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From the Department of Ophthalmology, Niigata University School of Medicine, Niigata, Japan.
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Abstract |
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METHODS. MVEPs of normal subjects (n = 28) and of patients with glaucoma (n = 12) or ocular hypertension (OH, n = 1) were recorded. A multi-input procedure was used to obtain 37 local VEP responses to each scaled hexagon, composed of 24 triangular patterns, reversing in a counterphase manner. Two pattern contrasts of 32% and 8% were used for measuring the contrast threshold. To improve the signal-to-noise ratio, 37 MVEPs were averaged into 20 groups. The root-mean-square (RMS) measures at both contrasts were calculated. Contrast thresholds were estimated by extrapolating the regression line of the amplitude versus contrast to the mean noise levels.
RESULTS. RMS amplitudes of each local MVEP decreased as the eccentricity increased and as the pattern contrast decreased in normal subjects. It was also revealed that the amplitudes were smaller in the upper-half field than those in the lower-half field. Compared with the RMS amplitudes, CSFs estimated by MVEPs were relatively constant without being strongly influenced by retinal eccentricity. In patients with glaucoma, the CSFs, even from the locations where the mean perimetric sensitivities ranged to more than 30 dB, were significantly smaller than those in the normal control subjects (P < 0.001, Mann-Whitney test). CSFs in the 20- to 30-dB and 100 to 20-dB groups were also significantly smaller than those in the more-than-30-dB or 20- to 30-dB groups, respectively (P < 0.001, Mann-Whitney test). A significant correlation was found between the logarithmic function of the CSF and perimetric sensitivity (r = 0.57, P < 0.001, n = 216). The CSFs were evaluated on the basis of normal SD. Mappings of the CSFs agreed well with those of the perimetric sensitivity in all patients with glaucoma and was even more sensitive in detecting slight optic nerve damage by glaucoma than was perimetry.
CONCLUSIONS. Local optic nerve damage caused by glaucoma can be sensitively detected by measuring contrast sensitivity using the MVEP.
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Introduction |
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Recently, Baseler et al.3 reported that many local responses of the VEPs could be obtained by using the multi-input method originally developed for electroretinograms (ERGs) by Sutter and Tran,4 but they concluded that large intersubject variability is one of the obstacles to clinical use. However, Klistorner et al.5 reported that MVEP responses could be obtained from a wider field area by appropriate positioning of the electrodes.
Large interindividual variability and sharp amplitude reduction with an increase in retinal eccentricity in the MVEPs remain as two major problems. Hood et al.6 reported that local optic nerve damage could be quantitatively measured by interocular comparison of the MVEP. This technique solved the problem of intersubject variability to some degree and enabled substantial progress to be made in objective visual field measurements. This method works well in patients in whom the visual field defects are not symmetrical. However, the majority of patients with glaucoma, for example, have visual field defects in both eyes. In such a case, it may be difficult to detect local optic nerve dysfunction by a method of interocular comparison.
Thus, a method for evaluating the MVEP from only one eye to detect optic nerve dysfunction is needed. A method that enables detection of optic nerve dysfunction in the early stage of the disease is also needed. In the present study, we tried to find a solution to these problems.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Analysis
The first slice of second-order kernel was extracted using VERIS
3.1. static perimetry (program 30-2; Humphrey), which was also
performed for comparison with the MVEP (Fig. 1C)
. In the present study,
procedures such as artifact removal that may affect the original MVEP
waveforms were not used. To evaluate response magnitude, the RMS
measure was calculated.
RMSi–j(C) is
defined as the RMS of the MVEP response at contrast (C)
calculated from i to j msec. As in the previous
report,6
RMSi–j was defined
as follows:
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A contrast (supra-) threshold was determined as the point at which the extrapolating regression line intersected the line of mean noise level calculated from RMS0–49(32) and RMS0–49(8) for each location.
To increase the signal-to-noise ratio, the local MVEP responses were grouped and averaged (Fig. 1B) based on the response magnitudes in normal subjects. The upper two groups (Fig. 1B , upper [U]1 and U2) were averaged from four responses. The upper middle group (U3) and lower two groups (lower [L]5 and L9) were averaged from three responses. The upper two groups (U4 and U5), middle two groups (central [C] 1 and C5), and a lower group (L10) were averaged from two responses.
Figure 1C shows the two-dimensional relationship between the field location of the MVEPs and testing points of the Humphrey 30-2 visual field. To compare with the MVEPs, perimetric sensitivities of two testing points (Fig. 1C ; first, third, fifth, and seventh rows; dotted arrow and black ellipse) or four testing points (second, fourth, and sixth rows; black arrow and black circle) that were within or near the corresponding hexagon of the MVEP were averaged.
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Results |
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Figure 2A shows an example of MVEPs from a normal subject at four contrasts. The five locations were selected from 20 grouped locations (U3, U5, C3, L3, and L8). In each location, the peak-to-trough amplitude gradually decreased as the pattern contrast decreased. No substantial response that was distinguishable from noise was found at the initial part of the MVEP from 0 to 49 msec at each location. However, substantial responses were perceived from 50 to 180 msec. MVEPs in the upper area were inverted in waveform compared with those in the horizontal and lower areas. Although the MVEP waveforms varied considerably with location, those at the same location were almost identical, irrespective of the contrast.
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Figure 2C shows the contrast (supra-) threshold measurements in a normal subject, by using the regression line of the RMS amplitude versus the logarithmic function of contrast. In the figure, mean noise of 0.5 x [RMS0–49(32) + RMS0–49(8)] have been subtracted from the RMS amplitudes for each location. A contrast (supra-) threshold was determined as the point at which the extrapolating regression line intersected the x-axis at each location.
Mean and SDs of RMS50–150(32),
RMS50–150(8) in Normal Subjects
Approximately 1 hour was needed to record a single session of the
MVEPs at four pattern contrasts. This is too long for a patient with
glaucoma to maintain a good fixation during recordings. Thus, only
pattern contrasts of 32% and 8% were used to evaluate contrast
thresholds in patients with glaucoma. The mean ± 1 SD of
RMS50–150(32) and
RMS50–150(8) in 28 normal control subjects
are plotted against location in Figures 3A
and 3B , respectively. Three peaks of means were found at C3, L3, and L7
(Figs. 3A
3B)
. All these locations were near the vertical meridian
intersecting the center point of the viewing map. The largest peak was
at C3, which is located in the central area, and the next largest peak
was at L3, which is located in the lower area. The mean amplitudes of
RMS50–150(8) were smaller than those of
RMS50–150(32). The means of the
coefficient of variation were 0.53 for
RMS50–150(32) and 0.63 for
RMS50–150(8) at all 20 locations. Thus,
the intersubject variability was so large for both
RMS50–150(32) and
RMS50–150(8) that it was difficult to
detect slight changes in the MVEP in the patients with glaucoma.
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CSF Measured by MVEPs in 28 Normal Control Subjects
The contrast (supra-) threshold was calculated at each of the 20
locations in the 28 normal subjects. The data were obtained by
extrapolating the regression line (RMS amplitudes of the MVEP versus
logarithmic function of the pattern contrast) to the mean noise level.
The CSF is a reciprocal of the contrast threshold. In the present
study, we could not determine a threshold higher than 0.32 (32%),
because MVEPs were not measured at contrasts higher than 32%. Thus, in
calculating the contrast threshold, if neither
RMS50–150(32) nor
RMS50–150(8) was significant, the
threshold was estimated to be 0.32 (32%, CSF, 3.1) as the maximum
threshold.
Figure 3C shows a graph of the means ± 1 SD of CSFs (plotted in logarithmic function 10) to the location. The distribution of the mean CSFs to the location was quite different from that of the RMS amplitudes. The mean CSF was not highest in the central area, unlike that of the RMS amplitude. The mean CSFs were relatively constant throughout the locations. The mean coefficient of variation was 0.37 for CSF at all 20 locations.
Detection of Local Optic Nerve Dysfunction by the MVEP-CSF Method
Figure 4
shows maps of the CSFs measured by the MVEP from the 12 patients with
glaucoma. CSFs in the patients with glaucoma were scaled for each of
the 20 locations based on the normal SD from the 28 normal control
subjects. Gray-scale maps of the perimetric sensitivity within 25° of
visual field angle are also shown in the figure. Each of the 20 grouped
locations was scaled from black to white. The black shading indicates
the decrease over 2 SD from the normal mean. The white shading
indicates the decrease within mean ± 1 SD. The shadings of the
fine and coarse dots indicate the decreases of over 1 and 1.5 SD from
the normal mean, respectively. These mappings of the CSFs agreed well
with those of the perimetric sensitivity in the patients with lower
field loss (P5 and P6), upper field loss (P7 and P8) and severe field
loss (P10–P13). It was noted that the CSF was more sensitive to local
damage to the optic nerve than was perimetry in some areas of the map.
Thus, slight optic nerve dysfunction even in cases in which perimetric
sensitivity loss was slight could be sensitively detected by using the
MVEP-CSF method. This method may also enable detection of local optic
nerve dysfunction that could not be detected by perimetry in patients
with early-stage glaucoma (P1–P3).
CSF and Perimetric Sensitivity in Patients with Glaucoma
CSFs evaluated by MVEPs were compared with perimetric
sensitivities for all patients with glaucoma. CSFs at C1 and C5,
located on the horizontal line, were excluded from the comparison,
because of the low response and because of the low signal-to-noise
ratio at C5 and large intersubject variability at C1. Moreover, the
mean of the perimetric sensitivity was not reliable because C5
contained a blind spot. Thus, 18 CSFs were compared with the mean
sensitivities of the corresponding spots (Fig. 1C)
for each of the 18
locations in all patients.
The CSF decreased as the perimetric sensitivity decreased in patients with glaucoma. Figure 5A shows that the CSFs were significantly decreased, even in the area where the perimetric sensitivity was over 30 dB, compared with normal data (P < 0.001, n = 62, Mann-Whitney test). The CSFs from the locations where the mean perimetric sensitivities ranged from 20 to 30 dB were significantly decreased compared with those of the more-than-30-dB group (P < 0.002, n = 68, Mann-Whitney test). There was also a significant difference between the mean CSFs in the 20- to 30-dB and 10- to 20-dB groups. However, there was no significant difference between the mean CSFs in the 10- to 20-dB and 0- to 10-dB groups.
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MVEP Changes in Early Stages of Glaucoma
Figure 6
shows four sets of MVEPs from a normal subject and from three patients
with different stages of glaucoma. The uppermost row shows MERGs from a
normal subject of 63 years of age. There was no decrease in the CSF
over 1 SD from the normal mean. P7 was selected as an example of
moderately progressed glaucoma (NTG) and had visual field defects in
the upper-half field. As shown in the total deviation of the perimetry
in Figure 6
, the perimetric sensitivity was decreased significantly
only in the upper-half field. However, although both
RMS50–150(32) and
RMS50–150(8) decreased under the noise
levels in the locations of U1 to U4, C1, C5, and L5 (***; a decrease
over 2 SD), CSFs were also reduced in the lower field of L1, L2 (*; a
decrease over 1 SD) and L7 (**; a decrease over 1.5 SD). CSFs were also
decreased in the locations of C3 (*) and L7 (**).
P2 was selected as an example of early-stage glaucoma (POAG). Local optic nerve dysfunction in the lower field was detected by both MVEPs and perimetry. The mapping of CSF loss agreed well with that of the total deviation. OH was diagnosed in the right eye of P13. There was no significant decrease in the indices of the static perimetry (Humphrey), but there were a few locations where the CSFs decreased over 1 or 1.5 SD from the normal means (* or **).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Interocular comparison could be effective for detecting local optic nerve damage if the MVEPs from the affected area were compared with those from the corresponding normal area of the opposite eye. However, the precise degree of optic nerve damage could not be determined if both corresponding areas were affected.
Estimation of the absolute amplitudes of MVEPs is not an optimal method for detecting a local visual field loss because of its dependence on electrode placement and anatomic variations in the visual cortex. The VEP amplitude and polarity vary with the location and orientation of the underlying cortical sources relative to the electrodes. There is also a large intersubject variability in anatomy. In contrast, coefficients of variance in the ratio of CSF were greatly reduced compared with the RMS amplitudes over all locations (Fig. 3C) . Thus, the contrast threshold, which is a relative value determined from the regression line, is more appropriate for evaluation of the visual field, because its variability can be reduced much more than that of the absolute value of the MVEP amplitude itself.
The absence of a substantial response does not necessarily imply an actual perimetric sensitivity loss. It is important to know whether the local MVEP is significant. If the signal-to-noise ratio of the response is not sufficiently high to determine the CSF, the data will be impossible to evaluate. In the group of 37 MVEPs without averaging, the rates of significant response obtained from the 28 normal subjects decreased as the retinal eccentricity increased, especially in the upper areas. However, substantial MVEP responses from normal subjects could be recorded from most field locations by averaging and grouping MVEPs into 20 groups. Thus, we can partially overcome these major problems by evaluating the CSF and by averaging the responses. Further study on recording conditions is needed to improve the signal-to-noise ratio of the responses in the periphery. Klistorner et al.5 and Klistorner and Graham7 reported that improved and larger signals could be derived when two additional electrodes were placed horizontally on either side of the inion. If these multiple-channel recordings were applied to the MVEP-CSF method, local optic nerve dysfunction would be more sensitively detected.
CSFs have generally been measured from VEP recordings by extrapolating the regression line (VEP RMS amplitude versus log pattern contrast) to zero amplitude. The technique was originally introduced by Campbell and Maffei.8 In a strict sense, sinusoidal grating should be used for CSF evaluation when using VEPs. However, the triangular pattern used in the present study was effective for deriving relatively clear MVEP responses, even from peripheral areas, because the pattern simultaneously stimulates several spatial frequencies and orientations. Researchers have used a single and large visual stimulus that activated large areas of the visual cortex for recording VEPs. However, small stimuli reduce the cancellation effect of the response from cortical sources between the upper and lower fields. Thus, the multifocal technique has the advantage of enabling recording of MVEPs, even from peripheral areas by using the type of recording parameters used in this study. A good signal-to-noise ratio can be obtained by averaging adjacent responses if the responses have the same polarity and have no cancellation effect on each other.
The current results showed that the distribution of CSFs according to the location is quite different from that of the MVEP amplitudes. This distribution is related to those of parallel pathways9 of parvocellular (P) and magnocellular layers (M). The M system is tuned to low spatial frequencies and high temporal frequencies. M neurons have high-contrast gain but are saturated at fairly low contrasts, whereas the P system has lower contrast gain but is saturated at much higher contrasts. Although the 75-Hz frame rate used in this study is thought to be suitable for an M system, 32% contrast may also stimulate P system because MVEP amplitudes tend to saturate at 32% contrast. Thus, if a contrast lower than 16% was used to derive MVEPs, a more linear function between the amplitude and contrast might be obtained. Baseler and Sutter10 suggested that contributions to the VEP from the M pathway precede those from the P pathway and that the ratio of P-to-M contributions decreases with eccentricity. The stimulus used in this study was effective for deriving responses from these two systems.
In the present study, there were discrepancies between the MVEP and visual field, as shown in Figure 5B . Hood et al.6 gave four possible explanations for such discrepancies in their study: reliability of the tests (false negative-positive or artifacts) varied from subject to subject, data from some field locations were less reliable than data from other locations, there was a difference in the sensitivities of MVEP and perimetry to pathologic changes, and there were differences in the testing stimulus—pattern in MVEP and spot in the visual field. These also seem to be reasonable explanations for the discrepancies in the present study. We think that the fourth explanation is the best explanation for the difference between the objective and subjective test results.
To overcome intersubject variability and to sensitively detect local optic nerve dysfunction, we compared, within an eye, two sets of MVEPs at different pattern contrasts. In conclusion, evaluation of contrast sensitivity using multifocal VEPs is a novel, sensitive technique for detection of local optic nerve dysfunction that can be used clinically in patients with glaucoma.
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Footnotes |
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Commercial relationships policy: N.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be marked
"advertisement" in accordance with 18 U.S.C. 
1734
solely to indicate this fact.
Corresponding author: Shigeru Hasegawa, Department of Ophthalmology, Niigata University School of Medicine 1-757 Asahimachi-dori, Niigata 951-8510, Japan. hasesig2{at}med.niigta-u.ac.jp
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References |
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