Evaluation of the Structure–Function Relationship in Glaucoma Using a Novel Method for Estimating the Number of Retinal Ganglion Cells in the Human Retina

Given that glaucoma is a disease of the retinal ganglion cells (RGCs), it is not surprising that there is interest in relating visual sensitivity to estimates of the number of RGCs. Harwerth et al.1–3 previously developed a model for estimating the number of RGC bodies based on visual sensitivity as well as the number of RGC axons based on optical coherence tomography (OCT) scans of the optic nerve. However, because this model uses information at the optic disc, it must make assumptions about the relationship between the RGC axons and the location of the corresponding RGC bodies in the form of a topographic map. In fairness, with a few notable exceptions,4,5 the vast majority of work using the older time-domain OCT technology to study RGCs has been based on imaging of the optic disc as a proxy for RGC axons. However, newer frequency-domain OCT (fdOCT) technology allows for higher-resolution imaging of the RGC layer within the macula.6 In particular, the combined RGC layer and inner plexiform layer (IPL) thickness can be obtained from volume scans covering approximately the central 10° of visual angle. We have used this newer fdOCT technology to measure the combined RGC and IPL thickness, and also to relate this structural measurement to local sensitivity loss in a group of glaucomatous eyes.7,8 This work illustrated the importance of correcting for the centripetal displacement of macular RGC bodies away from the fovea,8 and we accounted for this by adjusting our data based on the histological estimates of displacement by Drasdo et al.9 As we were comparing local sensitivity at many regions within the central 10° (i.e., the 10-2 protocol), we used volume scans instead of the higher-quality averaged line scans. However, given the quality of the fdOCT volume scans at the time, the use of volume scans prevented us from confidently separating the RGC layer from the IPL. Therefore, we took a conservative approach and simply combined the two. We later found that, in regions corresponding to severe glaucomatous visual field (VF) loss, the thickness of the IPL decreased by a relatively smaller amount than did the thickness of the RGC layer.10 Thus, the ability to separate the two layers is important from the standpoint of simplifying future evaluations of structure–function models as well as for advancing our general understanding of glaucoma. Recently, swept-source OCT (ssOCT) technology,11,12 which has a faster acquisition rate than fdOCT, has become available. With ssOCT, it now is easier to separate the RGC layer from the IPL in volume scans, and, thus, to determine RGC layer thickness in the macula. This creates the possibility of estimating the number of RGCs directly from structural measures, and in this study, we demonstrated a simple yet novel method for using ssOCT data to estimate the number of RGCs in the macula for a group of healthy and glaucomatous eyes. Previously, Curcio and Allen13 published densely sampled estimates of RGC density along the horizontal and vertical meridians of the human retina, and Garway-Heath et al.14 subsequently interpolated the data of Curcio and Allen13 into a 2-dimensional estimate of RGC density. To estimate the number of RGCs for a particular eye, a method comparable to that of Garway-Heath et al.14 was needed to apply the Curcio and Allen13 RGC density estimates to 2-dimensional thickness measurements obtained from ssOCT. A similar approach has been presented previously by Turpin et al.,15 although it was used in a different context and was based on the combined thickness of the retinal nerve fiber layer (RNFL), RGC layer, and IPL. In this study, we isolated the thickness of the RGC layer by leveraging our previously developed segmentation techniques.8,16,17 The resulting RGC estimates are compared to the previous method by Harwerth et al.3 as well as to RGC estimates from independent histological studies. Finally, our approach for estimating the number of RGCs allows for evaluation of models of structure–function (see Table) that relate visual sensitivity with the number, density, or receptive field density of RGCs.1–3,18–25 This is illustrated by assessing the conclusions of a well-cited study by Kerrigan-Baumrind et al.25 in the context of our results. Table An Overview of Several Structure–Function Models Described in the Literature