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The Electroretinogram in Diabetic Retinopathy
SURVEY OF OPHTHALMOLOGY VOLUME 44 • NUMBER 1 • JULY–AUGUST 1999
CURRENT RESEARCH EDWARD COTLIER AND ROBERT WEINREB, EDITORS
The Electroretinogram in Diabetic Retinopathy R. Tzekov, MD, PhD,1 and G. B. Arden, MD, PhD, FRCOphth2 1 Retina Foundation of the Southwest, Dallas, Texas, USA, and 2 Center for Applied Vision Research, Department of Optometry and Visual Science, City University, London, United Kingdom
Abstract. Electroretinography (ERG) is an objective method of evaluating retinal function. Since its introduction to clinical practice in the 1940s, it has become a useful and routine diagnostic clinical tool in ophthalmology. This review summarizes the role of ERG as a clinical technique for evaluating the progression of diabetic retinopathy and as a research tool for increasing our understanding of the pathophysiology of diabetic retinopathy. Most studies show unequivocally that the different types of ERG tests detect local abnormalities or widespread pathology, even in very early stages of the disease. It seems plausible that measurements from ERG recordings, particularly the oscillatory potentials, may be useful for predicting progression from nonproliferative to the more sight-threatening stages—preproliferative or proliferative—of diabetic retinopathy. Some recent work implies that the ERG can also be a useful diagnostic method for discriminating between eyes with diabetic retinopathy and those without the condition. (Surv Ophthalmol 44:53–60, 1999. © 1999 by Elsevier Science Inc. All rights reserved.) Key words. diabetes mellitus oscillatory potentials
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diabetic retinopathy
Diabetic retinopathy is a potentially blinding complication of diabetes mellitus. During the 1940s, capillary microaneurysms were first described in diabetic eyes, a landmark finding in understanding of the disease. More recently, several large, multicenter, randomized clinical trials have given new insight into key aspects of the epidemiology, natural course, and treatment of this significant medical problem.1,3,29,35 The evaluation of the functional properties of the diabetic retina with objective methods, such as electroretinography (ERG), electro-oculography (EOG), and visual evoked cortical potentials, is an important aspect of the diagnostic and therapeutic approach to diabetic retinopathy. The focus of this review will be studies using the ERG, because these illuminate ma-
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jor issues in relating retinal function to pathophysiology and stage of progression of diabetic retinopathy. The ERG can be elicited by different kinds of stimulation: by diffuse flashes of light (the classic method), by patterned stimulation (pattern ERG [pERG]), or by focal stimulation (focal ERG [fERG]).
Components of Electroretinography The first human ERG recordings were obtained by Dewar in 1877,30 but it was not until the 1920s that equipment became sensitive enough to characterize the temporal course of the waves, and it was not until the introduction of the contact lens electrode by Riggs in 194176 that quantitative results could be obtained. 53
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Since then, significant progress has been made in the clinical implementation of the ERG. However, the variety of stimulation and recording parameters makes it difficult to evaluate and interpret the results from old studies. In response to this problem, a recognized international standard, the International Society for Clinical Electrophysiology of Vision (ISCEV) standard, for recording and reporting ERG was developed.4,65 In this review, we will focus on studies with techniques comparable to the ISCEV standard for full-field ERG. Much of the older literature was summarized in 1981 (oscillatory potentials)89 and 1984 (ERG).12 We will also briefly describe recent findings using the paradigms including the pERG, fERG, and multifocal ERG. FULL-FIELD ELECTRORETINOGRAPHY
According to the current ISCEV standard, five major ERG responses are defined: rod response, maximal combined response, oscillatory potentials, cone response, and 30-Hz flicker response (Fig. 1). A variety of measures have been used to quantify these standard responses. The a-wave is a fast, negative ERG component obtained primarily from the maximal combined response. The leading edge reflects the membrane current in photoreceptors.50,51 For clinical purposes, a-wave amplitude is measured from baseline to a-wave trough (Fig. 1). The b-wave is a large, positive ERG potential present in the rod response, the maximal combined response, and the photopic response. Under scotopic conditions, the rising phase (up to the peak) is directly generated by bipolar cells.49,78,79 Under photopic conditions, several types of neurons contribute to its generation.86 The amplitude of the b-wave is measured from the trough of the a-wave to the peak of the b-wave. The implicit time of the b-wave is measured from flash onset to the peak of the b-wave (Fig. 1). The oscillatory potentials (OPs) are four to six low-amplitude, high-frequency wavelets superimposed on the ascending limb of the ERG b-wave. They were first reported in the human ERG by Cobb and Morton in 195325 and named by Yonemura et al in 1962.104 Analog filtering of the ERG can isolate OPs. Alternatively, fast Fourier transform, followed by digital filtration and reconstruction of the residual waveform, can be used.83 The OPs are thought to result from a feedback between the amacrine cells and the bipolar cells and/or feedback from ganglion cells to amacrine cells. They are more vulnerable to disturbances of the retinal circulation (central retinal vein occlusion, etc.6,58,94) than the b-wave. Several methods for quantifying OPs have been proposed. Frequently, peak-to trough amplitudes of the
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waves are summed to give an overall measure of OP amplitude. Alternatively, the amplitudes of individual wavelets may be recorded. The latter may be preferable, because the OPs are complex in origin and individual wavelets may be generated at different sites within the retina.59,98 There are also newer and less common ERG techniques, which are not covered by the ISCEV standard protocol. For example, the scotopic threshold response is the cornea-negative response of amacrine cells,85 which is present below b-wave threshold. So far, only one study has been published, and it shows deterioration of the scotopic threshold response in advanced cases of diabetic retinopathy.11 PATTERN ELECTRORETINOGRAPHY
The pERG is an electrical retinal response to a phase-reversing patterned stimulus (most often a grating or checkerboard) and reflects mostly ganglion cell activity.64,77 Under most recording conditions, it has three major components: one small cornea-negative wave named N35, followed by a major positive wave, P50, and later, a negative trough at 95 msec (N95 [Fig. 2]). Guidelines for pERG parameters, such as luminance and contrast of the stimulator, have been issued recently.66 FOCAL AND MULTIFOCAL ELECTRORETINOGRAPHY
The fERG is a specialized technique developed for recording local electrical retinal responses to focal light stimuli, usually within the macula.9 With slow stimulus repetition rates, its waveform may be similar to the full-field ERG. With rates faster than 7 Hz, the response becomes sinusoidal and is thought to have a contribution from photoreceptor and bipolar cells.13 The multifocal ERG is evoked by a patterned stimulus, each element of which changes independently. By complex mathematical analysis, one can record (simultaneously) the responses of more than 100 retinal sites (including the macula) and distinguish separate responses of inner and outer retina.91 Outer retinal abnormalities confined to small retinal regions can be seen in diabetic retinopathy, and inner retinal abnormalities may appear before clinically apparent retinopathy.69
ERG Changes According to Severity of Diabetic Retinopathy Typically, there is a considerable time period between the diagnosis of diabetes mellitus and the development of diabetic retinopathy. Within the first 5 years after diagnosis, only about 5% of all patients develop nonproliferative diabetic retinopathy (NPDR),
ERG IN DIABETES
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Fig. 1. Examples of normal human ERG. A: Scotopic response. B: Maximal response. C: Oscillatory potentials after digital filtration (80–300 Hz). D: 30-Hz flicker ERG. E: Photopic ERG. Solid arrows represent measurement of b-wave implicit time; short dash arrows indicate measurement of a- or b-wave amplitude. In case of the 30-Hz flicker response, asterisks indicate position of the time-mark, super-imposed on the signal. (Records obtained by one of the authors [RT].)
and the incidence of proliferative diabetic retinopathy (PDR) is negligible.52 With time, the proportion of people developing diabetic retinopathy increases steadily, and after 20 years of diabetes more than 90% of patients with type I and about 60% with type II diabetes have some degree of retinopathy.56 The modified Airlie House classification (based on fundus photography) describes six grades of severity of diabetic retinopathy.2 This discussion is limited to ERG abnormalities in the absence of clinically apparent retinopathy, and how they develop in mild NPDR, severe NPDR, and PDR. These changes occur before sight-treatment PDR occurs. NO CLINICALLY APPARRENT RETINOPATHY
Electroretinography abnormalities can be present at a very early stage of disease while there are no visible changes in the fundus. The most consistent alteration is a significant increase in the OP1 implicit time.16,48,57,84,88,103,106 For example, in 572 eyes of 303 patients with non–insulin-dependent diabetes melli-
tus, the OP1 peak was significantly delayed, and the delay in OP1 was greater than any other peak or trough. Increase in implicit time of OP1 occurs in almost all the “stage 0” cases (i.e., not only before ophthalmoscopic changes are apparent, but also before fluorescein angiography and vitreous fluorophotometry changes can be seen). Overall reduction of OPs has also been reported (Table 1). Significant reduction of scotopic b-wave amplitude has also been found in children with insulindependent diabetes mellitus who have no diabetic retinopathy detectable on fluorescein angiography.61,63 This finding was later confirmed in a group of juvenile diabetics without photographic evidence of retinopathy.54,70 Blue cone (S-cone) amplitude was also reduced in similar cases.102 Results from pERG have been controversial for this group (Table 1), probably because of differences in the technique used among studies. A study following the ISCEV recommendations for pERG recording could provide more clinically valuable information.
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rameters between patients with NPDR with or without macular edema and normal subjects.101 SEVERE AND VERY SEVERE NONPROLIFERATIVE DIABETIC RETINOPATHY
Oscillatory potential amplitudes correlate well with the severity of diabetic retinopathy.17,89 The few studies published to date that include patients with severe NPDR showed significantly reduced and sometimes absent OPs (Table 1). The ERG sensitivity (measured by the increase of b-wave amplitude over a range of different stimulus intensities) and photopic b-wave implicit times also correlate well with the severity of diabetic retinopathy.24,81 EARLY AND HIGH-RISK PROLIFERATIVE DIABETIC RETINOPATHY
Several studies have investigated ERG changes in PDR. Significant abnormalities have been reported in all ERG parameters, including decrease of the OP amplitude (up to complete disappearance of the OPs) or delay of the implicit time of the OPs (Table 1), decrease of photopic and scotopic a- and b-waves, and 30-Hz flicker delay.7,42,55,57,62,74,75,92
Tightness of Diabetic Control and Electroretinography Data
Fig. 2. Example of ERG for series of check sizes in a normal subject. The signal was digitally filtered to remove frequencies above 50 Hz. Three primary components are labeled on the lower trace. (Modified with permission from Birch.13)
Focal ERG showed early diabetes to cause selective neurosensory deficits of inner retina layers in patients without visible retinopathy.31,41,43 MILD AND MODERATE NONPROLIFERATIVE DIABETIC RETINOPATHY
Virtually all studies using OPs report distinctive changes in cases with mild NPRD (Table 1). Recently, more detailed studies have revealed that several ERG parameters can be affected in cases of mild NPDR: scotopic b-wave implicit times, 30-Hz flicker amplitude and implicit times, OP amplitudes to both blue and white flashes (including selective reduction of OP3 and OP2), OP implicit times, and photopic ERG implicit times.48,54,95 The majority of the pERG studies to date report a decrease in amplitude and delays in implicit time in cases with NPDR (Table 1). Foveal cone ERG measurements have demonstrated significant changes in both amplitude and time pa-
Until the early 1980s, the necessity of strict diabetic control for amelioration or delay of the natural course of diabetic retinopathy was not recognized. Initially, some reports showed improvement of retinal function (e.g., OP amplitude) with multiple subcutaneous insulin injections and achievement of strict metabolic control.5,38,60 However, later studies produced contradictory results.20,21 Apparently, many factors affect the relationship between ERG parameters and diabetic control, and further work is needed to clarify this issue.
Blood-Retinal Barrier Breakdown in Diabetes It is widely recognized that the permeability of the blood-retinal barrier (BRB) is compromised in advanced diabetic retinopathy.32 However, the results from different vitreous fluorophotometry studies that estimate the integrity of the BRB in cases without visible retinopathy have been controversial.28,71,73,99 This may be because of differences in subject selection, sensitivity of the measuring device, and analysis of results. It has been shown in other diseases (e.g., cone-rod dystrophy) that changes in BRB correlate well with changes in ERG parameters.36 To the best of our knowledge, there is only one study that directly com-
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ERG IN DIABETES TABLE 1
Diabetic Status and Number of Subjects or Eyes Tested in Works Published During 1962–1997, Considering OP or pERG Changes in Diabetic Retinopathy Degrees of Diabetic Retinopathy No Diabetic Retinopathy
Studies evaluating OPs Gjotterberg (1974)42 Yonemura and Kawasaki (1978)103 dSimonsen (1965,88 198087) Brunette and Lafond (1983)22 Wanger and Persson (1985)100 Coupland (1987)27 Zaharia et al (1987)106 Moschos et al (1987)67 dBresnick and Palta (1987)17 Van der Torren (1989)96 Juen and Kieselbach (1990)54 Yoshida et al (1991)105 Shirao et al (1991)84 Li et al (1992)62 Holopigian et al (1992)48 Van der Torren and Mulder (1993)95 Hardy et al (1995)44 Holopigian et al (1997)47 Studies evaluating pERG Wanger and Persson (1985)100 Arden et al (1986)10 Coupland (1987)27 Trick et al (1988)93 Boschi et al (1989)14 Falsini et al (1989)33 Prager et al (1990)72 Jenkins and Cartwright (1990)53 Caputo et al (1990)23 Nesher and Trick (1991)68
Mild NPDR
Severe NPDR
All PDR
Eyes/Patients
N
C
N
C
N
C
N
C
36/36 218/# 267/137 57/57 24/24 35/35 12/12 240/240 174/174 71/46 #/31 36/36 572/303 87/87 14/14 58/58
10 # 120 30 11 21 12 95 2 31 18 36 326 24 4 29
2 1 1 1 2 1 1 1 2 1 1 1 1 2 1 1
20 # 116 11 13 14 na 75 10 23 13 na 186 34 10 29
2 1 1 1 2 1 na 1 1 1 1 na 1 1 1 1
na na na na na na na na 91 18 na na 60 na na na
na na na na na na na na 1 1 na na 1 na na na
6 # 31 16 na na na 70 71 na na na na 29 na na
1 1 1 1 na na na 1 1 na na na na 1 na na
10/10 12/12
10 2
1 1
na 8
na 1
na 1
na 1
na 1
na 1
24/24 53/53 35/35 56/56 38/38 80/80 72/72 40/40 40/40 58/58
11 8 14 34 20 62 38 40 32 27
2 2 2 1 2 1 1 2 1 2
13 30 21 21 20 18 34 na 8 31
2 2 1 1 2 1 1 na 1 1
na 15 na na na na na na na na
na 1 na na na na na na na na
na na na na na na na na na na
na na na na na na na na na na
N 5 number of eyes in that category; C 5 presence (1) or absence (2) of significant change of OP parameter (or pERG parameter) in that group compared to normal subjects; d 5 longitudinal study; # 5 data not available; na 5 not applicable.
pares the results of vitreous fluorophotometry and ERG.105 It showed changes in OP implicit time before changes in the BRB.
The Electroretinogram in Diabetic Retinopathy With Media Opacities Media opacities (including cataract, vitreous hemorrhages, etc.) are frequently associated with advanced diabetic retinopathy. How can this influence the ERG results? Opacities act as a neutral-density filter and attenuate the effective light reaching the eye.40 To circumvent this light attenuation, use of flashes of increasing intensity (bright-flash ERG) has been recommended.39 The same approach can be used successfully to evaluate patients with diabetes before vitrectomy.90 However, in cases with dense vitreous hemorrhages, the results could be contradictory.8
Because the full-field ERG is generally a mass response, it can provide unreliable results if the retinal damage is in a small area at the very center of the macula. Conversely, if a small region of the fovea has been conserved and the majority of the remaining retina is compromised, it is possible to find a flat ERG preoperatively and good visual acuity postoperatively. The presence of the cataract can exacerbate these problems from light scatter. One way to enhance the diagnostic resolution of the ERG in the central retina is to use flicker ERG and flicker visual evoked potential (VEP) to exclude optic nerve damage or macular disease.26,37,97 The use of flicker ERG and/or VEP has been successful in the process of evaluation and prediction of the visual outcome of diabetics before vitrectomy.90 However, in cases with dense vitreous hemorrhages, the results may be contradictory8 and should be interpreted cautiously.
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Diagnostic and Predictive Power of Electroretinographic Findings If the ERG is to be used as an objective and noninvasive method of evaluating the functional status of the retina, it is necessary to demonstrate that it has good diagnostic power (ability to distinguish patients with retinal disease from subjects without it or to distinguish among patients with different stages of the same disease). Such diagnostic power has been demonstrated, for example, in eyes with central retinal vein occlusion.19,45,46,82 To date, only one study has attempted a rigorous evaluation of diagnostic power of ERG in distinguishing patients with diabetes from normal subjects.80 The authors showed that several rod ERG parameters were roughly comparable in such discrimination. The predictive (prognostic) power of the ERG has been demonstrated in two longitudinal studies.15,18,87 In the first study,88 137 type I diabetic patients were tested at baseline and followed up to 15 years after the initial examination. With diabetes of more than 5 years’ duration, the presence of normal or hypernormal OPs at baseline excluded to a great extent the existence of PDR (4% versus 53% in the low-OP group). In the second study,15,18 85 (mostly insulindependent) patients were followed up for 55 to 73 months. Oscillatory potential amplitudes were shown to predict progression to diabetic retinopathy with “high-risk characteristics” at least as well as fluorescein leakage and better than the retinopathy level as assessed by fundus photography. Unfortunately, this model has not been validated yet for noninsulindependent diabetic patients. This could be quite relevant, because recent results from the Early Treatment Diabetic Retinopathy Study show that this group of patients could benefit more from early photocoagulation than the insulin-dependent group.34
Conclusions The ERG test provides a noninvasive technique for assessing retinal function. With use of readily available commercial equipment, the ERG test is easily administered, and it provides useful, objective, and quantitative information. It is evident that the ERG is abnormal very early in diabetic retinopathy. Specialized techniques such as pERG and fERG can demonstrate local abnormalities, but the abnormalities in the flash OP and b-wave demonstrate the widespread nature of diabetic retinopathy. Electroretinography has several uses in diabetic retinopathy. First, it can discriminate between patients who are more likely to develop PDR and patients with a lesser chance of doing so. It can be used in follow-up as a noninvasive objective measure of
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the progression of the disease and, thus, can supplement other clinical measures. Also, with some caution, it can be used to assess the status of the retina when there are complicating factors, such as the presence of cataract. The significance of these findings has not been generally appreciated. Before the onset of clinically apparent diabetic retinopathy, there is a prolonged period in which pathologic changes are occurring. The ERG could occupy a key position in assessing treatment directed to preventing or slowing down these earlier, subclinical processes. The presence of notable ERG functional abnormalities that worsen with disease has been amply demonstrated.
Method of Literature Search The literature was based mainly on MEDLINE (1966 -1997). Key words used were electroretinography, electroretinogram, ERG, oscillatory potentials, diabetic retinopathy, and diabetes mellitus. Only articles published in English were considered. The emphasis of the search was on works published after 1980, for reasons described in the article. The inclusion criteria were human studies, ERG as a main diagnostic subject, and patients with diabetic retinopathy. Exclusion criteria were case reports, reports in which the stage of diabetic retinopathy was not indicated, and works concerning ERG after photocoagulation.
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Li X, Sun X, Hu Y, Huang J, Zhang H: Electroretinographic oscillatory potentials in diabetic retinopathy: An analysis in the domains of time and frequency. Doc Ophthalmol 81:173–9, 1992 63. Lovasik J, Spafford M: An electrophysiological investigation of visual function in juvenile insulin-dependent diabetes mellitus. Am J Optom Physiol Opt 65:236–53, 1988 64. Maffei L, Fiorentini A, Bisti S, Hollander H: Pattern ERG in the monkey after sections of the optic nerve. Exp Brain Res 59:423–5, 1995 65. Marmor MF: An updated standard for clinical electroretinography. Arch Ophthalmol 113:1375–6, 1995 66. Marmor MF, Holder GE, Porciatti V: Guidelines for basic pattern electroretinography: Recommendations by the International Society for Clinical Electrophysiology of Vision. Doc Ophthalmol 91:291–8, 1996 67. Moschos M, Panagakis E, Angelopulos A: Changes of oscillatory potentials of the ERG in diabetic retinopathy. Ophthalmic Physiol Opt 7:477–9, 1987 68. Nesher R, Trick GL: The pattern electroretinogram in retinal and optic nerve disease: A quantitative comparison of the pattern of the visual dysfunction. Doc Ophthalmol 77: 225–35, 1991 69. Palmowski A, Sutter E, Bearse M, et al: Mapping of retinal function in diabetic retinopathy using the multifocal electroretinogram. Invest Ophthalmol Vis Sci 38:2586–96, 1997 70. Papakostopulos D, Hart J, Corrall R, Harney B: The scotopic electroretinogram to blue flashes and pattern reversal visual evoked potentials in insulin dependent diabetes. Int J Psychophysiol 21:33–43, 1996 71. Prager TC, Chu HH, Garcia CA: The use of vitreous fluorophotometry to distinguish between diabetics with and without observable retinopathy: effect of vitreous abnormalities on the measurement. Invest Ophthalmol Vis Sci 24:57–65, 1983 72. Prager TC, Garcia CA, Mincher CA, et al: The pattern electroretinogram in diabetes. Am J Ophthalmol 109:279–84, 1990 73. Prager TC, Wilson DJ, Avery GD: Vitreous fluorophotometry: identification of sources of variability. Invest Ophthalmol Vis Sci 21:854–64, 1981 74. Ramsay WJ, Ramsey RC, Purple RL, Knobloch WH: Involutional diabetic retinopathy. Am J Ophthalmol 84:851–8, 1977 75. Rankov B, Dabov S, Gavriiski V: Electroretinographic investigations in diabetes. Rep Bulg Acad Sci 18:678–9, 1965 76. Riggs LA: Continuous and reproducible records of the electrical activity of the human retina. Proc Soc Exp Biol Med 48:204–7, 1941 77. Riggs LA, Johnson EP, Schick AM: Electrical responses of the human eye to moving stimulus pattern in man. Science 144:567, 1964 78. Robson JG, Frishman LJ: Photoreceptor and bipolar cell contributions to the cat electroretinogram: a kinetic model for the early part of the flash response. J Opt Soc Am 13:613–22, 1996 79. Robson JG, Frishman LJ: Response linearity and kinetics of the cat retina: the bipolar cell component of the darkadapted electroretinogram. Vis Neurosci 12:837–50, 1995 80. Roecker EB, Pulos E, Bresnick GH, Severns M: Characterization of the electroretinographic scotopic b-wave amplitude in diabetic and normal subjects. Invest Ophthalmol Vis Sci 33:1575–83, 1992 81. Satoh S, Iijima H, Imai M, Abe K, Shibuya T: Photopic electroretinogram implicit time in diabetic retinopathy. Jpn J Ophthalmol 38:178–84, 1994 82. Severns M, Johnson M: Predicting outcome in central retinal vein occlusion using the flicker electroretinogram. Arch Ophthalmol 111:1123–30, 1993 83. Severns M, Johnson M, Bresnick G: Methodologic dependence of electroretinogram oscillatory potential amplitudes. Doc Ophthalmol 86:23–31, 1994 84. Shirao Y, Okumura T, Ohta T, Kawasaki K: Clinical importance of electroretinographic oscillatory potentials in early detection and objective evaluation for diabetic retinopathy. Clin Vis Sci 6:445–50, 1991 85. Sieving PA, Nino C: Scotopic threshold response of the human electroretinogram. Invest Ophthalmol Vis Sci 29: 1049–61, 1988
TZEKOV AND ARDEN 86.
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91. 92. 93.
94. 95. 96. 97. 98. 99. 100. 101. 102. 103.
104. 105.
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Sieving PA, Murayama K, Naarendorp F: Push-pull model of the primate photopic electroretinogram: a role for hyperpolarizing neurons in shaping the b-wave. Vis Neurosci 11:519–32, 1994 Simonsen SE: The value of oscillatory potential in selecting juvenile diabetics at risk of developing proliferative retinopathy. Acta Ophthalmol 58:403, 1980 Simonsen SE: Electroretinographic study of diabetics: Preliminary report. Acta Ophthalmol 43:841–3, 1965 Speros P, Price J: Oscillatory potentials: History, techniques and potential use in the evaluation of disturbances of retinal circulation. Surv Ophthalmol 25:237–52, 1981 Summanen P: Vitrectomy for diabetic eye disease: The prognostic value of pre-operative electroretinography and visual evoked cortical potentials. Ophthalmologica 199:60– 71, 1989 Sutter EE, Tran D: The field topography of ERG components in man, I: The photopic luminance response. Vision Res 32:433–46, 1992 Tahara K, Matsuura T, Otori T: Diagnostic evaluation of diabetic retinopathy by 30-Hz flicker electroretinography. Jpn J. Ophthalmol 37:204–10, 1993 Trick G, Burde R, Gordon M: Retinocortical conduction time in diabetics with abnormal pattern reversal electroretinograms and visual evoked potentials. Doc Ophthalmol 70:19–28, 1988 Usami E: Studies on oscillatory potentials in the cases of occlusion of the retinal artery and thrombosis of the retinal vein. Jpn J Ophthalmol 10(Suppl):113–9, 1965 Van der Torren K, Mulder P: Comparison of the second and third oscillatory potential power in early diabetic retinopathy. Doc Ophthalmol 83:111, 1993 Van der Torren K, van Lith G: Oscillatory potentials in early diabetic retinopathy. Doc Ophthalmol 71:375–9, 1989 Vrijland H, Van Lith G: The value of pre-operative electroophthalmological examination before cataract extraction. Doc Ophthalmol 55:153–6, 1963 Wachtmeister L: Basic research and clinical aspects of the oscillatory potentials of the electroretinogram. Doc Ophthalmol 66:187–94, 1987 Waltman SR, Krupin T, Singer P: Effects of therapy on vitreous fluorophotometry in diabetes mellitus. Trans Ophthalmol Soc UK 99:8–9, 1979 Wanger P, Persson H: Early diagnosis of retinal changes in diabetes: a comparison between electroretinography and retinal biomicroscopy. Acta Ophthalmol 63:716–20, 1985 Weiner A, Christopoulos V, Gussler C: Foveal cone function in nonproliferative diabetic retinopathy and macular edema. Invest Ophthalmol Vis Sci 38:1443–9, 1997 Yamammoto S, Kamiyama M, Nitta K, Yamada T, Hayasaka S: Selective reduction fo the S cone electroretinogram in diabetes. Br J Ophthalmol 80:973–5, 1996 Yonemura D, Kawasaki K: Electrophysiological study on activities of neuronal and non-neuronal retinal elements in man with reference to its clinical application. Jpn J Ophthalmol 22:198–213, 1978 Yonemura D, Tsusuki K, Aoki T: Clinical importance of the oscillatory potential in the human ERG. Acta Ophthalmol 70:115–23, 1962 Yoshida A, Kojima M, Ogasawara H, Ishiko S: Oscillatory potentials and permeability of the blood-retinal barrier in noninsulin-dependent diabetic patients without retinopathy. Ophthalmology 98:1266–71, 1991 Zaharia M, Olivier P, Lafond G: Lobular delayed choroidal perfusion as an early angiographic sign of diabetic retinopathy: a preliminary report. Can J Ophthalmol 22:257–61, 1987
We are grateful to Dr. David Birch for helpful discussions. Supported in part by the Department of Optometry and Visual Science, City University, London, UK. Reprint address: Radouil T. Tzekov, MD, PhD, Retina Foundation of the Southwest, 9900 N. Central Exressway #400, Dallas, TX 75231, USA.
CURRENT RESEARCH EDWARD COTLIER AND ROBERT WEINREB, EDITORS
The Electroretinogram in Diabetic Retinopathy R. Tzekov, MD, PhD,1 and G. B. Arden, MD, PhD, FRCOphth2 1 Retina Foundation of the Southwest, Dallas, Texas, USA, and 2 Center for Applied Vision Research, Department of Optometry and Visual Science, City University, London, United Kingdom
Abstract. Electroretinography (ERG) is an objective method of evaluating retinal function. Since its introduction to clinical practice in the 1940s, it has become a useful and routine diagnostic clinical tool in ophthalmology. This review summarizes the role of ERG as a clinical technique for evaluating the progression of diabetic retinopathy and as a research tool for increasing our understanding of the pathophysiology of diabetic retinopathy. Most studies show unequivocally that the different types of ERG tests detect local abnormalities or widespread pathology, even in very early stages of the disease. It seems plausible that measurements from ERG recordings, particularly the oscillatory potentials, may be useful for predicting progression from nonproliferative to the more sight-threatening stages—preproliferative or proliferative—of diabetic retinopathy. Some recent work implies that the ERG can also be a useful diagnostic method for discriminating between eyes with diabetic retinopathy and those without the condition. (Surv Ophthalmol 44:53–60, 1999. © 1999 by Elsevier Science Inc. All rights reserved.) Key words. diabetes mellitus oscillatory potentials
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diabetic retinopathy
Diabetic retinopathy is a potentially blinding complication of diabetes mellitus. During the 1940s, capillary microaneurysms were first described in diabetic eyes, a landmark finding in understanding of the disease. More recently, several large, multicenter, randomized clinical trials have given new insight into key aspects of the epidemiology, natural course, and treatment of this significant medical problem.1,3,29,35 The evaluation of the functional properties of the diabetic retina with objective methods, such as electroretinography (ERG), electro-oculography (EOG), and visual evoked cortical potentials, is an important aspect of the diagnostic and therapeutic approach to diabetic retinopathy. The focus of this review will be studies using the ERG, because these illuminate ma-
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electroretinogram •
jor issues in relating retinal function to pathophysiology and stage of progression of diabetic retinopathy. The ERG can be elicited by different kinds of stimulation: by diffuse flashes of light (the classic method), by patterned stimulation (pattern ERG [pERG]), or by focal stimulation (focal ERG [fERG]).
Components of Electroretinography The first human ERG recordings were obtained by Dewar in 1877,30 but it was not until the 1920s that equipment became sensitive enough to characterize the temporal course of the waves, and it was not until the introduction of the contact lens electrode by Riggs in 194176 that quantitative results could be obtained. 53
© 1999 by Elsevier Science Inc. All rights reserved.
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Since then, significant progress has been made in the clinical implementation of the ERG. However, the variety of stimulation and recording parameters makes it difficult to evaluate and interpret the results from old studies. In response to this problem, a recognized international standard, the International Society for Clinical Electrophysiology of Vision (ISCEV) standard, for recording and reporting ERG was developed.4,65 In this review, we will focus on studies with techniques comparable to the ISCEV standard for full-field ERG. Much of the older literature was summarized in 1981 (oscillatory potentials)89 and 1984 (ERG).12 We will also briefly describe recent findings using the paradigms including the pERG, fERG, and multifocal ERG. FULL-FIELD ELECTRORETINOGRAPHY
According to the current ISCEV standard, five major ERG responses are defined: rod response, maximal combined response, oscillatory potentials, cone response, and 30-Hz flicker response (Fig. 1). A variety of measures have been used to quantify these standard responses. The a-wave is a fast, negative ERG component obtained primarily from the maximal combined response. The leading edge reflects the membrane current in photoreceptors.50,51 For clinical purposes, a-wave amplitude is measured from baseline to a-wave trough (Fig. 1). The b-wave is a large, positive ERG potential present in the rod response, the maximal combined response, and the photopic response. Under scotopic conditions, the rising phase (up to the peak) is directly generated by bipolar cells.49,78,79 Under photopic conditions, several types of neurons contribute to its generation.86 The amplitude of the b-wave is measured from the trough of the a-wave to the peak of the b-wave. The implicit time of the b-wave is measured from flash onset to the peak of the b-wave (Fig. 1). The oscillatory potentials (OPs) are four to six low-amplitude, high-frequency wavelets superimposed on the ascending limb of the ERG b-wave. They were first reported in the human ERG by Cobb and Morton in 195325 and named by Yonemura et al in 1962.104 Analog filtering of the ERG can isolate OPs. Alternatively, fast Fourier transform, followed by digital filtration and reconstruction of the residual waveform, can be used.83 The OPs are thought to result from a feedback between the amacrine cells and the bipolar cells and/or feedback from ganglion cells to amacrine cells. They are more vulnerable to disturbances of the retinal circulation (central retinal vein occlusion, etc.6,58,94) than the b-wave. Several methods for quantifying OPs have been proposed. Frequently, peak-to trough amplitudes of the
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waves are summed to give an overall measure of OP amplitude. Alternatively, the amplitudes of individual wavelets may be recorded. The latter may be preferable, because the OPs are complex in origin and individual wavelets may be generated at different sites within the retina.59,98 There are also newer and less common ERG techniques, which are not covered by the ISCEV standard protocol. For example, the scotopic threshold response is the cornea-negative response of amacrine cells,85 which is present below b-wave threshold. So far, only one study has been published, and it shows deterioration of the scotopic threshold response in advanced cases of diabetic retinopathy.11 PATTERN ELECTRORETINOGRAPHY
The pERG is an electrical retinal response to a phase-reversing patterned stimulus (most often a grating or checkerboard) and reflects mostly ganglion cell activity.64,77 Under most recording conditions, it has three major components: one small cornea-negative wave named N35, followed by a major positive wave, P50, and later, a negative trough at 95 msec (N95 [Fig. 2]). Guidelines for pERG parameters, such as luminance and contrast of the stimulator, have been issued recently.66 FOCAL AND MULTIFOCAL ELECTRORETINOGRAPHY
The fERG is a specialized technique developed for recording local electrical retinal responses to focal light stimuli, usually within the macula.9 With slow stimulus repetition rates, its waveform may be similar to the full-field ERG. With rates faster than 7 Hz, the response becomes sinusoidal and is thought to have a contribution from photoreceptor and bipolar cells.13 The multifocal ERG is evoked by a patterned stimulus, each element of which changes independently. By complex mathematical analysis, one can record (simultaneously) the responses of more than 100 retinal sites (including the macula) and distinguish separate responses of inner and outer retina.91 Outer retinal abnormalities confined to small retinal regions can be seen in diabetic retinopathy, and inner retinal abnormalities may appear before clinically apparent retinopathy.69
ERG Changes According to Severity of Diabetic Retinopathy Typically, there is a considerable time period between the diagnosis of diabetes mellitus and the development of diabetic retinopathy. Within the first 5 years after diagnosis, only about 5% of all patients develop nonproliferative diabetic retinopathy (NPDR),
ERG IN DIABETES
55
Fig. 1. Examples of normal human ERG. A: Scotopic response. B: Maximal response. C: Oscillatory potentials after digital filtration (80–300 Hz). D: 30-Hz flicker ERG. E: Photopic ERG. Solid arrows represent measurement of b-wave implicit time; short dash arrows indicate measurement of a- or b-wave amplitude. In case of the 30-Hz flicker response, asterisks indicate position of the time-mark, super-imposed on the signal. (Records obtained by one of the authors [RT].)
and the incidence of proliferative diabetic retinopathy (PDR) is negligible.52 With time, the proportion of people developing diabetic retinopathy increases steadily, and after 20 years of diabetes more than 90% of patients with type I and about 60% with type II diabetes have some degree of retinopathy.56 The modified Airlie House classification (based on fundus photography) describes six grades of severity of diabetic retinopathy.2 This discussion is limited to ERG abnormalities in the absence of clinically apparent retinopathy, and how they develop in mild NPDR, severe NPDR, and PDR. These changes occur before sight-treatment PDR occurs. NO CLINICALLY APPARRENT RETINOPATHY
Electroretinography abnormalities can be present at a very early stage of disease while there are no visible changes in the fundus. The most consistent alteration is a significant increase in the OP1 implicit time.16,48,57,84,88,103,106 For example, in 572 eyes of 303 patients with non–insulin-dependent diabetes melli-
tus, the OP1 peak was significantly delayed, and the delay in OP1 was greater than any other peak or trough. Increase in implicit time of OP1 occurs in almost all the “stage 0” cases (i.e., not only before ophthalmoscopic changes are apparent, but also before fluorescein angiography and vitreous fluorophotometry changes can be seen). Overall reduction of OPs has also been reported (Table 1). Significant reduction of scotopic b-wave amplitude has also been found in children with insulindependent diabetes mellitus who have no diabetic retinopathy detectable on fluorescein angiography.61,63 This finding was later confirmed in a group of juvenile diabetics without photographic evidence of retinopathy.54,70 Blue cone (S-cone) amplitude was also reduced in similar cases.102 Results from pERG have been controversial for this group (Table 1), probably because of differences in the technique used among studies. A study following the ISCEV recommendations for pERG recording could provide more clinically valuable information.
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rameters between patients with NPDR with or without macular edema and normal subjects.101 SEVERE AND VERY SEVERE NONPROLIFERATIVE DIABETIC RETINOPATHY
Oscillatory potential amplitudes correlate well with the severity of diabetic retinopathy.17,89 The few studies published to date that include patients with severe NPDR showed significantly reduced and sometimes absent OPs (Table 1). The ERG sensitivity (measured by the increase of b-wave amplitude over a range of different stimulus intensities) and photopic b-wave implicit times also correlate well with the severity of diabetic retinopathy.24,81 EARLY AND HIGH-RISK PROLIFERATIVE DIABETIC RETINOPATHY
Several studies have investigated ERG changes in PDR. Significant abnormalities have been reported in all ERG parameters, including decrease of the OP amplitude (up to complete disappearance of the OPs) or delay of the implicit time of the OPs (Table 1), decrease of photopic and scotopic a- and b-waves, and 30-Hz flicker delay.7,42,55,57,62,74,75,92
Tightness of Diabetic Control and Electroretinography Data
Fig. 2. Example of ERG for series of check sizes in a normal subject. The signal was digitally filtered to remove frequencies above 50 Hz. Three primary components are labeled on the lower trace. (Modified with permission from Birch.13)
Focal ERG showed early diabetes to cause selective neurosensory deficits of inner retina layers in patients without visible retinopathy.31,41,43 MILD AND MODERATE NONPROLIFERATIVE DIABETIC RETINOPATHY
Virtually all studies using OPs report distinctive changes in cases with mild NPRD (Table 1). Recently, more detailed studies have revealed that several ERG parameters can be affected in cases of mild NPDR: scotopic b-wave implicit times, 30-Hz flicker amplitude and implicit times, OP amplitudes to both blue and white flashes (including selective reduction of OP3 and OP2), OP implicit times, and photopic ERG implicit times.48,54,95 The majority of the pERG studies to date report a decrease in amplitude and delays in implicit time in cases with NPDR (Table 1). Foveal cone ERG measurements have demonstrated significant changes in both amplitude and time pa-
Until the early 1980s, the necessity of strict diabetic control for amelioration or delay of the natural course of diabetic retinopathy was not recognized. Initially, some reports showed improvement of retinal function (e.g., OP amplitude) with multiple subcutaneous insulin injections and achievement of strict metabolic control.5,38,60 However, later studies produced contradictory results.20,21 Apparently, many factors affect the relationship between ERG parameters and diabetic control, and further work is needed to clarify this issue.
Blood-Retinal Barrier Breakdown in Diabetes It is widely recognized that the permeability of the blood-retinal barrier (BRB) is compromised in advanced diabetic retinopathy.32 However, the results from different vitreous fluorophotometry studies that estimate the integrity of the BRB in cases without visible retinopathy have been controversial.28,71,73,99 This may be because of differences in subject selection, sensitivity of the measuring device, and analysis of results. It has been shown in other diseases (e.g., cone-rod dystrophy) that changes in BRB correlate well with changes in ERG parameters.36 To the best of our knowledge, there is only one study that directly com-
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ERG IN DIABETES TABLE 1
Diabetic Status and Number of Subjects or Eyes Tested in Works Published During 1962–1997, Considering OP or pERG Changes in Diabetic Retinopathy Degrees of Diabetic Retinopathy No Diabetic Retinopathy
Studies evaluating OPs Gjotterberg (1974)42 Yonemura and Kawasaki (1978)103 dSimonsen (1965,88 198087) Brunette and Lafond (1983)22 Wanger and Persson (1985)100 Coupland (1987)27 Zaharia et al (1987)106 Moschos et al (1987)67 dBresnick and Palta (1987)17 Van der Torren (1989)96 Juen and Kieselbach (1990)54 Yoshida et al (1991)105 Shirao et al (1991)84 Li et al (1992)62 Holopigian et al (1992)48 Van der Torren and Mulder (1993)95 Hardy et al (1995)44 Holopigian et al (1997)47 Studies evaluating pERG Wanger and Persson (1985)100 Arden et al (1986)10 Coupland (1987)27 Trick et al (1988)93 Boschi et al (1989)14 Falsini et al (1989)33 Prager et al (1990)72 Jenkins and Cartwright (1990)53 Caputo et al (1990)23 Nesher and Trick (1991)68
Mild NPDR
Severe NPDR
All PDR
Eyes/Patients
N
C
N
C
N
C
N
C
36/36 218/# 267/137 57/57 24/24 35/35 12/12 240/240 174/174 71/46 #/31 36/36 572/303 87/87 14/14 58/58
10 # 120 30 11 21 12 95 2 31 18 36 326 24 4 29
2 1 1 1 2 1 1 1 2 1 1 1 1 2 1 1
20 # 116 11 13 14 na 75 10 23 13 na 186 34 10 29
2 1 1 1 2 1 na 1 1 1 1 na 1 1 1 1
na na na na na na na na 91 18 na na 60 na na na
na na na na na na na na 1 1 na na 1 na na na
6 # 31 16 na na na 70 71 na na na na 29 na na
1 1 1 1 na na na 1 1 na na na na 1 na na
10/10 12/12
10 2
1 1
na 8
na 1
na 1
na 1
na 1
na 1
24/24 53/53 35/35 56/56 38/38 80/80 72/72 40/40 40/40 58/58
11 8 14 34 20 62 38 40 32 27
2 2 2 1 2 1 1 2 1 2
13 30 21 21 20 18 34 na 8 31
2 2 1 1 2 1 1 na 1 1
na 15 na na na na na na na na
na 1 na na na na na na na na
na na na na na na na na na na
na na na na na na na na na na
N 5 number of eyes in that category; C 5 presence (1) or absence (2) of significant change of OP parameter (or pERG parameter) in that group compared to normal subjects; d 5 longitudinal study; # 5 data not available; na 5 not applicable.
pares the results of vitreous fluorophotometry and ERG.105 It showed changes in OP implicit time before changes in the BRB.
The Electroretinogram in Diabetic Retinopathy With Media Opacities Media opacities (including cataract, vitreous hemorrhages, etc.) are frequently associated with advanced diabetic retinopathy. How can this influence the ERG results? Opacities act as a neutral-density filter and attenuate the effective light reaching the eye.40 To circumvent this light attenuation, use of flashes of increasing intensity (bright-flash ERG) has been recommended.39 The same approach can be used successfully to evaluate patients with diabetes before vitrectomy.90 However, in cases with dense vitreous hemorrhages, the results could be contradictory.8
Because the full-field ERG is generally a mass response, it can provide unreliable results if the retinal damage is in a small area at the very center of the macula. Conversely, if a small region of the fovea has been conserved and the majority of the remaining retina is compromised, it is possible to find a flat ERG preoperatively and good visual acuity postoperatively. The presence of the cataract can exacerbate these problems from light scatter. One way to enhance the diagnostic resolution of the ERG in the central retina is to use flicker ERG and flicker visual evoked potential (VEP) to exclude optic nerve damage or macular disease.26,37,97 The use of flicker ERG and/or VEP has been successful in the process of evaluation and prediction of the visual outcome of diabetics before vitrectomy.90 However, in cases with dense vitreous hemorrhages, the results may be contradictory8 and should be interpreted cautiously.
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Diagnostic and Predictive Power of Electroretinographic Findings If the ERG is to be used as an objective and noninvasive method of evaluating the functional status of the retina, it is necessary to demonstrate that it has good diagnostic power (ability to distinguish patients with retinal disease from subjects without it or to distinguish among patients with different stages of the same disease). Such diagnostic power has been demonstrated, for example, in eyes with central retinal vein occlusion.19,45,46,82 To date, only one study has attempted a rigorous evaluation of diagnostic power of ERG in distinguishing patients with diabetes from normal subjects.80 The authors showed that several rod ERG parameters were roughly comparable in such discrimination. The predictive (prognostic) power of the ERG has been demonstrated in two longitudinal studies.15,18,87 In the first study,88 137 type I diabetic patients were tested at baseline and followed up to 15 years after the initial examination. With diabetes of more than 5 years’ duration, the presence of normal or hypernormal OPs at baseline excluded to a great extent the existence of PDR (4% versus 53% in the low-OP group). In the second study,15,18 85 (mostly insulindependent) patients were followed up for 55 to 73 months. Oscillatory potential amplitudes were shown to predict progression to diabetic retinopathy with “high-risk characteristics” at least as well as fluorescein leakage and better than the retinopathy level as assessed by fundus photography. Unfortunately, this model has not been validated yet for noninsulindependent diabetic patients. This could be quite relevant, because recent results from the Early Treatment Diabetic Retinopathy Study show that this group of patients could benefit more from early photocoagulation than the insulin-dependent group.34
Conclusions The ERG test provides a noninvasive technique for assessing retinal function. With use of readily available commercial equipment, the ERG test is easily administered, and it provides useful, objective, and quantitative information. It is evident that the ERG is abnormal very early in diabetic retinopathy. Specialized techniques such as pERG and fERG can demonstrate local abnormalities, but the abnormalities in the flash OP and b-wave demonstrate the widespread nature of diabetic retinopathy. Electroretinography has several uses in diabetic retinopathy. First, it can discriminate between patients who are more likely to develop PDR and patients with a lesser chance of doing so. It can be used in follow-up as a noninvasive objective measure of
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the progression of the disease and, thus, can supplement other clinical measures. Also, with some caution, it can be used to assess the status of the retina when there are complicating factors, such as the presence of cataract. The significance of these findings has not been generally appreciated. Before the onset of clinically apparent diabetic retinopathy, there is a prolonged period in which pathologic changes are occurring. The ERG could occupy a key position in assessing treatment directed to preventing or slowing down these earlier, subclinical processes. The presence of notable ERG functional abnormalities that worsen with disease has been amply demonstrated.
Method of Literature Search The literature was based mainly on MEDLINE (1966 -1997). Key words used were electroretinography, electroretinogram, ERG, oscillatory potentials, diabetic retinopathy, and diabetes mellitus. Only articles published in English were considered. The emphasis of the search was on works published after 1980, for reasons described in the article. The inclusion criteria were human studies, ERG as a main diagnostic subject, and patients with diabetic retinopathy. Exclusion criteria were case reports, reports in which the stage of diabetic retinopathy was not indicated, and works concerning ERG after photocoagulation.
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We are grateful to Dr. David Birch for helpful discussions. Supported in part by the Department of Optometry and Visual Science, City University, London, UK. Reprint address: Radouil T. Tzekov, MD, PhD, Retina Foundation of the Southwest, 9900 N. Central Exressway #400, Dallas, TX 75231, USA.