May 2008
Volume 49, Issue 5
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Visual Neuroscience  |   May 2008
Correlation between Photopic Negative Response and Retinal Nerve Fiber Layer Thickness and Optic Disc Topography in Glaucomatous Eyes
Author Affiliations
  • Shigeki Machida
    From the Department of Ophthalmology, Iwate Medical University, School of Medicine, Iwate, Japan.
  • Yasutaka Gotoh
    From the Department of Ophthalmology, Iwate Medical University, School of Medicine, Iwate, Japan.
  • Yoshiharu Toba
    From the Department of Ophthalmology, Iwate Medical University, School of Medicine, Iwate, Japan.
  • Aki Ohtaki
    From the Department of Ophthalmology, Iwate Medical University, School of Medicine, Iwate, Japan.
  • Muneyoshi Kaneko
    From the Department of Ophthalmology, Iwate Medical University, School of Medicine, Iwate, Japan.
  • Daijiro Kurosaka
    From the Department of Ophthalmology, Iwate Medical University, School of Medicine, Iwate, Japan.
Investigative Ophthalmology & Visual Science May 2008, Vol.49, 2201-2207. doi:10.1167/iovs.07-0887
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      Shigeki Machida, Yasutaka Gotoh, Yoshiharu Toba, Aki Ohtaki, Muneyoshi Kaneko, Daijiro Kurosaka; Correlation between Photopic Negative Response and Retinal Nerve Fiber Layer Thickness and Optic Disc Topography in Glaucomatous Eyes. Invest. Ophthalmol. Vis. Sci. 2008;49(5):2201-2207. doi: 10.1167/iovs.07-0887.

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      © 2015 Association for Research in Vision and Ophthalmology.

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Abstract

purpose. To investigate whether there is a significant correlation between the photopic negative response (PhNR) of the electroretinogram (ERG) and retinal nerve fiber layer thickness and optic disc topography in glaucomatous eyes.

methods. Ninety-nine eyes of 53 patients with open-angle glaucoma (OAG) and 30 eyes of 28 normal volunteers were studied. Photopic ERGs were elicited by red stimuli (644 nm, 1600 cd/m2) on a blue background (470 nm, 40 cd/m2). The mean deviation (MD) of the visual field was obtained by static visual field analyses. The topography of the optic nerve head was determined by confocal scanning laser ophthalmoscopy. The retinal nerve fiber layer thickness (RNFLT) around the optic nerve head was measured with a scanning laser polarimeter.

results. The amplitude of the PhNR and the PhNR/b-wave ratio decreased with an increase in visual field defects. The logarithmic values of the PhNR amplitude and PhNR/b-wave amplitude ratio were significantly correlated with the MD better than the linear values. The PhNR amplitude and PhNR/b-wave amplitude ratio were significantly correlated with the RNFLT and the rim area of the optic disc and with the cup/disc area ratio. These correlations were higher when expressed linearly than when stated logarithmically. The sensitivity and specificity were 77% and 90% for the PhNR amplitude and 70% and 87% for the PhNR/b-wave amplitude ratio when the optimal cutoff values were used. Although the a-wave amplitude correlated with the MD, the a-wave amplitudes of most of the patients fell within the normal range. The correlation between the b-wave amplitude and MD was not significant.

conclusions. The PhNR amplitudes correlate with the decrease in function and morphology of retinal neurons in eyes with OAG. The linear relationship between the PhNR and the structural parameters indicates that inner retinal function declines proportionately with neural loss in eyes with glaucoma.

It was generally believed that the neural activity of retinal ganglion cells (RGCs) contributes little to shaping the corneally recorded ERGs. However, the scotopic threshold response (STR), a response elicited by weak stimuli under dark-adapted conditions has been shown to reflect the neural activity of RGCs in primates. 1 In addition, a response driven by RGCs receiving signals from cones was newly discovered 2 and called the photopic negative response (PhNR). 3 The PhNR is strongly attenuated in primates with experimentally induced glaucoma and after an intravitreous injection of tetrodotoxin 3 that blocks the voltage-gated sodium channels in retinal neurons including RGCs, amacrine cells, cone bipolar cells, and cones. 4 5 6  
In the clinic, the PhNR amplitude is reduced in patients with open-angle glaucoma (OAG), and the decrease in amplitude correlates with the degree of optic nerve damage represented by optic disc cupping and visual field loss. 7 In addition, it has been reported that the PhNR is selectively attenuated in eyes with optic nerve atrophy induced by trauma, compression, inflammation, gene mutation, and ischemia. 8 9 10 Of interest, the retinal nerve fiber layer thickness (RNFLT) measured by optical coherence tomography (OCT) correlated highly with the amplitudes of the PhNR in eyes with optic nerve atrophy. 8 This association indicates that the amplitude of the PhNR is a good measure of the decrease in the RNFLT in patients with optic nerve atrophy. 
It has been demonstrated that anatomic changes in RGCs can precede the functional loss of RGCs. Earlier studies 11 12 have shown that a loss of nearly 50% of the RGCs is necessary before visual field defects appear in the static visual fields in glaucomatous eyes, although more recent work shows that common scaling yields a linear relationship (see later). If this is the case for the functional parameters of RGCs, the amplitude of the PhNR should remain normal at the early stage of glaucoma. Therefore, it is important to clarify how the amplitude of the PhNR correlates with the morphology of the retinal neurons in eyes with glaucoma. 
Recently, topographic analysis of the optic nerve head has been advanced considerably by confocal scanning laser ophthalmoscopy. The rim and cupping of the optic nerve head can be quantitatively evaluated, which helps in the diagnosis of glaucoma. The Heidelberg Retina Tomograph (HRT II; Heidelberg Engineering, Heidelberg, Germany) is a commercially available confocal scanning laser ophthalmoscope that can be used to assess the morphology of the optic nerve head. The RNFLT can be measured by scanning laser polarimetry and OCT. Earlier studies have shown that these new diagnostic instruments can be used to obtain quantitative and objective evaluations of the morphology of the optic nerve head and RNFL. 13 14 15 16  
The purpose of this study was to evaluate the clinical significance of the PhNRs recorded from eyes with open angle glaucoma (OAG) by correlating the amplitudes of the PhNR with the RNFLT and morphologic parameters of the optic disc obtained in glaucomatous eyes by the newer instruments. 
Methods
Patients
Ninety-nine eyes of 53 patients with OAG were studied. The patients were being treated in the Glaucoma Unit of the Iwate Medical University Hospital, and their ages ranged from 45 to 86 years with a mean ± SD of 67.1 ± 9.2 years. The diagnosis of OAG was based on the presence of a glaucomatous optic disc associated with visual field defects measured by static visual field perimetry. All patients underwent gonioscopy to confirm that the anterior chamber angles were open. According to the diagnostic criterion for minimal abnormality in the visual field, 17 the visual field defect was determined to be glaucomatous when it met one of three criteria: (1) The pattern deviation plot showed a cluster of three or more nonedge points that had lower sensitivities than that in 5% of the normal population (P < 0.05), and one of the points had a sensitivity that was lower than that in 1% of the population (P < 0.01); (2) the value of the corrected pattern SD was lower than that of 5% of the normal visual field (P < 0.05); and (3) the Glaucoma Hemifield Test indicated that the field was outside normal limits. Of the 99 eyes of the patients with glaucoma, 13 did not meet the criteria and were classified as suspected glaucoma. In all glaucomatous eyes, the intraocular pressure was controlled at lower than 21 mm Hg by means of antiglaucoma eye drops at the time of the ERG recordings. 
Thirty eyes of 28 age-matched normal volunteers, ranging in age from 53 to 78 years with a mean of 68.7 ± 7.1 years were studied. 
This research was conducted in accordance with the Institutional Guidelines of Iwate Medical University, and the procedures conformed to the tenets of the Declaration of Helsinki. An informed consent was obtained from all subjects after a full explanation of the nature of the experiments. 
Recording Photopic ERG
The photopic ERGs were elicited by red stimuli of 1600 cd/m2max = 644 nm, half-amplitude bandwidth = 35 nm) on a blue background of 40 cd/m2max = 470 nm, half-amplitude bandwidth = 18 nm). This recording condition is similar to that used in the experiments by Viswanathan et al. 3 7 18 and Rangaswamy et al. 9 The duration of the stimuli was 3 ms. Before the recordings began, all subjects were light adapted to the background light for more than 10 minutes. 
The stimulus and background lights were produced by light-emitting diodes (LEDs) embedded in the active contact lens electrodes which were translucent to diffuse the stimulus and background lights. The intensity and duration were controlled by an electronic stimulator (LS-C; Mayo Co., Nagoya, Japan). The reference and ground electrodes were placed on the forehead and right ear lobe, respectively. The responses were digitally bandpass filtered from 0.5 to 1000 Hz and amplified 105 times (Neuropack μ, MEB 9102; Nihonkoden, Tokyo, Japan). Forty to 100 responses were computer-averaged with an interstimulus interval of 1 second. 
The a- and b-wave amplitudes were measured from the baseline to the trough of the first negative response and from the first trough to the peak of the following positive wave, respectively. The PhNR amplitude was measured from the baseline to the negative trough at ∼70 ms, which always appeared after the i-wave (Fig. 1A)
Twenty two eyes of patients and 22 eyes of normal control subjects were tested twice, and the second recordings were made at least 2 days but no more than 2 weeks after the first. To evaluate the within-subject variability, the coefficient of variation (CV = SD/mean × 100) was calculated for PhNR amplitudes. 
Visual Field Analyses
The Humphrey Visual Field Analyzer (model 750; Carl Zeiss Meditec, Inc., Dublin, CA) was used for the static visual field analyses. The SITA Standard strategy was applied to program 24-2, and the measurements of the visual sensitivity were made after at least 3 minutes of adaptation to the background lights. The mean deviation (MD) was defined as the mean of the differences between the measured sensitivity and normal values of age-matched control eyes. Thus, the MDs represented the depression of sensitivity over the whole visual field. From the MD, we classified patients with glaucomatous visual fields into three groups; early (MD > −6 dB), moderate (−6 dB ≧ MD ≧ −12 dB), and severe (MD < −12 dB) defect of the visual field. 
Quantitative Assessment of the Optic Nerve Head and RNFL
To determine the topography of the optic nerve head, we used a retinal tomograph (HRTII; Heidelberg Retinal Tomograph; Heidelberg Engineering, Heidelberg, Germany), which employs confocal scanning diode technology. Three 15° field-of-view scans, centered on the optic nerve head, were obtained and automatically averaged by the program of the instrument (IR1-V1.7.2/4622). Experienced operators (YT, AO) evaluated the quality of the image and outlined the disc margin while viewing the photograph of the optic nerve head. The rim area and cup-to-disc area ratio were included in the analysis. 
The RNFLT around the optic nerve head was measured by the GDx-VCC scanning laser polarimeter (Carl Zeiss Meditec, Inc.), with a conversion to variable corneal compensation. The average temporal, superior, nasal, and inferior (TSNIT) thicknesses were obtained and analyzed. 
The test–retest variability of TSNITs with the GDx-VCC was determined, and the CV was found to be more than 6% for both normal and glaucomatous eyes. The CVs were stable across a wide range of disease stages. 19 20 The results of a recent study demonstrated that the repeatability of the rim area and cup–disc area ratio measured by HRTII is high but is affected by the severity of the glaucoma. 20  
Statistical Analyses
The significance of the differences was determined by the Student’s two-tailed t-test for paired data. Pearson’s coefficient of correlation was calculated to determine the degree of correlation between the functional and morphologic parameters and the amplitude of the PhNR. The Deming regression was also used to evaluate the association between these parameters. 
The sensitivity of the PhNR indicates how well it can detect a glaucomatous eye, and the specificity shows how well it can differentiate normal from glaucomatous eyes. The sensitivity and specificity were calculated with standard formulas for the PhNR amplitudes and PhNR/b-wave amplitude ratios. Receiver operating characteristic (ROC) curves were used to determine the cutoff values that yielded the highest combined sensitivity and specificity with respect to distinguishing glaucomatous from normal eyes. 
Results
ERG Changes with Advancing Visual Field Defects
Patients were divided by their MDs into those with mild (n = 34), moderate (n = 25), or severe (n = 27) visual field defects. Representative photopic ERGs are shown in Figure 1A . These ERGs were recorded from a normal eye and from a glaucomatous eye that was classified as having a moderate visual field defect. The amplitude of the PhNR was smaller in the glaucomatous eye than in the normal eye, whereas the amplitudes of the a- and b-waves were not different. 
The average a-wave amplitudes was significantly smaller in glaucomatous eyes than that of normal eyes (P < 0.05, Fig. 1B ). However, there was no significant difference in the a-wave amplitude among the glaucomatous eyes with different degrees of visual field defects. This is similar to earlier reports that a significant reduction of the photopic a-wave amplitude was found in patients with glaucoma and with optic neuropathy. 7 9  
The reduction of the average amplitudes of the b-wave with advancing visual field defects was not significant. However, the PhNR amplitude was significantly decreased in glaucomatous eyes with mild, moderate, or severe visual field defects in comparison to normal eyes (P < 0.05). 
To reduce the variations of the PhNR amplitude among individuals, the ratios of the amplitudes of the PhNR to the a-wave (PhNR/a-wave amplitude ratio) or b-wave (PhNR/b-wave amplitude ratio) were examined (Figs. 1C 1D) . Both ratios decreased with advancing visual field defects. Even in glaucomatous eyes with mild visual field defects, the PhNR amplitude and the amplitude ratio of the PhNR/a-wave as well as PhNR/b-wave were significantly reduced compared with that of normal eyes (P < 0.05). The b-wave amplitudes did not differ significantly between the normal and glaucomatous eyes, but the a-wave amplitudes decreased with a progression of the visual field defects (Fig. 1B) . Therefore, we decided to use the PhNR/b-wave amplitude ratio in the following studies, because it reflects the change of the PhNR amplitude better than the PhNR/a-wave amplitude ratio. 
Correlation between ERG Amplitudes and MD of Visual Fields
The correlations between the ERG a- and b-wave amplitudes and MDs obtained by static perimetry are shown in Figure 2 . Although the a-wave amplitude was significantly correlated with the MD (Fig. 2A , linear r = 0.35, P < 0.001; Deming: P < 0.001), only a small number of points fell outside the normal range (from 17 to 44 μV), indicating that it was difficult to discriminate glaucomatous eyes based on the a-wave amplitude. In addition, the correlation between the b-wave amplitude and MD was not significant (Fig. 2B)
In contrast, the reduction of the PhNR amplitude (Fig. 3A)and PhNR/b-wave amplitude ratio (Fig. 3B)correlated significantly with the decrease in the MD. The correlation coefficients were higher when the PhNR amplitude and PhNR/b-wave amplitude ratio were expressed in logarithmic units rather than linear units (Table 1 , log r = 0.62, linear r = 0.58, P < 0.001, Deming: P < 0.001 for the PhNR amplitude; log r = 0.65, linear r = 0.60, P < 0.001, Deming: P < 0.001 for the PhNR/b-wave amplitude ratio). 
Correlation between the PhNR and Structural Parameters
The correlations between the PhNR and structural parameters obtained by HRTII and GDx-VCC are shown in Figures 4 5 and 6 . The PhNR amplitudes and PhNR/b-wave amplitude ratio correlated linearly with a decrease in the rim area (Fig. 4 , Table 1 ; linear r = 0.49, log r = 0.45, P < 0.001, Deming: P < 0.001 for the PhNR amplitude; linear r = 0.49, log r = 0.47, P < 0.001, Deming: P < 0.001 for the PhNR/b-wave amplitude ratio) and with an increase in cup-to-disc area ratio (Fig. 5 , Table 1 ; linear r = −0.47, log r = −0.43, P < 0.001, Deming: P < 0.001 for the PhNR amplitude; linear r = −0.48, log r = −0.44, P < 0.001, Deming: P < 0.001 for the PhNR/b-wave amplitude ratio). 
The correlation between the PhNR and RNFLT measured by GDx-VCC is shown in Figure 6 . The PhNR amplitude correlated linearly with the RNFLT (Fig. 6A , Table 1 ; linear r = 0.53, log r = 0.49, P < 0.001, Deming: P < 0.001). A significant correlation was found between the PhNR/b-wave amplitude ratio and RNFLT with a better correlation than with the PhNR amplitudes (Fig. 6B , Table 1 ; linear r = 0.55, log r = 0.51, P < 0.001, Deming: P < 0.001). 
The logarithmic scaling of the PhNR amplitudes could not explain the relationship between the PhNR and these morphometric parameters better than the linear scaling (Table 1) . The correlations in the a- and b-wave amplitudes with the morphometric parameters of the optic nerve head were not significant (not shown). 
In general, the correlation coefficients were greater for the PhNR/b-wave than for the PhNR amplitude (Table 1)
Sensitivity and Specificity of the PhNR Amplitude and PhNR/b-Wave Amplitude Ratio
To obtain the optimal cutoff values, we varied them in decrements of 1 μV and 0.1 for the PhNR amplitude and the PhNR/b-wave amplitude ratio, respectively, in the range of values from patients with glaucoma and normal controls. The sensitivity and specificity were obtained for each cutoff and plotted to determine the ROC curve. Optimal cutoffs, giving the maximum combination of sensitivity and specificity, were 23 μV for the PhNR amplitude and 0.24 for the PhNR/b-wave amplitude ratio. 
When these optimal cutoffs were used, the sensitivity and specificity were 77% and 90% for the PhNR amplitude and 70% and 87% for the PhNR/b-wave amplitude ratio. The area under the curve (AUC) was 0.79 for the PhNR amplitude and 0.75 for the PhNR/b-wave amplitude ratio. 
Among patients with early stage of visual field defect, the sensitivity using the optimal cutoff was 57% and 53% for the PhNR amplitude and PhNR/b-wave amplitude ratio, respectively. For eyes with a moderate defect of the visual field, the sensitivity increased to 88% and 65%. In patients with severe defects of the visual fields, the sensitivity further increased to 89% and 93%. These results indicate that the PhNR can discriminate only one-half of glaucomatous eyes during early-stage glaucoma. 
Intersession Reproducibility
The CVs for the PhNR amplitude in normal control subjects and patients with glaucoma were 8.70% ± 5.37% and 14.62% ± 10.93%, respectively. The corresponding values for the PhNR/b-wave amplitude ratio were 12.08 ± 7.18 and 16.31 ± 14.51 for the two measures. The CV for the PhNR amplitude was significantly larger in glaucoma patients than for the normal control subjects (P < 0.05). 
Discussion
The amplitude of the PhNRs in our study decreased with the advancement of glaucoma, as assessed by static perimetry. In addition, the reduction of the PhNR amplitude not only correlated with the degree of visual field defect but also with the neural loss assessed by anatomic structure of the optic nerve head and RNFL. 
Correlation of PhNR with MD of Static Visual Field
Viswanathan et al. 7 were the first to show that the PhNR amplitude correlates linearly with the MD determined by the static visual field tests. We attempted to confirm their results in a larger number of patients and a wider range of disease stages. However, we found some differences from their results. In plotting the PhNR amplitude or the PhNR/b-wave amplitude ratio against the MD, we found that a curvilinear regression was a better fit than a linear regression. When the PhNR amplitude and PhNR/b-wave amplitude ratio were plotted on a logarithmic scale, the correlation coefficients were higher than with a linear scale. 
This is not the first study to show a curvilinear relationship between the inner retinal response and visual sensitivity obtained by visual field testing. It has been demonstrated that the amplitude of the pattern ERG correlates with visual sensitivity in a curvilinear fashion. 21 The pattern ERG response is known to represent RGC activity in animals and humans and has been used to study glaucoma and other optic nerve diseases. 18 22 23 These curvilinear relationships between visual sensitivity and inner retinal responses can be partially explained by the fact that the visual sensitivity is recorded in logarithmic units (decibels). 
The curvilinear association of the PhNR with the MD (dB) indicates that large changes of the PhNR amplitude correspond with small loss of the MD, and the MDs could still be in the normal range. In fact, although there was a wide range of variation, some of the PhNR amplitude or PhNR/b-wave amplitude ratio of patients with subtle visual field defects fell in the abnormal range (Fig. 3)
Correlation of the PhNR with Structural Parameters
It is generally believed that retinal function is relatively preserved despite a significant loss of RGCs in glaucomatous eyes. This idea is supported by earlier clinicopathologic studies that demonstrated that an approximate 50% loss of RGCs is necessary before a detectable loss of the sensitivity (decibels) is detected in the conventional static visual field. 11 12 In fact, a curvilinear relationship has been reported between visual sensitivity (dB) obtained by the static visual field and the RNFLT and morphology of the optic nerve head. 21 24 This relationship indicates that a large change in the structural values occurs with a small decrease of visual sensitivity at the early stage of glaucoma. 
However, in this study, the PhNR amplitude and PhNR/b-wave amplitude ratio correlated linearly with RNFLT and the structure of the optic disc, indicating that the function of RGCs declines proportionately with the neural loss in glaucoma. These findings suggest that compensational mechanisms do not work at the RGC level in glaucomatous eyes. Ours is not the first study to document a linear relationship between electrical signals from RGCs and anatomic structure of the RNFL and optic nerve head. It has been demonstrated that the pattern ERG amplitude correlates linearly with the temporal rim area of the optic nerve head. 21  
In our study, the PhNR amplitude correlated highly with the RNFLT measured by OCT in patients with optic nerve atrophy induced by trauma, compression, and optic neuritis. 8 However, in the present study, we found that the coefficient of correlation was much lower (r = 0.53 vs. 0.88). Two reasons can be considered to explain the differences. First, we have to consider the pathologic differences between glaucoma and optic nerve atrophy. In glaucomatous eyes, the RNFL is regionally impaired at the early stage of disease. On the other hand, the RNFL is diffusely affected by the disease process in eyes with optic nerve atrophy. We measured the averaged RNFLT around the optic nerve head because the PhNR is supposed to reflect the function of RGCs throughout the ocular fundus. Measuring the PhNR and RNFL seems more suitable for the optic nerve diseases in which RGCs are diffusely affected than for glaucoma at early and moderate stages when RGCs are locally impaired. Second, differences in the accuracy of the two methods for measuring RNFLT may contribute to the results. In previous reports, it was demonstrated that RNFLT obtained by OCT correlated with visual sensitivity better than the data obtained by GDx. 25 In addition, the RNFLT measured by OCT correlated better with the s-wave amplitude of the multifocal ERGs, which represents RGC responses, than with that measured by the GDx. 26 Therefore, the differences in the instrument used to measure RNFLT could affect the results. 
Sensitivity and Specificity
The sensitivity and specificity at the optimal cutoff values as well as the AUC are comparable to those of a previous report. 7 However, even with the optimal cutoffs, the sensitivity was low in patients in the early stage of glaucoma with mild visual field defects. This result indicates that the PhNR is not suitable for detecting or screening patients during the early stage. 
It has been reported that an RGC loss of nearly 50% is necessary before the static visual field demonstrates the abnormal loss of sensitivity in glaucoma. 11 12 The results from our laboratory have shown that there was a strong linear correlation between the PhNR amplitude and RNFLT around the optic nerve head representing the loss of RGCs in patients with optic nerve atrophy. 8 Based on these findings, a 50% loss of RGCs should result in reduction of the PhNR amplitude by 50%. From these results, we expected that the PhNR may detect a functional change in RGCs earlier than would visual field testing. The poor ability of the PhNR to discriminate early glaucomatous changes seems to be due to the large variation among individuals and the nature of the recordings. 
One of the disadvantages of the PhNR is that it reflects the function of RGCs receiving signals from cones throughout the ocular fundus. The early defect of the visual field begins in the paracentral field which is not detected by the full-field ERGs. Thus, a refining of the recording method of the PhNR is necessary to apply the PhNR in the clinic and ensure its clinical value. 
Future Studies
To increase the ability to discriminate changes that occur earlier than visual field defects, it is necessary to record local responses from the retina, especially from parafoveal areas that are preferentially affected by glaucoma in the early stage. Therefore, focal ERGs recorded from the parafoveal region while viewing the ocular fundus 27 28 29 may improve the sensitivity for discriminating glaucomatous eyes at the early stage. 
Colloto et al., 30 recorded the PhNR of the focal macular ERG from patients with mild visual field defects induced by glaucoma. They found that the correlation coefficients for the PhNR amplitude and MD or structural parameters of the optic nerve head were higher than those obtained in our study, raising the possibility that focal macular ERGs are more sensitive in detecting functional loss in glaucomatous eyes. However, comparative studies between focal macular and full-field ERGs are necessary to establish an advantage of the PhNR recorded by the focal macular ERG in glaucomatous eyes. 
Variability of PhNR
Previously, the test–retest variability has been reported for the pattern ERG, 31 in which the CV was comparable to that of the normal subjects in our study. In glaucomatous eyes, the CV significantly increased in comparison with that in normal eyes, indicating that reproducibility declines in eyes with low PhNR amplitudes. This finding implies that the PhNR is not a suitable measure for observing the progression of the disease in patients with severe glaucoma. 
We expected that the PhNR/b-wave amplitude ratio could reduce the variability between individuals. In fact, correlation coefficients between the PhNR and functional or structural parameters were slightly improved by employing this ratio. However, the ratio failed to improve the sensitivity and specificity as well as reproducibility, suggesting that the PhNR/b-wave amplitude ratio is no better than the PhNR amplitude in discriminating and observing patients with glaucoma. 
Conclusions
The amplitudes of the PhNR are linearly correlated with structural parameters of the RNFL and optic disc, and thus the PhNR could be a measure for tracking the morphologic state of the optic disc and RGC axons. Linear structure–function correlations suggest that inner retinal function declines proportionately with neural loss in glaucoma. 
 
Figure 1.
 
(A) Representative ERGs recorded from a normal and a glaucomatous eye with moderate defects in the visual fields. (B) Averaged amplitudes of the a- and b-wave and PhNR amplitudes recorded in normal control subjects and patients with glaucoma at different stages of visual field defect (white: normal eyes, n = 30; light gray: suspected glaucoma, n = 13; gray: mild visual field defects, n = 34; dark gray: moderate visual field defects, n = 25; black: severe visual defects, n = 27). (C) Averaged ratio of the PhNR/a-wave amplitude from normal control subjects and patients with different stage of visual field defect. (D) Averaged ratio of the PhNR/b-wave amplitude from normal control subjects and patients with different severity of visual field defects. Error bars, SD.
Figure 1.
 
(A) Representative ERGs recorded from a normal and a glaucomatous eye with moderate defects in the visual fields. (B) Averaged amplitudes of the a- and b-wave and PhNR amplitudes recorded in normal control subjects and patients with glaucoma at different stages of visual field defect (white: normal eyes, n = 30; light gray: suspected glaucoma, n = 13; gray: mild visual field defects, n = 34; dark gray: moderate visual field defects, n = 25; black: severe visual defects, n = 27). (C) Averaged ratio of the PhNR/a-wave amplitude from normal control subjects and patients with different stage of visual field defect. (D) Averaged ratio of the PhNR/b-wave amplitude from normal control subjects and patients with different severity of visual field defects. Error bars, SD.
Figure 2.
 
The (A) a- and (B) b-wave amplitudes against MD.
Figure 2.
 
The (A) a- and (B) b-wave amplitudes against MD.
Figure 3.
 
PhNR amplitudes (A) and PhNR/b-wave amplitude ratio (B) against MD.
Figure 3.
 
PhNR amplitudes (A) and PhNR/b-wave amplitude ratio (B) against MD.
Table 1.
 
Comparison of the Correlation Coefficients between PhNR and Visual Field or Structural Parameters
Table 1.
 
Comparison of the Correlation Coefficients between PhNR and Visual Field or Structural Parameters
Linear Logarithmic
PhNR amplitude vs. MD
 Correlation coefficient 0.58 0.62
P <0.001 <0.001
PhNR/b-wave amplitude ratio vs. MD
 Correlation coefficient 0.60 0.65
P <0.001 <0.001
PhNR amplitude vs. rim area
 Correlation coefficient 0.49 0.45
P <0.001 <0.001
PhNR/b-wave amplitude ratio vs. rim area
 Correlation coefficient 0.49 0.47
P <0.001 <0.001
PhNR amplitude vs. cup/disc area ratio
 Correlation coefficient −0.47 −0.43
P <0.001 <0.001
PhNR/b-wave amplitude ratio vs. cup/disc area ratio
 Correlation coefficient −0.48 −0.44
P <0.001 <0.001
PhNR/b-wave amplitude ratio vs. cup/disc area ratio
 Correlation coefficient −0.48 −0.44
P <0.001 <0.001
PhNR amplitude vs. RNFLT
 Correlation coefficient 0.53 0.49
P <0.001 <0.001
PhNR/b-wave amplitude ratio vs. RNFLT
 Correlation coefficient 0.55 0.51
P <0.001 <0.001
Figure 4.
 
PhNR amplitudes (A) and PhNR/b-wave amplitude ratio (B) against rim area.
Figure 4.
 
PhNR amplitudes (A) and PhNR/b-wave amplitude ratio (B) against rim area.
Figure 5.
 
PhNR amplitudes (A) and PhNR/b-wave amplitude ratio (B) against cup–disc area ratio.
Figure 5.
 
PhNR amplitudes (A) and PhNR/b-wave amplitude ratio (B) against cup–disc area ratio.
Figure 6.
 
PhNR amplitudes (A) and PhNR/b-wave amplitude ratio (B) against RNFLT.
Figure 6.
 
PhNR amplitudes (A) and PhNR/b-wave amplitude ratio (B) against RNFLT.
FrishmanLJ, ShenFF, DuL, et al. The scotopic electroretinogram of macaque after retinal ganglion cell loss from experimental glaucoma. Invest Ophthalmol Vis Sci. 1996;37:125–141. [PubMed]
SpileersW, Falcao-ReisF, SmithR, HoggC, ArdenGB. The human ERG evoked by a Ganzfeld stimulator powered by red and green light emitting diodes. Clin Vision Sci. 1993;8:21–39.
ViswanathanS, FrishmanLJ, RobsonJG, HarwerthRS, SmithEL, 3rd. The photopic negative response of the macaque electroretinogram: reduction by experimental glaucoma. Invest Ophthalmol Vis Sci. 1999;40:1124–1136. [PubMed]
NarahashiT. Chemicals as tools in the study of excitable membranes. Physiol Rev. 1974;54:813–889. [PubMed]
BloomfieldSA. Effect of spike blockade on the receptive-field size of amacrine and ganglion cells in the rabbit retina. J Neurophysiol. 1996;75:1878–1893. [PubMed]
OhkumaM, KawaiF, HoriguchiM, MiyachiE. Patch-clamp recording of human retinal photoreceptors and bipolar cells. Photochem Photobiol. 2007;83:317–322. [CrossRef] [PubMed]
ViswanathanS, FrishmanLJ, RobsonJG, WaltersJW. The photopic negative response of the flash electroretinogram in primary open angle glaucoma. Invest Ophthalmol Vis Sci. 2001;42:514–522. [PubMed]
GotohY, MachidaS, TazawaY. Selective loss of the photopic negative response in patients with optic nerve atrophy. Arch Ophthalmol. 2004;122:341–346. [CrossRef] [PubMed]
RangaswamyNV, FrishmanLJ, DorotheoEU, et al. Photopic ERGs in patients with optic neuropathies: comparison with primate ERGs after pharmacological blockade of inner retina. Invest Ophthalmol Vis Sci. 2004;45:3827–3837. [CrossRef] [PubMed]
MiyataK, NakamuraM, KondoM, et al. Reduction of oscillatory potentials and photopic negative response in patients with autosomal dominant optic atrophy with OPA1 mutations. Invest Ophthalmol Vis Sci. 2007;48:820–824. [CrossRef] [PubMed]
QuigleyHA, DunkelbergerGR, GreenWR. Retinal ganglion cell atrophy correlated with automated perimetry in human eyes with glaucoma. Am J Ophthalmol. 1989;107:453–464. [CrossRef] [PubMed]
HarwerthRS, Carter-DawsonL, ShenF, SmithEL, 3rd, CrawfordMLJ. Ganglion cell losses underlying visual field defects from experimental glaucoma. Invest Ophthalmol Vis Sci. 1999;40:2242–2250. [PubMed]
VassC. Modern diagnostic methods for suspected glaucoma and glaucoma. Klin Monatsbl Augenheilkd. 2004;221:227–246. [CrossRef] [PubMed]
RenardJP, GiraudJM, MayF, et al. Diagnostic laser in glaucoma: scanning laser polarimetry (GDx VCC) and confocal scanning laser tomography (HRT). J Fr Ophtalmol. 2005;28:177–184. [PubMed]
HarasymowyczP, Kamdeu FansiA, PapamatheakisD. Screening for primary open-angle glaucoma in the developed world: are we there yet?. Can J Ophthalmol. 2005;40:477–486. [CrossRef] [PubMed]
RenardJP, GiraudJM. Glaucoma: structural imagery—HRT, GDX, OCT. J Fr Ophthalmol. 2006;29:64–73. [CrossRef]
AndersonDR, PatellaVM. Interpretation of a single field. Automated Static Perimetry. 1999; 2nd ed. 121–190.Mosby St. Louis.
ViswanathanS, FrishmanLJ, RobsonJG. The uniform field and pattern ERG in macaques with experimental glaucoma: removal of spiking activity. Invest Ophthalmol Vis Sci. 2000;41:2797–2810. [PubMed]
IaconoP, Da PozzoS, FuserM, MarchesanR, RavalicoG. Intersession reproducibility of retinal nerve fiber layer thickness measurements by GDx-VCC in healthy and glaucomatous eyes. Ophthalmologica. 2006;220:266–271. [CrossRef] [PubMed]
DeLeón OrtegaJE, SakataLM, KakatiB, et al. Effect of glaucomatous damage on repeatability of confocal scanning laser ophthalmoscope, scanning laser polarimetry, and optical coherence tomography. Invest Ophthalmol Vis Sci. 2007;48:1156–1163. [CrossRef] [PubMed]
Garway-HeathDF, HolderGE, FitzkeFW, HitchingsRA. Relationship between electrophysiological, psychophysical, and anatomical measurements in glaucoma. Invest Ophthalmol Vis Sci. 2002;43:2213–2220. [PubMed]
MaffeiL, FiorentiniA. Electroretinographic responses to alternating gratings before and after section of the optic nerve. Science. 1981;211:953–955. [CrossRef] [PubMed]
HolderGE. The pattern electroretinogram.FishmanGA BirchDG BringnellMG eds. Ophthalmology Monographs 2: Electrophysiologic Testing in Disorders of the Retina, Optic Nerve and Visual Pathway. 2001; 2nd ed. 197–235.The Foundation of American Academy of Ophthalmology San Francisco.
HoodDC, AndersonSC, WallM, KardonRH. Structure versus function in glaucoma: an application of a linear model. Invest Ophthalmol Vis Sci. 2007;48:3662–3668. [CrossRef] [PubMed]
BowdC, ZangwillLK, MedeirosFA, et al. Structure-function relationship using confocal scanning laser ophthalmoscopy, optical coherence tomography, and scanning laser polarimetry. Invest Ophthalmol Vis Sci. 2006;47:2889–2895. [CrossRef] [PubMed]
NittaJ, TazawaY, MuraiK, et al. Relationship between the s-wave amplitude of the multifocal electroretinogram and the retinal nerve fiber layer thickness in glaucomatous eyes. Jpn J Ophthalmol. 2005;49:481–490. [CrossRef] [PubMed]
HiroseT, MiyakeY, HaraA. Simultaneous recording of electroretinogram and visual evoked response: focal stimulation under direct observation. Arch Ophthalmol. 1977;95:1205–1208. [CrossRef] [PubMed]
MiyakeY, ShiroyamaN, HoriguchiM, OtaI. Asymmetry of focal ERG in human macular region. Invest Ophthalmol Vis Sci. 1989;30:1743–1749. [PubMed]
MiyakeY. Macular oscillatory potentials in humans: macular OPs. Doc Ophthalmol. 1990;75:111–124. [CrossRef] [PubMed]
ColottoA, FalsiniB, SalgarelloT, et al. Photopic negative response of the human ERG: losses associated with glaucomatous damage. Invest Ophthalmol Vis Sci. 2000;41:2205–2211. [PubMed]
YangA, SwansonWH. A new pattern electroretinogram paradigm evaluated in terms of user friendliness and agreement with perimetry. Ophthalmology. 2007;114:671–679. [CrossRef] [PubMed]
Figure 1.
 
(A) Representative ERGs recorded from a normal and a glaucomatous eye with moderate defects in the visual fields. (B) Averaged amplitudes of the a- and b-wave and PhNR amplitudes recorded in normal control subjects and patients with glaucoma at different stages of visual field defect (white: normal eyes, n = 30; light gray: suspected glaucoma, n = 13; gray: mild visual field defects, n = 34; dark gray: moderate visual field defects, n = 25; black: severe visual defects, n = 27). (C) Averaged ratio of the PhNR/a-wave amplitude from normal control subjects and patients with different stage of visual field defect. (D) Averaged ratio of the PhNR/b-wave amplitude from normal control subjects and patients with different severity of visual field defects. Error bars, SD.
Figure 1.
 
(A) Representative ERGs recorded from a normal and a glaucomatous eye with moderate defects in the visual fields. (B) Averaged amplitudes of the a- and b-wave and PhNR amplitudes recorded in normal control subjects and patients with glaucoma at different stages of visual field defect (white: normal eyes, n = 30; light gray: suspected glaucoma, n = 13; gray: mild visual field defects, n = 34; dark gray: moderate visual field defects, n = 25; black: severe visual defects, n = 27). (C) Averaged ratio of the PhNR/a-wave amplitude from normal control subjects and patients with different stage of visual field defect. (D) Averaged ratio of the PhNR/b-wave amplitude from normal control subjects and patients with different severity of visual field defects. Error bars, SD.
Figure 2.
 
The (A) a- and (B) b-wave amplitudes against MD.
Figure 2.
 
The (A) a- and (B) b-wave amplitudes against MD.
Figure 3.
 
PhNR amplitudes (A) and PhNR/b-wave amplitude ratio (B) against MD.
Figure 3.
 
PhNR amplitudes (A) and PhNR/b-wave amplitude ratio (B) against MD.
Figure 4.
 
PhNR amplitudes (A) and PhNR/b-wave amplitude ratio (B) against rim area.
Figure 4.
 
PhNR amplitudes (A) and PhNR/b-wave amplitude ratio (B) against rim area.
Figure 5.
 
PhNR amplitudes (A) and PhNR/b-wave amplitude ratio (B) against cup–disc area ratio.
Figure 5.
 
PhNR amplitudes (A) and PhNR/b-wave amplitude ratio (B) against cup–disc area ratio.
Figure 6.
 
PhNR amplitudes (A) and PhNR/b-wave amplitude ratio (B) against RNFLT.
Figure 6.
 
PhNR amplitudes (A) and PhNR/b-wave amplitude ratio (B) against RNFLT.
Table 1.
 
Comparison of the Correlation Coefficients between PhNR and Visual Field or Structural Parameters
Table 1.
 
Comparison of the Correlation Coefficients between PhNR and Visual Field or Structural Parameters
Linear Logarithmic
PhNR amplitude vs. MD
 Correlation coefficient 0.58 0.62
P <0.001 <0.001
PhNR/b-wave amplitude ratio vs. MD
 Correlation coefficient 0.60 0.65
P <0.001 <0.001
PhNR amplitude vs. rim area
 Correlation coefficient 0.49 0.45
P <0.001 <0.001
PhNR/b-wave amplitude ratio vs. rim area
 Correlation coefficient 0.49 0.47
P <0.001 <0.001
PhNR amplitude vs. cup/disc area ratio
 Correlation coefficient −0.47 −0.43
P <0.001 <0.001
PhNR/b-wave amplitude ratio vs. cup/disc area ratio
 Correlation coefficient −0.48 −0.44
P <0.001 <0.001
PhNR/b-wave amplitude ratio vs. cup/disc area ratio
 Correlation coefficient −0.48 −0.44
P <0.001 <0.001
PhNR amplitude vs. RNFLT
 Correlation coefficient 0.53 0.49
P <0.001 <0.001
PhNR/b-wave amplitude ratio vs. RNFLT
 Correlation coefficient 0.55 0.51
P <0.001 <0.001
Copyright 2008 The Association for Research in Vision and Ophthalmology, Inc.
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