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Comparing three different modes of electroretinography in experimental glaucoma: diagnostic performance and correlation to structure

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Abstract

Purpose

To compare diagnostic performance and structure–function correlations of multifocal electroretinogram (mfERG), full-field flash ERG (ff-ERG) photopic negative response (PhNR) and transient pattern-reversal ERG (PERG) in a non-human primate (NHP) model of experimental glaucoma (EG).

Methods

At baseline and after induction of chronic unilateral IOP elevation, 43 NHP had alternating weekly recordings of retinal nerve fiber layer thickness (RNFLT) by spectral domain OCT (Spectralis) and retinal function by mfERG (7F slow-sequence stimulus, VERIS), ff-ERG (red 0.42 log cd-s/m2 flashes on blue 30 scotopic cd/m2 background, LKC UTAS-E3000), and PERG (0.8° checks, 99% contrast, 100 cd/m2 mean, 5 reversals/s, VERIS). All NHP were followed at least until HRT-confirmed optic nerve head posterior deformation, most to later stages. mfERG responses were filtered into low- and high-frequency components (LFC, HFC, >75 Hz). Peak-to-trough amplitudes of LFC features (N1, P1, N2) and HFC RMS amplitudes were measured and ratios calculated for HFC:P1 and N2:P1. ff-ERG parameters included A-wave (at 10 ms), B-wave (trough-to-peak) and PhNR (baseline-to-trough) amplitudes as well as PhNR:B-wave ratio. PERG parameters included P50 and N95 amplitudes as well as N95:P50 ratio and N95 slope. Diagnostic performance of retinal function parameters was compared using the area under the receiver operating characteristic curve (A-ROC) to discriminate between EG and control eyes. Correlations to RNFLT were compared using Steiger’s test.

Results

Study duration was 15 ± 8 months. At final follow-up, structural damage in EG eyes measured by RNFLT ranged from 9% above baseline (BL) to 58% below BL; 29/43 EG eyes (67%) and 0/43 of the fellow control eyes exhibited significant (>7%) loss of RNFLT from BL. Using raw parameter values, the largest A-ROC findings for mfERG were: HFC (0.82) and HFC:P1 (0.90); for ff-ERG: PhNR (0.90) and PhNR:B-wave (0.88) and for PERG: P50 (0.64) and N95 (0.61). A-ROC increased when data were expressed as % change from BL, but the pattern of results persisted. At 95% specificity, the diagnostic sensitivity of mfERG HFC:P1 ratio was best, followed by PhNR and PERG. The correlation to RNFLT was stronger for mfERG HFC (R = 0.65) than for PhNR (R = 0.59) or PERG N95 (R = 0.36), (p = 0.20, p = 0.0006, respectively). The PhNR flagged a few EG eyes at the final time point that had not been flagged by mfERG HFC or PERG.

Conclusions

Diagnostic performance and structure–function correlation were strongest for mfERG HFC as compared with ff-ERG PhNR or PERG in NHP EG.

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Acknowledgements

The authors wish to thank Galen Williams, Luke Reyes, Karin Novitsky and Juan Reynaud for their expert technical assistance during data collection and processing.

Funding

National Institutes of Health, National Eye Institute provided financial support in the form of research grant funding: R01-EY019327 (BF), R01-EY011610 (CFB); Legacy Good Samaritan Foundation provided financial support in the form of research funding. The sponsors had no role in the design or conduct of this research.

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Authors and Affiliations

  1. Discoveries in Sight Research Laboratories, Devers Eye Institute, Legacy Research Institute, Legacy Health, 1225 NE Second Avenue, Portland, OR, 97232, USA

    Laura Wilsey, Grant Cull, Christy Hardin, Claude F. Burgoyne & Brad Fortune

  2. Department of Ophthalmology, Boston Children’s Hospital, Boston, MA, USA

    Sowjanya Gowrisankaran

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  1. Laura Wilsey
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Correspondence to Brad Fortune.

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As this article does not contain any studies with human participants performed directly by any of the authors, the concept of informed consent is not applicable.

Conflict of interest

Claude F. Burgoyne is a consultant to and receives unrestricted research support from Heidelberg Engineering, GmbH. All other authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements) or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.

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This article does not contain any studies with human participants performed by any of the authors.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All experimental methods and care procedures were approved and monitored by the Institutional Animal Care and Use Committee (IACUC) at Legacy Health (USDA license 92-R-0002 and OLAW assurance A3234-01) and carried out in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health and the Association for Research in Vision and Ophthalmology’s Statement for the Use of Animals in Ophthalmic and Vision Research.

Appendix

Appendix

Measurement of PhNR amplitude has been done using a variety of methods in different laboratories. These various approaches include measuring the voltage difference between the pre-stimulus baseline or the peak of the B-wave and either the trough (minima) following the B-wave or a fixed post-stimulus criterion time [36, 67, 68, 70–72]. Previously, we had determined that PhNR amplitude measurements from the peak of the B-wave to a fixed criterion time of 70 ms provided the best reproducibility for the flash intensity used in the current study. However, the larger sample size and inclusion of glaucomatous eyes available for the current study presented an opportunity to re-evaluate this question. Therefore, we compared diagnostic performance of 8 different derivations of PhNR amplitude and selected the best performing method to use in the main part of the study for comparison to mfERG and PERG parameters. The eight PhNR amplitude derivations evaluated were measured as follows: (1) from B-wave peak to a criterion time of 60 ms; (2) 65 ms; (3) 70 ms; (4) from the ERG baseline to a criterion time of 60 ms; (5) 65 ms; (6) 70 ms; (7) from the B-wave peak to the PhNR trough; (8) from the ERG baseline to the PhNR trough. The results of this comparison demonstrated unequivocally that the best diagnostic performance was obtained using method 8: from the ERG baseline to the PhNR trough (see Tables 5, 6). Therefore, PhNR amplitude measurements obtained using that method were included in the main study for comparison to other parameters of the photopic full-field flash ERG, the mfERG and PERG.

Table 5 Diagnostic sensitivity across various PhNR amplitude derivations, raw values
Full size table
Table 6 Diagnostic sensitivity across various PhNR amplitude derivations, change from baseline
Full size table

Although diagnostic performance was clearly better for the baseline-to-trough PhNR amplitude derivation, it was also useful to compare repeat reliability across these eight approaches. To this end, we calculated the coefficient of variation (CoV) as the standard deviation of pre-laser baseline measurements divided by the mean of the same measurements for each eye. Alternatively, since the average value of a given parameter in healthy eyes might not be an adequate representation of its dynamic range, we also scaled the median standard deviation of baseline measurements by the median effect size (i.e., the difference between the amplitude in the glaucomatous eye and the amplitude in the fellow control eye at the final time point). The results revealed that the median value for the CoV was always approximately half as large for PhNR amplitude measurements made from the B-wave peak as compared with those made from the ERG baseline (17 vs. 30%, on average, respectively). However, the inverse was true when intersession variation was scaled by the effect size instead of by the average magnitude of each parameter: By this metric, the PhNR amplitude measurements taken from the B-wave peak were about twice as variable as those made from the ERG baseline (65 vs. 27%, on average, respectively). Ironically, this result for repeat reliability did not manifest as better diagnostic performance of PhNR measurements made from the ERG baseline compared to those made from the B-wave peak for longitudinal (baseline normalized) data as compared with strictly cross-sectional data (compare Tables 5, 6). In any case, the method of PhNR amplitude derivation based on ERG baseline-to-trough had the best diagnostic performance and among the best repeat reliability by either metric (median CoV = 21%; intersession variation scaled by effect size = 29%). Thus it was clearly the measurement of choice for the comparison to other ERG parameters in the main portion of this study.

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Wilsey, L., Gowrisankaran, S., Cull, G. et al. Comparing three different modes of electroretinography in experimental glaucoma: diagnostic performance and correlation to structure. Doc Ophthalmol 134, 111–128 (2017). https://doi.org/10.1007/s10633-017-9578-x

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  • DOI: https://doi.org/10.1007/s10633-017-9578-x

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