Characteristics of the Peripapillary Structure and Vasculature in Patients With Myopic Anisometropia

Abstract

Purpose: To evaluate the interocular differences of the peripapillary structural and vascular parameters and that of association with axial length (AL) in participants with myopic anisometropia using swept-source optical coherence tomography.

Methods: This prospective cross-sectional study included 90 eyes of 45 participants. Each participant's eyes were divided into the more and less myopic eye respectively according to spherical equivalent. The β- and γ-parapapillary atrophy (PPA) areas, Bruch's membrane opening distance, border length, and border tissue angle were measured manually. Peripapillary choroidal vascularity index and choroidal thickness (CT) values in superior, nasal, inferior, and temporal were calculated using a custom-built algorithm based on MATLAB.

Results: The interocular difference in AL and spherical equivalent was 0.62 ± 0.26 mm and −1.50 (−2.13, −1.25) diopters (D), respectively. The interocular difference in spherical equivalent was highly correlated with that of the AL. The β- and γ-PPA areas were significantly greater in more myopic eyes. The mean and inferior peripapillary choroidal vascularity index and all regions of peripapillary CT were significantly lower in the more myopic eyes. The interocular difference in AL was significantly positively correlated with the interocular differences in γ-PPA area and border length and negatively correlated with the interocular differences in temporal choroidal vascularity index and mean, inferior, and temporal peripapillary CT. There was an independent correlation between the interocular differences in AL and the interocular differences in γ-PPA area, inferior, and temporal peripapillary CT.

Conclusions: Significant differences between both groups were detected in most peripapillary parameters, especially in peripapillary CT. The γ-PPA area, border length, and peripapillary CT were significantly correlated with the elongation of AL.

Translational Relevance: The current study characterized and analyzed the peripapillary parameters in myopic anisometropia, which helped to monitor myopic progression.

Introduction

Myopia is an increasingly common visual disorder worldwide, particularly in East Asia.^1–3 Myopia is often considered a failure of emmetropization owing to asymmetrically excessive ocular axial elongation.^1,4–7 Asymmetrical mechanical or optical factors can contribute to unequal ocular growth, potentially resulting in myopic anisometropia.⁶ Genetic predisposition is considered to contribute significantly to the development of myopic anisometropia.⁸ Myopic anisometropia causes various visual function disorders and complications associated with myopia, such as diplopia, decreased stereopsis, and potential development of amblyopia in the more myopic eye.^6,9 

Myopic eyes are known to be susceptible to glaucomatous changes and the myopic glaucomatous eyes display a faster rate of retinal nerve fiber layer and visual field progression.^10,11 Recently, myopic changes in the optic nerve head (ONH) have attracted significant interest.^12–14 There are a series of retinal and choroidal complications surrounding the ONH, such as choroid neovascularization, optic disc tilted and rotation, and the parapapillary temporal crescent of chorioretinal atrophy.^15–17 Previous studies have identified that certain structural changes in the ONH in myopic eyes have been linked to the progressive mechanical stretch of the globe posterior, such as parapapillary atrophy (PPA), nasal elevation (i.e., superior traction), tilted and rotated discs, and scleral deformation between the macula and the ONH.^{14,16,18–21} Anisometropia is also associated with alterations in ONH morphology.^6,22,23 Significant anisometropia is often associated with abnormal ocular development, leading to retinal and choroidal abnormalities, including optic nerve hypoplasia²⁴ and unilateral extensive myelination.²⁵ However, the specific characteristics of the ONH in myopic asymmetrical ocular growth are not yet fully understood.^26–30 Therefore, it is necessary to investigate the peripapillary characteristics of individuals with myopic anisometropia to demonstrate the potential mechanisms of myopia. 

With the advent of swept-source optical coherence tomography (SS-OCT) technology, visualization of a larger area and detailed imaging of the choroidal vasculature system with reduced motion artifact is possible.²⁶ SS-OCT permits high-speed, high-resolution imaging and better visualization of the ONH.^26,27,31 In addition, SS-OCT showed excellent repeatability and reproducibility in ONH parameters.³² In recent years, SS-OCT has been widely applied in studies on myopia and ocular diseases centered on the fovea.^2,33–38 However, despite the advantages of these techniques, research concerning the characteristics of the peripapillary structure and vasculature using SS-OCT is limited. Therefore, the current study used SS-OCT to analyze ONH characteristics in myopic anisometropia. 

This study aims to demonstrate the myopic anisometropic changes in the peripapillary structure and vasculature. In this study, we assessed the characteristics of the β- and γ-PPA areas, Bruch's membrane opening distance (BMOD), border length (BL), border tissue angle (BTA), peripapillary choroidal vascularity index (CVI), and choroidal thickness (CT) in patients with myopic anisometropia. In addition, we analyzed the relationship between interocular differences in these parameters and interocular difference in axial length (AL). This method of examining the interocular differences between the eyes of each participant was applied to minimize the influences of individual and external differences, such as age, gender, and environment. Therefore, the results are expected to be more typical within a smaller sample size.³³ 

Materials and Methods

Participants

This study was approved by the Ethics Committee of the Eye Hospital affiliated with Wenzhou Medical University. All the procedures in this study adhered to the tenets of the Declaration of Helsinki. Written informed consent was obtained from all participants prior to their involvement. A total of 45 participants were enrolled from among patients who visited the Refractive Surgery Center at the Affiliated Eye Hospital of Wenzhou Medical University, Hangzhou, between October 2021 and January 2022. 

The inclusion criteria were as follows: age between 18 and 40 years old; myopic anisomyopes with an interocular difference in spherical equivalent (SE) of ≥1.00 D⁶; SE of <−8.00 D^39,40; best-corrected visual acuity of ≥0.00 logarithm of minimum angle of resolution in each eye; stable myopia for >2 years; intraocular pressure (IOP) of ≤21 mm Hg; and normal ONH without glaucomatous changes, such as neuroretinal rim narrowing and peripapillary hemorrhage. The exclusion criteria were as follows: complications of pathological myopia, including posterior staphyloma, lacquer cracks, and myopic choroidal neovascularization; vitreoretinal disorders such as macular holes or chorioretinal atrophy⁴¹; previous intraocular or refractive surgery; and a history of ocular or systemic diseases, including congenital cataract and glaucoma, hypertension, and diabetes.⁴² Both eyes of all participants were included in this study. Each participant's two eyes were divided into the more myopic eye and the less myopic eye according to SE and enrolled into the corresponding groups. 

Ophthalmic Examination and Measurements

All participants enrolled in this study underwent a series of ophthalmic screening examinations, including noncycloplegic subjective refraction measurements, ocular health evaluations, and noncontact IOP measurement. Subjective refractive indices were obtained by a trained optometrist. Refractive data were converted to SE, which was calculated as the spherical dioptric power plus half the cylindrical dioptric power. The ocular health evaluations were conducted by an experienced ophthalmologist (CD). 

The enrolled participants were instructed to undergo a comprehensive ophthalmologic evaluation after the screening. Ocular biometric parameters were measured using IOL Master (Zeiss 700; Carl Zeiss Meditec, Inc, Dublin, CA), including central corneal thickness (CCT), anterior chamber depth (ACD), lens thickness (LT), and AL. The vitreous chamber depth (VCD) was defined as AL − (CCT + ACD + LT). The choroidal and peripapillary structures were measured using SS-OCT.² All measurements were conducted between 9 am and 4 pm. 

SS-OCT Image Acquisition and Analysis

The commercial SS-OCT device (VG200; SVision Imaging, Ltd., Henan, China) contained an SS laser with a central wavelength of approximately 1050 nm (990–1100 nm full width) and a scanning rate of 200,000 A-scans per second.⁴³ Detailed information on the acquisition protocols for this device has been previously reported.³³ Based on a review by an experienced researcher, OCT, and OCT angiography images were selected according to the following exclusion criteria: (1) signal score of <6, (2) poor clarity, (3) residual motion artifacts visible as irregular vessel patterns or disc boundary on en face angiogram, (4) local weak signal, and (5) choroidal layer segmentation unclarity.^44,45 

The en face images were acquired from an ONH of 6 × 6 mm² (Fig. 1A1). The β-PPA area was defined as the size of the zone with complete retinal pigment epithelium loss with the presence of BM. The γ-PPA area was defined as the size of the zone without the BM (Figs. 1A2, A3). The structural OCT B-scan image was acquired by focusing on the intersection of the longest axial and shortest axial of the ONH. Both ends of the BMO were marked, and the two points were connected to draw the BMO reference plane. The distance between these two points in the BMO was defined as the BMOD. BL was measured and defined as the distance between the temporal BMO point and the border tissue and scleral end where the BM was absent, provided there was border tissue at the temporal parapapillary optic disc (Fig. 1B). BMOD and BL were measured using the SS-OCT software. The BTA was defined as the angle between the BMOD and BL planes and was measured using the ImageJ image processing software (available at http://rsb.info.nih.gov/ij/index.html).²⁰ The image size was adjusted for differences in magnification owing to the difference in AL among the eyes.² 

Figure 1.

 

Measurement of peripapillary structural and vascular parameters. Measurement method using the right eye as an example. (A) Determination of the β- and γ-PPA areas. The orange, white, and blue lines present the boundaries of the retinal pigment epithelium (RPE), BM, and optic disc edge, respectively (A1 and A2). The β-PPA is marked in light green and the γ-zone PPA is marked in dark green (A3). (B) Measurement of the BMOD, border length (BL), and BTA. BMOD was measured as the distance between the two sides of the BMO. The BL was measured as the distance between the temporal BMO end and the scleral end. The BTA was defined as the angle between the BMOD and BL. (C) The peripapillary CVI and CT were measured from the 3.4-mm-sized ONH circle scan image (C1 and C2) and analyzed using the custom-built algorithm based on MATLAB. CVI and CT values were calculated for five regions, including the superotemporal (TS), superior (S), nasal (N), inferior (I), and inferotemporal (TI) regions. TS and TI were combined into a single temporal (T) region (C3).

The choroidal area on OCT was defined as the zone between the retinal pigment epithelium–BM complex and the lower border of the light pixels at the choroid–scleral interface.⁴⁴ The CVI was defined as the ratio of vascular area to the total choroidal area.²⁸ The CT was defined as the thickness of the choroidal area. Peripapillary CVI and CT were measured based on a 3.4 mm-sized ONH circular scan (Fig. 1C1) using MATLAB R2021a (MathWorks, Natick, MA). The custom-built algorithm based on MATLAB we used was verified in previous studies.^2,33 After segmenting semiautomatically, the borders of the choroidal area were adjusted. The CVI and CT of each region were calculated following binarization with Niblack's autolocal threshold.² The circular B-scan image was separated into five regions, including superotemporal, superior, nasal, inferior, and inferotemporal regions from left to right in the right eye; this order was reversed in the left eye. The superotemporal and inferotemporal regions were combined into a single temporal (T) region (Figs. 1C2, C3). 

Statistical Analysis

Statistical analysis was performed using SPSS Statistics 25.0 (IBM, Armonk, NY). The normality of the data was evaluated using the Shapiro–Wilk test. The normally distributed data was given as the means and standards. The nonnormally distributed data was shown as median, first quartile, and third quartile. For adjusting the correlation between both eyes of the same patient, the generalized estimating equations were performed to assess the differences between the more myopic eyes group and the less myopic eyes group. The interocular differences were calculated by subtracting the less myopic eye from the more myopic eye. We use Pearson's correlation to analyze the associations between the interocular difference in AL and all peripapillary parameters when the data show a normal distribution; otherwise, Spearman's correlation was performed. A multiple linear regression model was established to explore the association between the interocular differences in parameters that were significantly correlated with that of AL and the interocular difference in AL. All P values were two-sided, and a P value of <0.05 was considered significant. 

Results

Demographic Data

Forty-five patients (90 eyes) were enrolled in this study. Eleven were male patients (24.44%) and 34 were female patients (75.56%). The mean age was 27.37 ± 5.72 years (range, 18–39 years). 

There were significant differences in terms of SE, AL, ACD, and VCD between the more myopic eyes and the less myopic eyes. Compared to the less myopic eyes, the more myopic eyes had lower SE (P < 0.001) and higher AL, ACD, and VCD (all P < 0.001). No significant differences were found in IOP, CCT, and LT between two groups (P = 0.886, 0.405, and 0.059, respectively) (Table 1). 

Table 1.

 

Ocular Biometrics Parameters in Myopic Anisometropic Patients

 

Interocular Differences in Peripapillary Structure and Vasculature

The β- and γ-PPA areas were both significantly greater in the more myopic eyes (P = 0.045 and P = 0.002, respectively). There was no significant difference in the BMOD, BL, and BTA (P = 0.078, 0.050, and 0.995, respectively) (Table 2). 

Table 2.

 

Characteristics of the Peripapillary Structure and Vasculature in Myopic Anisometropic Patients

 

For peripapillary CVI values, all regions of peripapillary CVI values were greater in the less myopic eyes (Fig. 2A). The mean and inferior peripapillary CVI values in the less myopic eyes were significantly greater (P = 0.003 and P = 0.005, respectively), whereas no significant differences were found in the superior, nasal, and temporal peripapillary CVI values (all P > 0.05) (Table 2). 

Figure 2.

 

Distribution of peripapillary CVI (A) and CT (B) in fellow eyes of myopic anisometropic patients (n = 45).

For peripapillary CT values, all regions of peripapillary CT values were greater in the less myopic eyes (Fig. 2B). All regions of peripapillary CT values in the less myopic eyes were significantly greater than those in the more myopic eyes (P < 0.001, P = 0.003, P = 0.026, P = 0.007, and P < 0.001, respectively) (Table 2). 

Factors Associated With the Interocular Difference in AL

The interocular difference in AL was significantly positively correlated with that in VCD (r = 0.983; P < 0.001) and negatively correlated with that in SE (r = −0.686; P < 0.001). There was a correlation between the interocular differences in γ-PPA (r = 0.361; P = 0.015) (Fig. 3B) and BL (r_s = 0.342; P = 0.023) (Fig. 3D) and the interocular difference in AL. The interocular difference in AL was significantly correlated with the interocular differences in temporal peripapillary CVI values (Fig. 3J) and the mean, inferior, and temporal CT values (Figs. 3K, N, O) (r = −0.295, P = 0.049; r = −0.339, P = 0.023; r = −0.394, P = 0.007, and r = −0. 504, P < 0.001, respectively). 

Figure 3.

 

Scatter plot of the correlation between the interocular differences in peripapillary parameters and the interocular difference in AL. (A) β-PPA area. (B) γ-PPA area. (C) BMOD. (D) BL. (E). TA. (F). VI_Mean. (G) CVI_Superior. (H) CVI_Nasal. (I) CVI_Inferior. (J) CVI_Temporal. (K) CT_Mean. (L) CT_Superior. (M) CT_Nasal. (N) CT_Inferior. (O) CT_Temporal. Regression lines were fitted for the parameters with a significant correlation with the interocular difference in AL. BL, border length.

The interocular difference in AL was positively correlated with the interocular difference in area of γ-PPA (P = 0.003), whereas it was negatively correlated with the interocular differences in the inferior and temporal peripapillary CT values (P = 0.015 and P = 0.007, respectively) (Table 3). 

Table 3.

 

Multiple Linear Regression Analysis of Interocular Differences in AL and in Parameters in Myopic Anisometropic Patients

 

Discussion

In this study, SS-OCT was used to investigate the characteristics of the peripapillary structure and vasculature in patients with myopic anisometropia. We also investigated the relationships between the interocular difference in AL and the interocular difference in these peripapillary parameters. The results showed that the areas of β-PPA, and γ-PPA were significantly larger in the more myopic eyes than in the less myopic eyes. In contrast, the mean and inferior peripapillary CVI values and all regions of peripapillary CT values were significantly lower in the more myopic eyes. The interocular difference in AL was significantly positively correlated with the interocular differences in γ-PPA area and BL, whereas it was significantly negatively correlated with the interocular differences in temporal peripapillary CVI and the mean, inferior, and temporal peripapillary CT. Moreover, the interocular difference in AL was positively associated with the γ-PPA area difference and negatively correlated with the interocular differences in inferior and temporal CT. 

We found that the areas of β-PPA and γ-PPA were significantly larger in the more myopic eyes, and the interocular difference in the γ-PPA area was positively correlated with the interocular difference in AL. Previous studies have demonstrated that with the elongation of the ocular axis—retinal stretching—might not be the same as scleral growth, resulting in scleral slipping to the retina.⁴⁶ Some clinical studies showed that β-PPA was associated with glaucoma and myopia, whereas the γ-PPA was merely associated with myopia.^47,48 Lee et al.⁴⁹ suggested that the enlargement of the area of β-PPA during axial elongation was affected by the extent and direction of vascular trunk dragging, thus implicating disproportionate growth between the retina and sclera. In the current study, our findings suggested that the changes in the PPA area mostly resulted from myopic ocular axial elongation, because all participants enrolled in the study were not diagnosed with glaucoma. These results are similar to those of the previous studies.^47–49 However, we hypothesized that the more myopic eyes in myopic anisometropic adults might be more vulnerable to glaucomatous damage owing to the increasing β-PPA area. It might be necessary to monitor the IOP and screen for glaucoma regularly in myopic anisometropic patients. 

There was no significant difference in the BMOD, BL, and BTA between the two groups. Kim et al.¹⁴ conducted a longitudinal observational study involving 31 myopic children over a span of 2 years. They found that the nasal BL increased and the BTA decreased, whereas the BMOD was relatively stable when the ONH structure was changed by axial elongation. They believed that the changes in BL and BTA were associated with the elongation of AL, and the distance from the fovea to the nasal BMO margin did not change after the AL increase.¹⁴ In a separate study, Patel et al.⁵⁰ evaluated longitudinal changes in ONH parameters in 352 infants and children. They reported an increasing trend in BMOD during the development of myopia, although this trend did not show statistical significance.⁵⁰ In our study, the difference in BMOD, BL, and BTA between the two groups was not significant. The interocular difference in BL was significantly positively correlated with the interocular difference in AL. The result of stable BMOD was predictable and consistent with previous studies.^14,51 The changes in BTA were not significant while the BL was increased in the more myopic eyes. Based on these results, we hypothesize that the stretching of BM occurs earlier than the tilting of the ONH structure, which may be the reason why the difference in BTA is not significant. The BL seemed to be a potentially sensitive variable that can be monitored to assess the progression of myopia. 

Few investigations have focused on peripapillary CVI values in patients with myopic anisometropia. In this study, we found significant differences in the peripapillary CVI values between eyes of myopic anisometropic patients. We found that the mean and inferior peripapillary CVI values were significantly lower in the more myopic eyes, and a negative correlation between the temporal CVI and AL difference was also found. These findings suggest that the temporal peripapillary CVI may be a predictor of asymmetric ocular axial elongation. Compared with choroidal blood flow changes in fovea, the decrease in peripapillary CVI was not significant. However, characteristics of the peripapillary choroid were investigated as an entity in our study. The detailed layers of the choroid were not observed. This unexplored field holds potential for advancing comprehension of myopic anisometropia. 

Previous studies on peripapillary CT values in myopic eyes remain controversial. Bitirgen et al.⁵² evaluated peripapillary CTs in children with unilateral hyperopic anisometropic amblyopia using SD-OCT and found that hyperopic amblyopic eyes had significantly higher CT values in all regions compared to control eyes. In addition, differences in average, temporal, and inferior peripapillary CT values remained significant after adjusting for the effects of AL.⁵² Cui et al.⁵³ compared the peripapillary CT in young myopic patients and found that the superonasal CT was the thickest and the inferotemporal CT was the thinnest. Kim et al.⁵⁴ reported that the global and sectoral peripapillary CT and the retinal nerve fiber layer were not changed in myopic patients during myopic axial elongation and for 4 years. Our results were similar to the results proposed by Bitirgen et al. and Cui et al. In our study, we found that the peripapillary temporal and inferior CT values were thinner than the peripapillary superior and nasal CT values. All regions of peripapillary CT values were significantly greater in the less myopic eyes than in the more myopic eyes. In addition, there was a significant association between the interocular differences in the mean, temporal, and inferior peripapillary CT values and that of AL. The dysfunction of the whole choroid was obvious. We propose that interocular differences in peripapillary CT result from the interocular differences in AL. In addition, peripapillary CT values may be more sensitive parameters than peripapillary CVI values in the development of myopia. The peripapillary CT value might be an important predictable parameter of myopia. 

The choroid is one of the most vascularized structures in the human body, supplying most of the blood, nutrients, and oxygen to the outer retina.^17,27,55 More evidence has shown two other functions of the choroid: adjusting the position of the retina by changing the CT and releasing growth factors to regulate the modulation of vascularization and scleral remodeling, as well as promoting ocular growth.^56,57 Numerous studies have confirmed that variations in CT show a significant positive correlation with choroidal blood perfusion during myopia development.^2,58 A cross-sectional study of characteristics surrounding ONH reported regional peripapillary CT and CVI decreased after the AL elongating in myopic patients.⁵⁹ In this study, we find that the interocular difference in peripapillary CT was more significant than that in peripapillary CVI. In the progression of myopic anisometropia, there is an unequal growth of AL between both eyes. We suppose that the decreased choroidal blood flow is mainly due to the thinning of CT instead of the decreasing of CVI, which aggravates the unequal growth of AL between both eyes. 

There are certain limitations in this study. The first was the small sample size. A larger sample size is needed in future studies to confirm the findings of this study. Second, longitudinal studies are needed to reveal the relationship between human body development and changes in parameters surrounding ONH. Therefore, we hope to follow up with pediatric patients with myopic anisometropia until they reach a stable stage of refraction error. Third, further animal experiments are required to reveal the mechanism of the peripapillary changes during the progression of myopic anisometropia. 

In conclusion, we found a strong relationship between interocular differences in AL and that of ONH parameters in myopic anisometropic adults in this study. These findings may provide new insights into the function of the choroid in the development of myopia. Further longitudinal investigations are necessary regarding the predictive value of decreased peripapillary CVI and CT values with increased asymmetry of ocular axial elongation. Early interventions can be aimed at delaying the development of myopia. 

Acknowledgments

Supported by research grants from the National Natural Science Foundation of China (Grant No. 81900910), and the Basic Scientific Research Project of Wenzhou (Y20210194). 

Author Contributions: YQ participated in data collection, statistical analysis, and writing the manuscript; DC: conducted statistical analyses and wrote the manuscript; KR and JY conducted analyses and interpretation; ZZ conducted statistical analyses; WG, MW, XZ, and YY participated in data collection and critical revision; MS provided program technical support and data analysis; LS participated in conception, design, and critical revision. 

Disclosure: Y. Qiao, None; D. Cheng, None; X. Zhu, None; K. Ruan, None; Y. Ye, None; J. Yu, None; Z. Zhang, None; W. Gao, None; M. Wu, None; M. Shen, None; L. Shen, None