Course of Glaucoma and the Importance of Early Detection
Glaucoma starts when communication between the ganglion cell axons and the ganglion cell body is compromised, either mechanically or due to vascular impairment, near the optic disc. Ultimately the ganglion cells atrophy, be it through necrosis or apoptosis, whereas bipolar cells and the photoreceptors remain nearly normal. Until a decade ago glaucoma was almost synonymous with raised interocular pressure (IOP), then importance of IOP became de-emphasized to the degree that it was no longer mentioned in glaucoma definitions.1 More recently, the tables were turned again due to the completion of a number of longitudinal multicenter studies, namely the Early Manifest Glaucoma Trial2 and the Ocular Hypertension (OHT) Treatment Study.3 Briefly, these studies suggest that (1) the progression of glaucoma is indeed slowed down by reducing IOP (rule of thumb: 1 mm Hg reduction reduced risk of damage progression by 10%) and (2) the conversion from OHT to manifest glaucoma is reduced by reducing IOP.
Even although elevated IOP thus is a major risk factor for developing glaucoma, only about 1% of patients with an IOP of 25 mm Hg actually do develop manifest glaucoma each year. Prospective studies have reported incidences ranging from 0.4 to 17.4%.4–9 This wide range is largely due to differing study populations with different risk factors or degrees of pressure elevation. Because a sizeable proportion of the ganglion cells, i.e., 25 to 30%, is already lost when visual field losses are apparent,10,11 the aim of early detection is to identify those patients with elevated IOP who have early stage glaucoma damage before visual field changes occur. Thus therapy can be applied before irreversible retinal damage and visual field loss has occurred, while sparing patients who have “just” an elevated IOP. Early detection could well profit from electrophysiological techniques as demonstrated in the present review.
Magnocellular vs. Parvocellular Pathways—Not of Major Relevance in Glaucoma
Research on early diagnosis has been dominated for more than a decade by the “magnocellular paradigm,” starting with Quigley et al.’s observation12: “in early glaucoma … [there is] preferential damage to large nerve fibers.” Previous subdivisions of the visual pathway had been based on psychophysical intricacies,13 but Quigley et al.’s observation came at a time when division of the visual system into (at least) two major subsystems was rekindled.14,15 The two major subsystems that Quigley et al. considered for the selectivity of early glaucoma damage were the magnocellular stream, with large axons, making it the candidate for Quigley et al.’s observation, and the parvocellular stream, which was presumed to be relatively spared. This clear-cut hypothesis had two major consequences: First, it spurred basic scientists to challenge this simple view, to find exceptions, and to test the limits of its applicability. Second, it led some applied researchers to oversimplified16 stimulus paradigms aiming at a selective stimulation of the magnocellular system. For more than a decade, research on early diagnosis of glaucoma was dominated by this “magnocellular damage paradigm.” Although it inspired interesting methodological developments, many researchers now feel that magnocellular damage in early glaucoma is only marginally greater—if at all—than parvocellular damage.17 Recent work is unequivocal on this: Crawford et al.,18 comparing psychophysical findings, reported no evidence for specific magnocellular damage, and Yücel et al.,19,20 using an experimental glaucoma model, found both magno and parvo loss in the lateral geniculate nucleus, if anything there was more parvo loss. Finally, the well-known early blue deficits in glaucoma21 cannot readily be conciled with a magnocellular mechanism. In summary, the hypothesis of “preferential magnocellular damage in early glaucoma” is not a valid guideline. As a consequence, specifically targeting the magnocellular system in glaucoma research is not topical any more. Efforts of electrophysiological investigations may therefore concentrate on other issues, such as the isolation of retinal ganglion cell activity and the reduction of signal variability.
Targeting Retinal Ganglion Cell Function with Visual Electrophysiology
Visual electrophysiology commands a broad arsenal and nearly each of its methods has been applied to glaucoma.22 For each of the various processing stages that a visual input passes through, there is an investigative technique to assess functional integrity. The targets of electrophysiological investigation of glaucoma are threefold, namely: (1) early diagnosis, (2) monitoring the course of the disease, and (3) furthering our understanding of the pathophysiological mechanisms. When we consider the pathophysiology of glaucoma, it is not surprising that many of the techniques used in visual electrophysiology have had little success. Stages prior to the ganglion cells are comparatively unaffected especially at the onset of glaucoma. The pattern electroretinogram (PERG) reflects ganglion cell activity itself and is therefore a direct and promising approach to assist early detection of glaucoma. Although this method is the topic of the present review, we wish to indicate that other electrophysiological approaches to investigate glaucoma have also attracted attention: (1) the photopic negative response,23,24 a novel promising retinal signal, is under testing in various laboratories to determine its value in early glaucoma detection. (2) The S-cone Visual Evoked Potentials (VEP)25 appear to reflect psychophysical findings which demonstrated that the S-cone (koniocellular26) pathway appears to be affected by glaucoma before standard subjective perimetry is affected.27 A delay of these VEP responses may precede morphologically evident glaucomatous damage by 2 years.28 The S-cone ERG also shows alteration in glaucoma.29 (3) Multifocal pattern-reversal VEPs prove to be useful for the objective assessment of visual field loss caused by advanced glaucoma.30,31 Some potential for early detection of glaucoma has been attributed to this technique,32 but recently a similar diagnostic performance of mfVEP and standard automated perimetry was reported.33 (4) Experience with the conventional VEP suggests that it might not be of major relevance for the early detection of glaucoma as conventional pattern-reversal VEPs are less affected by glaucoma than PERGs.34 This can be understood on the grounds that VEPs do not tap the primary locus of glaucoma-caused damage, but reflect the activity of later stages in the visual processing chain which are subject to gain control—possibly masking early changes—between retinal ganglion cell activity and cortical response.35–37
The PERG is a direct indicator of ganglion cell function38,39 and thus a promising candidate to indicate early glaucoma damage. The methodology is only briefly covered here, more detail can be found in the International Society for Clinical Electrophysiology of Vision (ISCEV) PERG standard.40 As stimulus a checkerboard pattern is used, which reverses its local luminance while keeping average luminance constant. Thus, the ERG signals cancel out and non-linearities remain that have been shown to originate mainly in the ganglion cells.41–45 Retinal potentials are recorded with a corneal electrode. Various types of electrodes may be used, such as gold foil,46,47 DTL46 or HK-loop.48 In contrast to recording the ERG, is very important that the electrode does not degrade the optical image on the retina, as reduced retinal contrast leads to a marked reduction of the PERG.49–51 With an appropriate technique, a high stability and reproducibility can be obtained (we found the inter-session coefficient of variation is approximately 10%52).
History of PERG in Glaucoma
The first article reporting PERG recordings in a glaucoma patient was by May et al. in 1982.53 In 1983, two articles appeared, namely by Bobak et al.54 and the first of Wanger and Persson’s seminal work with 11 patients.55 This initiated a steady stream of reports (Fig. 1) that is still going strong.56–73 All but one of these articles reported PERG amplitude reduction in glaucoma without sizable effects on latency. The one exception is a study by van den Berg et al.,74 who did not find a correlation between visual field loss and PERG amplitude, which can in hindsight be understood as a consequence of the experimental design applied. To reduce interindividual variability, the authors used the fellow eyes as reference. However, the incidence of glaucoma in the fellow eye is very high and PERG reduction seems to precede obvious visual field loss (see below). It is likely, therefore, that in van den Berg et al.’s study the PERG amplitudes were also reduced in the reference eye, thus the effect of glaucoma did not show up in the interocular difference.
P50 vs. N95, Steady-State vs. Transient Responses
The frequency of the checkerboard reversal determines whether the transient response (<4 rev/s) or the steady-state response (≥8 rev/s) is evoked (see the ISCEV PERG standard75). When the transient PERG is recorded, a positive (P50) and a negative (N95) component can be discerned. These can be affected differently in retinal and optic nerve diseases.38 When reducing the spiking activity of ganglion cells by application of Tetrodotoxin in macaque monkeys, Viswanathan et al.23 found a reduction of the P50 down to 60%, of the N95 down to 23%. Hood et al.76 reported an overlap of controls and patients for both the N95/P50-ratio and the N95 raw amplitude, which was more pronounced for the ratio [a ratio of ∼1.5 (range 1.2 to 1.9) for normal controls and a ratio of ∼1.3 (range 1.1 to 2.1) for glaucoma patients]. Our own data indicate that the P50 and N95 are rather similarly reduced. In a group of eight normal control eyes and 23 eyes of 12 glaucoma patients, the PERGs to transient stimulation and to steady-state stimulation were compared. Fig. 2 shows that in the transient response, the P50 and the N95 component were affected rather similarly by glaucoma. In contrast, the steady-state response is relatively much more affected by glaucoma, rapid stimulation at 16 rev/s showed a much more pronounced amplitude reduction than did transient stimulation, when compared in the same glaucoma patients (right of Fig. 2 63). When reversal rates become higher than 18 rev/s, the PERG becomes less effective for discrimination between normal and glaucoma, probably, because of decreasing signal/noise ratio.77 These frequency-dependent effects have also been shown by Trick78 and correspond well with psychophysical work that showed more glaucomatous effects at higher temporal frequencies.25,79,80
Altogether, the evidence of three studies suggests that steady-state PERG recording at temporal frequencies between 10 and 20 rps is most efficacious for detecting incipient glaucoma damage.63,77,78 The higher sensitivity of the PERG to early glaucoma using high temporal frequencies seems important for any clinical study design and deserves a more thorough investigation. Stimulation frequencies in the steady-state region (above ∼6 rev/s) have additional technical advantages: (1) they lend themselves to automatic analysis once the intricacies of Fourier analysis are mastered, and (2) there is less degradation by eye movements or blinks; to record a reliable transient N95 one must employ demanding procedures.81
Check Size-Specific PERG Reduction in Early Glaucoma
The PERG to large stimulus checks is relatively spared in early glaucoma. This is illustrated in Fig. 3, where recordings from a normal individual, a patient with early glaucoma, and a patient with advanced glaucoma are depicted.59 In the left column, ERG responses to a flash stimulus show little change in glaucoma (they do, however, show a shape difference which may be related to a reduced photopic negative response as discussed in “Targeting retinal ganglion cell function” above). In contrast, the PERG to small check sizes (0.8°, center column) is affected in early and late glaucoma, whereas the PERG to large stimulus checks (16°, right column) is relatively normal in early glaucoma, but markedly reduced in the advanced stage of the condition.
The check size-specific effect is shown in Fig. 4 in further detail. At the top, there are findings from 15 glaucoma eyes, whereas results from experiments with experimentally induced glaucoma in monkeys are depicted at the bottom.34 Both experiments show that the PERG to large checks is relatively little affected in early glaucoma, with increasing effect with decreasing check size. Similar examples are found in Zrenner et al.82 There is also an indication that with very small checks (<0.5°) the glaucoma effects become smaller again as also reported by Trick.78 These differential effects of check size have useful implications when using the PERG in early diagnosis of glaucoma as will be detailed in the following section.
“PERG Ratio” Paradigm for Glaucoma
Highly significant group differences in the PERG amplitude between normal controls and glaucoma patients do not necessarily imply that a useful risk assessment can be performed on an individual basis. In group comparisons, the high inter-individual variability can be counteracted by high case numbers. For individuals, the results need to be compared with the population distribution, where an octave up or down comprises the 95% confidence interval.52 To tackle this problem, the Freiburg group arrived at the following paradigm. First, steady-state stimulation of 16 rev/s is employed. This frequency is believed to be in the optimum range as described in a preceding section. The exact reversal rate also depends on the equipment, as aliasing by the frame rate of the stimulus monitor must be avoided.83 Second, we combine two check sizes, 0.8° and 16°. Recalling Fig. 3, we note that the PERGs to 0.8° checks are strongly affected by glaucoma, whereas the PERGs to 16° checks are less affected. The interindividual variability is multiplicative,52 such that an individual with a large 0.8° PERG will also have a large 16° PERG. Thus it makes sense to compute the ratio:
In Fig. 5, the data from an earlier publication85 is extended and shows the scatter of a normal control population. There is a high correlation between the amplitudes to 0.8° and 16° check size in normals. In glaucoma, this correlation is decoupled as described in the previous section: initially the 0.8° response is reduced, then later the 16° response. Consequently, an untreated or treatment-resistant glaucoma eye will likely follow the hypothetical curve indicated by the curved dashed arrow in Fig. 5. A constant PERG ratio of 1 corresponds to the 45° line in this figure (the slight difference in amplitude between the two check sizes is factored out here by age normalization). For individual diagnosis, the lower and upper lines indicate the 5 and 95% confidence interval for the PERG ratio, respectively. PERGs from individual eyes that fall below the lower confidence line may be at risk of developing glaucoma (more on this in the section on longitudinal studies below).
As attractive as the ratio approach may seem, there are two caveats to be kept in mind: First, as with any ratio approach (as used, for instance, in the Electro-oculogram (EOG) Arden ratio, or the b/a-wave ratio in the ERG), a ratio becomes unreliable when the denominator becomes too small. Thus, for advanced stages of glaucoma, the PERG ratio will loose value as a surrogate marker. Second, the PERG ratio can be visualized as a projection of all data points on a line orthogonal to the 45° line in Fig. 5. Along this line some interindividual variability remains. As the time course of the disease starts vertically down, part of the variability is projected onto the disease course, and the PERG ratio looses some of its advantage—though it still improves on evaluating the 0.8° amplitude alone (see section on longitudinal studies below).
The “PERGLA” Paradigm
Another well-standardized paradigm to employ the PERG in glaucoma is the one called “PERGLA” by the authors, Porciatti and Ventura,85 for a review see ref. 86, a commercial system is available. A main feature of their approach is the use of skin electrodes, which avoid the contact to the cornea. The use of a grating rather than a checkerboard is a minor difference, the dominant spatial frequency is very similar to a 0.8° checkerboard. The value of this approach has been demonstrated in glaucoma,73 also from an independent laboratory,87 and was found to be sensitive in detecting pressure-related changes.88 Using a skin electrode certainly feels less invasive to the patient. The amplitude is lower (about a factor of 3, widely differing between subjects), but that is of no matter, as intrusions from eye movements are also lower. We found the signal-to-noise ratio of skin electrodes only marginally below the one obtained by DTL electrodes (unpublished observation). The PERGLA paradigm and the PERG ratio described above do not really differ in their essence and could be easily combined. In Table 1 some details can be compared. Clearly an investigation comparing the PERGLA approach to others is warranted.
A Caveat—Effect of Retinal Image Quality on PERG
Any degradation of retinal imaging (e.g., by cataract or defocus) leads to PERG amplitude reduction.89–92 Dioptric defocus is the more problematic case here, because it affects the PERG evoked by 0.8° checks and not the PERG evoked by 16° checks,59 thus changing the PERG ratio in the same manner as glaucoma would. This is illustrated in Fig. 6, where visual acuity was reduced by dioptrical defocus, covering a decimal acuity range from 0.1 to 1.6. Increasing defocus markedly reduces PERG amplitude when 0.2° and 0.8° checks are employed, but has no significant effect with a 16° check size. Wide-angle scattering, as occurs with cataracts, also affects the 16° response, leading to less marked effects on the PERG ratio. The effects are readily understood when the low-pass nature of defocus92–94 and the PERGs linear contrast-amplitude characteristic are taken into account.49,51 To avoid false positive results, we perform PERG-glaucoma testing only on eyes with a visual acuity ≥0.8, tested at the PERG-stimulus distance of 57 cm with a semiautomatic procedure.95 Although optimal optical correction is just a matter of diligence, unfortunately a number of glaucoma patients have beginning media opacities, thus precluding reliable interpretation of PERG findings in such cases.
Predictive Value of PERG in OHT—Longitudinal Studies
To test the utility of the PERG as a biomarker for early glaucoma, longitudinal studies have been performed to assess whether the PERG identifies eyes with elevated IOP that later develop manifest glaucoma. There is a relative scarcity of such studies, largely due to the need of long-term investment of sizeable resources in a time-varying clinical environment and the loss of patients to follow-up. In an early study, we addressed the problem by selecting high-risk eyes (e.g., glaucoma in the patient’s other eye, family history) and recorded the history of 29 eyes in 18 individuals for 1 to 3 years.68 Initially, in 12 of these eyes the PERG was abnormal, and five of these eyes did develop glaucomatous field defects. In contrast, none of the eyes with initially normal PERG developed glaucomatous field defects.
In a more recent prospective study,96 we recorded the history of 95 eyes of 54 patients with initial IOP >25 mm Hg and no apparent visual field damage for up to 10 years (mean follow-up time 8.2 years). Over this time, eight eyes of five patients developed manifest glaucoma. By varying the pathology threshold of the PERG ratio (defined above), we compared the sensitivity and specificity of the technique. Based on the PERG ratio we found a receiver operating characteristic (ROC) area of 0.78; sensitivity was 80% and specificity 71% at a threshold PERG ratio of 1.06. Based on the PERG amplitude at 0.8° (Fig. 7, thin line) we found a ROC area of 0.68. This sensitivity/specificity analysis (ROC analysis) 1 year before manifest glaucoma is depicted in Fig. 7 (data from an intermediate analysis72). The results suggest that the PERG ratio is a slightly better biomarker than the raw PERG amplitude, and that the PERG indeed can pick up incipient glaucoma damage before manifest field defects.
The matter clearly deserves more research, but the present data suggest that the PERG is of value in defining eyes that are at higher risk of developing manifest glaucoma.
PERG and “Panretinal Ganglion Cell Damage” in Glaucoma
In hindsight it is unexpected for the PERG to detect glaucoma changes so effectively, considering that the stimulus covers only the central 15°, while early field defects arise typically in the more peripheral Bjerrum area. There was already indirect evidence that the PERG reflects diffuse, non-focal, damage to the ganglion cells,84 but to test this more directly we looked at the PERG in eyes that had no field damage within the retinal area covered by the PERG stimulus. An example of such a field is seen in Fig. 8A right. Fig. 8B shows PERG amplitude vs. field defect for the two field areas. When we restrict analysis to those patients where the center was normal but the mean peripheral defect was >2 dB (right of the vertical dashed line), we find that most have pathological PERG amplitudes (below the horizontal dashed line), and some are normal. Evidently, and as recently confirmed,76 visual field loss and early ganglion cell damage are not congruent. This suggests that the PERG picks up a “panretinal” damage mechanism, which affects the ganglion cells before reliable field damage is observed. It is intriguing to investigate the spatial extent of the glaucoma-induced PERG reduction with multifocal techniques, which allow one to record independent responses from a large number of visual field locations simultaneously. In general, this is an ambitious approach, as PERG amplitudes from a 15° by 15° patch are already small, and will be reduced even further, if smaller patches are used for multifocal stimulation. As a consequence, multifocal PERG (mfPERG) studies are hampered by small signal-to-noise-ratios and ways to enhance the signal-to-noise-ratio of the mfPERG must be found to increase its value for the spatially resolved assessment of retinal ganglion cell function.97 To date, only few studies exist on the mfPERG in glaucoma.98–101 In these studies reduced mfPERG amplitudes are reported in glaucoma patients. Furthermore, they confirm that the amplitude reduction does not appear to be in a close topographical relationship to the visual field loss observed in these patients and thus support the above interpretation that the PERG is affected “panretinally” in glaucoma. Possibly, this panretinal mechanism mirrors the toxic effects of activated glia in the optic nerve head.102,103 Currently, the value of the mfPERG would rather lie in advancing our understanding of the underlying pathophysiology than in early detection of glaucoma.
The PERG has shown to be of use in early diagnosis of glaucoma: With appropriate recording techniques and paradigms, it can identify eyes at risk one year before manifest field damage with a sensitivity and specificity of >70%. It should be recognized that PERG recording is one of the more demanding electrophysiological techniques, and that experience and care is required to achieve reliable and reproducible results. Nevertheless, at the present state of knowledge the PERG is a promising electrophysiological technique for detecting early glaucoma damage. It is expected to assist the identification of those patients with elevated IOP in whom glaucoma damage is incipient before visual field changes occur.
Sektion Funktionelle Sehforschung
1.Heijl A, Bengtsson B. Long-term effects of timolol therapy in ocular hypertension: a double-masked, randomised trial. Graefes Arch Clin Exp Ophthalmol 2000;238:877–83.
2.Heijl A, Leske MC, Bengtsson B, Hyman L, Hussein M. Reduction of intraocular pressure and glaucoma
progression: results from the early manifest glaucoma
trial. Arch Ophthalmol 2002;120:1268–79.
3.Kass MA, Heuer DK, Higginbotham EJ, Johnson CA, Keltner JL, Miller JP, Parrish RK II, Wilson MR, Gordon MO. The ocular hypertension treatment study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma
. Arch Ophthalmol 2002;120:701–13.
4.Graham PA. The definition of pre-glaucoma
. A prospective study. Trans Ophthalmol Soc UK 1969;88:153–65.
5.Armaly MF. Ocular pressure and visual fields. A ten-year follow-up study. Arch Ophthalmol 1969;81:25–40.
6.Perkins ES. The Bedford glaucoma
survey. I. Long-term follow-up of borderline cases. Br J Ophthalmol 1973;57:179–85.
7.Walker WM. Ocular hypertension. Follow-up of 109 cases from 1963 to 1974. Trans Ophthalmol Soc UK 1974;94:525–34.
8.Jensen JE. Glaucoma
screening a 16-year follow-up of ocular normotensives. Acta Ophthalmol (Copenh) 1984;62:203–9.
9.Lundberg L, Wettrell K, Linner E. Ocular hypertension. A prospective twenty-year follow-up study. Acta Ophthalmol (Copenh) 1987;65:705–8.
10.Quigley HA, Kerrigan–Baumrind LA, Pease ME, Kerrigan DF, Mitchell RS. The number of retinal ganglion cells in glaucoma
eyes compared to threshold visual field data in the same eyes. Invest Ophthalmol Vis Sci 1999;40:S582.
11.Kerrigan-Baumrind LA, Quigley HA, Pease ME, Kerrigan DF, Mitchell RS. Number of ganglion cells in glaucoma
eyes compared with threshold visual field tests in the same persons. Invest Ophthalmol Vis Sci 2000;41:741–8.
12.Quigley HA, Sanchez RM, Dunkelberger GR, L’Hernault NL, Baginski TA. Chronic glaucoma
selectively damages large optic nerve fibers. Invest Ophthalmol Vis Sci 1987;28:913–20.
13.Lennie P, Trewarthen C, Van Essen D, Wässle H. Parallel processing of visual information. In: Spillmann L, Werner JS, eds. Visual Perception: The Neurophysiological Foundations. San Diego, CA: Academic Press; 1990:103–28.
14.Livingstone MS, Hubel DH. Psychophysical evidence for separate channels for the perception of form, color, movement, and depth. J Neurosci 1987;7:3416–68.
15.Livingstone M, Hubel D. Segregation of form, color, movement, and depth: anatomy, physiology, and perception. Science 1988;240:740–9.
16.Skottun BC, Skoyles JR. Some remarks on the use of visually evoked potentials to measure magnocellular activity. Clin Neurophysiol 2007;118:1903–5.
17.Johnson CA, Spry PGD, Cioffi GA, Mansberger SL. Evaluation of a variety of visual function tests in ocular hypertension and early glaucoma
patients. Invest Ophthalmol Vis Sci 2000;41:S104.
18.Crawford ML, Harwerth RS, Smith EL 3rd, Shen F, Carter-Dawson L. Glaucoma
in primates: cytochrome oxidase reactivity in parvo- and magnocellular pathways. Invest Ophthalmol Vis Sci 2000;41:1791–802.
19.Yücel YH, Zhang Q, Weinreb RN, Kaufman PL, Gupta N. Atrophy of relay neurons in magno- and parvocellular layers in the lateral geniculate nucleus in experimental glaucoma
. Invest Ophthalmol Vis Sci 2001;42:3216–22.
20.Yücel YH, Zhang Q, Weinreb RN, Kaufman PL, Gupta N. Effects of retinal ganglion cell loss on magno-, parvo-, koniocellular pathways in the lateral geniculate nucleus and visual cortex in glaucoma
. Prog Retin Eye Res 2003;22:465–81.
21.Sample PA. Short-wavelength automated perimetry: it’s role in the clinic and for understanding ganglion cell function. Prog Retin Eye Res 2000;19:369–83.
22.Hood DC, Greenstein VC. Multifocal VEP and ganglion cell damage: applications and limitations for the study of glaucoma
. Prog Retin Eye Res 2003;22:201–51.
23.Viswanathan S, Frishman LJ, Robson JG. The uniform field and pattern ERG in macaques with experimental glaucoma
: removal of spiking activity. Invest Ophthalmol Vis Sci 2000;41:2797–810.
24.Viswanathan S, Frishman LJ, Robson JG, Walters JW. The photopic negative response of the flash electroretinogram in primary open angle glaucoma
. Invest Ophthalmol Vis Sci 2001;42:514–22.
25.Korth MJ, Junemann AM, Horn FK, Bergua A, Cursiefen C, Velten I, Budde WM, Wisse M, Martus P. [Synopsis of various electrophysiological tests in early glaucoma diagnosis
–temporal and spatiotemporal contrast sensitivity, light- and color-contrast pattern-reversal electroretinogram, blue-yellow VEP.] Klin Monatsbl Augenheilkd 2000;216:360–8.
26.Gouras P. The role of S-cones in human vision. Doc Ophthalmol 2003;106:5–11.
27.Johnson CA, Adams AJ, Casson EJ, Brandt JD. Blue-on-yellow perimetry can predict the development of glaucomatous visual field loss. Arch Ophthalmol 1993;111:645–50.
28.Horn FK, Jonas JB, Budde WM, Junemann AM, Mardin CY, Korth M. Monitoring glaucoma
progression with visual evoked potentials of the blue-sensitive pathway. Invest Ophthalmol Vis Sci 2002;43:1828–34.
29.Aldebasi YH, Drasdo N, Morgan JE, North RV. S-cone, L + M-cone, and pattern, electroretinograms in ocular hypertension and glaucoma
. Vision Res 2004;44:2749–56.
30. Goldberg I, Graham SL, Klistorner AI. Multifocal objective perimetry in the detection of glaucomatous field loss. Am J Ophthalmol 2002;133:29–39.
31. Hood DC, Thienprasiddhi P, Greenstein VC, Winn BJ, Ohri N, Liebmann JM, Ritch R. Detecting early to mild glaucomatous damage: a comparison of the multifocal VEP and automated perimetry. Invest Ophthalmol Vis Sci 2004;45:492–8.
32. Hood DC. Objective measurement of visual function in glaucoma
. Curr Opin Ophthalmol 2003;14:78–82.
33. Fortune B, Demirel S, Zhang X, Hood DC, Patterson E, Jamil A, Mansberger SL, Cioffi GA, Johnson CA. Comparing multifocal VEP and standard automated perimetry in high-risk ocular hypertension and early glaucoma
. Invest Ophthalmol Vis Sci 2007;48:1173–80.
34. Johnson MA, Drum BA, Quigley HA, Sanchez RM, Dunkelberger GR. Pattern-evoked potentials and optic nerve fiber loss in monocular laser-induced glaucoma
. Invest Ophthalmol Vis Sci 1989;30:897–907.
35. Heinrich TS, Bach M. Contrast adaptation in human retina and cortex. Invest Ophthalmol Vis Sci 2001;42:2721–7.
36. Heinrich TS, Bach M. Contrast adaptation in retinal and cortical evoked potentials: no adaptation to low spatial frequencies. Vis Neurosci 2002;19:645–50.
37. Solomon SG, Peirce JW, Dhruv NT, Lennie P. Profound contrast adaptation early in the visual pathway. Neuron 2004;42:155–62.
38. Holder GE. Pattern electroretinography (PERG
) and an integrated approach to visual pathway diagnosis
. Prog Retin Eye Res 2001;20:531–61.
39. Bach M, Hoffmann MB. The origin of the pattern electroretinogram
). In: Heckenlively JR, Arden GB, eds. Principles and Practice of Clinical Electrophysiology
of Vision. Cambridge, MA: MIT Press; 2006:185–96.
40. Holder GE, Brigell MG, Hawlina M, Meigen T, Vaegan, Bach M. ISCEV standard for clinical pattern electroretinography–2007 update. Doc Ophthalmol 2007;114:111–16.
41. Bach M, Gerling J, Geiger K. Optic atrophy reduces the pattern-electroretinogram for both fine and coarse stimulus patterns. Clin Vision Sci 1992;7:327–33.
42. Sieving PA, Steinberg RH. Proximal retinal contributions to the intraretinal 8-Hz pattern ERG of cat. J Neurophysiol 1987;57:104–20.
43. Zrenner E. The physiological basis of the pattern electroretinogram
. Prog Retinal Res 1989;9:427–64.
44. Groneberg A, Teping C. Topodiagnostik von Sehstörungen durch Ableitung retinaler und kortikaler Antworten auf Umkehr-Kontrastmuster. Ber Zusammenkunft Dtsch Ophthalmol Ges 1980;77:409–15.
45. Mafei L, Fiorentini A. Electroretinographic responses to alternating gratings before and after section of the optic nerve. Science 1981;211:953–5.
46. Dawson WW, Trick GL, Litzkow CA. Improved electrode for electroretinography. Invest Ophthalmol Vis Sci 1979;18:988–91.
48. Hawlina M, Konec B. New noncorneal HK-loop electrode for clinical electroretinography. Doc Ophthalmol 1992;81:253–9.
49. Hess RF, Baker CL Jr. Human pattern-evoked electroretinogram. J Neurophysiol 1984;51:939–51.
50. Thompson D, Drasdo N. The effect of stimulus contrast on the latency and amplitude of the pattern electroretinogram
. Vision Res 1989;29:309–13.
51. Zapf HR, Bach M. The contrast characteristic of the pattern electroretinogram
depends on temporal frequency. Graefes Arch Clin Exp Ophthalmol 1999;237:93–9.
52. Otto T, Bach M. Retest variability and diurnal effects in the pattern electroretinogram
. Doc Ophthalmol 1996;92:311–23.
53. May JG, Ralston JV, Reed JL, Van Dyk HJ. Loss in pattern-elicited electroretinograms in optic nerve dysfunction. Am J Ophthalmol 1982;93:418–22.
54. Bobak P, Bodis-Wollner I, Harnois C, Maffei L, Mylin L, Podos S, Thornton J. Pattern electroretinograms and visual-evoked potentials in glaucoma
and multiple sclerosis. Am J Ophthalmol 1983;96:72–83.
55. Wanger P, Persson HE. Pattern-reversal electroretinograms in unilateral glaucoma
. Invest Ophthalmol Vis Sci 1983;24:749–53.
56. Wanger P, Persson HE. Pattern-reversal electroretinograms in ocular hypertension. Doc Ophthalmol 1985;61:27–31.
57. Papst N, Bopp M, Schnaudigel OE. The pattern evoked electroretinogram associated with elevated intraocular pressure. Graefes Arch Clin Exp Ophthalmol 1984;222:34–7.
58. Porciatti V, Falsini B, Brunori S, Colotto A, Moretti G. Pattern electroretinogram
as a function of spatial frequency in ocular hypertension and early glaucoma
. Doc Ophthalmol 1987;65:349–55.
59. Bach M, Hiss P, Rover J. Check-size specific changes of pattern electroretinogram
in patients with early open-angle glaucoma
. Doc Ophthalmol 1988;69:315–22.
60. Price MJ, Drance SM, Price M, Schulzer M, Douglas GR, Tansley B. The pattern electroretinogram
and visual-evoked potential in glaucoma
. Graefes Arch Clin Exp Ophthalmol 1988;226:542–7.
61. Trick GL, Bickler-Bluth M, Cooper DG, Kolker AE, Nesher R. Pattern reversal electroretinogram (PRERG) abnormalities in ocular hypertension: correlation with glaucoma
risk factors. Curr Eye Res 1988;7:201–6.
62. Weinstein GW, Arden GB, Hitchings RA, Ryan S, Calthorpe CM, Odom JV. The pattern electroretinogram
) in ocular hypertension and glaucoma
. Arch Ophthalmol 1988;106:923–8.
63. Bach M, Speidel-Fiaux A. Pattern electroretinogram
and ocular hypertension. Doc Ophthalmol 1989;73:173–81.
64. Korth M, Horn F, Storck B, Jonas J. The pattern-evoked electroretinogram (PERG
): age-related alterations and changes in glaucoma
. Graefes Arch Clin Exp Ophthalmol 1989;227:123–30.
65. Garway-Heath DF, Holder GE, Fitzke FW, Hitchings RA. Relationship between electrophysiological, psychophysical, and anatomical measurements in glaucoma
. Invest Ophthalmol Vis Sci 2002;43:2213–20.
66. Parisi V, Manni G, Centofanti M, Gandolfi SA, Olzi D, Bucci MG. Correlation between optical coherence tomography, pattern electroretinogram
, and visual evoked potentials in open-angle glaucoma
patients. Ophthalmology 2001;108:905–12.
67. Bach M. Electrophysiological approaches for early detection of glaucoma
. Eur J Ophthalmol 2001;11(suppl 2):S41–S49.
68. Pfeiffer N, Tillmon B, Bach M. Predictive value of the pattern electroretinogram
in high-risk ocular hypertension. Invest Ophthalmol Vis Sci 1993;34:1710–15.
69. Maddess T, James AC, Goldberg I, Wine S, Dobinson J. Comparing a parallel PERG
, automated perimetry, and frequency-doubling thresholds. Invest Ophthalmol Vis Sci 2000;41:3827–32.
70. Bayer AU, Maag KP, Erb C. Detection of optic neuropathy in glaucomatous eyes with normal standard visual fields using a test battery of short-wavelength automated perimetry and pattern electroretinography. Ophthalmology 2002;109:1350–61.
71. Unsoeld AS, Walter S, Meyer J, Funk J, Bach M. Pattern ERG as early risk indicator in ocular hypertension–an 8-year prospective study. Invest Ophthalmol Vis Sci 2001;42:S146.
72. Philippin H, Unsoeld AS, Maier P, Staubach F, Walter HS, Funk J, Bach M. Pattern ERG as early risk indicator in ocular hypertension–a long-term follow-up study. Invest Ophthalmol Vis Sci 2005;46:E-Abstract 3757.
73. Ventura LM, Porciatti V, Ishida K, Feuer WJ, Parrish RK II. Pattern electroretinogram
abnormality and glaucoma
. Ophthalmology 2005;112:10–19.
74. van den Berg TJ, Riemslag FC, de Vos GW, Verduyn Lunel HF. Pattern ERG and glaucomatous visual field defects. Doc Ophthalmol 1986;61:335–41.
75. Bach M, Hawlina M, Holder GE, Marmor MF, Meigen T, Vaegan, Miyake Y. Standard for pattern electroretinography. International society for clinical electrophysiology
of vision. Doc Ophthalmol 2000;101:11–18.
76. Hood DC, Xu L, Thienprasiddhi P, Greenstein VC, Odel JG, Grippo TM, Liebmann JM, Ritch R. The pattern electroretinogram
patients with confirmed visual field deficits. Invest Ophthalmol Vis Sci 2005;46:2411–18.
77. Hiss P, Fahl G. [Changes in the pattern electroretinogram
and ocular hypertension are dependent on stimulus frequency.] Fortschr Ophthalmol 1991;88:562–5.
78. Trick GL. Retinal potentials in patients with primary open-angle glaucoma
: physiological evidence for temporal frequency tuning deficits. Invest Ophthalmol Vis Sci 1985;26:1750–8.
79. Tyler CW. Specific deficits of flicker sensitivity in glaucoma
and ocular hypertension. Invest Ophthalmol Vis Sci 1981;20:204–12.
80. Horn FK, Velten IM, Junemann A, Korth M. The full-field flicker test in glaucomas: influence of intraocular pressure and pattern of visual field losses. Graefes Arch Clin Exp Ophthalmol 1999;237:621–8.
81. Holder GE. Recording the pattern electroretinogram
with the Arden gold foil electrode. J Electrophysiol Technol 1988;14:183–90.
82. Zrenner E, Ziegler R, Voss B. Clinical applications of pattern electroretinography: melanoma, retinal detachment and glaucoma
. Doc Ophthalmol 1988;68:283–92.
83. Bach M, Meigen T, Strasburger H. Raster-scan cathode-ray tubes for vision research–limits of resolution in space, time and intensity, and some solutions. Spat Vis 1997;10:403–14.
84. Bach M, Pfeiffer N, Birkner-Binder D. Pattern-electroretinogram reflects diffuse retinal damage in early glaucoma
. Clin Vision Sci 1992;7:335–40.
85. Porciatti V, Ventura LM. Normative data for a user-friendly paradigm for pattern electroretinogram
recording. Ophthalmology 2004;111:161–8.
86. Ventura LM, Porciatti V. Pattern electroretinogram
. Curr Opin Ophthalmol 2006;17:196–202.
87. Yang A, Swanson WH. A new pattern electroretinogram
88. Ventura LM, Porciatti V. Restoration of retinal ganglion cell function in early glaucoma
after intraocular pressure reduction: a pilot study. Ophthalmology 2005;112:20–7.
89. van den Berg TJ, Boltjes B. The point-spread function of the eye from 0 degrees to 100 degrees and the pattern electroretinogram
. Doc Ophthalmol 1987;67:347–54.
90. Leipert KP, Gottlob I. Pattern electroretinogram
: effects of miosis, accommodation, and defocus. Doc Ophthalmol 1987;67:335–46.
91. Ver Hoeve JN, Danilov YP, Kim CB, Spear PD. VEP and PERG
acuity in anesthetized young adult rhesus monkeys. Vis Neurosci 1999;16:607–17.
92. Bach M, Mathieu M. Different effect of dioptric defocus vs. light scatter on the pattern electroretinogram
). Doc Ophthalmol 2004;108:99–106.
93. Smith G. Ocular defocus, spurious resolution and contrast reversal. Ophthalmic Physiol Opt 1982;2:5–23.
94. Drasdo N, Aldebasi YH, Mortlock KE, Chiti Z, Morgan JE, North RV, Wild JM. Ocular optics, electroretinography and primary open angle glaucoma
. Ophthalmic Physiol Opt 2002;22:455–62.
95. Bach M. The Freiburg visual acuity test—automatic measurement of visual acuity. Optom Vis Sci 1996;73:49–53.
96. Bach M, Unsoeld AS, Philippin H, Staubach F, Maier P, Walter HS, Bomer TG, Funk J. Pattern ERG as an early glaucoma
indicator in ocular hypertension: a long-term, prospective study. Invest Ophthalmol Vis Sci 2006;47:4881–7.
97. Hoffmann MB, Flechner JJ. Slow pattern-reversal stimulation facilitates the assessment of retinal function with multifocal recordings. Clin Neurophysiol 2008;119:409–17.
98. Klistorner A, Graham SL. Objective perimetry in glaucoma
. Ophthalmology 2000;107:2283–99.
99. Lindenberg T, Horn FK, Korth M. [Multifocal steady-state pattern-reversal electroretinography in glaucoma
patients.] Ophthalmologe 2003;100:453–8.
100. Stiefelmeyer S, Neubauer AS, Berninger T, Arden GB, Rudolph G. The multifocal pattern electroretinogram
. Vision Res 2004;44:103–12.
101. Harrison WW, Viswanathan S, Malinovsky VE. Multifocal pattern electroretinogram
: cellular origins and clinical implications. Optom Vis Sci 2006;83:473–85.
102. Pekny M, Johansson CB, Eliasson C, Stakeberg J, Wallen A, Perlmann T, Lendahl U, Betsholtz C, Berthold CH, Frisen J. Abnormal reaction to central nervous system injury in mice lacking glial fibrillary acidic protein and vimentin. J Cell Biol 1999;145:503–14.
103. Pekny M, Wilhelmsson U, Bogestal YR, Pekna M. The role of astrocytes and complement system in neural plasticity. Int Rev Neurobiol 2007;82:95–111.
104. Bach M, Sulimma F, Gerling J. Little correlation of the pattern electroretinogram
) and visual field measures in early glaucoma
. Doc Ophthalmol 1997;94:253–63.