Myopia is the leading cause of distance refractive error in the world, affecting 1.89 billion of the global population in 2017 (1), and it is believed that this number will continue to grow due to the myopia boom as a result of a modern lifestyle (2). Mild-to-moderate myopia is a common condition, often due to axial elongation, that can be corrected with appropriate spectacles, contact lenses, and refractive surgery (3).

High myopia, on the other hand, due to excessive ocular elongation (4) can predispose the eye to a risk of permanent vision loss through the development of pathologic myopia (PM), which often manifests clinically as one or a combination of the following conditions: myopic macular degeneration (MMD) (5, 6), myopic choroidal neovascularization (mCNV), or myopic traction maculopathy (MTM) (6–12). While the WHO defines high myopia as spherical equivalent (SE) of five diopters (D) of myopia and above (13), definitions of high myopia vary in the current literature, with most defining high myopia as ≥5.0–8.0 D of myopia (14–16), or axial length (AL) 25–27 mm and above (17–20). High myopia is the second major cause of vision impairment worldwide, having affected approximately 2.8% (170 million) of the global population, with the highest prevalence in East and Southeast Asia, such as China, Japan, the Republic of Korea, and Singapore (2, 13). The prevalence of high myopia continues to grow rapidly, and it is estimated that by 2050, 9.8% (938 million) people globally will be highly myopic (HM) (16). Consequently, the prevalence of PM-related visual impairment is likely to rise in tandem with the prevalence of high myopia (21, 22).

In addition to PM, HM eyes are more likely to develop associated myopic pathologies, such as peripapillary atrophy (PPA) (23), myopic tilted disc (24), posterior staphyloma (PS) (25), dome-shaped macula (DSM) (26), vitreomacular adhesion (VMA) (27), and the epiretinal membrane (ERM) (28). Determining the characteristics of patients with HM at high risk of developing these pathologic changes is critical in guiding the optimal monitoring of patients with HM, so as to administer timely interventions to mitigate or prevent permanent visual loss (29).

In this study, we aimed to assess the prevalence of the aforementioned myopia-related pathologies in a cohort of hospital-based patients with HM using multimodal imaging, including widefield swept-source optical coherence tomography (SS-OCT) and fundus photography/autofluorescence. To further evaluate the impact of AL on PM (13, 30), we stratified patients into two groups based on a cut-off threshold derived from quartile analysis in the hopes of providing credence to an AL-based system to guide the frequency of clinical follow-up for patients with HM.

We conducted a cross-sectional analysis of high myopes from the Myopic and Pathologic Eyes in Singapore (MyoPES) cohort. In brief, high myopes defined by an SE refractive error of ≥5.0 D of myopia and/or AL ≥ 25.0 mm in the study eye, and aged 18 years old and above were enrolled from the High Myopia clinic at the Singapore National Eye Centre, Singapore, from January 2017 to December 2018. The study was performed with approval from the SingHealth Institutional Review Board and in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants. Participants with any existing or previous ocular diseases in either eye that may confound measurements from SS-OCT, and fundus photography were excluded from the study. Such conditions included corneal opacities, uveitis, dense cataracts, vitreous hemorrhage, diabetic retinopathy/diabetic macular edema, central serous chorioretinopathy, previous retinal laser photocoagulation or photodynamic therapy, retinal dystrophies, and macular scarring from any cause other than myopic maculopathy, retinopathy due to any cause other than myopia, previous retinal vein or artery occlusion, and ocular ischemic syndrome.

All enrolled participants underwent the following investigations: (1) ocular biometry, (2) dilated retinal examination, (3) color fundus photography, (4) fundus autofluorescence, and (5) SS-OCT.

Overall, 495 subjects were included in the study. A total of 990 eyes were imaged: 923 eyes were included in the analysis after excluding 45 unilateral eyes with AL <25.0 mm, and 22 eyes due to poor image signal or inability to obtain images. In total, 326 (65.9%) of included subjects were female, and the mean age was 61.7 ± 13.7 years old (range 19–91 years old). The overall mean AL was 29.2 ± 2.2 mm (range 25.0–36.7 mm).

Overall, there were 231 (25.0%) eyes in Q1, 231 (25.0%) eyes in Q2, 231 (25.0%) eyes in Q3, and 230 (25.0%) eyes in Q4. The mean ALs were 26.5 ± 0.6, 28.2 ± 0.5, 29.8 ± 0.5, and 32.3 ± 1.2 mm for Q1, Q2, Q3, and Q4, respectively. Characteristics of patients and a summary of the χ²-test analysis are found in Table 1. In summary, the identified threshold for MMD, PPA, myopic tilted disc, ERM, and for concurrent MMD+MTM was AL > 27.5 mm, whereas for MTM and for concurrent MMD+MTM+DSM, the threshold was AL > 29.0 mm. The summary of the χ²-test analysis based on the threshold identified is found in Table 2.

In this study, we established the prevalence of MMD, MTM, and associated myopic features in a cohort of hospital-based patients with HM using multimodal imaging. Overall, we observed that even among HM eyes, i.e., AL ≥ 25.0 mm, longer eyes were associated with a higher prevalence of MMD, mCNV, MTM, and associated myopic features, namely, myopic tilted disc, PPA, PS, DSM, ERM, and VMA when compared to relatively shorter HM eyes. Our quartile analysis suggested an AL threshold above which the prevalence of certain myopic pathologies was significantly higher, namely, for MMD (AL ≥ 27.5 mm), MTM (AL ≥ 29.0 mm), PPA (AL ≥ 27.5 mm), myopic tilted disc (AL ≥ 27.5 mm), MMD+MTM concurrently (AL ≥ 27.5 mm), and MMD+MTM+DSM concurrently (AL ≥ 29.0 mm).

The presence of MMD in HM eyes has been well-described in the literature. The prevalence of MMD has been reported to be 1.3–6.0% in the general population (36–45). Specifically, the prevalence of MMD among subjects with HM was observed to be 25.3–71.4%, which varies depending on the population reported (36–45). In our study, we observed a prevalence of 78.4% among hospital-based subjects with HM, which is slightly higher than the upper end of the previously reported number. This is likely attributed to the fact that this cohort of patients (MyoPES cohort) was recruited from a tertiary referral center (Singapore National Eye Centre High Myopia Clinic, Singapore), which specifically looks after high myopes, in which a vast majority have PM as compared to population studies that involve subjects from the general population. In addition, although eyes from both groups were considered to be HM, we observed that long HM eyes (AL ≥ 27.5 mm) were found to have a higher prevalence of MMD (88.2 vs. 49.4%; p < 0.001). This finding is consistent with Choudhury et al.'s findings, which found that longer AL is an independent risk factor for MMD (46). Similarly, this finding is also supported by the Hisayama study (47), which established an association between AL elongation and the likelihood of MMD. While AL has been identified as an independent risk factor for MMD development (48), the exact mechanism of what drives the pathology is unknown. Ohsugi et al. previously reported that AL was the greatest in those with mCNV (49), thus suggesting that the presence of MMD could be mainly driven by AL elongation. Our study shared a similar observation, where the prevalence of mCNV (both active and quiescent forms) was found to be significantly higher in eyes with longer AL (≥27.5 mm). We found a significantly higher prevalence of MMD and mCNV in HM eyes with AL ≥ 27.5 mm, and therefore, it is important to monitor such patients more frequently vs. eyes <27.5 mm.

Overall, we observed an overall prevalence of 28.1% for the presence of MTM among our HM eyes, which was similar to what was reported by Panozzo and Mercanti (34.4%) (9). Long AL has been a common theme in eyes with MTM (50, 51). In particular, we have found that the prevalence of MTM was significantly higher among eyes with extremely long AL, especially after the threshold AL of ≥ 29.0 mm. Similar observations were made by Xia et al. (50–54). Patients with MTM can have a prolonged subclinical phase in which they remain asymptomatic, and early changes can be difficult to diagnose on routine fundus examination (8). With OCT and an identified threshold, i.e., AL ≥ 29.0 mm, however, MTM can now be detected even in its early stages (55), enabling the timely diagnosis and treatment of patients at risk.

We also examined other pathological features that have been commonly described among HM eyes, as mentioned below. Peripapillary atrophy is more commonly seen in HM eyes (56, 57) and is an important feature to be identified given that it is not only a hallmark of HM but also an important factor for higher risk of glaucomatous damage (58). Myopic tilted disc and PS have also been reported to be progressive in nature in eyes with severe myopia (17, 59, 60). Axial length was identified as a risk factor for the presence of ERM (61), and similarly, DSM and VMA are conditions that are commonly seen in patients with HM (26, 27), and although these conditions alone might not affect visual function, they may increase the risk of developing further sight-threatening complications (26, 27). We found that the prevalence of PPA, myopic tilted disc, PS, DSM, ERM, and VMA was significantly higher in eyes with longer AL even among HM eyes. The association between the presence of these features and AL elongation has also been seen in other studies as well (26, 58, 62, 63). This suggests that AL elongation not only drives the pathogenic pathway of MMD and MTM but may in part lead to the development of these associated features as a by-product (24, 63–65). These patients should be followed up regularly with multimodal imaging for a comprehensive evaluation of these pathologies, and patients should be counseled about the symptoms of sight-threatening conditions, such as mCNV and MTM, to allow for early detection and appropriate interventions.

In this study, we also looked at the prevalence of accumulated eye conditions, namely, MMD+MTM concurrently and MMD+MTM+DSM concurrently. Overall, we found that MMD+MTM is of higher prevalence in eyes with AL ≥ 27.5 mm as compared to eyes with AL <29.0 mm. Our study findings concur with our previous study where we found that eyes with MTM are at higher risk of developing MMD (12), as the tractional changes may lead to stretching of retinal layers, which may be associated with degenerative changes seen in MMD. In this study, we have further established the threshold where the prevalence of both events occurs concurrently, which is an AL of 27.5 mm. Similarly, we see a higher prevalence of MMD, MTM, and DSM occurring concurrently in eyes with AL ≥ 29.0 mm as compared to eyes with AL <29.0 mm, and the implication of these findings would be interesting to be explored in a further longitudinal study.

The strengths of our study include the relatively large sample size with comprehensive multimodal imaging to accurately capture the prevalence of multiple HM-related pathologies. Our limitations include first, the cross-sectional design of our study precludes the analysis of incidence and causation. Ideally, a longitudinal study design would be preferred, although difficult in the context of a slowly progressive disease, such as MMD. Second, participants in our study are patients with HM recruited from a tertiary referral center, who are more likely to have worse pathology. Our results, therefore, may not be generalizable to the entire population of individuals with HM. Third, we are not able to establish the threshold of PS, DSM, and VMA, which is likely due to the relatively low prevalence of these phenotypes observed in our study group when subdivided into quartiles.Analyses of these parameters did reach significance when subdivided into two groups (Table 2).

In conclusion, our study described the overall prevalence of PM (MMD and MTM) and associated myopic pathological features in a cohort of hospital-based patients with HM. We found that longer eyes are more likely to have MMD, PPA, myopic tilted disc, ERM, and chances of MMD and MTM concurrently if AL ≥ 27.5 mm, and mCNV, MTM, myopic tilted disc, PS, DSM, VMA and chances of MMD, MTM, and DSM concurrently if AL ≥ 29.0 mm. We recommend a relatively closer follow-up with multimodal imaging for the timely diagnosis and treatment of sight-threatening complications in these extremely myopic individuals.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by SingHealth Institutional Review Board. The patients/participants provided their written informed consent to participate in this study.

QH and CW conceptualized and supervised the study and obtained the data. KT, IL, YD, QW, DY, and VY curated the data and conducted formal analysis of data. All authors wrote, reviewed, edited, and approved the manuscript.

This work was supported in part by the SingHealth-Duke-NUS Eye Academic Clinical Program Nurturing Clinician Scientist Scheme (NCSS/R1364/50/2016, CW, Singapore), the National Eye Institute/National Institutes of Health (Grant K08 EY023595, QH, USA), and the National Medical Research Council (Grant CSA/MOH-000151/2019, QH, Singapore). The funding organizations had no role in the design or conduct of this research.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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