The objective assessment of the macular function and subsequent visual pathways can be carried out by using pattern electroretinography (PERG) and pattern visual evoked potentials (PVEPs).1 Parameters measured by PERG and PVEPs are compared with normative data determined by each laboratory for their own individual population according to the standards of the International Society for Clinical Electrophysiology of Vision (ISCEV).2,3 Normal responses are reproducible, and their coefficients of variability have been determined.4–6
Some data have been reported on histological and functional interocular differences,7–11 but PERG and PVEP results on the same subjects have not been reported to date, although testing of the whole visual pathway from the retina to the visual cortex may be important in evaluating monocular pathologies. Both PERG and PVEPs are applied to test central vision: PERG is recorded to examine the function of the macular area, whereas PVEPs reflect the function of the consecutive retinal ganglion cells, the optic nerve, and the visual pathway up to the visual cortex.
We set out to determine whether interocular differences can serve as an important parameter for evaluation of the asymmetric macular and optic nerve functions, because their variability may also be of value in pathological follow-ups. Furthermore, the correspondence of the amplitude values of the two tests within each eye might be important. A strong correlation would imply an anatomical or physiological reason for the individual lateralization at the level of the retina, as the responses of the consequent structures of the visual pathway depend on the function of the structures situated before them. A difference in the retinal response between eyes would affect the response of the visual pathway and the visual cortex. To the best of our knowledge, no previous study has compared the lateralization (correspondence within but not between eyes) of PERG and PVEP responses and, therefore, an additional aim of this study was to determine its possible existence.
A total of 77 subjects free of any ophthalmologic pathology (men, n =16; women, n = 61; mean age, 35.6 ± 12.9 years) were tested. The subjects gave their written consent for the anonymous analysis of their test results in harmony with the institutional ethical rules. On ophthalmologic examination, no alteration of the refractive media or fundus was detected, and the best corrected visual acuity was 20/20. Subjects were selected from a group of normal control patients free of any systemic disease (n = 32) and from among patients referred for PVEP examination because of a suspicion of multiple sclerosis, which was excluded by subsequent cerebrospinal fluid and magnetic resonance imaging diagnostics (n = 45).
Electrophysiological examinations were performed with the RetiPort Science 18.104.22.168. program (Roland Consult Stasche & Finger Gmbh, Brandenburg an der Havel, Germany) according to the ISCEV standards, with the modification of the standard 0.8-degree check pattern size in the case of PERG. This difference from the standard ISCEV protocol was applied to stimulate the same retinal ganglion cells as stimulated by the PVEPs. Briefly, PERG was recorded with the correction of refractive errors to the viewing distance of the display by binocular stimulation under ambient light conditions (the room illuminance was 10 to 30 lux) with nondilated pupils. The active electrode (a DTL electrode) was placed in the lower conjunctival fold, the reference electrode (a gold cup skin electrode) was attached to the skin near the ipsilateral outer canthus, and the ground electrode (a gold cup skin electrode) was placed at the middle of the forehead (Fpz point).2 For stimulation, a black-and-white checkerboard pattern reversal (1.8 Hz) was used with a check size of 0.5 degrees. Contrast was determined at a level of 97%. Active and bandpass voltages were set at ±100 μV and 5 to 50 Hz, respectively. On evaluation, 200 responses were averaged; peak time and P50 and N95 peak-to-peak amplitudes were analyzed (i.e., the P50 amplitude is the peak of N35 to the peak of P50, etc.).
The PVEPs were also recorded with nondilated pupils by monocular stimulation under ambient light conditions. The right eye was always tested first to avoid any confusion caused by compliance. According to the ISCEV standards, the active electrode was placed in the midline—2.5 cm above the external occipital protuberance (Oz), the reference electrode was in the Fz, and the ground electrode was attached to the Cz localization.3 The stimulation size and pattern, contrast, reversal rate, and active voltage were the same as in the case of PERG. The bandpass was 1 to 100 Hz. The averages of 100 responses were analyzed. Peak times and P100 and N135 peak-to-peak amplitudes were assessed.
In both PERG and PVEPs, the luminance of the screen was set to 59 cd/m2.
Statistical analysis was carried out with the SigmaStat 3.5 statistical software (Statcon Software Ltd., Witzenhausen, Germany). On determination of the side differences, the statistical grouping was as follows: comparison of the responses of the right eyes and the left eyes and comparison as groups of higher and lower amplitudes or longer and shorter peak times with the Wilcoxon signed rank test, as the normality of the samples failed. The correlation between the amplitudes and the peak times of PERG and PVEPs was calculated with the Spearman test. The absolute values of the side (eye) differences were determined, and the percentage of the difference between the right and the left eyes was calculated for each subject by using the absolute difference (higher minus lower amplitude) divided by the higher amplitude or, in the case of the peak times, the longer minus the shorter peak time divided by the longer peak time. Intersubject coefficients of variability (CVs) were calculated as SD divided by the mean. Results are given as median (5 to 95%) CV or percentage, as appropriate.
The association of laterality between the amplitudes and the P50 and P100 peak times of PERG and the latency of PVEPs was calculated with the χ2 test. Differences in the values of the right and left eyes were calculated and analyzed as nonparametric variables.
No significant differences were found between the averaged amplitudes and peak times of the responses of the right and left eyes either in PERG or in PVEP. Side differences in the functions of the two eyes of the individual subjects disappeared on averaging, as some of them exhibited higher amplitude in the right and some in the left eye. In contrast, on comparison of the higher and lower response amplitudes for both the PERG and the PVEP parameters with the Wilcoxon signed rank test, side differences were significant (p < 0.001). The P50 and N95 peak times and the P50 and N95 amplitudes of the PERG are shown in Table 1. The P100 and N135 latencies and P100 and N135 amplitudes of the PVEPs are presented in Table 2.
The intersubject CVs of the peak times and amplitudes did not differ when the parameters were grouped by side or by higher and lower values for both the PERG and the PVEPs (Tables 1, 2). Mean (±SD); CV; 5, 25, 50 (median); 75 and 95 percentiles; and maximum values of percentage differences are shown in Table 3.
For the PVEP P100 and PERG P50 peak times, the maximum percentage interocular differences were less than 7%. The percentage side differences of the PERG P50 and N95 and the PVEP P100 and N135 amplitudes were as high as 50%, but in more than 95% of the cases (regarded as a cutoff point), the interocular amplitude differences were less than 30.5%. The latter can be used as the threshold of the normal interocular difference in clinical practice. The usefulness of interocular differences is supported by its lower variability than that of the monocular responses (Table 4).
The lateral correspondence of the longer and shorter peak times of P50 and P100 with the χ2 test was 0.015 (p = 0.9), and the power of the test was 0.049. The differences in the PERG and PVEP amplitudes of right and left eyes were not related. For the PERG P50 and PVEP P100 amplitudes, the χ2 value was 0.008 (p = 0.93), with the power of the test 0.048; whereas for the PERG P50 and PVEP N135 amplitudes, the χ2 value was 0.236 (p = 0.63), with the power of the test 0.073. For the PERG N95 and PVEP P100 amplitudes, the χ2 value was 0.686 (p = 0.41), with the power of the test 0.122; and for the PERG N95 and PVEP P100 amplitudes, the χ2 value was less than 0.001 (p = 0.98), with the power of the test 0.047.
Determination of the interocular differences in the PERG and PVEP parameters in normal subjects may be useful in the evaluation of monocular macular pathologies or asymmetric macular ganglion cell or optic nerve diseases. Clinically, PERG can be used in a patient with an abnormal VEP to establish whether a retinal (macular) disorder is present and, therefore, to differentiate between a macular and an optic nerve dysfunction as a cause of the VEP abnormality. It can also directly demonstrate retinal ganglion cell dysfunction.2 In the event of a high interocular difference, the side difference may be interpreted as abnormal.
Previous histological and imaging studies revealed an interocular difference as high as 8% in the foveolar cone density.12 Asymmetry in macular thickness was detected by optical coherence tomography as 6.4 ± 14.7 μm (average foveal thickness, 207 ± 24 μm vs. 200 ± 23 μm).13 With regard to the normal retinal nerve fiber layer thickness measured by optical coherence tomography, the side difference was approximately 9 to 12 μm, depending on the scanning algorithm applied.14 These data may explain the visual acuity differences determined by psychophysical methods and the PERG and PVEP amplitude differences.
The retinal blood flow of the macula has been shown to display no interocular difference in the absence of light stimulation of the eyes.15,16 We found no previously published studies involving light stimulation. A recent article on hemispheric asymmetry from the aspect of lateralization of the visual evoked response revealed a general dominance of the right occipital lobe in the visual process. In addition, functional transcranial Doppler demonstrated a higher blood flow velocity in the right posterior cerebral arteries in response to white light stimuli.17
The occipital blood flow (visual evoked flow responses) was found to correlate with the VEP N145 amplitude of the PVEP on hemifield visual stimulation and showed a side difference.18 In this study, there was a tendency to an increase in the N145 amplitude on the dominant side in young subjects.
Other groups have shown that pattern stimulation can cause amplitude and latency disparities of VEP between the dominant and nondominant eyes, providing electrophysiological evidence of lateralization in the nervous system at a cortical level.19 The PERG side difference was independent of the eye dominance.20 Our study was not aimed at finding dependences on eye dominance.
An interocular difference of the full-field ERG was described earlier.21 In 95% of that cohort, the interocular difference in the five standard ISCEV stimuli was in the range 27 to 36%, which is similar to the interocular difference of the PERG and PVEP parameters in our study (the amplitude difference was approximately 30%). We have previously reported an interocular difference of multifocal ERG of 21.55% on binocular stimulation and of 18.69% on monocular stimulation.22
Our present study revealed interocular side differences in both the PERG and PVEP parameters. If retinal anatomical differences were responsible for the lateralization, for example, differences in retinal ganglion cell density and the corresponding area of the visual cortex, the PERG and PVEP parameters would correlate, or the side correspondence would be higher. These two examinations test the consecutive elements of the visual pathway. If the PERG of one eye is influenced by a pathological or anatomical cause, the subsequent PVEP on stimulation of the same eye would be influenced in a similar way. The side differences we observed are therefore presumed to be independent of the electrophysiological method used and to be attributable to normal variability.
It is possible that artifacts, such as biological or technical noise, may contribute to side differences. Although it was beyond the scope of this report, biological noise could be examined by the repeated testing of subjects on separate visits. Technical noise could be caused by differences in electrode characteristics or amplifier characteristics. This possibility could be assessed by reversing the electrodes and recording channels between the eyes on retesting within a session. We used the same electrodes as in the daily routine, in which such technical noise is not observed (unpublished data). On the other hand, for PVEPs, the electrodes were placed in the midline, and technical noise was therefore unlikely to cause any side difference.
On determination of the normative values, an interocular difference should be considered regardless of its cause. If the differences previously described are neglected, misinterpretation of the results might occur in the event of the existence of some monocular pathology.
Department of Ophthalmology
Albert Szent-Györgyi Clinical Center
University of Szeged
H-6720, Szeged Korányi Fasor 10-11
This study was supported by grant K83810 OTKA/Hungary.
We thank Dr. Goran Petrovski and David Durham for proofreading this manuscript. We are also grateful to Ms. Kati Majer for her kind technical help.
Received June 8, 2013; accepted December 12, 2013.
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