Doc Ophthalmol (2014) 128:111–120 DOI 10.1007/s10633-014-9428-z

ORIGINAL RESEARCH ARTICLE

Visual evoked potential and psychophysical contrast thresholds in glaucoma Siti Nurliyana Abdullah • Gordon F. Sanderson Andrew C. James • Vaegan • Ted Maddess



Received: 5 September 2013 / Accepted: 5 February 2014 / Published online: 11 March 2014 Ó Springer-Verlag Berlin Heidelberg 2014

Abstract Purpose We compared the diagnostic power of electrophysiologically and psychophysically measured contrast thresholds for the diagnosis of glaucoma. Additionally, we investigated whether combining results from the two methods improved diagnostic power. Methods Seven-eight subjects between 40 and 88 years formed the main study group: 21 normal controls (9 males) and 57 glaucoma patients (30 males) were tested. Twenty-two younger control subjects were also tested. Contrast thresholds were determined for a 1 cpd sinusoidal grating, subtending 41° 9 52° modulated at 14.3 rps. The thresholds were based on the same staircase method applied to visual evoked potential Vaegan: Deceased. S. N. Abdullah  Vaegan School of Optometry and Vision Science, University of New South Wales, Sydney, Australia S. N. Abdullah Orthoptic Unit, Eye Centre, RIPAS Hospital, Jalan Putera Al-Muhtadee Billah, Bandar Seri Begawan BA1710, Brunei Darussalam G. F. Sanderson Ophthalmology Section, Department of Medicine, Otago University, Dunedin, New Zealand A. C. James  T. Maddess (&) Eccles Institute for Neuroscience, John Curtin School of Medical Research (Bldg 131), Australian National University, Canberra, ACT 0200, Australia e-mail: [email protected]

(VEP) and psychophysical responses (Psyc). Diagnostic power was assessed by the percent area under the curve (%AUC) of receiver operating characteristic plots. Results Psyc showed significant age dependence, -0.10 ± 0.02 dB, while VEPs did not. Diagnostic performance for moderate and severe eyes combined was modest: Psyc 74 ± 9.0 % and VEP 72 ± 9.1 %, but improved significantly (p \ 0.05) for a simple combined method, up to 90 ± 6.0 % for moderate disease. The combined method improved %AUC for all severities on average (p \ 0.03). Canonical correlation analysis indicated that the four threshold measures contained independent information and that these independent dimensions were each correlated with glaucoma severity (p \ 0.0015). Conclusion Combining the VEP and Psyc thresholds appeared to improve diagnostic power. Canonical correlation analysis indicated that they measured statistically independent aspects of glaucoma possibly related to disease severity. Adding the 20-s psychophysical test to a VEP test produced a significant benefit for a small time cost. Keywords Contrast thresholds  Visual evoked potential  Glaucoma  Combined thresholds Introduction Early psychophysical studies of contrast thresholds revealed that testing at temporal frequencies (TF) of

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8–10 Hz and spatial frequencies (SF) B1 cpd had good sensitivity for glaucoma [1, 2]. These results were largely confirmed in steady-state visual evoked potential (VEP) studies [3, 4]. Subsequently, low SF stimuli modulated at somewhat higher TF, such that they displayed the frequency doubling (FD) illusion, were reported to provide improved ability to diagnose glaucoma [5–8]. VEP-based contrast thresholds have also been attempted [9–13]. Detailed contrast-response functions for stimuli with such low spatial frequencies (\0.25 cpd) and high temporal frequencies (20–23 Hz) have been reported to be somewhat non-monotonic [13–15]. If that is the case, then a VEP contrast threshold determined by an iterative method may be more reliable than attempting to infer a threshold by linear extrapolation from responses to higher contrasts. The present study sought to compare psychophysical and VEPbased thresholds for diagnosing glaucoma. Given the information above, we elected to use a low SF and a TF of 14.3 rps when determining both types of contrast threshold, using the same threshold estimation strategy. A few reports have indicated that the threshold contrasts obtained by the psychophysical and VEP methods in glaucoma can be relatively uncorrelated, especially at low spatial frequencies [10, 11, 13]. This opens up the possibility that the two methods are measuring somewhat independent aspects of glaucoma. Improved diagnostic power is expected if the two methods measure different aspects (statistically independent) of a disease [16–18]. Therefore, we have also examined whether or not combining the results of the methods improved diagnostic power, and whether the four threshold types contained independent (orthogonal) dimensions, and also whether those independent dimensions are significantly correlated with glaucoma. If such improvement is available, then the addition of a quick psychophysical test might (20 s) add considerable value to VEP testing at minimal time cost.

Methods Subjects and recruitment Contrast thresholds from a total of 113 eyes of 100 subjects were measured with a psychophysical test, Psyc (Table 1). Of those 100 subjects, 96 (108 eyes) thresholds were also measured using VEPs. Table 1 summarizes the number of subjects and eyes, mean

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age, eyes and genders tested. The number of those who participated in all or part of the two tests is tabulated in their respective subgroups in Table 1. Glaucoma patients were recruited from four sources: (1) the Optometry Clinic, School of Optometry and Vision Science, UNSW (SOVS), (2) the Eye Practice (TEPS), (3) the Ophthalmology Section, Department of Medicine, Otago University, NZ (ODNZ) and (4) the Ophthalmology Department, Prince of Wales Hospital, NSW (POWH). Screening and diagnosis Normal subjects had either normal corrected vision (6/6 or better measured using a Bailey–Lovie chart), refractive errors B±6 spherical diopters and B1.50 diopters of cylinder. Normal visual fields are assessed by the screening (C-20-1) program of the FDT perimeter (Carl Zeiss Meditec, Dublin, CA). None of the normal subjects had a self-reported history of glaucoma or was under medication for any systemic or ocular disorders. Optometrists and resident glaucoma sub-specialists diagnosed the glaucoma patients’ eyes using a predefined scale of glaucoma severity (Vaegan et al. [11] and Table 2). Patient diagnosis was masked to the experimenter (SNA) until after the tests were completed. Inclusion criteria for glaucoma patients in this study were 40 years or older and best-corrected visual acuity of 6/12 or better. The eye with the best acuity was tested, with the consequence that only two tested patient eyes were 6/12 and 16 patients were 6/9. Recall that at the spatial frequencies used here, several diopters of refractive error would be required to demodulate the stimuli [19]. Patients also had no more than mild cataract, no history of eye disease or eye trauma and no other systemic disease or medication use that could influence visual field sensitivity or contrast. Subjects with minor cortical and nuclear lens changes were permitted, provided their acuity was acceptable. For some analyses, subjects were divided into six groups numbered as (0) normal \40 years, (1) normal [40 years, (2) suspect, (3) mild, (4) moderate and (5) severe glaucoma. Neither eyes with minor cataract nor acuities of 6/9 in the tested eye were concentrated in any particular severity group. In the event of equal acuities, an eye was selected at random. The untested eye was occluded with a black

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Table 1 Subject data Groups

Normal \40

Normal [40

Suspect

Mild

Moderate

Severe

Total

Steady-state VEPs—1 region (VEP) No. of subjects

21

20

16

17

13

9

96

Mean age ± SD No. of eyes tested

26.1 ± 6.9 24

65.5 ± 6.5 20

68.7 ± 10.5 16

72.8 ± 9.3 22

73.7 ± 10.5 15

74.7 ± 14.5 11

108

Gender (M:F)

6:18

14:6

8:8

12:10

10:5

8:3

54:54

Eyes tested (OD:OS)

18:6

15:5

7:9

13:9

7:8

4:7

64:44

21

17

17

14

9

100

Psychophysics—1 region (Psyc) No. of subjects

22

Mean age ± SD

26.2 ± 6.8

65.6 ± 6.6

68.7 ± 10.2

72.8 ± 9.3

74.4 ± 10.5

74.7 ± 14.5

No. of eyes tested

26

21

17

22

16

11

Gender (M:F)

7:19

9:12

9:8

11:11

11:5

8:3

55:58

Eyes tested (OD:OS)

19:7

16:5

7:10

13:9

8:8

4:7

67:46

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Summary of the total number of subjects and eyes tested for both psychophysical and electrophysiological contrast threshold tests. SD and SEM denote standard deviations and standard errors of the mean, respectively. OD is the right eye and OS, left eye. Letters M and F indicate male and female subjects

patch throughout the recording sessions. If subjects were willing, the fellow eye was tested later. Twentythree subjects volunteered to have both eyes tested. Subjects with pupil diameters\2 mm were not tested. Patients’ preparation and instruction Subjects viewed the stimuli from a distance of 40 cm. The order of psychophysical (‘‘Psyc’’) and visual evoked potential (VEP) testing was randomized. For the electrophysiological tests, the skin at electrode locations was cleaned with an ethanol wipe and rubbed with a mild abrasive gel (OmniPrep, Weaver & Co or NeuroPrep, D.O. Weaver and Co, Aurora, USA). The electrodes were attached to the head with an electrode paste (Elfix, Nihon Kohden, Tokyo, Japan, or Ten20, D. O. Weaver and Co, Aurora, USA), and impedance at 16 Hz was kept below \3 KX (C.H. Electronics, London, UK). The electrodes were held firmly in position by 1-cm Micropore Tape (3 M Corp, MN) and an elastic bandage around the head (Bandafix, Size 4, International Medical, Zetphen, NL). The electrode configuration is shown in Fig. 1. For both test methods, subjects were instructed to fixate on a small central fixation target, a 2 9 2 pixel red square. Both tests were completed in one session with a rest period B30 min between tests. The average test durations for Psyc and VEP were approximately 20 s and 9 min, respectively.

Visual stimuli All stimuli were generated by Vista graphics card (Truevision, Shadeland Station, IN) and were displayed on a HP 1,230 CRT monitor at a resolution of 512 by 424 pixels measuring 300 by 400 mm, subtending 41° 9 53°. The mean luminance of the screen was 52 cd/m2 as measured using an IL700 Research Photometer (International Light, Newburyport, MA). The monitor was refreshed at 101.5 frames/s. The contrast of the stimulus was sinusoidally reversed at 14.3 rps, i.e., the continuously varied contrast was C(t) = cos(2pf), f = 7.14 Hz. The gratings had vertical stripes and a spatial frequency of 1.0 cpd at the center of the flat display. Threshold procedures Contrast detection thresholds were estimated using the same adaptive staircase procedure for both the Psyc and VEP tests. There were 15 possible Michelson grating contrasts which, with correction for ambient light, were as follows: 0.0075, 0.01, 0.015, 0.02, 0.03, 0.04, 0.06, 0.08, 0.12, 0.16, 0.24, 0.32, 0.48, 0.64 and 0.96. The steps of the threshold method were as follows: 1. 2.

The starting contrast was -11.0 dB (i.e., 0.08). The duration of stimulus display was 1 s for Psyc and 20.2 s for a single VEP repeat.

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Table 2 Glaucoma severity definitions Potential characteristics

Possible optic nerve head findings

Possible VF findings

Suspect

Borderline intraocular pressure (IOP) ([21 mm Hg)

Borderline cupping (vertical cup-todisk ratio (VCDR) of about 0.6–0.7)

Normal

Mild

Early signs of glaucomatous disease

Mild VCDR asymmetry (C0.2 difference), vertical cupping with intact rims, concentric enlargement of the cup, mild nerve fiber layer loss

Normal or diffuse loss of sensitivity, defects generally MD B6 dB in depth, early nasal step or para-central depressions

Stage

Moderate

Definite disease with minimal functional impairment

Extension of VCDR, disk hemorrhage, bared vessels, diffuse thinning of neuroretinal rim

Loss of sensitivity, 6 dB CMD B12 dB, diffusely or at isolated points or small clusters, welldefined nasal steps, focal defects from loss of nerve fiber bundles

Severe

Significant disease

VCDR [0.8–0.9, segmental loss of rim

Loss of both sides of the VF horizontal meridian, large nerve fiber bundle defects or altitudinal loss/requires change to larger size to measure temporal and central islands remaining (areas with total deviations B30 dB) and MD [12 dB

Criteria used for classifying patients, as adapted from part of Table 2.3 in ‘Atlas of Glaucoma,’ Classification of glaucoma by stages of disease. Mean deviation levels (MD) are based on HFA 24–2 visual field (VF)

3. 4. 5.

If the stimulus was detected (a ‘‘yes’’ response), the contrast was stepped down by 2 contrast steps. If the stimulus contrast was not detected (a ‘‘no’’ response), contrast was stepped up by 1 contrast level. The process terminated the following 6 reversals and 3 hits, and separate thresholds were determined as the mean of each of those two criteria.

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Hits were the contrasts of the last few correct responses (Fig. 2). Previous findings suggested the starting contrast of 0.08 [11]. The main difference between the VEP and Psyc tests was the decision factor. For Psyc thresholds, the contrast decrements and increments were decided on button presses, whereas for the VEPs, this was determined by a signal-to-noise ratio (SNR) measured as follows: zSNR ¼ ðS  Nmean Þ=Nsd where S is the signal amplitude; Nmean is the absolute value of the mean amplitude in the complex plane of the nearest 88 frequencies surrounding the test frequency; and Nsd is the standard deviation in the 88 noise frequencies on either side of the response in the DFT-derived spectrum (a band ±0.198 Hz wide given the frequency resolution of 0.0495 Hz). The selection of those particular noise frequencies made this study directly comparable to two previous studies [14]. The zSNR metric has a chi distribution, and a value above 1.55 was deemed to be significant, approximating a one-tailed t test at p = 0.05 [11]. For the VEPs, the average value for a minimum of two 20.2-s repeats was completed, but up to 4 repeats were done when the zSNR differed from the previous responses by [2. A significant signal on any of the recording channels was taken to be detection (a ‘‘yes’’ response). Likewise, if all zSNRs were\1.55, this was considered a ‘‘no’’ response. Included in this decision was a virtual channel that was the root mean square of the recorded channels. ROC analysis The main aim of this study was to compare the diagnostic power for different methods as assessed by the percent area under the curve (%AUC) of receiver operating characteristic (ROC) plots using MATLAB software (the MathWorks, Natick, MA). A %AUC value of 100 % indicates perfect sensitivity and specificity, and 50 % represents chance performance. The data for the analyses were the four contrast sensitivities derived from the two tests, VEP and Psyc. The methods are described in detail elsewhere [20, 21], but are summarized below. If more than one eye had been tested, we used only the first tested eye. We selected a subset of subjects

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Fig. 1 Schematic representation of the placement of electrodes relative to the inion. The side view (left) illustrates Channel 1 (A-inion), which was the reference placed at mid-position of the forehead, and Channel 2 (B– inion). The view of the posterior pole (right) shows Channel 3 (C-inion) to the right of the inion and Channel 4 (D-inion) to the left of the inion. The ground electrode was placed on the mastoid bones behind the ears and yoked together

Fig. 2 An example of the threshold strategy drawn from a real Psyc experiment (subject’s code GEOB). The ordinate represents the contrasts in dB and the abscissa, time in seconds. The circles represent the reversal points in the staircase. Hits correspond to a detected grating following an increase in contrast and are illustrated by the asterisk. Numbers in shaded boxes are dB contrasts, whereas those in bold are the Michelson contrasts

between 43 and 80 years to achieve age-matched groups; these included 19 normal subjects (14 males), and 46 glaucoma patients and suspects (22 males). The mean age of the normal controls, 64.6 ± 2.0 (SE) years, did not vary significantly from the patients at 69.3 ± 1.3 years (p = 0.057). Normative data for each threshold type were computed as the median threshold of the old control subjects (group 1 above). Second, the differences between the normative data and each subject’s threshold(s) were computed, providing a set of deviations from normal. The deviations from normal were transformed to z-scores, and these were entered into the ROC analysis. Before the ROC analysis, the

z-scores were mapped onto the z-scores of a standard normal distribution. This is a fairly common transformation for medical data, but more usually, the mapping is done via a quartile–quartile plot (QQ-plot), and so the results are in units of percentiles of a standard normal distribution [22]. There was one extra feature, a leaveone-out (LOO) cross-validation scheme. For the LOO process, the deviations for each normal subject were derived by first re-computing the normative data with the threshold from that normal subject left out. In this way, no normal subject influenced their own ROC classification, which improved the validity of the relatively small normative data set.

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Results Contrast sensitivities for psychophysical tests were on average higher than for their corresponding electrophysiological tests by a mean of 2.28 ± 0.85 dB (mean ± SE), or a 1.7-fold difference (cf. Fig. 3a, b). The VEPs produced no difference between the younger and the older control group, but it showed a larger difference between moderate and severe eyes than for the Psyc data. A multiple regression linear model was fitted to quantify the independent effects of factors such as gender, tested eye, disease severity group and the covariate age. The reference condition for each method was the mean contrast threshold of the left eyes of male normal subjects. The various factors were fitted as contrasts to a reference value. That way, as well as the mean threshold controlled for the other variables, the significance of the difference between males and females, normal and severe disease, etc., was obtained. For example, for the 6-reversal VEP thresholds, the difference from normal was -3.10 ± 1.30 dB (p \ 0.02, Table 3), i.e., the mean threshold for severe glaucoma was 10.37–3.10 = 7.27 dB. Females were not significantly different than males for any threshold. ROC analysis Figure 4 provides a summary of the %AUC for the various patient groups. The analyses were also conducted for three groups of pooled patients: the group of suspect and mildly affected eyes (sus ? mild), the group of moderately and severely affected eyes (mod ? sev) and all patient eyes (All). The pooled data provided estimates of %AUC from larger numbers of subjects per group. With the exception of the severe group, %AUCs for Psyc were generally higher than for the VEP. As a precaution, we redid the analyses for the suspect group taking out the two eyes with acuities of 6/12. This reduced the suspect group %AUC for VEPs from 59.5 ± 10.4 to 57.0 ± 10.7 (mean ± SE) and for the combined measure from 70.0 ± 10.3 to 68.9 ± 10.6, but these changes were not significant. The %AUC for the psychophysical thresholds in suspect eyes was not changed. We also used the analytical method of Bell et al. [20] to combine the Psyc and VEP data for ROC analysis. Since the results for 6-reversal and 3-hit thresholds were similar (Fig. 4), we first took the means of these two

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thresholds for VEP and Psyc data. Combined VEP ? Psyc scores for each eye are derived from a Fisher’s linear discriminant analysis, and these scores were entered into the ROC analysis. Percentage AUC values for the combined scores are shown in Table 4. For all but the severe glaucoma category, the combined measures gave significantly improved performance (Table 4). Canonical correlation analysis A possible reason for the improved performance of the combined VEP and psychophysical measures is that they each contain some independent (uncorrelated) information about glaucoma. A parsimonious way to quantify such a possibility is canonical correlation analysis, which converts the independent and dependent variables to produce so-called canonical variables and examines the correlation between them. The conversions are similar to principle component analysis where the main independent sources of variation within a larger set of variables are extracted. In the present case, we call the resulting two sets of canonical variables: S based on glaucoma severity and F based on the functional VEP and psychophysical measures. Formally, S and F are matrices, each of N columns, where each of the contents of each column is linear combinations of the original N variables, and as mentioned, these new canonical variables within each matrix are uncorrelated with each other. The first issue is whether the functional data contain significant variation in these new variables (mathematically that their rank is[1), i.e., which of the N are real variables describing a significant amount of the data. The next issue is whether the independent F variables (threshold data) are correlated with the S variables (severity data). In summary, these calculations will determine whether the functional measures (thresholds) contain significant independent components and how they in turn are correlated with glaucoma. The initial step is a QR decomposition of each set of the initial severity and functional variables, which examines whether those original variables have more than one dimension, i.e., rank [1. In the second step, the correlation between the components of S and F is computed, with the null hypothesis of no correlation. For this analysis, we included two glaucoma severity variables: the original five-level scale of normal to severe glaucoma (groups 1–5, ‘‘Methods’’) and a second variable that discriminated the severe eyes

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117 Psyc Thresholds

VEP Thresholds

18

a

Contrast Sensitivity (dB)

16

b

14 12 10 8 6 4 2 0 N40

Sus

Mild

Mod

Sev

N40

Sus

Mild

Mod

Sev

Subject Class

Fig. 3 Mean contrast sensitivities in dB = 10*log (1/threshold contrast). a Psychophysical thresholds (n = 113). b VEP thresholds (n = 108), both based on the last 6 reversals. The acronyms for groups used on the abscissa mean: N \ 40, normal

\40 years; N [ 40 normal 40 years or older; sus, POAG suspect eye; mild, mod and sev indicate mild, moderate and severe glaucomatous damage. Error bars are SE

from all others. The latter variable was suggested by the differing thresholds for moderate and severe eyes (cf. Fig. 3a, b), and the resulting form is given in Fig. 4. These two variables proved to have full rank (two), and accordingly, S also had two orthogonal (uncorrelated) dimensions defined as linear combinations of the original variables. The four sets of functional variables were entered, i.e., the 3-hit and 6-reversal data for the VEP and psychophysical methods. These also proved to have full rank (four), but only the two dimensions explaining the largest proportion of variance were used to compute F. Note that the inclusion of two diagnostic variables to make S does not influence the number of dimensions of F. The correlation between the pairs of dimensions of S and F were 0.639 and 0.416, respectively (p \ 10-8 and p \ 0.0015). Thus, as suggested by the ROC analysis for the combined scores, the VEP and psychophysical variables collectively contain at least two independent factors that are each significantly correlated with independent aspects of glaucoma severity.

of glaucoma and to compare that with psychophysical thresholds when using a closely related threshold strategy. This study was motivated by findings of two previous studies where different threshold schemes and smaller numbers of subjects were used [10, 11], and by steady-state multifocal PERG studies of glaucoma by Maddess et al. [23], which also used M-cell-biased stimuli. The findings here are in general agreement with the two previous studies from this laboratory [10, 11]. In particular, those studies reported that VEP and Psyc thresholds can be quite uncorrelated with glaucoma, as reported by others [13]. This might suggest that the two types of thresholds contain independent information about glaucoma that could be usefully combined [16–18]. Therefore, we examined combinations of the thresholds. In terms of %AUC, the VEP seemed to outperform the Psyc test for severe glaucoma (Fig. 4, Table 4); however, there were only six eyes in this group. When the methods were combined, diagnostic performance increased significantly on average (p \ 0.03, Table 4). The best values achieved being 89.5 ± 5.99 % for moderate disease and 84.2 ± 7.25 % for moderate ? severe eyes together. Although %AUC values up to 90 % are not excellent, it is possible that the present results indicate a way forward to optimize the types of Psyc and VEP variables and tests used. The canonical correlation analysis showed that the ROC results for the combined scores were based on the two types of thresholds measuring independent

Discussion The basic purposes of the current study were to investigate whether the VEP contrast threshold method could provide good diagnostic power for early detection

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Psyc (6revs)

Psyc (3hits)

VEP (6revs)

VEP (3hits)

Values of coefficient (dB)

Percentage ROC Area

Table 3 Linear model outputs

80 70 60 50 40

Reference

19.52

18.4

10.37

8.35

Female

-0.35

-0.10

-1.09

-0.95

0.43

0.37

0.69

0.74

10 0

Right eye Suspect

-0.54

-1.01

-0.67

-0.52

Mild

-1.37

-1.45

-1.51

-1.36

Moderate

-2.27

-2.60

-1.14

-1.17

Severe

-1.98

-0.97

-3.10

-2.99

Age

-0.10

-0.11

0.01

0.01

1.27

1.13

1.07

Standard errors (dB) Reference

1.18

Female

0.71

0.77

0.67

0.63

Right eye

0.70

0.76

0.66

0.62

Suspect

1.16

1.25

1.08

1.02

Mild Moderate

1.09 1.25

1.18 1.35

1.01 1.18

0.96 1.11

Severe

1.52

1.52

1.30

1.23

Age

0.02

0.02

0.02

0.02

30 Psych 6 rev Psych 3 hits VEP 6 rev VEP 3 hits

20

sus

mild

mod

sev

sus+mild mod+sev

Fig. 4 Percentage area under the ROC curves (%AUC) for different levels of glaucoma severity and pooled severities, for Psyc and VEP contrast thresholds. Two measures of contrast thresholds were used: the means of the last 6 reversals and of the last 3 hits (Fig. 2). In addition to the original four severity classes, suspect (sus), mild, moderate (mod) and severe (sev), three pooled severity groups were examined. The number of eyes in each severity group was as follows: suspect (n = 13), mild (n = 17), moderate (n = 10) and severe (n = 6). To reduce clutter, error bars are presented only for the 6-reversal psychophysical data (Psych 6 rev). The median SE was 9.2 %, and the SE ranged from 6.6 to 17.6 %, where the smaller values were associated with the larger %AUC values

Independent effects contributing to the measured thresholds using a linear model are shown in the upper half, and SEs are shown below. All the values are dB of contrast sensitivity; the values for the factors in rows 2–7 are the differences from the references (grand mean contrast sensitivity for left eyes of normal males). Only severe glaucoma and age were significant for some threshold types (bold numerals, p \ 0.02, all others p [ 0.05). The covariate age has units of dB/year

Table 4 Percentage AUC values

Severe

65.8

81.6

75.4

(uncorrelated) types of information about glaucoma based in part of the severity of the disease. It is not difficult to imagine sources of somewhat independent types of thresholds. For example, particular thresholds might be differentially influenced by the number of ganglion cells remaining versus the health of each cell, or by the relative amount of retinal compared to cortico-thalamic degeneration, where the VEP might pick up more of the latter. The inclusion of a second severity measure in the canonical correlation analysis did not influence the dimensionality of the threshold variables. Further analysis revealed that the second severity measure used was not very critical. For example, redoing the analysis picking severity 4 (moderate) as the second severity variable produced very similar results with canonical correlations of 0.594 and 0.343 (p \ 5 9 10-7 and p \ 0.017). Overall, this suggests that the independent information about glaucoma reported by the two tests is

Suspect ? mild

67.4

65.3

75.6

Moderate ? severe

73.7

72.0

84.2

All groups

69.6

67.6

78.6

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all

Visual Field Severity Group

Groups

Psyc

VEP

VEP ? Psyc

Suspect

64.4

59.5

70.0

Mild

69.7

69.7

79.9

Moderate

78.4

66.3

89.5

Percentage AUC for the Psyc and VEP tests, where the inputs were the means of the 6-reversal and 5-hit thresholds, and those measured combined by the use of scores derived from a linear discriminant analysis (column 3, VEP ? Psyc). Some groups improved significantly when the thresholds were combined. Significant increased values are marked by bolding of the AUC value for the combined condition (p \ 0.05). Paired t tests on the two sets of seven values were also significant. The SE ranged from 5.9 to 16.3 % and median 8.9 %, with smaller values being associated with the large %AUC values (see Fig. 4)

perhaps mainly at the higher severity end. Differences at those severities were somewhat borne out by the raw threshold data (Figs. 3, 4). Indeed, some evidence has recently been presented that the disposition of scotomas in late-stage glaucoma is at least in part controlled by a binocular cortical process [24].

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In the present study, a simple and conservative method for combining the Psyc and VEP variables, a Fisher’s linear discriminant analysis, appeared to add value. More complex models based on logistic regression or quadratic discriminant analysis might yield better results [8], but being more complex would require considerable data to validate the method. A further step might be to combine a structural measure with the VEP and Psyc [25]. To combine structural and functional data, methods such as the forest of random trees have been recently introduced with good success [16–18]. Slightly different functional data might be more efficient. Several multifocal VEP studies have found that to detect glaucoma effectively, it is important to have stimuli subtending more than 15° eccentricity to improve the detection of peripheral visual field defects [23, 26, 27]. The tests in the present study subtended 53° 9 41°. The relatively poor performance for severe disease here may reflect the inability of one large test stimulus to detect deep but localized scotomas. This might be especially the case for psychophysical tests where a subject might rely on a part of their field to make discriminations. We used an iterative threshold method to try to avoid the effects of non-monotonic contrastresponse functions occurring near threshold that we have observed for similar stimulus conditions [15], but the present results suggest that VEP responses obtained to a single-criterion contrast of about 10 % contrast could be a reasonable test for glaucoma (Fig. 3a). This may seem to be quite a low-criterion contrast, but it is only at such low contrasts that stimuli like these are not saturating [14, 15, 28]. Saturation can mask the difference between a mildly damaged field and a normal one. Given more test time, it might be better to perform a multifocal steady-state VEP with a few large regions [14], possibly a dichoptic version to allow between-eye comparisons and possibly using stimuli where the spatial frequency doubling illusion is visible in all regions [28]. An interesting finding has been that arrays of multifocal stimuli can be scaled by several octaves, corresponding to viewing distance being changed by several octaves, with little change in VEP amplitude [14, 29]. This result appears to be due to the log-polar representation of the visual field in V1 and means that the same method can be used for macular and wide field functional assessment. More generally, the peak temporal frequency tuning during high-speed vision appears to be at about 10 Hz [30], suggesting something fundamental about the sort of frequencies used here.

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Overall, the present results suggest that if one has measured a pattern VEP, then doing a rapid contrast threshold for the same stimulus would add considerable diagnostic value for relatively little cost. The design of future tests should perhaps include how efficient particular tests are when used in combination, i.e., the degree to which they measure independent information about a given disease should also be considered. Acknowledgements This research was supported by the Australian Research Council through the ARC Centre of Excellence in Vision Science (CE0561903), and SN Abdullah received a PhD scholarship from the Government of Brunei Darussalam. Conflict of interest T Maddess receives royalties for the sale of the FDT/matrix perimeters from Carl Zeiss Meditec.

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Visual evoked potential and psychophysical contrast thresholds in glaucoma.

We compared the diagnostic power of electrophysiologically and psychophysically measured contrast thresholds for the diagnosis of glaucoma. Additional...
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