Doc Ophthalmol (2014) 128:191–200 DOI 10.1007/s10633-014-9432-3

ORIGINAL RESEARCH ARTICLE

Visual evoked potential-based acuity assessment: overestimation in amblyopia Yaroslava Wenner • Sven P. Heinrich • Christina Beisse • Antje Fuchs • Michael Bach

Received: 26 October 2013 / Accepted: 3 March 2014 / Published online: 13 March 2014 Ó Springer-Verlag Berlin Heidelberg 2014

Abstract Background/Aims When visual acuity (VA) is assessed with spatially repetitive stimuli (e.g., gratings) in amblyopes, VA can be markedly overestimated. We evaluated to what extent this also applies to VEP-based objective acuity assessment, which typically uses gratings or checkerboards. Methods Seventeen subjects with amblyopia (anisometropic and strabismic) participated in the study; decimal VA range of their amblyopic eye covered 0.03–1.0 (1.5–0.0 logMAR). Using the Freiburg Acuity VEP (FrAVEP) method, checkerboard stimuli with six check sizes covering 0.02°–0.4° were presented in brief-onset mode (40 ms on, 93 ms off) at

No commercial relationship for authors Y.W., S.P.H., C.P.-B., and A.F. Author M.B. reports licensing the FrAVEP paradigm to a company through the Freiburg University technology transfer center. Y. Wenner Department of Ophthalmology, Phillips-University Marburg, Universita¨tsklinikum Giessen & Marburg GmbH, Marburg, Germany S. P. Heinrich  A. Fuchs  M. Bach (&) Eye Center, University of Freiburg, Freiburg, Germany e-mail: [email protected] C. Beisse University Eye Hospital, Heidelberg, Germany

7.5 Hz. All VEPs were recorded with a Laplacian montage. Fourier analysis yielded the amplitude and significance at the stimulus frequency. Psychophysical VA was assessed with the Landolt-C-based automated Freiburg Visual Acuity Test (FrACT). Results Test–retest limits of agreement for both FrACT and FrAVEP were ±0.20 logMAR. In all but two dominant eyes and high-acuity amblyopic eyes (VA \0.3 logMAR), FrACT and FrAVEP agreed within the expected limits of ±0.3 logMAR. However, the VEP-based acuity procedure overestimated single Landolt-C acuity by more than 0.3 logMAR in 9 of 17 (53 %) of the amblyopic eyes, up to 1 logMAR. While all subjects had a psychophysical acuity difference [0.2 logMAR between the dominant and amblyopic eye, only three of them showed such difference with the FrAVEP. Conclusion Both measurements of visual acuity with the VEP and FrACT were highly reproducible. However, as expected, in amblyopia, acuity can be markedly overestimated using the VEP. We attribute this to the use of repetitive stimulus patterns (checkerboards), which also lead to overestimation in psychophysical measures. The VEP-based objective assessment never underestimated visual acuity, but needs to be interpreted with appropriate caution in amblyopia. Keywords Visual acuity  Objective assessment  Visual evoked potentials  Amblyopia

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Introduction Visual acuity relies on a tiny patch of the retina and yet rightly remains the most basic and widely employed measure of visual function. Objective visual acuity estimation is clinically highly relevant for subjects in whom behavioral testing may be inaccurate or unreliable. Clinical target groups in which VEP-acuity estimates are undertaken include infants [e.g., 1, 2], children with cerebral visual impairment [e.g., 3], and children, teenagers or adults suspected of non-organic/ functional visual loss, including malingering [e.g., 4, 5]. Specifically, malingering becomes more important in the context of forensic compensatory issues. A currently widely employed approach [2, 4–7] uses rapid stimulus presentation allowing for steadystate analysis [8–10]. With this, visual acuity can be determined over a range from about 0.1–2.0 decimal acuity with a 95 % confidence interval of a factor of two up and down or ±0.3 logMAR [5, 11]. The stimuli employed for VEP-acuity estimation are checkerboards [12] or gratings [8, 13]. The latter are now more commonly used because they suffer less from the ‘‘notch’’ [14–17], a marked amplitude reduction in the spatial frequency region where psychophysical threshold is optimal. One likely reason for this amplitude reduction is destructive superposition of steady-state responses [18]. The notch makes exploration of the high spatial frequency region more difficult. Tyler et al. [13] speeded up measurement by sweeping through the major parameter of interest (e.g., spatial frequency) over 10–20 s; hence, the technique is frequently termed ‘‘sweep VEP,’’ even if the continuous sweep is replaced by a stepwise approach to avoid response confounds by latency. Be it gratings or checkerboards, in amblyopia, an overestimation of visual acuity with such repetitive stimuli is likely. Psychophysically, it was found that amblyopes correctly identify gratings with a higher spatial frequency than predicted from their singleoptotype acuity [19–22]. Amblyopes further frequently exhibit a stronger-than-normal crowding effect (coined by [23]): optotypes with flanking elements need to be larger for equal hit rates than isolated optotypes. Therefore, Chen et al. [24] used Vernier stimuli for acuity assessment. Ridder and Rouse [25] used sine-wave grating based acuity VEPs (sweep VEP) specifically in amblyopes and found that pre-treatment sweep VEP can successfully predict

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post-treatment acuity. They do not comment on acuity estimation in amblyopia with repetitive stimuli, but note that pre-treatment Snellen acuity was lower than VEP acuity—possibly this overestimation is in itself a good outcome predictor. Given that VEP-based acuity assessment is a very relevant methodology, it seems necessary to assess to what degree VEP-acuity results are sensitive to visual acuity loss from amblyopia. Given that the stimuli comprise repetitive patterns, overestimation is a possibility in amblyopia. We assessed two groups: amblyopic eyes and their normal (dominant) fellow eyes.

Materials and methods Subjects Seventeen patients with unilateral amblyopia between 19 and 58 years of age (mean 41.4) participated in the study. The decimal VA of their amblyopic eye ranged from 0.03 to 1.0 (from 1.5 to 0.0 logMAR, respectively). Amblyopia was defined as a difference in VA of at least 0.2 logMAR (single or crowded optotypes) between the dominant and the amblyopic eye in the absence of any organic eye pathology. The patients were recruited at the Eye Center, University of Freiburg. Prior to participation, written consent was obtained from the patients after the nature of the tests was fully explained. All subjects underwent a complete eye examination conducted by one of the authors (Y. W.). It included slit-lamp examination, fundus biomicroscopy and measurement of the intraocular pressure that had to be between 10 and 21 mmHg to be included in the study. Details of the examination are given in Table 1. All procedures followed the guidelines of the Declaration of Helsinki [26] and were approved by the local Ethics Committee. A thorough orthoptic examination was performed by the study orthoptist (A. F.). It included squint angle for far and near fixation, eccentric fixation point and stereo function. The squint angle was tested mainly with the prism and cover test and in cases of fixation loss of the amblyopic eye with the Krimsky corneal light reflection test at 30 cm and 5 m viewing distance. Details of the orthoptic examination of the amblyopes and their history are given in Table 1. Eleven had strabismic amblyopia with or without

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Table 1 Data of the 11 strabismic and 6 anisometropic amblyopes Subject

Age

Clinical data

Eye

Refraction

FrACT single

Crowded

FrAVEP

1

2

1

2

1

2

?2.0/-0.5 9 50°

0.96

0.84

0.88

0.99

0.78

0.84

Strabismic amblyopes 1

57

Cons. XT, no OcTh

RE LE

2

38

ET, no OcTh

a

?5.5/-1.5 9 30°

0.29

0.20

0.20

0.18

0.88

0.88

REa

?4.5/-2.0 9 0°

0.033

0.057

0.08

0.061

0.45

0.48

LE

?4.0/-0.5 9 160°

2.00

1.71

1.71

1.60

1.60

1.60

REa

?1.75/-1.25 9 60°

0.90

0.81

0.33



0.88

0.85

3

57

Cons. XT, no OcTh

LE

?0.5 sph

1.77

2.00

1.59



1.01

1.55

4

47

ET, OcTh of unclear duration

RE

?2.0/-0.5 9 35°

1.10

0.92

0.83

0.97

0.94

1.43

LEa

?6.0/-1.0 9 40°

0.47

0.43

0.26

0.33

0.92

1.27

ET LE, LE was dominant before chemical burn

REa

-3.0/-0.25 9 140°

0.34

0.29





0.61



5

6

58

47

LE

HM

ET, short period of OcTh

RE

?1.25 sph

1.17

1.03

1.11



1.41

1.6

LEa

?3.0/-3.5 9 85°

0.041

0.04

0.027



0.49

0.5

REa

Plano

1.00

0.80

0.58

0.66

0.95

1.27

LE

?0.5 sph

1.21

1.44

1.46

1.21

1.08

0.98

RE

?2.25 sph

0.93

0.88

0.5

0.64

0.95

0.88

LEa

?2.0/-0.5 9 10°

0.22

0.22

0.14

0.13

0.88

0.9

REa

?1.5/-0.5 9 130°

0.31

0.3

0.19

0.17

0.89

0.88

LE

-0.5/-0.5 9 70°

1.38

1.31

1.4

1.13

1.01

1.06

REa

?1.0 sph

0.36

0.66

0.28

0.29

0.87

0.56

7

45

XT, no OcTh

8

51

XT, no OcTh

9

32

ET & hypertropia, OcTh from age 1

10

42

XT, OcTh from age 7 for 6–8 month

LE

?0.75 sph

1.40

1.65

0.82

0.91

0.9

0.51

11

28

ET, OcTh from age 3 for 2 h daily

RE

?0.75

1.06

1.15

2.00

2.00

0.49

0.58

LEa

?1.5

0.33

0.35

0.35

0.34

0.58

0.59

Orthophoria, no OcTh

REa

?5.5/-2.5 9 175°

0.27

0.32

0.15

0.18

0.60

0.57

LE

?4.5/-2.5 9 175°

1.04

1.06

1.01

1.00

0.82

0.56

REa

?4.5/-1.75 9 165°

0.44

0.35

0.22



0.75

0.67

LE

?1.25 sph

1.8

1.77

1.70



1.50

1.54 1.11

Anisometropic amblyopes 12 13 14 15

16 17

45 53 33 31

19 37

Esophoria, no OcTh Exo- and hyperphoria, no OcTh Orthophoria, no OcTh, higher anisometropia in childhood Orthophoria, no OcTh Esophoria, OcTh from age 7 years, fulltime

RE

a

?2.25/-0.75 9 90°

0.29

0.24

0.32



0.89

LE

?0.25 sph

1.09

1.49

1.03



1.37



RE

-4.0/-0.25 9 100°

1.27

1.13

1.17

1.00

1.42

0.96

LEa

-4.0/-0.75 9 14°

0.41

0.30

0.31

0.30

0.87

0.87

RE

Plano

2.00

2.00

1.98

2.00

1.29

1.27

LEa

?4.5/-0.5 9 70°

0.47

0.31

0.24

0.26

0.89

1.00

REa

?7.0 sph

0.34

0.38

0.30

0.28

1.03

0.80

LE

?2.5/-1.5 9 25°

1.82

1.40

1.20

1.40

0.87

0.93

a

Amblyopic eye. ET esotropia, XT exotropia, cons. consecutive, OcTh occlusion therapy, HM hand movement. Age is given in years, and ‘‘1’’ and ‘‘2’’ indicate test repetitions. Decimal visual acuity as originally obtained is presented for FrACT and FrAVEP

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anisometropia ([1 D sphere and/or [1 D astigmatism). Six patients with anisometropic amblyopia without manifest strabismus were tested. The refraction data are included in Table 1. Psychophysical acuity and VEP data were assessed for the 17 amblyopic and also for 16 dominant fellow eyes and are shown as decimal acuity in Table 1. In one patient, the VEP-acuity assessment of the dominant eye was not performed; this was due to severe corneal damage caused by a chemical burn. None of the subjects showed any evidence of media opacification, and in the amblyopic eye, there was no history of ocular trauma, ocular diseases affecting the retina or optic nerve, or previous eye surgery other than strabismus surgery. The Freiburg Visual Acuity Test Monocular assessment of best-corrected psychophysical VA was performed at the same distance as the VEP stimulation (114 cm) with the automated Freiburg Visual Acuity Test (FrACT) [27]. Patients with decimal VA lower than 0.1 were tested at half the distance (57 cm), a special miniature display precluded any near-distance measurement artifacts [28, 29]. FrACT is a Landolt-C-based computerized VA test that has been developed by one of the authors. It has been validated in previous studies [30, 31], is equivalent to ETDRS [32], and can be downloaded at \http://michaelbach.de/fract.html[. Single and crowded optotypes were presented in separate runs, each with 24 trials. The size of each individual optotype was determined by the ‘‘best PEST’’ algorithm [33, 34], based on the subject’s responses in all preceding trials. VA with single optotypes was assessed twice for each eye using an ‘‘ABBA’’ scheme. The eye with lower acuity was tested first. Then, VA was tested, with each optotype accompanied by a pair of closed Landolt Cs of the same size, located to the left and right of the test optotype at a distance of one optotype diameter. Again, an ABBA scheme was employed. Visual evoked potential-based acuity assessment The VEP-based objective test has been validated and described in detail by one of the authors [5]. Stimulation and recording employed the ‘‘EP2000’’ evoked potential system [35].

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Stimulation Checkerboard stimuli with 6 logarithmically equidistant check sizes covering 0.021–0.4° and for low acuities sizes covering 0.09°–0.8° were presented rapidly in brief-onset mode (75 Hz frame rate; 3 frames = 40 ms on, and 7 frames = 93 ms off) at 7.5 Hz. Observation distance was 114 cm. Spaceaveraged mean luminance was 45 cd/m2; the contrast was set at 40 %. Each check size was presented for 10 sweeps of 1,067 ms each with the stimulus sequence repeated after the largest check size. Over six cycles, 60 sweeps or 480 onsets per check size were performed. To ensure subject alertness, fixation and accommodation, random digits from 0 to 9 appeared in random intervals in the center of the screen and were reported by the participants. In case of low acuity, these digits were doubled in size. Recording technique All VEPs were recorded with a Laplacian montage with gold-cup electrodes at Oz (occipital pole) versus RO and LO (placed at 15 % of the subjects half-head circumference to the left and right) [36]. Signals were amplified (50,0009), analog-bandpassed in the range of 1–100 Hz, and digitized at a rate of 1 kHz with 16-bit resolution. Acuity extrapolation For analysis, check size was converted to spatial frequency, taking into account that the dominant spatial frequency is at 45° to the check orientation, using the formula [37]: SF ¼ Spatial p frequency ðcpdÞ ¼ 1= 2  check size ð Þ: Fourier analysis yielded the magnitude at the stimulus frequency. This value was corrected for noise based on noise estimates that were obtained at the neighboring spectral frequencies [38]. An automated ‘‘stepwise heuristic algorithm’’ [5], was used to estimate SF0 (the highest spatial frequency where the VEP amplitude just drops to zero), as SF0 showed the best correlation with subjective acuity [39]. Finally, spatial frequency was converted to visual acuity using the empirical relationship VA = SF0/(17.6 cpd) [from 5].

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Like psychophysical acuity obtained with FrACT, visual acuity with FrAVEP was assessed twice using an ‘‘ABBA’’ scheme. The eye with lower acuity was tested first.

amblyopic eyes were 0.16 logMAR, in dominant eyes 0.26 logMAR. The means of the differences of the two tests were for amblyopic and dominant eyes close to zero.

Statistical analysis

Comparison of FrACT with FrAVEP

Analysis and figure production was performed with the R statistical system [40]. Bland–Altman plots were generated to evaluate the test–retest reproducibility of FrACT and FrAVEP. For further analysis, the test– retest values were averaged, and a regression model assessed the power of VEP-based acuity to predict psychophysical acuity and the relation between singleoptotype and crowded psychophysical acuities.

Freiburg Visual Acuity Test with single optotypes was performed twice in both eyes of each of the amblyopic subjects, except for the one dominant eye with severe chemical corneal burn. FrACT with crowding was performed once in all but one, and twice in 70 % of the dominant and amblyopic eyes. Typical tuning curves [‘‘true’’ amplitude vs. log(spatial frequency)] recorded in the amblyopic and the dominant eye are shown in Fig. 1. FrAVEP could be performed twice in all eyes with amblyopia, except one. In one dominant eye, FrAVEP was performed only once; the dominant eye with severe chemical corneal burn was not eligible for the study, and therefore, no FrAVEP was performed. Otherwise, both for FrACT and FrAVEP the reason for not performing the planned number of tests was patient’s fatigue.

Figure 3 compares VEP-based acuity on the ordinate with psychophysical acuity on the abscissa. There was a small (0.1 logMAR) but significant (p = 0.008, t test) mean difference between VAFrACT (mean ± SD: -0.12 ± 0.12 logMAR) and VAFrAVEP (-0.02 ± 0.15 logMAR) for the dominant eyes. For amblyopic eyes the mean difference between VAFrACT (0.54 ± 0.36 logMAR) and VAFrAVEP (0.12 ± 0.12 logMAR) was 4 times higher (0.42 logMAR), which was highly significant (p \ 0.001, t test). Inspection of Fig. 3 shows that for high acuities (all dominant eyes and the few amblyopic eyes with decimal acuity[0.5 (0.3 logMAR)), the two measures agreed within the expected limits of ±0.3 logMAR. For most amblyopic eyes with lower acuity, however, the VEP method markedly overestimated psychophysical acuity by more than 0.3 logMAR. This was the case in 9 of 17 (53 %) of the amblyopic eyes, up to 1.1 logMAR. While the correlation between VAVEP and VAsingleOptotype of the amblyopic eyes was highly significant (r = 0.65, p \ 0.001), this is not the full story. So a regression model was set up as VAsingleOptotype versus the predictors VAVEP 9 group. We found a highly significant effect of VAVEP and group, both with p \ 0.001, and a significant interaction (p = 0.006). These results underscore the obvious demonstration in Fig. 3 that VAVEP is a good predictor of VAsingleOptotype for dominant eyes, but a poor predictor for amblyopic eyes.

Test–retest reproducibility of FrACT and FrAVEP

Interocular difference with FrACT and FrAVEP

The results of test–retest reproducibility of the psychophysical (FrACT) and electrophysiological tests (FrAVEP) are shown in Fig. 2. The test–retest limits of agreement [41] of the two tests happened to be virtually identical for combined amblyopic and dominant eyes, namely 0.20 logMAR. Test–retest limits of agreement for FRACT in amblyopic eyes were 0.26 logMAR, in dominant eyes 0.15 logMAR. Test–retest limits of agreement for FrAVEP in

Mean interocular difference between the dominant and amblyopic eye with single FrACT was 0.66 ± 0.37 logMAR, with crowded FrACT 0.76 ± 0.33 logMAR and with FrAVEP it was 0.13 ± 0.18 logMAR. While all subjects showed an acuity difference[0.2 logMAR between the dominant and amblyopic eye with the crowded FrACT and 94 % of subjects with the single FrACT, only three of them showed such a difference with the VEP-based test.

Results

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1.0

0.5

extrapolated spatial frequency: 19.5 cpd estimated decimal VEP acuity: 1.11 (#6905E)

6

1.5

Amplitude [µV]

Amplitude [µV]

7

extrapolated spatial frequency: 15.6 cpd estimated decimal VEP acuity: 0.89 (#6905C)

2.0

5 4 3 2 1

VA=0.1

VA=0.3

VA=1.

VA=0.1

0.5

1.0

1.5

0.5

log (spatial frequency) [cpd]

VA=1.

1.0

1.5

log (spatial frequency) [cpd]

Fig. 1 Examples of tuning curves from one participant. Left eye with amblyopia, psychophysical decimal acuity 0.27 (0.58 logMAR). Right dominant fellow eye, decimal acuity 1.29 (=-0.1 logMAR). The noise-corrected response magnitude at 7.5 Hz is plotted versus the logarithm of the dominant spatial frequency of the checkerboard stimulus. Asterisk markers indicate significant responses (p \ 0.05), a circle indicates a nonsignificant response. The thick straight line represents the

regression line to the points selected by the ‘‘stepwise heuristic algorithm.’’ Extrapolated spatial frequency for zero amplitude (SF0) is calculated from the crossing of the regression line with the abscissa. For the amblyopic eye, the VEP acuity of 0.89 overestimates the singe-optotype psychophysical acuity of 0.27 by a factor of 3, whereas in the dominant fellow eye (right) the VEP acuity of 1.11 (decimal) matches the psychophysical acuity of 1.29

0.50

0.50

0.25

0.25

Test2 minus Test1 [logMAr]

Test2 minus Test1 [logMAr]

VA=0.3

0

0.0

0.00

−0.25

0.00

−0.25 group dominant strabismic anisometropic

−0.50

−0.50 1.5

1.0

0.5

0.0

−0.5

Acuity (single optotype), mean of test1 & 2 [logMAR]

1.5

1.0

0.5

0.0

−0.5

VEP−based acuity, mean of test1 & 2 [logMAR]

Fig. 2 Test–retest reproducibility of psychophysical (FrACT, left) and VEP-based (FrAVEP, right) visual acuity measures. Bland–Altman plot of the logMAR differences, on the ordinate; the abscissa depicts the average acuity value. Filled circles represent dominant eyes, amblyopic eyes are indicated by

crosses (strabismic) or open circles (anisometropic). The dotted line represents the mean of the differences in VA; the dashed lines indicate the 95 % limits of agreement. Both VEP-based and psychophysical acuity tests display quite similar test–retest limits of agreement of about ±0.2 logMAR

Psychophysical acuity with single versus crowded optotypes

significant effects for VAsingle (p \ 0.001) and for group (p = 0.0021), without a significant interaction (p = 0.86). The mean difference between crowded and single-optotype FrACT was 0.14 ± 0.15 logMAR for the amblyopic and 0.04 ± 0.11 logMAR for the

A regression model was set up as VAcrowded versus the predictors VAsingle 9 group. We found highly

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electrophysiological test, had nearly identical test– retest limits of agreement of ±0.20 logMAR. This result was even a little better than previously published [5] of ±0.30 logMAR. We conclude that the two methods provide reproducible estimates within these limits.

VEP−based acuity [logMAR]

−0.5

0.0

0.5

Psychophysical versus electrophysiological measures, amblyopic eyes 1.0

dominant

1.5

strabismic anisometropic

1.5

1.0

0.5

0.0

−0.5

Single optotype acuity [logMAR]

Fig. 3 Relation between psychophysical acuity (abscissa) and VEP-based acuity; symbols as in Fig. 2. The solid line is the identity line, the dashed lines represent deviation from this by ±1 octave (a factor of 2 up and down, or ±0.3 logMAR units, or 3 lines, or 15 ETDRS letters). Obviously, the VEP-based test is insensitive to amblyopic acuity loss

dominant eyes, being significantly higher for the amblyopic eyes (post hoc t test, p = 0.002) and nonsignificant for dominant eyes (p = 0.16).

Discussion Objective assessment of visual acuity needs thorough evaluation not just in normal, but also in diseased eyes. We looked at amblyopic eyes, where the characteristic visual impairments can be expected to differ markedly from those caused by optic blur or other diseases [5], and indeed we found a dissociation between psychophysical and VEP-based acuity estimates for amblyopic eyes. Quality estimates of psychophysical and electrophysiological acuity measures When comparing tests, first quality within each test must be estimated, specifically the test–retest reproducibility. Here, we found that the test–retest limits of agreement for the psychophysical test with single optotypes across all eyes spanned ±0.20 logMAR. This happens to be identical with the published value for FrACT [42] of 0.20 logMAR. FrAVEP, the

This was the main question of the study. Although there was a highly significant correlation (p \ 0.001) between both acuities for amblyopic eyes, the VEPbased acuity overestimated single Landolt-C acuity by more than 0.3 logMAR for amblyopic eyes in 58 % of the patients. This underscores that high correlation does not mean close agreement [43]. The overestimation occurred both for strabismic and anisometropic amblyopic eyes (Table 1). To show any difference between the two entities, a sample size larger than the present one is needed. Psychophysical versus electrophysiological measures, non-amblyopic eyes The correspondence between both acuities for dominant eyes was high, with a difference of 0.1 logMAR. While significant, this difference is clinically irrelevant. In only two subjects VAFrACT surpassed VAFrAVEP up to 0.35 logMAR. Thus, the dominant eye findings are in keeping with our previous experiences with VEP-based acuity assessment [5]. This expected outcome validates our methodology. Effect of crowding The effect of crowding on the amblyopic eyes is well known from the literature [44]. The difference of 0.14 ± 0.15 logMAR found here is similar to that between single and crowded optotypes of the Lea Test and lower than the difference between single and crowded optotypes in a previous study using Landolt Cs [45]. This can be understood, given that our crowding inducers were spaced as in the Lea Test, while in the ‘‘2.6’’ Landolt-C test (as used in [45]) the inducers were closer, namely 2.6 arcsec, thus producing a stronger crowding. Together these findings validate our methodology.

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Psychophysical versus electrophysiological measures, interocular difference The largest difference in visual acuity between the dominant and amblyopic eyes was found with crowded-optotype FrACT, due to the stronger crowding effect in amblyopic eyes [44], followed by singleoptotype FrACT. The difference in acuity between the dominant and amblyopic eyes with FrAVEP was 0.13 ± 0.18 logMAR. While this difference is statistically significant, it is clinically irrelevant, as in only three cases the definition of amblyopia with acuity reduction of at least 0.2 logMAR was met. This means that the FrAVEP method does not appear to be sensitive to visual loss from strabismic or anisometropic amblyopia. This method therefore cannot be used in preverbal patients for detection of amblyopia. Pathophysiological considerations Our findings indicate that FrAVEP is not an appropriate test to reveal exaggeration in amblyopic patients, as it can considerably overestimate the subjective visual acuity. We assume that the same holds for all other current VEP-based acuity tests. On the other hand FrAVEP never underestimated visual acuity in patients with amblyopia. Therefore, the actual visual acuity of the amblyopic patients will not be higher than the FrAVEP acuity, but it could be considerably lower. Why is acuity overestimated with FrAVEP in the first place? Our hypothesis here is that the same mechanisms are at play that cause the phenomenon of better grating and vernier acuity in amblyopic eyes in comparison with recognition acuity [46–48]. Phase encoding variability [49] might play a role: while the identity of an optotype would seriously suffer from phase scrambling, the orientation of a grating might still be recognizable after spatial pooling. For the VEP, specifically: a phase-scrambled checkerboard would still differ from homogenous gray and thus evoke a response. Objective visual acuity estimation using suppression of the optokinetic nystagmus was also of limited success in patients with strabismic amblyopia as it also overestimates considerably subjective acuity [50]. Sophisticated subjective methods of visual acuity estimation requiring a high amount of experience of the testing person and modification of standard test

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strategies are still required in questions of exaggeration in amblyopic patients, for example after the loss of the dominant eye [51]. Tests using grating acuity in patients with deprivation amblyopia (for example, aphakic patients after surgery of congenital cataract) seem to correlate better with recognition acuities [47]. Our study investigated only persons with strabismic and anisometropic amblyopia. Future study is required to compare subjective VA testing with FrAVEP in patients with deprivation amblyopia. In summary: Objective VA testing using checkerboard (or grating) stimuli can markedly overestimate psychophysical single-optotype acuity in amblyopia, up to a factor of 10 (=1.0 in logMAR units). Future research could try to relate the overestimation to the same observation with grating acuity, to elucidate the mechanisms underlying the overestimation of acuity, and eventually come up with stimulus paradigms that avoid overestimation. This could be for example P300-based acuity assessment [52], but with optotypes rather than gratings or checkerboards. Preliminary experiments are promising. We conclude that VEPbased acuity testing clearly is a useful tool, but in amblyopia, it can only provide an upper limit of acuity, which by itself can still be helpful information for many clinical questions.

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Visual evoked potential-based acuity assessment: overestimation in amblyopia.

When visual acuity (VA) is assessed with spatially repetitive stimuli (e.g., gratings) in amblyopes, VA can be markedly overestimated. We evaluated to...
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