April 2019
Volume 60, Issue 5
Open Access
Retina  |   April 2019
Visual Acuity in Pathological Myopia Is Correlated With the Photoreceptor Myoid and Ellipsoid Zone Thickness and Affected by Choroid Thickness
Author Affiliations & Notes
  • Jie Ye
    School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China
  • Meixiao Shen
    School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China
  • Shenghai Huang
    School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China
  • Yuchen Fan
    School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China
  • Aixia Yao
    School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China
  • Chen Pan
    School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China
  • Xiutong Shi
    School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China
  • Fan Lu
    School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China
  • Yilei Shao
    School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China
  • Correspondence: Yilei Shao, School of Ophthalmology and Optometry, Wenzhou Medical University, 270 Xueyuan Road, Wenzhou, Zhejiang 325027, China; magic_shao@163.com
  • Fan Lu, School of Ophthalmology and Optometry, Wenzhou Medical University, 270 Xueyuan Road, Wenzhou, Zhejiang 325027, China; lufan62@mail.eye.ac.cn
  • Footnotes
     JY and MS contributed equally to the work presented here and should therefore be regarded as equivalent authors.
Investigative Ophthalmology & Visual Science April 2019, Vol.60, 1714-1723. doi:10.1167/iovs.18-26086
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      Jie Ye, Meixiao Shen, Shenghai Huang, Yuchen Fan, Aixia Yao, Chen Pan, Xiutong Shi, Fan Lu, Yilei Shao; Visual Acuity in Pathological Myopia Is Correlated With the Photoreceptor Myoid and Ellipsoid Zone Thickness and Affected by Choroid Thickness. Invest. Ophthalmol. Vis. Sci. 2019;60(5):1714-1723. doi: 10.1167/iovs.18-26086.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: To quantify the thickness of the outer retinal sublayers and choroid in pathological myopia and examine associations between these factors and best-corrected visual acuity (BCVA).

Methods: The cohort was composed of 21 eyes with emmetropia and 70 eyes with high myopia (49 simple high myopia; 21 pathological myopia). Optical coherence tomography images were segmented to determine macular thicknesses of the choroid and the following outer retinal sublayers: outer plexiform layer (OPL), Henle fiber layer and outer nuclear layer (HFL + ONL), myoid and ellipsoid zone (MEZ), outer segment of photoreceptors (OS), and interdigitation zone and RPE/Bruch complex (IZ + RPE). Correlations between BCVA and thickness of the outer retinal sublayers and choroid were determined.

Results: In pathological myopia, the choroid, HFL + ONL, MEZ, and IZ + RPE were thinner than in emmetropia and simple high myopia (P < 0.05). Simple and multiple regression models showed that MEZ thickness was correlated with BCVA (both P < 0.001). The relationship between MEZ thickness and BCVA varied with choroidal thickness (P = 0.006). For a constant MEZ thickness, thinner choroids were associated with worse vision. In the final multiple regression predictive model, MEZ thickness, choroidal thickness, and interaction between MEZ and choroidal thickness (all P < 0.001) were predictors of BCVA.

Conclusions: Outer retinal alterations, especially thinning of the MEZ, occurred in pathological myopia. The MEZ thickness was associated with BCVA, and this relationship was affected by choroidal thickness.

Irreversible visual impairment and blindness due to high myopia is one of the most serious worldwide vision problems, especially in Asia.13 Holden et al.4 documented that the prevalence of myopia has increased drastically and predicted that by 2050 there would be nearly 1 billion people with high myopia. Moreover, Liu et al.5 estimated that nearly two of every three (65.4%) highly myopic patients develop pathological myopia. Further, visual impairment, with the best-corrected visual acuity (BCVA) worse than 20/60, has been identified in 30.8% of patients with pathological myopia.5 Therefore, to develop new preventive and therapeutic strategies, it is essential to understand the risk factors and pathogenesis of visual impairment in pathological myopia. 
The photoreceptor layer in the outer retina provides spatial information during the first stage of visual processing. Much of our understanding concerning the relationship between the disruption of photoreceptors and visual function in high myopia has been obtained from qualitative observations by using optical coherence tomography (OCT).68 For example, vision was poorer in eyes with foveal ellipsoid zone disruption and in eyes with inner and outer segment defects. The integrity of the ellipsoid zone at baseline was also one of the factors predicting better final visual acuity after anti-vascular endothelial growth factor treatment in patients with myopic neovascularization.9 These studies significantly improved our understanding of pathogenic mechanisms leading to vision loss in pathological myopia. Compared to qualitative observations, quantitative analysis would provide much more detailed information regarding small and seemingly minor changes, enabling early detection of photoreceptor degeneration. Investigating the minor anatomic abnormalities of the outer retinal sublayers and their associations with the BCVA may provide clues to the development of vision-threatening alterations and the pathophysiological mechanisms in pathological myopia. 
In the current study, we applied a segmentation algorithm to OCT images to identify the sublayers of the outer retina and the choroid. The goals of the current study were to investigate the changes in the thickness of the outer retinal sublayers and choroid in pathological myopia and then to develop a visual function predictive model to determine the significant variables that would affect BCVA. This model may deepen our understanding of the mechanism of visual impairment and has the potential to guide us to develop new preventive and therapeutic strategies in pathological myopia. 
Methods
Subjects
In this prospective, cross-sectional study, all subjects were recruited from August 2017 to May 2018 at The Affiliated Eye Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. This project was approved by the Ethics Committee of Wenzhou Medical University and performed in accordance with the tenets of the Declaration of Helsinki. All participating patients provided written informed consent. 
The enrolled subjects were divided into the following three groups: (1) emmetropia subjects with a spherical equivalent (SE) of −1.0 diopter (D) to + 0.5 D; (2) simple high myopia subjects with SE ≤ −6.0 D or axial length (AL) ≥ 26.5 mm, without any pathological changes; and (3) pathological myopia subjects with SE ≤ −6.0 D or AL ≥ 26.5 mm, with pathological changes. According to the International Meta-Analysis for Pathologic Myopia (META-PM) classification system, eyes with diffuse or severe atrophy were classified as pathological myopic eyes.10 Diffuse and severe atrophy includes eyes with a yellowish-white appearance of the posterior pole, or with well-defined, grayish-white lesions in the macular area and the optic disc, even in the foveal region. The diagnosis of emmetropia, simple high myopia, and pathological myopia was determined by two ophthalmologists. If the results from these two ophthalmologists were not consistent with each other, a senior ophthalmologist gave the final judgment. These three ophthalmologists all came from the High Myopia Department of the Affiliated Eye Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. Eyes with intraocular pressure (IOP) more than 21 mm Hg, visual field defects, history of intraocular surgery or related systemic diseases, or complications of high myopia such as retinoschisis and choroidal neovascularization were excluded. 
Clinical Examinations
All subjects underwent comprehensive clinical examinations, including refraction, BCVA measurement as the logarithm of the minimum angle of resolution (logMAR), and slit-lamp biomicroscopy. AL was measured by the IOL Master (Carl Zeiss, Jena, Germany), and noncontact IOP was measured by the Full Auto Tonometer TX-F (Topcon, Tokyo, Japan). Fundus photography was performed with a 45° digital retinal camera (Canon EOS 10D SLR backing; Canon, Inc., Tokyo, Japan). 
Image Acquisition Protocol and Analysis
All enrolled patients were imaged by an OCT system (Optovue RTVue XR Avanti; Optovue, Inc., Fremont, CA, USA). The scan speed was 70,000 A-scans per second with 5-μm axial resolution. The 8-mm radial line scan protocol was applied. Eighteen consecutive B-scan images were produced, and each scan was centered on the fovea. A good set of scans with a signal strength index of more than 40 was selected for further analysis. 
Following image collection, we divided the macula into three subfields (Fig. 1A): (1) the central foveal region with a diameter of 1 mm, (2) the parafoveal region ranging from 1 to 3 mm from the central foveal region, and (3) the perifoveal region ranging from 3 to 6 mm from the central foveal region. Global thickness measurements of the whole macula included all three subfields. Custom-developed software that included correction of the image magnification based on the AL was used to quantify the thickness of the following sublayers of the outer retina and the choroid in the fundus11,12: (1) the outer plexiform layer (OPL), (2) the Henle fiber layer and outer nuclear layer (HFL + ONL), (3) myoid and ellipsoid zone (MEZ), (4) the outer segment of photoreceptors (OS), (5) the interdigitation zone and retinal pigment epithelium/Bruch complex (IZ + RPE), and (6) the choroidal layer (Fig. 1B). The custom software for segmented image analysis was developed based on gradient information and the shortest path search, as our previous studies described.11,12 For the automated segmentation, each image was visually inspected after the segmentation algorithm was run. The standard of the segmentation for each layer was according to the definitions proposed and adopted by the International Nomenclature for Optical Coherence Tomography Panel.13 The criteria used to identify segmentation errors were reported in our previous papers and included small peaks and curve offsets.14,15 If the automated segmentation was wrong in a few images, which was more likely to occur at the posterior boundary of the choroid in emmetropic eyes, manual corrections were made. All analyses of the segmentation were done by one masked reader.11,12 
Figure 1
 
Macular regions analyzed by optical coherence tomography in the 18-radial line scanning mode. (A) The macula was divided into three subfields: the central foveal region with the diameter of 1 mm, the parafoveal region ranging from 1 to 3 mm from the central foveal region, and the perifoveal region ranging from 3 to 6 mm from the central foveal region. (B) The boundaries of fundus structure were segmented by an automated algorithm, and the thickness profiles of the macular outer retinal sublayers and choroid were determined. Bars: 300 μm.
Figure 1
 
Macular regions analyzed by optical coherence tomography in the 18-radial line scanning mode. (A) The macula was divided into three subfields: the central foveal region with the diameter of 1 mm, the parafoveal region ranging from 1 to 3 mm from the central foveal region, and the perifoveal region ranging from 3 to 6 mm from the central foveal region. (B) The boundaries of fundus structure were segmented by an automated algorithm, and the thickness profiles of the macular outer retinal sublayers and choroid were determined. Bars: 300 μm.
We used Bennett's formula, t = p × q × s (t as the real scan length, p as the magnification factor determined by the OCT imaging system camera, q as the magnification factor related to the eye, s as the original measurement from the OCT image), to adjust the image magnification based on the AL. The correction factor q was determined by the formula q = 0.01306 × (AL − 1.82). When imaging the eye with an AL of 24.46 mm, the actual scanning range t would be equal to the s. When imaging eyes with other ALs, the real scan length t was determined by the equation t = (AL − 1.82) / 22.64 × s
To evaluate measurement repeatability, two separate sets of images collected from 14 eyes from each of the three groups were measured and the global macular thicknesses of the outer retinal sublayers and choroid were compared. The intraclass correlation (ICC) and the percentage of coefficient of repeatability (CoR%) were calculated. The CoR% was defined as standard deviation of the difference between two sets of scanned image measurements divided by the average of the two repeated measurements. Bland-Altman plots were also used to assess the agreement between the two repeated measurements. 
Statistical Analyses
All data were calculated as means ± standard deviations and were analyzed with SPSS software (version 22.0; SPSS, Inc., Chicago, IL, USA). The SE of refractive error was calculated as the spherical dioptric power plus one-half of the cylindrical dioptric power. One-way analysis of variance (ANOVA) was used to compare the differences among the three groups, and post hoc procedures were used to compare differences between groups. The different frequencies of each sex among the three groups were tested by the χ2 test. Simple regression models (based on the generalized estimating equations, GEE) were used to analyze the associations and interactions of the imaged outer retinal sublayer thicknesses and other variables with the BCVA. Based on the GEE, results from the simple regression models and the models assessing interactions were then used to create a final multivariate model with BCVA as the outcome. A value of P < 0.05 was considered statistically significant. 
Results
Patient Characteristics
Of the 91 eyes analyzed, 21 were emmetropic, and 70 had high myopia, including 49 with simple high myopia and 21 with pathological myopia (Table 1). Pathological myopic eyes had worse BCVA, greater myopia, and longer ALs than did emmetropic and simple high myopic eyes. There were no significant differences among emmetropia, simple high myopia, and pathological myopia patients in age, sex, or IOP (P = 0.137, 0.329, and 0.206, respectively, Table 1). 
Table 1
 
Basic Characteristics of the Emmetropia, Simple High Myopia, and Pathological Myopia Groups
Table 1
 
Basic Characteristics of the Emmetropia, Simple High Myopia, and Pathological Myopia Groups
Thickness Differences of the Outer Retinal Sublayers and Choroid
Fundus photographs (Figs. 2A–C) and OCT images (Figs. 2D–F) with the detailed automated segmentation were acquired for emmetropic, simple high myopic, and pathological myopic eyes. For the two repeated measurements, the ICC for the thickness of the outer retinal sublayers and choroid in the three groups varied from 0.875 to 0.998, and the CoR% varied from 0.59 to 5.61 (Table 2). Bland-Altman analysis of the global thicknesses for the outer retinal sublayers and choroid in all groups showed that most of the differences between the means for the two repeated measurements were within the limits of agreement (Fig. 3). 
Figure 2
 
Representative fundus photographs and OCT images of emmetropia, simple high myopia, and pathological myopia eyes. Fundus photographs (AC) and OCT B-scan images (DF) with the detailed automated segmentation of emmetropia, simple high myopia, and pathological myopia eyes, respectively. For the emmetropic eye (A, D), the AL was 24.21 mm, the global macular MEZ thickness was 26.34 μm, and the global macular choroid thickness was 347.91 μm. For the simple high myopia eye (B, E), the AL was 27.24 mm, the global macular MEZ thickness was 25.75 μm, and the global macular choroid thickness was 100.94 μm. For the pathological myopia eye (C, F), the AL was 29.37 mm, the global macular MEZ thickness was 20.24 μm, and the global macular choroid thickness was 68.67 μm. Bars: 300 μm.
Figure 2
 
Representative fundus photographs and OCT images of emmetropia, simple high myopia, and pathological myopia eyes. Fundus photographs (AC) and OCT B-scan images (DF) with the detailed automated segmentation of emmetropia, simple high myopia, and pathological myopia eyes, respectively. For the emmetropic eye (A, D), the AL was 24.21 mm, the global macular MEZ thickness was 26.34 μm, and the global macular choroid thickness was 347.91 μm. For the simple high myopia eye (B, E), the AL was 27.24 mm, the global macular MEZ thickness was 25.75 μm, and the global macular choroid thickness was 100.94 μm. For the pathological myopia eye (C, F), the AL was 29.37 mm, the global macular MEZ thickness was 20.24 μm, and the global macular choroid thickness was 68.67 μm. Bars: 300 μm.
Table 2
 
Repeatability of Global Thickness Measurements for the Outer Retinal Sublayers and Choroid in the Emmetropia, Simple High Myopia, and Pathological Myopia Groups
Table 2
 
Repeatability of Global Thickness Measurements for the Outer Retinal Sublayers and Choroid in the Emmetropia, Simple High Myopia, and Pathological Myopia Groups
Figure 3
 
Bland-Altman analysis for two repeated measurements of the global thickness of the outer retinal sublayers and choroid in all groups (including emmetropia, simple high myopia, and pathological myopia). (A) Outer plexiform layer; (B) Henle fiber layer and outer nuclear layer; (C) myoid and ellipsoid zone; (D) outer segment of photoreceptors; (E) interdigitation zone and retinal pigment epithelium/Bruch complex; (F) choroidal layer. Values on the horizontal and vertical axes correspond to the mean and to the difference of the two repeated measurements, respectively. Solid lines and dashed lines indicate mean differences and limits of agreement. Error bars indicate 95% confidence interval of the mean difference and limits of agreement.
Figure 3
 
Bland-Altman analysis for two repeated measurements of the global thickness of the outer retinal sublayers and choroid in all groups (including emmetropia, simple high myopia, and pathological myopia). (A) Outer plexiform layer; (B) Henle fiber layer and outer nuclear layer; (C) myoid and ellipsoid zone; (D) outer segment of photoreceptors; (E) interdigitation zone and retinal pigment epithelium/Bruch complex; (F) choroidal layer. Values on the horizontal and vertical axes correspond to the mean and to the difference of the two repeated measurements, respectively. Solid lines and dashed lines indicate mean differences and limits of agreement. Error bars indicate 95% confidence interval of the mean difference and limits of agreement.
There were significant differences among the three groups in the thicknesses of the outer retinal sublayers and the choroid along the 6-mm diameter of the macula centered on the fovea (Table 3; Supplementary Table S1; Fig. 4). The global choroidal thickness of the emmetropia group was larger than that of the simple high myopia and pathological myopia groups (P < 0.001 each). The global IZ + RPE and HFL + ONL of the emmetropia group were thicker than in the simple high myopia and pathological myopia groups (P < 0.01 each). The global OS layer of the emmetropia and pathological myopia groups was thinner compared to the simple high myopia group (P = 0.001 and 0.040, respectively). The global MEZ thickness of the emmetropia group was not significantly greater than that of the simple high myopia group (P = 0.640), but it was greater than that of the pathological myopia group (P = 0.014). The global OPL was not significantly different among the three groups (ANOVA, P = 0.140). 
Table 3
 
Global Macular Thicknesses (μm) of the Outer Retinal Sublayers and Comparisons Among the Emmetropia, Simple High Myopia, and Pathological Myopia Groups
Table 3
 
Global Macular Thicknesses (μm) of the Outer Retinal Sublayers and Comparisons Among the Emmetropia, Simple High Myopia, and Pathological Myopia Groups
Figure 4
 
Box and whisker plots of global thickness comparisons of the outer retinal sublayers and choroid among the three groups. (A) Outer plexiform layer; (B) Henle fiber layer and outer nuclear layer; (C) myoid and ellipsoid zone; (D) outer segment of photoreceptors; (E) interdigitation zone and retinal pigment epithelium/Bruch complex; (F) choroidal layer. The median is represented by the middle line within each box, and the second and third quartiles are represented by the lower and upper segments of the box, respectively. The whiskers of the plot represent the minimum (bottom whisker) and the maximum (top whisker).
Figure 4
 
Box and whisker plots of global thickness comparisons of the outer retinal sublayers and choroid among the three groups. (A) Outer plexiform layer; (B) Henle fiber layer and outer nuclear layer; (C) myoid and ellipsoid zone; (D) outer segment of photoreceptors; (E) interdigitation zone and retinal pigment epithelium/Bruch complex; (F) choroidal layer. The median is represented by the middle line within each box, and the second and third quartiles are represented by the lower and upper segments of the box, respectively. The whiskers of the plot represent the minimum (bottom whisker) and the maximum (top whisker).
In comparisons between the simple high myopia and pathological myopia groups (Table 3), all of the outer retinal sublayers except the OPL were significantly thinner in the pathological myopia group. For the OPL, the thickness was marginally greater in the pathological myopia group (P = 0.05). Comparisons of the outer retinal sublayers and choroid in the central, parafoveal, and perifoveal regions followed similar, though not necessarily identical, patterns as seen for the global comparison (Supplementary Table S1). 
Association of Outer Retinal Sublayer Thicknesses and Other Variables With Best-Corrected Visual Acuity
Simple GEE-based regression models with BCVA as the outcome were constructed (Table 4). Sublayer thicknesses were based on the global values. Older age (P = 0.004), longer AL (P < 0.001), thicker OPL (P = 0.008), thinner HFL + ONL (P = 0.001), thinner MEZ (P < 0.001), thinner IZ + RPE (P < 0.001), and thinner choroid (P < 0.001) were significantly associated with worse BCVA. Sex (P = 0.138) and OS thickness (P = 0.813) were not correlated with BCVA. MEZ thickness had the greatest correlation coefficient among all of the fundus thickness variables. 
Table 4
 
Simple Regression Models Based on Best-Corrected Visual Acuity Outcome
Table 4
 
Simple Regression Models Based on Best-Corrected Visual Acuity Outcome
Interactions Between MEZ Thickness and Other Variables
Multiple regression models explored the interactions between the MEZ and other variables with BCVA as the outcome (Table 5). The only significant interaction was between the MEZ and choroidal thickness (P = 0.006). Interactions between MEZ thickness and age, AL, or IZ + RPE thickness were not significant (P = 0.283, 0.904, and 0.446, respectively). 
Table 5
 
Multiple Regression Models for Interactions Between the MEZ and Other Variables Based on Best-Corrected Visual Acuity Outcome
Table 5
 
Multiple Regression Models for Interactions Between the MEZ and Other Variables Based on Best-Corrected Visual Acuity Outcome
Predictive Models of BCVA Using MEZ Thickness and Other Variables
Because age, AL, and thickness of the OPL, HFL + ONL, MEZ, IZ + RPE, and choroid were significantly associated with BCVA in the simple regression models (Table 4), they were included in the final predictive model (Table 6). The interaction between the MEZ and choroidal thickness was also used in the final predictive model. The MEZ thickness (P < 0.001), choroidal thickness (P < 0.001), and the interaction between the MEZ and choroidal thickness (P < 0.001) were significant predictors of the BCVA. Age, AL, OPL, HFL + ONL, and IZ + RPE thicknesses were not significant predictors of BCVA (P = 0.064 ∼ 0.963) in this final predictive model. 
Table 6
 
Final Multiple Regression Models Based on Best-Corrected Visual Acuity Outcome
Table 6
 
Final Multiple Regression Models Based on Best-Corrected Visual Acuity Outcome
The final regression model demonstrated how the relationship between MEZ thickness and BCVA varied with choroidal thickness (Fig. 5). Analysis of the receiver operating characteristic (ROC) curve was used to calculate the choroidal thickness cutoff value that determined visual impairment, defined as BCVA (logMAR) worse than 0.10. The choroidal thickness cutoff value for visual impairment was 109.77 μm with an area under the ROC curve of 0.928 (Fig. 6). The correlation coefficient r between the MEZ thickness and BCVA for the entire cohort was −0.439 (P < 0.001). For the group above the cutoff value for choroidal thickness, the correlation coefficient r was −0.409 (P = 0.001), and for the group below the cutoff value, it was −0.468 (P = 0.021). This provides further evidence that the relationship between the MEZ thickness and BCVA varied with choroidal thickness. Pearson's correlation analysis also showed that the MEZ thickness was significantly correlated with the choroid thickness (r = 0.403, P < 0.001). 
Figure 5
 
Correlation between MEZ thickness and BCVA. (A) Scatterplot showing MEZ thickness versus BCVA in all eyes. (B) Scatterplot of subjects above the visual impairment cutoff value of choroidal thickness (109.77 μm). (C) Scatterplots of subjects below the visual impairment cutoff value of choroidal thickness. The dashed lines are the 95% confidence intervals for the solid trend lines. The correlation between MEZ thickness and BCVA in all eyes was significant (r = −0.439, P < 0.001), but the correlation was different between the subjects above the visual impairment cutoff value of choroidal thickness (r = −0.409, P < 0.001) and the subjects below the visual impairment cutoff value of choroidal thickness (r = −0.468, P < 0.001).
Figure 5
 
Correlation between MEZ thickness and BCVA. (A) Scatterplot showing MEZ thickness versus BCVA in all eyes. (B) Scatterplot of subjects above the visual impairment cutoff value of choroidal thickness (109.77 μm). (C) Scatterplots of subjects below the visual impairment cutoff value of choroidal thickness. The dashed lines are the 95% confidence intervals for the solid trend lines. The correlation between MEZ thickness and BCVA in all eyes was significant (r = −0.439, P < 0.001), but the correlation was different between the subjects above the visual impairment cutoff value of choroidal thickness (r = −0.409, P < 0.001) and the subjects below the visual impairment cutoff value of choroidal thickness (r = −0.468, P < 0.001).
Figure 6
 
ROC curve analysis of the global thickness comparisons of the outer retinal sublayers and choroid for visual impairment.
Figure 6
 
ROC curve analysis of the global thickness comparisons of the outer retinal sublayers and choroid for visual impairment.
Discussion
We used OCT to evaluate thickness changes in the outer retinal sublayers and in the choroid of eyes with simple high myopia and pathological myopia. Previous papers reported alterations of the intraretinal layer and choroid thicknesses in high myopia (Table 7), and our findings were consistent with those reports. However, few of the previously published papers differentiated between simple high myopia and pathological myopia. To our knowledge, this is the first report of changes in the thickness of outer retinal sublayers, including the photoreceptor layer, in pathological myopia. The MEZ thickness was significantly correlated with BCVA. Further, the relationship between MEZ thickness and BCVA was influenced by choroidal thickness, such that patients with relatively thin choroids had poorer visual acuities for a given MEZ thickness. Therefore, preventing further degeneration of the MEZ should be an important clinical goal for pathological myopia eyes. 
Table 7
 
Summary of Previous Studies on Retinal and Choroidal Microstructure in Myopia Patients
Table 7
 
Summary of Previous Studies on Retinal and Choroidal Microstructure in Myopia Patients
Previous studies only evaluated the disruption of photoreceptors in high myopia qualitatively to determine the influence on visual acuity.68 Disruption of the foveal ellipsoid zone and defects in the inner and outer segments were found in myopic eyes with poor vision.6,7 In the current study, we quantified the thickness of photoreceptor sublayers in high myopia with and without macular pathological change. The high repeatability of the outer retinal sublayer and choroidal thickness measurements shows that the OCT images can offer sufficient precision. The quantitative methods used in this study enabled detection of small changes in the outer retinal sublayers. Thus, the measurement of changes in photoreceptor sublayer thickness might be a valuable tool to provide insight into the origin of visual loss in pathological myopia. 
Thinning of the MEZ layer in pathological myopia was measured with high repeatability; that is, the ICC ranged from 0.983 to 0.992 and the CoR% ranged from 0.91 to 1.62. Importantly, MEZ thickness was the most relevant fundus microstructural factor related to visual impairment. The difference in AL between the emmetropia and simple high myopia groups was 3.60 mm (P < 0.001, Table 1), while the difference in the global MEZ thickness for these two groups, 0.26 μm, was not significant (P = 0.640, Table 3). Similarly, the difference in AL between the simple high myopia and the pathological myopia groups, 1.64 mm, was significant (P < 0.001, Table 1). However, in contrast to difference in MEZ thickness between the emmetropic and simple high myopic eyes, the difference in MEZ thickness between the simple high myopic and pathological myopic eyes, 1.42 μm, was significant (P < 0.014, Table 3). These results suggest that the significant thinning of MEZ occurred during the stage of pathological retinopathy and is unlikely to be due simply to retinal stretching by axial elongation. However, there might be a critical AL beyond which the retina and choroid are “overstretched,” triggering the pathological myopia and resulting in the changes in the MEZ thickness. In our future study, whether there was a critical AL to trigger pathological changes will be further studied by collecting larger sample sizes to validate this hypothesis. 
The MEZ is a specialized region in the photoreceptors that contains the mitochondria, Golgi, and endoplasmic reticulum, so it is important with regard to the production of ATP, G-proteins, photopsin, and other chemicals16,17 that are important to maintain photosensitivity. In simple high myopia without pathological change, the MEZ layer was slightly thinner than in emmetropic eyes, but the difference was not significant. This might explain why serious visual impairment always occurred in pathological myopia but not in simple high myopia. Therefore, along with BCVA, MEZ thickness can be a suitable biomarker in the clinic for pathological myopia. Further longitudinal studies are required to determine if early detection of MEZ thickness alteration would be a significant predictor of visual acuity during the progression of pathological myopia. 
In this study, MEZ thicknesses, together with other important clinical variables such as age and AL and OCT anatomic parameters such as the thickness of the choroid and IZ + RPE, were investigated to determine if they were correlated in any way with visual acuity in high myopia. The association between MEZ thickness and visual acuity was independent of age, AL, and RPE thickness. The statistical interaction between MEZ and choroidal thickness was significant, indicating that choroidal perfusion affects the relationship between MEZ and visual function in high myopia. For a given MEZ thickness, worse visual acuity occurred in eyes with a thinner choroid. It is well known that choroidal thinning is significantly associated with visual impairment in high myopia and other ocular diseases.1820 Our current study confirmed that MEZ thinning was correlated with visual acuity as well. Further analysis showed that MEZ thinning was correlated with the choroidal thinning, indicating that thinning of the MEZ might be due to the lack of oxygen and nutrition from the choroid, which is indispensable for MEZ metabolism.21,22 Additional studies are required to research the cellular mechanism of the interaction between MEZ and choroidal perfusion in pathological myopia. 
Although the associations between age and AL with BCVA were independent of the MEZ, they were excluded in the final predictive model. Nevertheless, age and AL might still be important factors associated with visual impairment in pathological myopia. Higher prevalence and severity of pathological myopia occur in patients with older age and longer ALs.1,5 With aging and axial elongation, choroidal thinning occurs.2326 Therefore, we hypothesize that aging and axial elongation might lead to decreasing choroidal perfusion, thus resulting in visual impairment. These factors will be investigated in the future. 
We acknowledge four limitations in the current study. First, the eyes with pathological myopia in category 4 of the META-PM classification system were not included because this would have required the inclusion of older patients with longer ALs.19 The images from older patients with longer ALs were always of low quality and could not be analyzed correctly. Moreover, that group constituted a small sample size and included more females in each of the three myopia groups, while our study required larger sample sizes and well-matched sex composition to attain reliable statistical results. Second, the definition of emmetropia in the current study (−1.00 to +0.50 D) was different from the World Health Organization definition (−0.50 to +0.50 D) for the high prevalence of myopia in China.27 However, this subtle discrepancy in the definition of emmetropia is unlikely to have influenced our conclusions because we were more concerned with the clinical and structural variables of the pathological myopia group. Third, while we were focused on OCT-documented changes in the photoreceptors, in the future, the use of advanced adaptive optics imaging might also be helpful in showing photoreceptor alterations, that is, the loss of cone/rod cells, and deepen our understanding of photoreceptor status in pathological myopia. Fourth, this was a cross-sectional study. Longitudinal studies would provide more reliable data regarding changes in the fundus as eyes transition from simple high myopia to pathological myopia, and they would help to discern the effect of changes in the MEZ on visual function. These too will be the subject of further studies. 
In summary, we demonstrated that changes in the thickness of the outer retinal sublayers and the choroid were correlated with visual impairment in pathological myopia. Thinning of the MEZ was significantly associated with worsening BCVA, and this correlation varied with choroidal thickness. MEZ thickness is an important retinal anatomic factor with high functional impact, and clinicians should closely examine and monitor alterations of the MEZ in pathological myopia. The interrelationship between the changes in MEZ, choroid, and visual functions over the natural course of pathological myopia warrants further study. 
Acknowledgments
Supported by research grants from the National Key Research and Development Program of China (Grant 2016YFC0102500, Grant 2016YFE0107000), the National Nature Science Foundation of China (Grant 81570880), Natural Science Foundation of Zhejiang Province (Grant LQ16H120007), and the Zhejiang Provincial Key Research and Development Program (Grant 2015C03029). 
Disclosure: J. Ye, None; M. Shen, None; S. Huang, None; Y. Fan, None; A. Yao, None; C. Pan, None; X. Shi, None; F. Lu, None; Y. Shao, None 
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Figure 1
 
Macular regions analyzed by optical coherence tomography in the 18-radial line scanning mode. (A) The macula was divided into three subfields: the central foveal region with the diameter of 1 mm, the parafoveal region ranging from 1 to 3 mm from the central foveal region, and the perifoveal region ranging from 3 to 6 mm from the central foveal region. (B) The boundaries of fundus structure were segmented by an automated algorithm, and the thickness profiles of the macular outer retinal sublayers and choroid were determined. Bars: 300 μm.
Figure 1
 
Macular regions analyzed by optical coherence tomography in the 18-radial line scanning mode. (A) The macula was divided into three subfields: the central foveal region with the diameter of 1 mm, the parafoveal region ranging from 1 to 3 mm from the central foveal region, and the perifoveal region ranging from 3 to 6 mm from the central foveal region. (B) The boundaries of fundus structure were segmented by an automated algorithm, and the thickness profiles of the macular outer retinal sublayers and choroid were determined. Bars: 300 μm.
Figure 2
 
Representative fundus photographs and OCT images of emmetropia, simple high myopia, and pathological myopia eyes. Fundus photographs (AC) and OCT B-scan images (DF) with the detailed automated segmentation of emmetropia, simple high myopia, and pathological myopia eyes, respectively. For the emmetropic eye (A, D), the AL was 24.21 mm, the global macular MEZ thickness was 26.34 μm, and the global macular choroid thickness was 347.91 μm. For the simple high myopia eye (B, E), the AL was 27.24 mm, the global macular MEZ thickness was 25.75 μm, and the global macular choroid thickness was 100.94 μm. For the pathological myopia eye (C, F), the AL was 29.37 mm, the global macular MEZ thickness was 20.24 μm, and the global macular choroid thickness was 68.67 μm. Bars: 300 μm.
Figure 2
 
Representative fundus photographs and OCT images of emmetropia, simple high myopia, and pathological myopia eyes. Fundus photographs (AC) and OCT B-scan images (DF) with the detailed automated segmentation of emmetropia, simple high myopia, and pathological myopia eyes, respectively. For the emmetropic eye (A, D), the AL was 24.21 mm, the global macular MEZ thickness was 26.34 μm, and the global macular choroid thickness was 347.91 μm. For the simple high myopia eye (B, E), the AL was 27.24 mm, the global macular MEZ thickness was 25.75 μm, and the global macular choroid thickness was 100.94 μm. For the pathological myopia eye (C, F), the AL was 29.37 mm, the global macular MEZ thickness was 20.24 μm, and the global macular choroid thickness was 68.67 μm. Bars: 300 μm.
Figure 3
 
Bland-Altman analysis for two repeated measurements of the global thickness of the outer retinal sublayers and choroid in all groups (including emmetropia, simple high myopia, and pathological myopia). (A) Outer plexiform layer; (B) Henle fiber layer and outer nuclear layer; (C) myoid and ellipsoid zone; (D) outer segment of photoreceptors; (E) interdigitation zone and retinal pigment epithelium/Bruch complex; (F) choroidal layer. Values on the horizontal and vertical axes correspond to the mean and to the difference of the two repeated measurements, respectively. Solid lines and dashed lines indicate mean differences and limits of agreement. Error bars indicate 95% confidence interval of the mean difference and limits of agreement.
Figure 3
 
Bland-Altman analysis for two repeated measurements of the global thickness of the outer retinal sublayers and choroid in all groups (including emmetropia, simple high myopia, and pathological myopia). (A) Outer plexiform layer; (B) Henle fiber layer and outer nuclear layer; (C) myoid and ellipsoid zone; (D) outer segment of photoreceptors; (E) interdigitation zone and retinal pigment epithelium/Bruch complex; (F) choroidal layer. Values on the horizontal and vertical axes correspond to the mean and to the difference of the two repeated measurements, respectively. Solid lines and dashed lines indicate mean differences and limits of agreement. Error bars indicate 95% confidence interval of the mean difference and limits of agreement.
Figure 4
 
Box and whisker plots of global thickness comparisons of the outer retinal sublayers and choroid among the three groups. (A) Outer plexiform layer; (B) Henle fiber layer and outer nuclear layer; (C) myoid and ellipsoid zone; (D) outer segment of photoreceptors; (E) interdigitation zone and retinal pigment epithelium/Bruch complex; (F) choroidal layer. The median is represented by the middle line within each box, and the second and third quartiles are represented by the lower and upper segments of the box, respectively. The whiskers of the plot represent the minimum (bottom whisker) and the maximum (top whisker).
Figure 4
 
Box and whisker plots of global thickness comparisons of the outer retinal sublayers and choroid among the three groups. (A) Outer plexiform layer; (B) Henle fiber layer and outer nuclear layer; (C) myoid and ellipsoid zone; (D) outer segment of photoreceptors; (E) interdigitation zone and retinal pigment epithelium/Bruch complex; (F) choroidal layer. The median is represented by the middle line within each box, and the second and third quartiles are represented by the lower and upper segments of the box, respectively. The whiskers of the plot represent the minimum (bottom whisker) and the maximum (top whisker).
Figure 5
 
Correlation between MEZ thickness and BCVA. (A) Scatterplot showing MEZ thickness versus BCVA in all eyes. (B) Scatterplot of subjects above the visual impairment cutoff value of choroidal thickness (109.77 μm). (C) Scatterplots of subjects below the visual impairment cutoff value of choroidal thickness. The dashed lines are the 95% confidence intervals for the solid trend lines. The correlation between MEZ thickness and BCVA in all eyes was significant (r = −0.439, P < 0.001), but the correlation was different between the subjects above the visual impairment cutoff value of choroidal thickness (r = −0.409, P < 0.001) and the subjects below the visual impairment cutoff value of choroidal thickness (r = −0.468, P < 0.001).
Figure 5
 
Correlation between MEZ thickness and BCVA. (A) Scatterplot showing MEZ thickness versus BCVA in all eyes. (B) Scatterplot of subjects above the visual impairment cutoff value of choroidal thickness (109.77 μm). (C) Scatterplots of subjects below the visual impairment cutoff value of choroidal thickness. The dashed lines are the 95% confidence intervals for the solid trend lines. The correlation between MEZ thickness and BCVA in all eyes was significant (r = −0.439, P < 0.001), but the correlation was different between the subjects above the visual impairment cutoff value of choroidal thickness (r = −0.409, P < 0.001) and the subjects below the visual impairment cutoff value of choroidal thickness (r = −0.468, P < 0.001).
Figure 6
 
ROC curve analysis of the global thickness comparisons of the outer retinal sublayers and choroid for visual impairment.
Figure 6
 
ROC curve analysis of the global thickness comparisons of the outer retinal sublayers and choroid for visual impairment.
Table 1
 
Basic Characteristics of the Emmetropia, Simple High Myopia, and Pathological Myopia Groups
Table 1
 
Basic Characteristics of the Emmetropia, Simple High Myopia, and Pathological Myopia Groups
Table 2
 
Repeatability of Global Thickness Measurements for the Outer Retinal Sublayers and Choroid in the Emmetropia, Simple High Myopia, and Pathological Myopia Groups
Table 2
 
Repeatability of Global Thickness Measurements for the Outer Retinal Sublayers and Choroid in the Emmetropia, Simple High Myopia, and Pathological Myopia Groups
Table 3
 
Global Macular Thicknesses (μm) of the Outer Retinal Sublayers and Comparisons Among the Emmetropia, Simple High Myopia, and Pathological Myopia Groups
Table 3
 
Global Macular Thicknesses (μm) of the Outer Retinal Sublayers and Comparisons Among the Emmetropia, Simple High Myopia, and Pathological Myopia Groups
Table 4
 
Simple Regression Models Based on Best-Corrected Visual Acuity Outcome
Table 4
 
Simple Regression Models Based on Best-Corrected Visual Acuity Outcome
Table 5
 
Multiple Regression Models for Interactions Between the MEZ and Other Variables Based on Best-Corrected Visual Acuity Outcome
Table 5
 
Multiple Regression Models for Interactions Between the MEZ and Other Variables Based on Best-Corrected Visual Acuity Outcome
Table 6
 
Final Multiple Regression Models Based on Best-Corrected Visual Acuity Outcome
Table 6
 
Final Multiple Regression Models Based on Best-Corrected Visual Acuity Outcome
Table 7
 
Summary of Previous Studies on Retinal and Choroidal Microstructure in Myopia Patients
Table 7
 
Summary of Previous Studies on Retinal and Choroidal Microstructure in Myopia Patients
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