Abstract
purpose. To investigate the cellular sources underlying the functional damage observed by multifocal electroretinography (mfERG) responses of glaucomatous eyes of monkeys.
methods. First- and second-order (K1 and K2, respectively) mfERG responses of three normal and three experimentally induced glaucomatous eyes of cynomolgus monkeys were measured at two different levels of luminance. Retinal contributors to the responses were isolated by intravitreal injections of pharmacological agents that suppress specific retinal cells. γ-Aminobutyric acid (GABA) and glycine were administered to block inner retinal function, followed by 2-amino-4-phosphonobutyric acid (APB), to block ON-bipolar cells.
results. An inner retinal component removed by GABA and glycine was found in both the normal and glaucomatous eyes. However, it was attenuated in the latter, correlating with changes observed in the baseline K1 responses. Delays in the latency of outer retinal components were found in the responses of the glaucomatous eyes. K2 responses were dominated by an inner retinal contribution and were diminished in the responses of glaucomatous eyes. The outer retina responded to increased luminance with a shorter implicit time. A distinct wave part of the inner retinal component responded to increased luminance with increased amplitudes.
conclusions. The integration of the retinal sources forming the mfERG response was compared between normal and glaucomatous monkey eyes. Both inner and outer retinal functions were aberrant in the responses of the glaucomatous eyes, with the attenuation of the inner retinal function more conspicuous. Nevertheless, glaucomatous eyes retained certain inner retinal activity, despite the advanced stage of disease. K2 responses were more sensitive to glaucomatous changes than were K1 responses.
Glaucoma is a sight-threatening disease of multifactorial etiology affecting more than 65 million people worldwide.
1 It is a progressive optic neuropathy that may often go undiagnosed due to the slow decline in vision. It has been estimated that up to 50% of the nerve fibers may be lost before obvious clinical symptoms.
2 3 However, because the damage is irreversible, diagnosis and treatment early in the course of the disease are crucial.
Retinal function can be evaluated objectively by electroretinography (ERG). Early detection of pathologic processes and their localization may be facilitated by choosing the stimulation and recording conditions. Evidence of glaucomatous damage encompassing inner and outer retinal layers has been found in both flash and pattern ERG studies.
4 5 6 7 8 9 10 Latency increases and amplitude decreases in pattern ERG studies were found suitable to distinguish between control and glaucomatous eyes, and also for detecting ocular hypertension.
6 9 10 Flash ERG studies have shown reduced amplitudes and delayed responses in glaucoma,
6 11 a photopic negative response sensitive to early stages of damage,
7 8 and diminished oscillatory potentials.
10 However, these tests are sensitive to widespread retinal damage. The multifocal electroretinography (mfERG) technique
12 generates high-resolution maps of discrete responses across the central and near-peripheral retina. It may thus be advantageous in the diagnosis and monitoring of glaucoma, which can affect the retina unevenly.
13 14 15 Recent mfERG studies showed clear evidence of functional loss in glaucoma, suggesting damage to inner and outer retinal layers.
16 17 18 19 20 21 These studies showed attenuation of the first- and second-order (K1 and K2, respectively) responses in glaucoma,
16 17 18 19 21 and the elimination of an optic nerve head component.
20 However, injury to specific retinal pathways was not established.
Pharmacological agents that selectively block retinal activity have been used to advance the understanding of the cellular contributions to ERG responses.
22 23 24 25 The origin of the mfERG response has been studied,
20 26 27 28 but only recently have the underlying sources of the mfERG response been explicitly explored.
23 29 30 Using pharmacological agents that block specific cell types, Hood et al.
29 presented a model of the precise retinal sources that constitute the mfERG response in primates. The model suggests that the bipolar cells dominate the mfERG response, with the inner retina and photoreceptors adding smaller contributions to the waveform. The purpose of this study was to investigate the cellular sources that underlie the functional damage observed in mfERG responses of glaucomatous eyes, by comparing the pharmacological dissection of the responses of normal and glaucomatous eyes.
Three normal and three glaucomatous eyes of six adult male cynomolgus monkeys (
Macaca fascicularis) were used in this study. Ocular hypertension was induced by photocoagulation of the trabecular meshwork 7 years before the experiment.
31 32 An argon laser beam (75–100 μm in diameter, 1100 mW, for 0.5 second) was applied to the entire trabeculum.
Intraocular pressure was measured with a calibrated tonometer (Tono-Pen XL; Mentor Ophthalmics, Inc., Norwell, MA) after intramuscular premedication with ketamine (10 mg/kg). During the mfERG recordings monkeys were anesthetized with an inhalation mixture of N2O and O2 supplemented with a continuous intravenous (IV) drip of propofol (5 mg/kg per hour). Eye movement was prevented by periodic IV boluses of muscle relaxants (vecuronium 0.1 mg/kg or rocuronium 0.45 mg/kg). Expired CO2, blood O2 saturation level, heart rate, respiration rate, core temperature, and blood pressure were monitored continuously and kept within normal ranges. Pupils were dilated with topical drops of tropicamide and atropine.
A noninvasive contact lens electrode (Jet; Metrovision, Perenchies, France) was placed on the cornea of the recorded eye, and a similar electrode was set on the contralateral covered eye for reference. Hydroxyethylcellulose gel (1.3%) was applied for corneal protection and for tight adhesion of the electrodes. A gold-cup electrode attached to the skin rostral to the ear served as the ground. Experimental and animal care procedures adhered to the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research and local regulations and ethical considerations for the use of animals.
In two monkeys from each group, outer retinal contributions were further dissociated by the administration of APB to block transmission from photoreceptors to ON-bipolar cells.
Figure 6A shows the responses that remained after administration of APB, representing the activity of OFF-bipolar cells and photoreceptors, whereas
Figure 6B shows the contribution of the ON-bipolar cells that was obtained by subtracting the response after APB
(Fig. 6A) from the responses after GABA+glycine
(Figs. 2 4) .
There was a small delay in the OFF-bipolar and photoreceptor component in glaucomatous eyes compared with that in the normal eyes. The latency of the onset of the leading slope was 4.15 and 6.64 ms for monkeys L4 and L5, respectively, versus 8.30 ms in both glaucomatous eyes. Otherwise, no consistent differences were found between normal and glaucomatous eyes in the responses of the ON and OFF pathways in the outer retina. In all four eyes, the OFF-bipolar and photoreceptor component was oscillatory in character, with reduced oscillations from approximately 80 msec. These oscillations, synthesized with the oscillations contributed by the inner retina, are apparent in K1 responses. The ON-bipolar contribution, in contrast, was restricted to the time window of 10 to 40 ms.
Based on the two-step pharmacological decomposition of the responses, the retinal contributors to the mfERG response were established
(Fig. 7) . Several observations can be made from this analysis: (1) The ON and OFF pathways of the outer retina dominated the waveform of the mfERG. (2) The inner retina contributed mainly to the region of N1 and P2. (3) The components varied in amplitude among the eyes, and the inner retinal contribution also varied in wave shape. Nevertheless, the relative contribution of each component remained alike. The root mean square, a general amplitude measure, revealed that the ratio between the components was similar among the four eyes, with the OFF-bipolar cells and photoreceptors constituting the major part of the response and the inner retina contributing the smallest portion
(Table 2) . The relative contribution of the components can be estimated at 20% to 25% for the inner retina, 25% to 35% for the ON-bipolar cells, and 45% to 55% for the OFF-bipolar and photoreceptor cells.
In this study we segregated the mfERG responses of normal and glaucomatous eyes into discrete retinal contributors by pharmacological dissociation to identify the site of attenuated function in the glaucomatous eyes. A primary finding was that the glaucomatous eyes, in spite of the prolonged period (7 years) of elevated intraocular pressure (50 ± 12 mm Hg), still retained inner retinal function
(Figs. 4 5B) . It has been shown before that, although suppression of the inner retina in normal eyes approximates responses of glaucomatous eyes, the signals are not identical.
17 The results of this study suggest that this discrepancy arises mainly from the drugs’ removal of all inner retinal contribution, whereas the inner retina still partakes in the responses of glaucomatous eyes.
Despite small variations from eye to eye, it is possible to construct a single model of mfERG response generators that is consistent with all the data
(Fig. 7) and agrees with a previous report.
29 The outer retinal contributors are the dominant source of the K1 mfERG response. The descending slope of N1 reflects the hyperpolarization of OFF-bipolar cells and photoreceptors. The ascending slope of N1 and the leading slope of P1 arise from light-induced depolarization of the ON-bipolar cells and from the depolarization of the OFF-bipolar cells as they recover from the light stimulus. Because of the short stimulus, the on phase of the ON-bipolar cells can combine with the off phase of the photoreceptors and OFF-bipolar cells, similar to the flash ERG that is elicited by bright stimulus in the light-adapted state.
23 29 The summated contributions of the ON- and OFF-bipolar cells is also expressed in P2 and N2 and the ongoing oscillations. The inner retinal function shapes N1, forming an additional peak (seen clearly in
Fig. 7A ) which is especially prominent in the nasal region.
16 17 Postreceptoral influences at early times of the response have also been shown in cone-driven flash ERG responses (Robson JG.
IOVS 2002;43:ARVO E-Abstract 1821). Further, a more conspicuous influence of the inner retina is evident in the segment of 30 to 40 ms in the responses of the normal eyes
(Fig. 5B) . A peak in the inner retinal contribution in this area yields P2 in the baseline responses. In the inner retinal contribution of the glaucomatous eyes this peak is attenuated, either absent, or delayed and thus integrated with the following signal elements, rendering P2 of the K1 responses diminished. The inner retinal contribution is also apparent in the oscillations after N2
(Fig. 7) .
Variations were observed in the inner retinal contribution to the mfERG responses. The general peak-trough-peak form, which was observed in previous studies
17 38 can be seen in all the eyes, but varied in shape and in amplitude
(Fig. 5B) . The simplest explanation to this variability assumes that the drugs did not have an identical effect in all eyes. However, this is less likely because the responses were steady for over 30 minutes, implying maximal effect of the drugs. Alternatively, the mixture of GABA and glycine that was used in the study to suppress inner retinal function probably acted on several cell types. Therefore, it is reasonable to assume that the inner retinal component is actually a superposition of several waveforms, similar to the TTX-sensitive component of the mfERG response,
26 29 and the difference between eyes reflects variation in the contributions of the different sources.
In light of the variability in the inner retinal contribution to the mfERG responses, the consistent difference between normal and glaucomatous eyes in the area of 30 to 40 ms, corresponding to P2 in K1, is even more remarkable. Although this study included a small number of eyes, the attenuation of P2 in responses of glaucomatous eyes was consistently documented,
16 17 39 and it is reasonable to assume that the underlying cause is the same. Because the ganglion cells are primarily damaged in glaucoma, we suggest that the second positive peak in the inner retinal responses (30–40 ms) reflects ganglion cell function, whereas other parts of this waveform represent activity of other inner retinal cells. This supports conclusions of a recently published study describing mfERG responses in optic neuritis.
40
It is interesting to note that signals that appear alike may envelop less congruent components, as was the case in the two normal eyes L4 and L5
(Figs. 7A 7B) . The baseline responses of the two normal eyes are almost identical in shape and in amplitude, whereas the individual components differ in amplitude and the inner retinal component also varies in shape. Nevertheless, we found that the amplitude ratio of the components is maintained in the K1 responses
(Table 2) . This ratio was unexpectedly similar for the glaucomatous eyes as well. The glaucomatous damage that was expected to be most severe in the inner retina was not expressed in a dramatic change of mfERG contributions toward the outer retinal components. It is possible that the long-standing increased IOP did not cause severe damage to the inner retina, or that the damage was severe to both inner and outer retinal layers, thus rendering a similar ratio. Moreover, the contribution of inner retinal function to K1 responses in the normal eyes was estimated at 26% or less
(Table 2) , and therefore a significant attenuation in inner retinal function would be expressed in only a small change in the ratio of contributing sources.
Direct evidence of glaucomatous damage to outer retinal cells is obtained from the initial part of the waveforms. The trough N1 was delayed in the responses of the glaucomatous eyes (
Fig. 1D ,
Table 1 ), in agreement with previous reports (Ofri R, et al.
IOVS 2000;41:ARVO Abstract 535; Ver Hoeve JN, et al.
IOVS 2000;41:ARVO Abstract 2772). This correlates with a similar delay in the outer retinal component
(Fig. 5A) , indicating that the delay in the K1 responses originates in this component. The usefulness of implicit time of mfERG responses as a diagnostic tool has been reported in other retinal diseases.
41 42 The pharmacological analysis shows that outer retinal cells are the principal source underlying N1. However, it was difficult to determine which of the outer retinal contributors in the glaucomatous eyes is responsible for the delayed implicit time of N1.
Second-order responses are a measure of retinal adaptation, reflecting the effect of successive flashes on the mfERG responses.
21 33 The first slice of the second-order kernel (K2) shown in this study represents the effect of an immediately preceding flash on the response. Waveforms of K2 were composed of positive-negative-positive potentials in the normal eyes
(Fig. 8) . By administration of GABA and glycine, we were able to show that the inner retina was the prominent underlying source of K2 responses, as was suggested before.
23 30 We estimate that inner retinal mechanisms are responsible for roughly 80% of the adaptation process that is expressed in the K2 responses of normal eyes. Nevertheless, K2 responses include outer retinal contribution as well. Frishman et al.
17 showed previously that suppression of the inner retina eliminated most of the K2 responses, similar to the effect of glaucoma. However, whereas the K2 responses of the glaucomatous eyes were practically eliminated, a negative potential at 25 to 30 ms remained in TTX-NMDA treated eyes.
17 The present study suggests that this negative potential of the K2 response originates in the outer retina.
Because K2 responses are dominated by the inner retinal contribution, they are likely to be a more sensitive measure of inner retinal function. If the inner retina constitutes 80% of the K2 response (compared with only 20% to 25% of the K1 response), impaired inner retinal function would be accentuated in K2 responses. For example, a 50% loss of inner retinal function would result in only a ∼10% decrease of the inner retinal contribution in the ratio of the retinal sources that constitute K1. However, the same loss of inner retinal function would result in a decrease of approximately 40% of the inner retinal contribution in the ratio of the retinal sources that constitute K2. In the glaucomatous eyes in this study, both inner and outer retinal contribution to K2 responses were diminished. However, the ratio of inner to outer retinal contribution decreased, suggesting that the inner retina sustained more severe damage than the outer retina
(Fig. 8) .
Increasing the maximum luminance of the stimulus was expressed in the mfERG responses by increased amplitudes and faster kinetics (
Table 1 ,
Fig. 9 ), in agreement with previous studies.
16 29 The pharmacological analysis demonstrated that in normal as well as in glaucomatous eyes, outer retinal components participated in the implicit time shift induced by luminance changes
(Fig. 10) . The pathophysiology underlying the changes in the responses of the glaucomatous eyes could be a decrease in number of cells while the remaining cells function normally, or an attenuated function of cells, or both. The implicit time of N1 in K1 responses suggests that the outer retina in the glaucomatous eyes did not perform as well as that of the normal eyes. The implicit time of N1 under the stimulus of lower luminance in the normal eyes was shorter than that of the glaucomatous eyes, even when the glaucomatous eyes were illuminated with stimuli of high luminance
(Table 1) . This suggests that outer retinal cells in the glaucomatous eyes, whether decreased in number or not, do not perform as cells in the normal retina.
The principal effect of increased luminance on the inner retinal component was the increased amplitude of the second positive peak (30–40 ms) in the responses of the glaucomatous eyes
(Fig. 11B) . This peak “recovered” to an amplitude comparable to the normal eyes under luminance of 600 cd/m
2. The difference in effect on this peak relative to the rest of the inner retinal contribution supports the previous assertion that this region reflects one group of cells, whereas other inner retinal cells are manifested in other parts of the waveform. We suggest that the sensitivity of ganglion cells to luminance changes is reflected in the region of 30 to 40 ms of the inner retinal contribution. These changes are not manifested in K1 responses, because they are masked by the outer retinal responses.
In light of the small number of eyes and a degree of intersubject variability in the responses the analysis presented in this study should be interpreted cautiously. Nevertheless, the findings helped elucidate the cellular contributions to the mfERG responses of normal and glaucomatous eyes. Inner retinal function was clearly portrayed in N1 and in P2 of the first order mfERG responses. It is conceivable that P2 reflects the activity of ganglion cells, whereas other inner retinal cells, possibly amacrine cells, are reflected in the region of N1. Both of these components were attenuated in the responses of the glaucomatous eyes. Outer retinal function was delayed in the responses of glaucomatous eyes. Together, the evidence suggests an attenuated function of inner and outer retinal layers in this glaucoma model.
Supported by a research grant from Novartis Ophthalmics, Basel, Switzerland.
Submitted for publication December 3, 2002; revised February 26, 2003; accepted March 17, 2003.
Disclosure:
D. Raz, Novartis Ophthalmics (F, R);
I. Perlman, None;
C.L. Percicot, Novartis Ophthalmics (E);
G.N. Lambrou, Novartis Ophthalmics (E);
R. Ofri, Novartis Ophthalmics (F, R)
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: Dorit Raz, National Eye Institute, Bldg. 50, Room 4340, 50 South Drive, MSC 8021, Bethesda, MD 20892;
[email protected].
Table 1. Implicit Time of N1 in Baseline (K1) Responses
Table 1. Implicit Time of N1 in Baseline (K1) Responses
| Lmax 200 cd/m2 | Lmax 600 cd/m2 |
| Normal | | |
| L4 | 12.45 | 10.79 |
| L5 | 14.95 | 12.45 |
| L8 | 10.79 | 10.79 |
| Glaucoma | | |
| 1331 | 15.77 | 15.77 |
| 468 | 13.28 | 13.28 |
| DP70 | 15.77 | 14.11 |
| Eye | Inner Retina:ON:OFF + Photoreceptors |
| Normal | |
| L4 | 20:36:44 |
| L5 | 26:30:44 |
| Glaucoma | |
| 1331 | 19:25:56 |
| 468 | 25:32:43 |
The authors thank Laura J. Frishman and Donald C. Hood for valuable advice and Christian Lambert, Isabelle Questel, and Emmanuel Faure for their dedicated work.
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