showed P100 latencies significantly delayed and N75
to P100 amplitudes significantly reduced when compared with control and
MSCE eyes. In MSCE eyes, the VEP obtained in response to 15-min arc
checks showed P100 latency significantly delayed compared with that of
control subjects. The P100 latency obtained with 60-min arc checks and
the N75–P100 amplitudes obtained at 60-min arc and 15-min arc checks
were similar to those of control subjects.
OCT versus PERG and VEP
The correlation between NFL thickness and PERG and VEP parameters
is shown in Figures 2
and 3
and in Table 3
. In MSON eyes the NFL Overall and NFL Temporal values
were significantly correlated (P < 0.01) to the PERG
P50 latency and PERG P50 to N95 amplitude (15-min arc checks). No
correlation (P > 0.01) between NFL values and the
other electrophysiological data (PERG N35–P50 amplitude recorded with
15-min arc checks, PERG parameters recorded with 60-min arc checks or
VEP recorded with 60-min arc and 15-min arc checks) was found. In
control and MSCE eyes, no significant correlation between
electrophysiological parameters and NFL thickness was observed.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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We observed a significant reduction of NFL thickness in MSON eyes that conforms with previous studies performed using different methods of retinal fiber assessment.36 37 38 39 This reduction could be because of a loss of those axons that form the head of the optic nerve. A high frequency of transected axons in the affected brain area in MS patients was observed in a recent neuropathologic study.40 It is likely that a similar degree of axonal involvement may develop in the optic nerve affected by the inflammatory process. Retrograde degeneration could then lead to the morphologic changes that we have observed.
It is worth noting that in MSON eyes NFL Overall and NFL Temporal reduced thicknesses were significantly correlated with the delayed P50 latencies and reduced P50 to N95 amplitudes and were not significantly correlated with reduced N35 to P50 amplitudes of PERG response to 15-min arc checks. These significant correlations can be understood based on previous studies of the sites of the PERG sources. Maffei and Fiorentini,19 41 after section of the optic nerve in cats with consequent axonal retrograde degeneration, observed a progressive reduction in amplitude and disappearance of the ERG response when evoked by patterned stimuli, whereas the ERG response evoked by homogeneous luminance stimuli was preserved. Hollander et al.42 found that ganglion cell shrinkage and ganglion cell loss in peripheral retina (particularly in the temporal area) began 3 weeks after section of the optic nerve, and these histologic findings were paralleled by the PERG reduction in amplitude. This was confirmed by experiments performed in monkeys by Maffei et al.43 On the basis of these animal models, the integrity of ganglion cells and their fibers seems to be essential for generation of a normal PERG response.44
That there was no correlation between NFL Overall and NFL Temporal thickness and N35 to P50 amplitudes suggests, in agreement with Holder,14 that not all the P50 component arises in the innermost retinal layer. When we used a large check size (60-min arc checks), the mean values of PERG parameters obtained in MSON eyes were not significantly different from those of control subjects. In addition, no correlation was observed between the electrophysiological and morphologic parameters. The dependence of transient PERG response on the spatial frequency of the visual stimulus has been described by Tobimatsu et al.45 in cats after section of the optic nerve. They found, after the retrograde degeneration of ganglion cells, an impairment of transient PERG in response to small check size stimulation, whereas the PERG response evoked by large-check stimulation was not significantly modified. According to these investigators, it is likely that, when using large checks, the transient PERG signal reflects not only the innermost retinal layers function, but also the response of those retinal elements that are sensitive to uniform luminance changes (preganglionic cells located in more distal retinal layers).
Our results in MSON eyes may therefore be interpreted as follows: The loss of retinal fibers may induce changes in the transient PERG response to small checks (15 min arc), whereas it does not modify PERG response to large checks (60-min arc), because this signal may reflect the preganglionic bioelectrical activity also.
In MSCE eyes without a history of optic neuritis, we observed a reduction in NFL Overall thickness with sparing of NFL Temporal thickness. The P50 latencies and the N35 to P50 and P50 to N95 amplitudes were delayed and reduced (but not significantly) when compared with those of control subjects, and no correlation between PERG parameters and NFL Overall and NFL Temporal thickness was observed. This finding could suggest that some degree of axonal involvement may develop at the retinal level in MS patients, even in the absence of clinical symptoms and electrophysiological abnormalities.
In MSON and MSCE eyes we observed that the NLF Overall and NFL Temporal thicknesses were not related to the visual cortical responses evoked by 60-min arc or 15-min arc check size stimuli, although delayed VEP P100 latencies and reduced VEP N75 to P100 amplitudes were found. Our VEP results indicate that MSON and MSCE eyes display impaired neural conduction in the visual pathways, which is in agreement with several previous studies.1 2 3 4 5 6 7 8 9 10 The absence of correlation between NFL thickness and VEP responses could be explained by considering that the abnormal visual cortical response observed in MS patients may result both from an impaired retinal function and a delayed neural conduction in the postretinal visual pathways.1 2 3 4 5 6 7 8 9 10 16
In conclusion, our results indicate that there is a correlation between PERG changes and NFL thickness, but there is no correlation between VEP changes and NFL thickness in MS patients previously affected by optic neuritis.
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Acknowledgements |
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Footnotes |
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Commercial relationships policy: N.
Corresponding author: Vincenzo Parisi, Via S. Maria Goretti 66, 00199 Roma Italy. E-mail: vparisi{at}tin.it
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), NFL Overall; (
), NFL
Temporal.