Discussion
The prevalence of GCs in at least one eye of glaucoma cases of African ancestry is around 15%. In the earliest report on GCs, 12% of 100 consecutive African American participants referred for evaluation of possible glaucoma had GC.1 The frequency of GC among consecutive African ancestry patients who presented to the Glaucoma Service of Yale University Eye Center as new or returning patients with glaucoma or glaucoma suspects during a 5-month period was 27%.2 The few articles that have reported on the frequency of GCs among African ancestry glaucoma cases have had much smaller numbers than the POAAGG cohort. The only other large epidemiological study conducted on GCs was the Reykjavik Eye Study in Iceland, which found that 22% of 1012 right eyes from a random white population of people 50 years or older had GCs. In this study, the GC definition was not restricted to the originally described slate grey appearance of these crescents, but also included what the authors reported as pigmented crescents, most likely including conus pigmentosus or type B crescents (examples in figure 1).4
GCs were more commonly found to be bilateral than unilateral in earlier studies, but in our study, we observed more GCs presenting unilaterally.1 2 4 The location and extent of the GCs in our study are similar to the findings in earlier reports, occurring more frequently in the temporal and inferior regions. In the Reykjavik Eye Study on a white population, however, inferior GCs were rare and in 16% of eyes, the GCs encircled the entire 360° of disc rim.4 In our study, extension beyond two quadrants was rare. Although comparison between African ancestry glaucoma cases and a general white population above 50 years in Iceland is not ideal, it does raise the possibility that the location and extent of GCs are quite different in these two populations of varying skin pigmentation.
The demographic associations of GCs appear to be varied among prior studies. We found that participants with glaucoma who had GC were younger than those who did not have GC, a finding that was also seen in a study that investigated GCs in patients with glaucoma.2 However, the association of GC in a younger age group persisted even after adjusting for other factors in our study, while it was not significant even in the unadjusted results of the other study. It is not clear why a younger population with glaucoma should have more GCs. It raises the possibility that over time, GCs may disintegrate and disappear, but this did not appear to be the reason in our study population. When we reviewed images with GCs at baseline with available follow-up visit images after several years, we found that in the few instances where there was discordance, it was either because the grader missed identifying the presence of GC or the images were not of sufficient quality to identify their presence with certainty. Both studies did not find any association between the presence of GC and the sex of patients with glaucoma, although the Reykjavik Eye Study on a white population found GC to be more common among women than men.5 One other finding that we did not anticipate or find in any of the earlier reports on GCs was its association with diabetes mellitus. Our study found 46% increased odds of having GC in African ancestry glaucoma cases with diabetes. The reason for this association remains unknown currently.
When the first few cases of GC were identified and reported in 1980, it was suggested that increased pigmentation of the skin would be associated with increased prevalence of GCs.1 This was evident by the finding in several studies where black people were reported to have more GCs than white people. The African ancestry population of the POAAGG cohort is an admixed population, with varying proportions from African ancestry individuals. We hypothesised that higher African ancestry would be associated with the presence of GCs among glaucoma cases within this population. We had earlier shown that in the POAAGG Study population, a higher degree of African ancestry was associated with an increased POAG risk.8 Applying a similar methodology, as described in our previous study, among POAAGG glaucoma cases with and without GCs, we found that the ancestral component q0 (shown to have a significant lower mean in participants with higher degree of African ancestry) was significantly associated with presence of GC. These results suggest that African ancestry is a risk factor for developing GC.
We identified several features on the optic disc head that were associated with GC. Eyes with stereoscopically identified optic disc tilt had 84% more likelihood of having GC. In a cross-sectional study of 136 patients with early-stage POAG, optic disc tilt (defined as discs having an ovality index >1.3) appeared to be associated with bihemispheric retinal nerve fibre layer (RNFL) defects in patients with early glaucoma, regardless of their refractive status.10 The disc images of representative cases showing the relationship of the extent of disc tilt and bihemispheric RNFL defects showed the presence of GC.11 On reviewing the optic disc photographs of these 136 patients, GC was found to be present in 23.5% of the eyes examined. The authors contended that because GCs tended to occur frequently in eyes with large, non-tilted optic discs that had large horizontal diameters of the optic disc, they would not alter the results of the association of the ovality index and the bihemispheric RNFL defect.12 While this is likely true when ovality index is used as a measure of optic disc tilt, when stereoscopically identified tilt is used, it might alter the results, as has been shown in a previous report.13 This study was performed on Korean eyes where optic disc tilt has been associated with myopic glaucoma.14 More investigation is required to understand the association of optic disc GC and stereoscopically identified tilt in an African ancestry population with glaucoma. The likelihood of having a sloping margin adjacent to the outer disc margin increased more than twofold in eyes that had GC. Imaging modalities such as SD-OCTs are beginning to describe the disc margins in glaucoma in more detail. This sloping margin feature perceived in stereoscopically visualised colour images needs to be investigated by more accurate imaging modalities to understand how this feature is related to GCs in participants with glaucoma.15 16
The presence of GC increased more than twofold in eyes that had beta peripapillary atrophy. However, though there has been no evidence of a link between GC and POAG to date, there has been an association shown between the presence and area of beta peripapillary atrophy and POAG.17–20 The presence of the GC did not correlate with the presence or degree of beta peripapillary atrophy in the study that investigated GC among both black and white glaucoma cases.2 In the Reykjavik Eye Study, the prevalence of GC was inversely related to the prevalence of peripapillary atrophy, which included both alpha and beta peripapillary atrophy.
Study limitations
There was considerable variability in glaucoma characteristics, severity and treatment history as can be expected in a cross-sectional study. We therefore confined our investigation for associations to demographic features and the qualitative optic disc features evaluated by the Reading Center. We acknowledge that there was only modest grade–regrade agreement which highlights the difficulty in grading features of the optic disc in general. Previous literature on the reliability of examining colour images to detect features on the optic disc has reported only moderate, slight-to-fair or poor intergrader agreements. Suboptimal reproducibility continues to be a problem in grading of optic disc features in glaucoma. This is not specific to GCs. Previous studies among patients with glaucoma do not report on intragrader or intergrader agreements on the identification of GCs.21 22 The large initial Reykjavik Eye Study had only single grading. In contrast, our study included a relatively large number of glaucoma disc images compared with other studies and applied a double-grading method with adjudication.
The POAAGG Study excluded individuals with high myopia (≥−6.00 D) and there were no comprehensive data on axial lengths. Refractive error was extracted from data on phakic eyes. After adjusting for refractive errors with available data, we found no substantial changes in the results except for age losing its significance. This study does not have enough power to substantiate an association of GCs with myopia. The glaucoma cases in the POAAGG Study consisted solely of individuals with African ancestry that precluded comparison with a white population. Medical history taken at enrolment may have been subject to misclassification due to recall bias. We could not use the available data from POAAGG controls without glaucoma since imaging in controls was confined to only those who had a medical reason for retinal imaging. Finally, due to the continuing recruitment of additional POAAGG subjects long after the genetic sample procurement was completed, there were a substantial number of missing values in the ancestry analysis (table 1). For this reason, we could not include ancestry for the multivariate analysis and therefore cannot say with certainty that this association is independent of other significant demographic associations.
In summary, 15% of POAG cases of African ancestry had a GC in the optic disc that was mostly unilateral. Younger patients and patients with diabetes mellitus had more GC. The presence of GC was associated with optic disc tilt, a sloping retinal region adjacent to the outer disc margin and the presence of beta peripapillary atrophy in this population with glaucoma. These associations should be taken into account when evaluating demographic and ocular characteristics in patients with POAG.
