Documenta Ophthalmologica 80: 31-41, 1992. 9 1992 Kluwer Academic Publishers'. Printed in the Netherlands.

Electrophysiologically determined contrast sensitivity in patients with ocular hypertension and chronic glaucoma JOHN WILLIAM

HOWE 1 & KEITH WILLIAM

M I T C H E L L 1'2

1University Department of Ophthalmology and 2Regional Department of Medical Physics, Royal Victoria Infirmary, Newcastle upon Tyne, England Accepted 19 December 1991

Key words: Contrast sensitivity, glaucoma, visual evoked potential Abstract. Subjectively assessed contrast sensitivity has been found to be abnormal in many

patients with glaucoma. We previously reported the use of onset-offset visual evoked potential measurements to determine contrast threshold objectively. We now studied 216 patients (79 with ocular hypertension and 137 with chronic simple glaucoma) with this technique. In comparison with an age-matched control group (68 subjects), mean contrast threshold was found to be significantly different in both patient groups, the degree of significance being greater in the patients with chronic simple glaucoma. Additionally, the slope of the CI-CII amplitude versus log contrast plot was shown to be depressed in the majority of affected eyes in patients with unilateral chronic simple glaucoma. This measure appears to give an indication of suprathreshold contrast processing and is related to the difference in luminance between pattern elements, rather than the quality of the border or "edge" between them. The data support not only an increase in contrast threshold (reduced sensitivity) in early glaucoma and some patients with ocular hypertension but also a suppression in suprathreshold function that is not readily measurable with standard psychophysical methods. The findings are consistent with recent theories concerning the effect of early chronic simple glaucoma on the function of Y-type units of the M (magnocellular)-type pathways. Abbreviations:

CSG--chronic simple glaucoma, IOP---intraocular pressure, OH--ocular

hypertension

Introduction

T h e s u b j e c t i v e m e a s u r e m e n t o f c o n t r a s t sensitivity was first d e s c r i b e d b y C a m p b e l l a n d G r e e n [1], a n d its o b j e c t i v e , e l e c t r o p h y s i o l o g i c c o r r e l a t e was d e t e r m i n e d with visual e v o k e d p o t e n t i a l s ( V E P s ) b y C a m p b e l l a n d M a f f e i [2]. T h e s e r e s e a r c h e r s u s e d s i n u s o i d a l gratings g e n e r a t e d o n o s c i l l o s c o p e s c r e e n s as stimuli, b u t S p e k r e i j s e [3] s u b s e q u e n t l y d e m o n s t r a t e d t h a t it c o u l d b e d o n e with c h e c k e r b o a r d s a n d o n s e t - o f f s e t t e m p o r a l m o d u l a t i o n . S u b s e q u e n t to A r d e n a n d J a c o b s o n ' s finding [4] t h a t s u b j e c t i v e c o n t r a s t s e n s i t i v i t y was a f f e c t e d in g l a u c o m a , w e [5] p r o p o s e d t h a t a r a t i o n a l i z e d e l e c t r o p h y s i o l o g i c a p p r o a c h d e r i v e d f r o m S p e k r e i j s e ' s m e t h o d was also useful in t h e d i a g n o s i s a n d m a n a g e m e n t of s e v e r a l o p h t h a l m i c c o n d i t i o n s . P a r t i c u l a r a d v a n t a g e s o v e r s u b j e c t i v e m e t h o d s w e r e t h a t the m e t h o d e l i c i t e d

32 objective data on the pathways being tested, in terms of not only threshold but also suprathreshold function, and was useful in those patients who were elderly and confused and therefore had difficulty in performing any test requiring subjective judgment (e.g., perimetry). We report the findings of a substantive study using an electrophysiologic method to assess contrast sensitivity in patients with ocular hypertension (OH) and those with chronic simple glaucoma (CSG) and to compare these with a group of control subjects.

Subjects and methods

Subjects Two hundred sixteen patients from our glaucoma clinic agreed to take part in the trial. The patients underwent a full ophthalmic investigation, which included Snellen acuity, ophthalmoscopy, applanation tonometry, gonioscopy, and Goldmann kinetic perimetry. In addition, 68 control subjects were tested. The O H group included 79 patients (38 male and 41 female), with a mean age (+- standard deviation) of 61.7 +-8.4 years. Each had an increased intraocular pressure (IOP) of greater than 21 mm Hg (but less than 32 mm Hg) recorded on at least two occasions. Results of optic disk examination were normal (with a cup-disk ratio of 4:10 or less), and Goldmann visual fields (performed with I4e and I2e targets, with particular attention being given to the threatened arcuate regions) were full. The CSG group included 137 patients (81 male and 56 female), with a mean age of 64.5-+ 8.2 years. Each patient was included in one of two subgroups, unilateral or bilateral CSG. In 74 of the patients (45 male and 29 female) we observed a unilateral glaucomatous field defect, pathologically cupped disk, elevated IOP and a gonioscopically observed open angle in one eye only, the contralateral eye being clinically normal. In 63 patients (36 male and 27 female), glaucomatous field defects were found in both eyes along with pathologically cupped disks, an increased IOP on at least two separate occasions and open angles. The control group included 68 subjects who were examined for normative data (31 males and 37 females), with a mean age of 61.0 +_8.6 years. All had full fields, healthy disks and an fOP of 21 mm Hg or less. Only patients and subjects whose corrected Snellen acuity was 6/12 or better (with correction worn if necessary) were included in the study. Those patients with any ocular abnormality that may influence the results of visual evoked potential (VEP) examination (e.g., diabetic retinopathy, macular degeneration, opacities in the ocular media), were excluded. Patients with glaucoma who were using miotic agents for control of IOP were also excluded because miosis can alter contrast sensitivity discrimination. All of

33 our treated patients were using either /3-blockers or, less commonly, a /3 -agonist.

Electrophysiology An onset-offset modulated checkerboard stimulus was produced on a highquality television monitor subtending a field size of 17~ 14~ and with a mean luminance of 10 cd/m 2. Pattern 'on' time was adjusted to 40 ms and 'off' time to 460 ms, i.e., a repetition rate of two per second. This rate was locked to the 50-Hz monitor rate. Stimulus check size was 19' when visual acuity was 6/9 or better and 25' when visual acuity was 6/12. Before the commencement of the test, the patient was preadapted to the luminance of the blank screen for 5 minutes. Monocular VEPs were elicited at contrast levels ranging from 95% to 2.5%, with the nonstimulated eye occluded with a patch. The patient was instructed to maintain fixation on a small light-emitting diode marker attached to the center of the television screen. Recordings were made at five or six discrete contrast levels within the range and presented in a pseudorandom sequence during the test procedure to try and eliminate any possible order effects [6]. The patients and subjects were given short periods of rest in between each contrast measurement to minimize fatigue and any concomitant increase in response variability. Silver-silver chloride disk electrodes were attached to the scalp with collodion in the following positions defined by Jasper [7]: active, Oz; reference, C z; and ground, Pz. Electrode impedences were measured before a test and adjusted to be 2 k o h m or less in both active and reference electrodes. A Medelec electrophysiologic recording unit was used to amplify, average and store the evoked potentials. The amplifier bandwidth was set at 0.8-80Hz, and either 64 or 128 epochs of 300-ms duration were averaged, depending on the size of the response. Two averages were obtained for each stimulus condition to check for consistency, and quantitive analysis was performed on the average of these two. Amplitude measures were recorded peak to peak between CI and CII, since this element of the onset-offset response has been determined to be the most contrast sensitive [8]. A permanent record was obtained on an X-Y plotter, and all the data were fed into a MINC PDP-11 computer for storage and further analysis. In all subjects, the amplitude of the CI-CII component showed a progressive reduction in amplitude as stimulus contrast was reduced (Fig. 1). The amplitude of this component at each contrast level was then plotted against log contrast for each eye, and extrapolation of the least-squares regression lines to zero amplitude gave the electrophysiologically determined contrast threshold (Fig. 2). Pupillary diameter was measured at the end of the procedure, but no difference between the control group (mean, 3.9 + 0.9mm) and patient groups (OH, 4.0 + 0.9 mm; CSG, 4.0 + 1.0 mm) was noted.

34

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Statistical treatment of results In the selection of absolute values from the OH, bilateral CSG and control groups, data from one eye of each individual was selected (at random), since data from both eyes do not constitute truly random variables [9]. In the unilateral CSG group, data from the glaucomatous eye were used. Interocufar differences between right and left eyes were computed for all individuals, the magnitude of this difference being used in the analyses. The effects of disease were assumed to produce excursions from normality in one direction only (i.e., threshold increase); thus, single-tailed Student's t-test analysis was applied to all data. The level of statistical significance selected was p < 0.01. Where distributions of data were observed to be markedly different in two groups being compared, an F-test of variance ratio was performed and, if significant, a correction was applied to the number of degrees of freedom [10].

Results

The VEPs from the right and left eyes of a control subject are illustrated in the top half of Fig. 1. These show a progressive reduction in CI-CII

36 a m p l i t u d e as s t i m u l u s c o n t r a s t is r e d u c e d . In Fig. 1 ( l o w e r half), r e s p o n s e s f r o m a p a t i e n t w i t h u n i l a t e r a l C S G affecting t h e left e y e are i l l u s t r a t e d . It can be seen from the left-eye data that the CI-CII complex showed a more s e v e r e a t t e n u a t i o n with d e c r e a s i n g c o n t r a s t t h a n d i d t h e u n a f f e c t e d right (a) o~

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37

eye. The CI-CII amplitude was plotted against log-contrast for both of these individuals; the resulting relationships are displayed in Fig. 2. Little difference can be seen in the dispersion of the data for each eye in the control subject, and extrapolation of the least-squares regression lines to zero (aL) 9 ~,.10,91

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38

amplitude estimates contrast threshold (the reciprocal of contrast sensitivity) as 3.4% in the right eye and 4.1% in the left. However, the data from the patient with unilateral CSG showed a divergence in the data from each eye, and the resulting threshold estimate was 4.8% in the left eye and 1.6% in the right eye, a marked difference. The slope of the left-eye regression line was also less than that in the right eye. This procedure was performed on all individuals in the trial, and scattergrams of raw threshold and slope data are presented in Figs. 3 and 4. Figure 3a shows the threshold distributions for each group. The unilateral and bilateral CSG cohorts clearly demonstrated increased threshold and variability in comparison to the control group. The OH and unilateral CSG contralateral (or unaffected) eye groups were not overtly different from controls, but there was a suggestion of 'skewness' to higher threshold in the OH group. In relation to the interocular differences shown in Fig. 3b, a clear difference in the glaucomatous groups compared to the control and OH cohorts is evident. With regard to slope, the scattergram in Fig. 4a reveals that not only has the measure large variability in the diseased and control populations, but there is little difference between them, apart from a possible skewness to lower values in the glaucoma groups (note that no meaningful lower 99% confidence limit could be defined for the control data). Interocular measures, of course, reduce variability, and Fig. 4b demonstrates definite differences in distribution in both unilateral and bilateral CSG groups, as

Table 1. Group statistical analysis for control and patient groups

Controls

OH

Unilateral

CSG

CSG

(contralateral eye) CONTRAST

THRESHOLD

Absolute Mean• p (dr)

2.2• --

2.8• < 0 . 0 1 (145)

2.6• NS (140)

6.3+6.9 < 0 . 0 0 1 (150)

0.7• --

0.9• NS(145)

---

3.6 + 6.9 < 0 . 0 0 1 (143)

7.0• --

8.1• NS (145)

7.2• NS (140)

6.84-_4.0 NS (203)

1.1 • 0.9 --

1.8 -+ 1.8 < 0 . 0 1 (145)

---

2,5+_2.9 < 0 . 0 0 1 (183)

Interocular difference Mean+_SD p (df) SLOPE

Absolute Mean• p (df)

Interocular dif~rence Mean -+ S D p (dr)

S D = standard deviation; df = degrees of freedom; NS = not significant.

39 Table 2.

Individual statistical analyses showing detection rates for control and patient groups Detection rate, No. (%) Controls

CONTRAST THRESHOLD Absolute 1 (1.5%) Interocular difference 2 (2.9%) SLOPE Absolute . Interocular difference 3 (4.4%)

.

OH

Unilateral CSG (contralateral eye)

CSG

6 (7.6%)

8 (10.8%)

58 (42.3%)

4 (5.1%)

--

49 (35.8%)

--

30 (21.9%)

. 9 (11.4%)

.

compared to the control group. The OH-control group comparison is much less convincing, but the two distributions appear potentially disparate. The results of the statistical analyses on these data are shown in Tables 1 and 2. Table 1 confirms the impressions from the scattergrams that contrast threshold was highly significantly elevated in the CSG group and significantly elevated in the O H group. Interocular differences confirmed the result for the CSG group only. With respect to slope, only interocular differences were significant, again in both OH and CSG groups, although the latter were much more highly so. Table 2 shows individual detection rates in each group. It can be seen that specificity in the control group is good, but sensitivity in the patient groups is low, 42.3% at best in the CSG group, and not markedly different from controls in the OH group.

Discussion

The findings in this study of increased VEP contrast threshold in patients with glaucoma and suspected glaucoma is consistent with recent investigations using subjective techniques. Using measurements made on contrastgrating perimeter, Neima and associates [11] found that sensitivity to large pattern elements is depressed in early glaucoma. They proposed that this is caused by the dendritic sites most distant from the cell body losing their ability to transmit neural signals earlier than those less distant from the cell body; these changes possibly precede axonal or ganglion cell abnormality. Neima et al. concluded that the largest dendritic trees would be the most vulnerable and that these presumably belong to ganglion cells with large receptive fields, i.e., those most sensitive to low-spatial frequency grating

40 (or large check size) stimuli. In primates and humans this would suggest loss or functional deterioration of M (magnocellular)-type elements in the visual pathway [12]. These pathways (which include X- and Y-type cells, having small and large receptive fields, respectively) have much higher contrast sensitivity than P (parvocellular)-type pathways (predominantly X-type cells), and recent electrophysiologic [13] and anatomic [14] evidence shows that artificially induced glaucoma in primates affects the magnocellular Y-elements first. We believe that the results we have obtained in this study, using a stimulus that is more likely to stimulate M- rather than P-cells (although it is difficult to separate M- and P-cell function in the experimental situation [15]), support such theories. They also support the recent work of Bodis-Wollner [16], who performed psychophysical and electrophysiologic testing in human glaucoma and concluded that the findings were consistent with the idea of a contrast-dependent abnormality of such units. It is common in a glaucoma clinic to see patients in whom the glaucomatous damage is asymmetric, and this can be clinically assessed by asymmetric degrees of disk cupping and field defect. This observation justifies analysis of interocular differences, and it is interesting that in our study this method of analysis revealed significant interocular differences in both the patients with bilateral and unilateral CSG. The regression line slope of the amplitude-contrast plot gives us supplementary information. This suprathreshold measure appears to be related to the difference in luminance of the individual squares (i.e., spatial contrast) rather than the quality of the border between them, since it has been observed that optical blurring does not modify it but merely results in an increased threshold [5]. At the retinal level, this feature seems to be related to the spike discharge rate of ganglion cells with center-surround antagonistic properties. In the present study, 70.6% of affected eyes in patients with unilateral CSG were shown to have significantly lower slopes in comparison to the contralateral unaffected eyes. We suggest that CSG has the effect of not only increasing threshold but, at an even earlier stage, suppressing the suprathreshold firing rate of ganglion cells in these individuals, consequently reducing slope. Furthermore, we would argue that this change is perhaps one of the earliest functional defects in the disease process. We conclude that the VEP method used for determining contrast threshold that we describe in this report suggests early damage of M-cells (although we cannot be certain that some contribution from the P-cells has not also been obtained in the VEP tracings) in the visual pathway in groups of patients suffering from OH and CSG. Although the method has acceptable specificity, it has relatively poor sensitivity in comparison to other VEP approaches [16]. Nevertheless, when such electrophysiologic abnormalities as we have described can be demonstrated in a patient undergoing investigation for possible glaucoma, then it provides the clinician with extra information that can be of value in helping decide whether or not to institute treatment.

41

Acknowledgment W e wish to express o u r sincere t h a n k s to K a r n e C o p e l a n d , C h i e f M e d i c a l Physics T e c h n i c i a n , who, with skill a n d alacrity, elicited m o s t of the e l e c t r o p h y s i o l o g i c d a t a in this study.

References 1. Campbell FW, Green DJ. Optical and regina factors affecting visual resolution. J Physiol 1965; 181: 576-93. 2. Campbell FW, Maffei L. Electrophysiological evidence for the existence of orientation and size detectors in the human visual system. J Physiol 1970; 207: 635-52. 3. Spekreijse H. Pattern evoked potentials. Principles, methodology and phenomenology. In: Barber C, ed. Evoked potentials. Lancaster, England: MTP Press, 1980: 55-74. 4. Arden GB, Jacobson JJ. A simple grating test of contrast sensitivity. Preliminary results indicate value in screening for glaucoma. Invest Ophthalmol Vis Sci 1978; 17: 23-32. 5. Howe JW, Mitchell KW. The objective assessment of contrast sensitivity function by electrophysiological means. Br J Ophthalmol 1984; 68: 626-38. 6. Regan D, Richards W. Brightness, contrast and evoked potentials. J Opt Soc Am 1973; 63: 606-11. 7. Jasper HH. Report of a committee of clinical examination in electroencephalography. Electroencephalogr Clin Neurophysiol 1958; 10: 370-5. 8. Jeffries DA, Axford JG. Source locations of pattern specific components of the human visual evoked potentials. Exp Brain Res 1972; 16: 1-21. 9. Ederer F. Refereeing clinical research papers for statistical content. Am J Ophthalmol 1985; 100: 735-7. 10. Bailey NTJ. Statistical methods in biology. London: Hodder & Stoughton, 1981: 49-51. 11. Neima D, Le Blanc R, Regan D. Visual field defects in ocular hypertension and glaucoma. Arch Ophthalmol 1984; 102: 1042-5. 12. Kaplan E, Shapley RM. X and Y ceils in the lateral geniculate nucleus of macaque monkeys. J Physiol 1982; 330: 125-43. 13. Marx MS, Podos SM, Bodis-Wollner I, Lee PY, Wang RF, Severin C. Signs of early damage in glaucomatous monkey eyes: Low spatial frequency losses in the pattern ERG and VEP. Exp Eye Res 1988; 46: 173-84. 14. Quigley HA, Hendrickson A. Chronic experimental glaucoma in primates: Blood flow study with iodantipyrine and pattern of selective ganglion cell loss. Invest Ophthalmol Vis Sci 1984; 25(suppl.): 225. 15. Merigan WH, Eskin TA. Spatio-temporal vision of macaques with severe loss of P-retinal ganglion cells. Vision Res 1986; 26: 1751-61. 16. Bodis-Wollner I. Differences in low and high spatial frequency vulnerabilities in ocular and cerebal lesions. In: Maffei L, ed. Pathophysiology of the visual system [DOPS 30]. The Hague: Dr W. Junk Publishers, 1981; 195-204. 17. Mitchell KW. The visual evoked potential in the differential diagnosis of ocular hypertension and chronic simple glaucoma [PhD thesis], University of Newcastle upon Tyne, England, 1987.

Address for correspondence: Mr JW Howe FRCS FCOphth, University Department of Ophthalmology, Ward Pavilion 2, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, England Tel: (09)232 5131, Ext. 24156

Electrophysiologically determined contrast sensitivity in patients with ocular hypertension and chronic glaucoma.

Subjectively assessed contrast sensitivity has been found to be abnormal in many patients with glaucoma. We previously reported the use of onset-offse...
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