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Through long-term surveillance using screening fundus photography, we found that glaucoma can develop from GLD (glaucoma conversion) at a median follow-up time of 5.1 years (range: 0.7–13.9 years). Vertical CDR \(\ge\) 0.7, vertical cupping, violation of the ISNT rule, disc ovality \(\ge\) 1.2, PPA-to-DA ratio \(\ge\) 0.4, nasalization of CRVT \(\ge\) 60%, history of DH, retinal arterial narrowing/sclerotic changes and baseline IOP \(\ge\) 14 mmHg were significant risk factors for glaucoma conversion by the multivariable model. Moreover, we devised a meaningful scoring system in which HR-matched variables from the initial fundus photography were used to predict glaucoma conversion.

Clinical examination of the ONH is the principal procedure in the management of glaucoma. It can be easily performed with high accessibility and cost-effectiveness for glaucoma screening. Optic disc cupping, often estimated by the CDRs, is the most common sign for general ophthalmologists to consider glaucomatous ONH changes. However, due to the high interindividual variability of the ONH configuration and its dependence on the size of the optic disc, CDRs have limited value for the screening and diagnosis of glaucoma. Nevertheless, the importance of optic disc cupping should not be underrated. In terms of glaucoma screening, accurate risk assessment and stratification of eyes at risk for glaucoma are essential, and close monitoring of selected cases can improve the outcomes of glaucoma screening programs. The present study has a strength in that it demonstrated the long-term follow-up results of eyes with large optic disc cupping, i.e., so-called glaucoma-like discs (GLDs), and investigated the risk factors for conversion to glaucoma. In particular, in addition to CDRs, variable parameters, which have been demonstrated to be associated with glaucomatous damage and can be easily identified on screening fundus photography, were used to analyze individual risks for glaucoma conversion.

The present study demonstrated that eyes with vertical CDR \(\ge 0.7\) were significantly associated with the risk of future glaucoma conversion. Other typical optic disc configuration changes, such as ISNT rule violation and vertical cupping, were also significant baseline risk factors for RNFLDs. These results imply that clinicians can find clues about ongoing glaucomatous damage before apparent RNFLDs are observed on fundus photography. In fact, nonhuman primate models of glaucoma have provided the insight that ONH surface height change precedes RNFL thinning^26,27. The temporal relationship between ONH cupping and RNFL thinning was further confirmed by Xu et al., who demonstrated that ONH surface depression occurred before RNFL thinning by up to 41 months (with a median of 16 months)²⁸. At the same time, large optic disc cupping has been well documented to be a significant risk factor for glaucoma in large, longitudinal epidemiologic studies. The OHTS study showed that baseline factors, including larger vertical or horizontal CDRs, old age, higher IOP, larger pattern standard deviations, and thinner central corneal measurements, predicted conversion to open-angle glaucoma (OAG)¹³. Another longitudinal population-based study from Ghana, the Tema Eye Survey, showed that a larger vertical CDR, male sex, older age, higher IOP, and thinner central corneal thickness (CCT) were significant baseline risk factors for incident OAG¹⁴. The present data are consistent with these previous findings, highlighting the importance of careful evaluation and monitoring of optic disc cupping in suspected cases.

The nasalization of CRVT (\(\ge 60\%)\) was significantly associated with glaucoma conversion. Interestingly, a greater PPA area (PPA-to-DA ratio \(\ge 0.4\)) and tilted optic disc configuration (disc ovality \(\ge 1.2)\) were also significant risk factors for RNFLDs. These findings are consistent with previous reports that investigated the effect of the location of CRVT on glaucoma susceptibility and PPA location. Jonas et al.²⁹ reported that glaucomatous neuroretinal rim loss was dependent on the distance from the region of the affected rim to the CRVT. The location of the CRVT was also spatially correlated with the location of enlarged PPA: the longer that the distance to the CRVT exit was, the larger that the PPA was, and the smaller that the neuroretinal rim was³⁰. Lee and colleagues recently proposed that the nasalization of CRVT is related to axial elongation in myopic eyes and demonstrated increased susceptibility to glaucomatous damage in these eyes³¹. During myopic axial elongation, the CRVT is dragged nasally, and the temporal border tissue of the ONH is further stretched temporally, resulting in an enlarged PPA and tilted optic disc configuration. The present longitudinal data support this idea, leading to incidental RNFLDs from increased ONH strain, as indicated by CRVT nasalization, larger PPA, and a tilted optic disc.

DH has been widely accepted to be associated with the development and progression of glaucoma^32,33, although the development of DH is unpredictable. In line with this theory, DH was a significant, and most detrimental risk factor for incident RNFLDs and their progression in the present longitudinal observation. In fact, the predictive power of the aforementioned scoring system could be improved, since the best cutoff score was 7.1 with sensitivity of 61.1% and specificity of 90.4% (AUROC = 0.856), by including the presence of DH, which added 6.02 to the final score. This finding emphasizes that the detection of DH, along with at least one other risk sign, would be decisive evidence to anticipate glaucoma conversion in the future. Considering that DH can only be identified through careful examination of the ONH, clinicians should not underestimate the importance of monitoring with fundus photography.

Fundus photography has the advantage of being able to observe morphological changes in blood vessels. A number of large epidemiological studies have cross-sectionally evaluated retinal vascular changes and shown that decreased retinal vessel caliber was significantly associated with glaucoma^34,35,36. It is controversial whether changes in the retinal vasculature are secondary findings due to decreased metabolic demands from RNFLDs or whether these retinal vasoconstrictions are primarily due to impaired local autoregulation and leakage of vasoactive substances³⁷. The present study supports the role of vasospasm of retinal vessels in glaucoma development by showing that baseline changes in which blood vessels narrow or stiffen are significantly associated with the risk of future RNFLDs.

IOP elevation significantly increased the risk for glaucoma conversion. Eyes with baseline IOP \(\ge 14\) mmHg had 1.70 times greater risk of incident RNFLD. Moreover, eyes with IOP fluctuation \(\ge 2\) mmHg had a 1.50 times greater risk of progression with marginal significance (P = 0.08). In a 5-year, prospective, observational study involving normal-tension glaucoma eyes with IOP less than 15 mmHg, Sakata et al.³⁸ revealed that long-term IOP fluctuation, along with DH and vertical CDR, was a significant risk factor for glaucoma progression, defined as VF deterioration or disc/peripapillary retina deterioration. The Advanced Glaucoma Intervention Study demonstrated a significant association between greater long-term IOP fluctuation and VF deterioration in the group with low mean IOP (10.8 mmHg) but not in the group with high mean IOP (20.6 mmHg)³⁹. Given that the mean follow-up IOP in the current study population was not high (median value less than 15 mmHg), long-term IOP fluctuations could play an important role in glaucoma progression, especially in patients with a low range of IOPs.

The present study has the following shortcomings. First, the proposed baseline scoring system for predicting future glaucoma conversion must be further validated in a new study population to achieve more accurate diagnostic performance, although the current scoring system provides intuitive insight from baseline parameters to estimate the clinical outcomes of suspected cases. Second, unfortunately, we were not able to measure CCT during the period when the present study was conducted, although we currently obtain CCT value using a noncontact tonopachymeter which offers good feasibility for IOP as well as CCT measurement in health screening centers⁴⁰. CCT has been well known as a risk factor for development of OAG, and therefore, might change the proposed scoring system. Third, the current study did not evaluate the VF of the subjects. Therefore, the present findings cannot be generalized to the prediction of functional outcomes of glaucoma because the progression of RNFLDs does not always mean the progression of VFs, especially in the very early stage of glaucoma. However, since structural progression usually precedes VF deterioration in glaucoma, the present findings still have strength in terms of the early detection of glaucomatous changes from suspected cases. Finally, with regard to assigning subjects to the control group, at least a 10-year duration of follow-up might not guarantee the absence of glaucoma conversion thereafter.

In conclusion, through long-term follow-up examinations, the present study demonstrated that some eyes with GLD (large optic disc cupping [vertical CDR ≥ 0.6] without RNFLDs) underwent conversion to glaucoma. Careful examination of screening fundus photography, including not only the ONH configuration but also retinal vascular changes, can predict the risk of glaucoma conversion and the progression of RNFLDs in these eyes. The current findings could provide clinicians with new insights to assess the risk of glaucoma in suspected cases and to identify patients who require close monitoring for glaucoma development. Although the proposed scoring system for predicting future glaucoma conversion should be further validated, we carefully suggest that subjects with high scores be followed up every 1–2 years while subjects with low scores be monitored every 3–5 years using screening fundus photography.