Choroidal thickness and axial length changes in myopic children treated with orthokeratology

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Choroidal thickness and axial length changes in myopic children treated with orthokeratology ⁎

Zhouyue Li1, Dongmei Cui1, Yin Hu, Sichun Ao, Junwen Zeng, Xiao Yang State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China

A R T I C L E I N F O

A B S T R A C T

Keywords: Orthokeratology Choroidal thickness Optical coherence tomography

Purpose: To analyze the change in subfoveal choroidal thickness (SFChT) and its relationship with changes in axial length (AL) in myopic children treated with Orthokeratology (Ortho-k). Methods: Fifty myopic children participated in this study: 29 subjects were treated with Ortho-k lenses and 21 with single vision distance spectacles. The SFChT and ocular biometrics, including AL, were measured at baseline, one month, and six months after lens wear in both groups. Results: AL significantly increased in both groups over time. In the Ortho-k group, SFChT also increased; however, there was no significant change in SFChT in the control group over time. At the six-month visit, the magnitude of eye growth was significantly reduced in the Ortho-k group compared to the control group (0.06 ± 0.10 mm vs. 0.17 ± 0.10 mm, P < 0.001). SFChT was significantly thicker in the Ortho-k group compared to the control group at the one-month and six-month visits (15.78 ± 11.37 μm vs. −2.98 ± 8.96 μm, P < 0.001 (one-month visit); 21.03 ± 12.74 μm vs. −2.50 ± 14.43 μm, P < 0.001 (sixmonth visit)), although there was no significant difference between the two follow-up visits (P = 0.102 for the Ortho-k group; P = 0.898 for the control group). Changes in the large choroidal vascular layer (LCVL) accounted for the majority of subfoveal choroidal thickening (approximately 77% and 80% at one-month and six-month visits, respectively). Conclusion: Ortho-k treatment induced significant choroidal thickening and a slowing of eye growth. LCVL thickening accounted for the majority of SFChT thickening. However, its potential mechanism in myopia control requires further investigation.

1. Introduction Experimental studies of both animals [1–6] and humans [7–11] shows that changes in choroidal thickness (ChT) are associated with eye growth. Imposed defocus can induce changes in ChT accompanied by the development of myopic or hyperopic refractive errors in animals, including chicks [1,2], macaque monkeys [3], and marmosets [4]. Negative spectacle lenses (hyperopic defocus) cause choroidal thinning, followed by an increase in eye growth [1–4]. Positive spectacle lenses (myopic defocus) cause choroidal thickening followed by a slowing of eye growth to minimize retinal defocus [1–4]. Despite being much smaller in magnitude, changes in ChT in response to defocus also occur in adult humans in the short term [12,13]. Moreover, pharmacologic treatments, such as dopaminergic agonists [5] and anti-muscarinic agents [6], have also been shown to induce transient choroidal thickening, followed by the inhibition of scleral growth in chicks. The choroid is thought to play a role in regulating scleral growth by ⁎

1

delivering a signal to the sclera in response to visual stimuli [14]. For example, studies of both chicks [15,16] and mammals [17] have shown that changes in proteoglycan synthesis, collagen synthesis, and extracellular matrix constituents occur in response to visual stimuli, which could lead to the remodeling of the sclera. Studies have consistently reported that Ortho-k treatment significantly inhibits myopia progression in children by slowing ocular growth [18–22]. It has been hypothesized that this effect may result from the induction of peripheral myopic defocus, due to the effects of the Ortho-k lens on the mid-peripheral cornea [23]. Several studies [24–26] have investigated the relationship between the change in ChT and the change in axial length (AL) in children treated with Ortho-k treatment with conflicting results. Both Chen et al. (using NIDEK spectral domain optical coherence tomography [SD-OCT]) [24] and Loertscher et al. [25] (using low-coherence reflectometry [Haag Streit Lenstar LS900]) found significant increases in ChT after short-term Ortho-k treatment. Chen et al. [24] examined primarily Asian children

Corresponding author at: Zhongshan Ophthalmic Center, 54 S. Xianlie Road, Guangzhou 510060, China. E-mail address: [email protected] (X. Yang). Zhouyue Li and Dongmei Cui contributed equally to this work and should be considered co-first authors.

http://dx.doi.org/10.1016/j.clae.2017.09.010 Received 22 March 2017; Received in revised form 1 September 2017; Accepted 11 September 2017 1367-0484/ © 2017 Published by Elsevier Ltd on behalf of British Contact Lens Association.

Please cite this article as: Li, Z., Contact Lens and Anterior Eye (2017), http://dx.doi.org/10.1016/j.clae.2017.09.010

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acuity with spectacle correction was worse than 20/25), ocular biometrics, SFChT, and LCVL thickness were measured at each visit.

over a short period (3 weeks) but did not perform a detailed analysis of the choroidal vascular layers, which might have enhanced the understanding of the potential mechanism of the effect of Ortho-k on ChT. Conversely, Gardner et al. [26] found no significant changes in subfoveal or parafoveal ChT in nine myopic children after short-term (1 month) and long-term (9 months) Ortho-k treatment using the Zeiss Cirrus HD-OCT. However, in this particular study [26], several methodological limitations may have limited the power to reliably detect a significant change in ChT including: the small sample size, the lack of a control group, non-registration of serial OCT images, a lack of control of the timing of follow up visits with respect to ChT diurnal changes, and possible effects of cycloplegia and ocular magnification upon OCT measurements. Due to these inconsistent results regarding the potential effect of Ortho-k treatment on ChT [24–26], we conducted this prospective controlled study to determine the effect of Ortho-k treatment on ChT and AL in myopic children with a relatively long-term follow-up period. Unlike previous studies, an analysis of different choroidal vascular layers was also performed to investigate their relative contribution to changes in subfoveal ChT (SFChT), in order to enhance the understanding of the effect of Ortho-k treatment on SFChT. Changes in ocular biometrics, such as AL, central corneal thickness (CCT), anterior chamber depth (ACD), and lens thickness (LT), were measured to enhance our understanding of the relationship between the changes in SFChT and ocular biometrics.

2.2. Lens fitting For the Ortho-k group, eligible participants were fitted with a fourzone reverse-geometry lenses (Euclid Systems Ortho-k; Euclid System Corp., Herndon, USA), made from BOSTON EQUALENS II (oprifocona) with a nominal Dk of 127 × 10–11 (cm2/s) (ml O2/ml_mmHg) (ISO/ Fatt) according to the manufacturer’s fitting guidelines. For the control group, cycloplegic manifest refractions were conducted and the single vision distance spectacle prescriptions were updated for all participants in our hospital before enrollment. 2.3. Measurements To avoid the potentially confounding influence of diurnal ocular variations on the results [27], in particular axial length and ChT, all procedures were performed at approximately the same time of day, between 3 pm and 6 pm at each visit. In addition, to standardize the influence of the administration of the cycloplegic agent [28] on ChT and other ocular parameters, all measurements were performed approximately 30 min after the administration of the mydriatics (0.5% tropicamide plus 0.5% phenylephrine hydrochloride; three times at five minutes apart). All measurements were taken twice in the right eye only and the order of the measurements was maintained for all children (visual acuity, cycloplegic manifest refraction, ocular biometrics, followed by OCT imaging).

2. Material and methods 2.1. Study design

2.3.1. Ocular biometrics measurements Ocular biometrics, including AL, CCT, ACD, and LT, were measured using a non-contact biometer (Lenstar LS 900; Haag Streit AG, Koeniz, Switzerland). As suggested by Cho et al. [29], anterior segment length (ASL = CCT + ACD + LT) was calculated to investigate the effect of Ortho-k treatment on the anterior segment. Furthermore, AL, as defined by the instrument, refers to the distance between the anterior cornea and the retinal pigment epithelium (RPE). In addition to AL, we also calculated internal axial length (IAL: anterior cornea to anterior sclera) by adding the SFChT determined by OCT imaging to the AL measured with the Lenstar, which more precisely reflects the true nature of the change in ocular growth [25]. Five consecutive measurements were collected from each subject at each measurement session, and the values were later averaged.

This prospective, nonrandomized study was conducted at Zhongshan Ophthalmic Center, Sun Yat-Sen University (Guangzhou, China). The study was conducted in accordance with the tenets of the Declaration of Helsinki and was approved by the ethical committee of Zhongshan Ophthalmic Center, Sun Yat-sen University. All the subjects included in the Ortho-k treatment group were recruited from a clinical trial (Register No.: ChiCTR-IPR-14005505, starting from November, 2014 to March, 2017). Prior to the study, the nature of the study and the potential risks were explained to the participants and their parents or guardian, and consent was obtained before the start of the study. Twenty-nine healthy children (13 males and 16 females; age: 12.31 ± 1.71 years) were enrolled for Ortho-k treatment, and another 21 subjects (9 males and 12 females; age: 11.52 ± 1.69 years) with single vision distance spectacles were enrolled as a control group. The inclusion criteria for both groups were an age between 8 and 15 years; corrected visual acuity of 20/20 or better, mean spherical equivalent refractive error (SER) between −1.00 and −4.00 D, and with-the-rule astigmatism no greater than −1.50D; and no use of any other myopia control modalities including rigid contact lenses, multifocal soft contact lenses, atropine, etc., except for single vision distance spectacles. For the Ortho-k group, after lens dispensing, the participants were advised to wear their Ortho-k lenses every night for at least seven consecutive hours. They were then instructed to return for a follow-up visit after one day, one week, one month, three month and six months. At each visit the participants underwent a slit-lamp examination to check for contact lens related complications and any adverse events. The fitting of the Ortho-k lens, unaided visual acuity, cycloplegic manifest refraction (if unaided visual acuity was worse than 20/25), slit lamp biomicroscopy, and corneal topography (Medmont E-300, Australia) were evaluated at each visit. Ocular biometrics, SFChT, and large choroidal vessel layer (LCVL) thickness were measured at the baseline, one-month and six-month visits. For the control group, participants were instructed to wear their spectacles throughout the day and return for follow-up visits at one month and six months after the first measurement session. Visual acuity with spectacle correction, cycloplegic manifest refraction (if visual

2.3.2. SD-OCT scanning and analysis SD-OCT scanning was performed by one experienced investigator using the Heidelberg Spectralis instrument (Spectralis HRA + OCT, Heidelberg Engineering, Heidelberg, Germany) on all subjects at baseline one-month and six-month visits. The instrument uses a super luminescent diode with a central wavelength of 870 nm, and has an axial resolution of 3.9 μm, and a transverse resolution of 14 μm in retinal tissue. The enhanced depth imaging (EDI) mode was used to enhance the visibility of the choroid using 100 averaged scans to improve the signal to noise ratio. All B-scans included for analysis had a quality index of no less than 25 dB (mean 28.9 ± 2.8 dB). The confocal scanning laser ophthalmoscope (SLO) was adjusted manually to obtain a clear image of the fundus prior to imaging. According to the manufacturer’s recommendation, to account for ocular magnification, each participant’s keratometry values were entered into the instrument prior to each measurement to correct each OCT scan. Repeat scans were captured with the aid of automatic registration, and the follow-up mode Spectralis was utilized to ensure the same retinal location was imaged at each visit. The linear scan pattern (vertical and horizontal line) was used for every subject at each visit. SFChT and LCVL thickness were measured by two independent observers experienced in analyzing OCT images using the Heidelberg 2

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Fig. 1. An illustration of the method used to analyze the choroidal vasculature on a spectral domain optical coherence tomography (SD-OCT) image of a myopic eye. Blue asterisks represent the large choroidal vessels seen in the closest proximity to the ChT subfoveal measurement lines, and closest to the choroidal- scleral border, which were selected for the large choroidal vessel layer measurements. Large choroidal vessel layer thickness was measured from the inner border of the choroid-scleral junction to the innermost point of the selected large choroidal vessel. The choriocapillaris layer and the Sattler’s layer (medium choroidal vessel layer) thickness was defined as the distance of the large choroidal vessel layer to Bruch’s membrane/RPE complex which was equivalent to the difference between the large choroidal vessel layer and from the total choroidal thickness. (Color should be used).

linear measurement tool at the foveal location of the horizontal line scan. All images were rescaled into a 1-to-1 scale (micron). The thinnest part of the macula in the image was defined as the location of the fovea. The thickness of the choroid was defined as the distance from the outer surface of the RPE to the inner surface of the chorioscleral interface (CSI). The thickness of the LCVL was measured perpendicularly from the CSI to the inner most point of the large choroidal vessel [30] located within the closest proximity to the fovea (as shown in Fig. 1). The measurements of the LCVL were subtracted from the total ChT to obtain the thickness of the choriocapillaris layer and the Sattler’s layer (medium choroidal vessel layer) (ChT-LCVL).

Table 1 Demographic and biometric and subfoveal choroidal thickness measures (mean ± SD) at baseline for the two study groups. Participant characteristics

2.4. Data analysis

SF

All statistical analyses were performed using SPSS Version 16.0 (SPSS 16.0, Inc., Chicago, IL). All values are presented as mean ± standard deviation except when stated otherwise. Data were first tested for normality using Sample K-S test. Baseline measurements of age; sphere, cylinder, spherical equivalent refractive error, and ocular parameters; and total SFChT, LCVL thickness, and ChT-LCVL thickness were compared between the two study groups using an independent samplest test. All measurements were taken twice, and the average was used for the purpose of analysis. The interclass correlation coefficient (ICC) and Bland-Altman analysis, the index of measurement reliability, were calculated for the measures of SFChT and LVCL. The changes in SFChT, LCVL thickness, ChT-LCVL thickness, and other parameters were examined using a repeated measures ANOVA (baseline, one month and six month visits), with post-hoc testing on indication and correction for multiple comparisons (All values are presented as mean ± standard error). The correlation between the change in SFChT and the change in AL at the one month and six month visits was assessed using Pearson correlation analysis for both groups. P < 0.05 was considered statistically significant.

Gender Age (years) Sphere (D) Cylinder (D) SER (D) CCT (mm) ACD (mm) LT (mm) AL(mm) ChT(μm) LCVL(μm) ChT-LCVL (μm)

Ortho-k (N = 29)

Control (N = 21)

P-values

16F/13M 12.31 ± 1.71 −2.86 ± 0.74 −0.59 ± 0.52 −3.16 ± 0.85 0.57 ± 0.04 3.25 ± 0.22 3.34 ± 0.13 25.18 ± 0.77 227.93 ± 55.57 165.28 ± 42.80 62.66 ± 28.40

12F/9M 11.52 ± 1.69 −2.80 ± 1.34 −0.37 ± 0.46 −2.98 ± 1.34 0.55 ± 0.03 3.26 ± 0.21 3.38 ± 0.14 24.82 ± 0.71 247.69 ± 51.03 179.00 ± 49.27 68.69 ± 32.69

0.890 0.114 0.829 0.120 0.569 0.146 0.977 0.251 0.103 0.205 0.299 0.490

SER: spherical equivalent refractive error; CCT: central corneal thickness; LT: lens thickness; ACD: anterior chamber depth. AL: axial length; SF: sub-fovea; ChT: subfoveal choroidal thickness; LCVL: large choroidal vessel layer thickness; ChT-LCVL: the choriocapillaris layer and the Sattler’s layer (medium choroidal vessel layer) thickness. P < 0.05 at two tails was considered to be statistically significant.

reliability at each visit (Table 2). Bland-Altman analysis of between observer agreement was also conducted for the measures of SFChT and subfoveal LCVL at baseline (As shown in Fig. 2). In the Ortho-k group, the mean apical corneal power (ACP) changed from 43.00 ± 1.26 D to 40.40 ± 1.55 D at 1 month and 40.43 ± 1.57 D at 6 months after Ortho-k treatment (mean change, −2.60 ± 0.70 D vs. −2.57 ± 0.70 D, P = 0.867). All subjects achieved unaided visual acuity of 20/25 or better throughout the follow-up. Therefore, no manifest refraction was performed for any subjects during follow-up visits. In the control group, all subjects wore their spectacles throughout the day and did not wear contact lenses during the study period. No statistically significant difference was observed between unaided visual acuity in the Ortho-k group and visual acuity with spectacle correction in the control group at any follow-up visit (decimal acuity, 0.97 vs. 1.00, P = 0.079; 0.97 vs. 1.00, P = 0.079; 0.94 vs. 0.97, P = 0.272 for baseline, one month and six month visits, respectively).

3. Results All participants completed the follow-up visits. At baseline, no significant differences were found in terms of gender, age, SER, and ocular parameters (All P > 0.05) (Table 1) between the Ortho-k and control groups. Total SFChT and LCVL were measured by two independent observers, and the average of these two measurements was used in the analysis. Total SFChT, LCVL thickness, and ChT-LCVL thickness at the fovea were comparable between the two study groups (All P > 0.05) (Table 1). In agreement with the suggestion of Portney and Watkins [31], an ICC analysis suggested “excellent” reliability for all variables at each visit (all ICC > 0.90). The mean intra-session difference and the 95% limits of agreement (LOA) between two repeated SFChT and subfoveal LCVL thickness measurements (derived from the average of the two independent observers) demonstrated good intra-session

3.1. Changes in the SFChT, LCVL thickness, and ChT-LCVL thickness at one-month and six-month visits Changes in the SFChT, LCVL thickness, and ChT-LCVL thickness from the baseline to the one-month and six-month visits in two study groups are shown in Fig. 3. A significant increase in the SFChT and LCVL thickness was observed at both the one- and six-month visits in the Ortho-k group (all P < 0.001). The control group showed no significant increase in both SFChT or LCVL thickness compared to baseline at both the one- and six-month visits (all P > 0.05). The magnitude of 3

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Table 2 Mean bias and 95% limits of agreement (LOA) between two repeated subfoveal choroidal thickness (SFChT) and large choroidal vessel layer (LCVL) thickness measurements by two independent observers at each visit. Ortho-k

Control

P-value

D ± SD

95% LOA

D ± SD

95% LOA

Baseline SFChT(μm) LCVL(μm)

0.83 ± 4.00 0.83 ± 4.17

[−7.01, 8.67] [−7.34, 8.99]

−0.52 ± 4.03 0.67 ± 4.61

[−8.43, 7.38] [−8.36, 9.70]

0.246 0.898

1-month visit SFChT(μm) LCVL(μm)

0.31 ± 3.29 0.14 ± 4.43

[−6.13, 6.75] [−8.54, 8.82]

−0.57 ± 4.56 −0.76 ± 4.24

[−9.50, 8.36] [−9.08, 7.55]

0.430 0.474

6-month visit SFChT(μm) LCVL(μm)

−0.28 ± 3.41 −0.52 ± 3.43

[−6.96, 6.41] [−7.24, 6.20]

−0.95 ± 4.10 −0.52 ± 4.40

[−9.00, 7.09] [−9.15, 8.10]

0.528 0.995

D ± SD: Within-observer difference; P-value was used to demonstrate the Intra-session difference between two groups. P < 0.05 at two tails was considered to be statistically significant.

Fig. 2. Bland-Altman plots illustrating the repeatability of the subfoveal choroidal thickness (SFChT) and subfoveal large choroidal vessel layer (LCVL) thickness measures by two independent observers collected at baseline. (A) Bland-Altman plots for SFChT; (B) Bland-Altman plots for subfoveal LCVL thickness.

change in ChT-LCVL thickness was significantly different between the two groups at the one-month visit, in the control group, no significant changes in ChT, LCVL thickness, and ChT-LCVL thickness were observed at the one- and six-month visits (all P > 0.05). In addition, the magnitude of the ChT-LCVL thickness changes in both groups were less

change was statistically significant between the two study groups at the one- and six-month visits (all P < 0.001). In the Ortho-k group, ChTLCVL thickness showed a small but significant increase at the onemonth visit (Mean ± SD, 3.51 ± 8.42 μm; P = 0.031) and six-month visits (Mean ± SD, 4.42 ± 9.31 μm; P = 0.017). Although the

Fig. 3. Changes in the subfoveal choroidal thickness (SFChT), large choroidal vessel layer (LCVL) thickness and the choriocapillaris layer and the Sattler’s layer (ChT-LCVL) thickness at 1 month-visit and 6 month-visit. (A) changes in SFChT at the temporal-nasal meridian; (B) changes in subfoveal LCVL thickness at the temporal-nasal meridian; (C) changes in subfoveal ChT-LCVL thickness at the temporal-nasal meridian. Error bars represent the standard error of the mean. *Means significant difference between Ortho-k group and control group. P < 0.05 at two tails was considered to be statistically significant. (Color should be used).

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Table 3 Changes in ocular parameters at the 1-month and 6-month visits. Parameters

CCT (mm) ACD (mm) LT (mm) ASL (mm) AL(mm) IAL(mm)

1 month

6 months

Ortho-k

Control

P-value#

Ortho-k

Control

P-value#

−0.01 ± 0.01 −0.02 ± 0.04 0.01 ± 0.02 −0.03 ± 0.04 0.02 ± 0.04 0.03 ± 0.04

0.00 ± 0.004 −0.01 ± 0.03 −0.00 ± 0.01 −0.01 ± 0.04 0.03 ± 0.02 0.02 ± 0.02

0.000 0.191 0.022 0.195 0.331 0.218

−0.01 ± 0.01 −0.02 ± 0.04 0.03 ± 0.02 0.00 ± 0.03 0.06 ± 0.10 0.08 ± 0.09

0.01 ± 0.03 0.00 ± 0.04 −0.00 ± 0.02 0.01 ± 0.05 0.17 ± 0.10 0.17 ± 0.10

0.001 0.034 0.000 0.598 0.000 0.001

CCT: central corneal thickness; ACD: anterior chamber depth; LT: lens thickness; ASL: anterior segment length; AL: axial length; IAL: internal axial length (i.e. the distance from the anterior cornea to the anterior sclera). Statistically significant changes (p < 0.05) are highlighted in bold. P < 0.05 at two tails was considered to be statistically significant.

than the axial resolution of the Heidelberg OCT (3.9 μm) used in this study.

in myopic children treated with Ortho-k compared to controls, but the underlying mechanism of this choroidal thickening remains unclear. In our study, the SFChT at the one-month visit was significantly thicker (15.78 μm thicker) than that at baseline. The magnitude of choroidal thickening did not change significantly between the one-month and sixmonth visit, which suggests the change in ChT stabilizes between 1 and 6 months after commencing treatment. Chen et al. [24] only examined the change in ChT over a short period (3 weeks), and found a significant increase of 21.8 μm after 3 weeks of Ortho-k treatment. We believe this thickness change can be ascribed to the vascular nature of the choroid. To investigate the nature of the changes in SFChT, we also analyzed the choroidal vasculature using a method described in a previous study [30]. In our study, LCVL thickness showed a similar but slightly smaller change than that of SFChT at both the one-month and six-month visits. LCVL thickening accounted for the majority of SFChT thickening (approximately 77% and 80% at the one-month and six-month visits, respectively) in the Ortho-k group. In this study, the choriocapillaris and medium choroidal vessel layer (Sattler’s layer) were analyzed as a complex (ChT-LCVL), because the axial resolution of the OCT used limits the ability to distinguish between these layers. Our study found that the ChT-LCVL thickness showed a trend toward being thicker at the subfoveal location at the six-month follow-up, even though the magnitude of this change was less than the axial resolution of the OCT used in this study. While the underlying physiological mechanism remains unclear, we speculate that Ortho-k could induce relaxation of the large choroidal vessel, which then increases blood supply to induce choroidal thickening. During this process, the blood supply to the choriocapillaris and medium choroidal vessel layer also increase, consistent with the observed trend towards thickening. According to previous animal studies [34,35], when the synthesis of nitric oxide (NO) was blocked, defocus-induced choroidal thickening and the inhibition of axial growth were also blocked, which supports the hypothesis that an increases in ChT is linked to the inhibition of axial growth. Moreover, NO may influence choroidal thickening, possibly by influencing the changes in blood flow or relaxation of the non-vascular smooth muscle [36], which may also play a role in choroidal blood flow auto-regulation [37]. However, the underlying mechanism of the changes in LCVL thickness and NO and their relationship with axial growth inhibition in children with Ortho-k treatment are still unclear, and further research is needed. Although AL is a widely used objective parameter to evaluate myopia progression, many instruments, including the Lenstar, define AL as the distance between the anterior surface of the cornea and the retinal pigment epithelium, not the outer boundary of the sclera. Therefore, this creates several concerns in terms of interpreting the results, especially those regarding Ortho-k treatment. First, due to the reverse-geometry design of the Ortho-k lens, CCT becomes thinner and central corneal curvature becomes flatter, as found in the current study and previous studies [38,39]. Thus, one might tend to expect that Ortho-k treatment would decrease ACD and subsequently cause AL to be underestimated. However, this was not the case in the current study, since ACD remained unchanged in the Ortho-k group at the one-month

3.2. Changes in ocular parameters at one-month and six-month visits Changes in ocular parameters at the one-month and six-month visits are summarized in Table 3. As expected, Ortho-k wear resulted in a thinner CCT and a thicker LT over time (all P < 0.01). ACD was unchanged at the one-month visit (P = 0.191) but became shallower at the six-month visit (P = 0.034), while ASL showed no significant change (P = 0.195 and 0.598 for the one-month and six-month visits, respectively). AL showed a significant increase over time in both groups (mean, 0.02 ± 0.04 mm and 0.06 ± 0.10 mm for the one-month and six-month visits in the Ortho-k group, respectively; mean, 0.03 ± 0.04 mm and 0.17 ± 0.10 mm for the one-month and sixmonth visits in the control group, respectively; all P < 0.05). The magnitude of change in AL showed no significant difference between the two study groups at the one-month-visit (P = 0.331), but was significantly reduced in the Ortho-k group compared to the control group at the six-month visit (P < 0.001). Similar results were found for IAL (P = 0.218 for the one-month visit and P < 0.01 for the six-month visit), wherein the change in SFChT was also considered. In the Ortho-k group, the change in AL was significantly correlated to the change in SFChT over time (one-month visit: r = −0.637, P < 0.001; six-month visit: r = −0.673, P < 0.001), while no significant correlation between the change in AL and the change in SFChT was found in the control group (one-month visit: r = −0.058, P = 0.803; six-month visit: r = 0.053, P = 0.819). 4. Discussion Several studies [24–26] have investigated the relationship between the changes in ChT and AL in children treated with Ortho-k, but report different results. In our study, a thickening of the SFChT and less AL elongation were found in myopic children after six months of overnight Ortho-k treatment compared with spectacle wear. In the Ortho-k group, the change in AL was significantly correlated to the change in SFChT over time, while this relationship was not observed in the control group. In addition, the LCVL also thickened and accounted for the majority of subfoveal choroidal thickening (approximately 77% and 80% at the one-month and six-month visits, respectively). To the best of our knowledge, this is one of a small number studies to investigate the effect of a relatively long period of overnight Ortho-k on SFChT and AL in myopic children using SD-OCT. This is also the first study to provide a prospective analysis of the choroidal vascular layers and their relationship with changes in SFChT in myopic children undergoing overnight Ortho-k treatment. Previous studies have revealed a rapid bidirectional change in ChT in response to different types of defocus induced by spectacle lenses in humans [32,33] and various animal models [1–6]. In a similar manner, previous studies [24,25] have found a greater thickening of the choroid 5

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References

visit compared with the control group, consistent with previous studies [29,40,41]. Inspired by Cho et al. [29,42], ASL (a summation of CCT, ACD, and LT) was also assessed in order to indicate the combined effect of Ortho-k on the anterior segment of the eyeball. Consistent with their study, we did not find that wearing Ortho-k lenses had a significant effect on ASL. The next concern is the potential effect of ChT changes on the value of AL. As found in the current study, Ortho-k treatment resulted in an increase in SFChT. Thus, despite Ortho-k treatment having no significant effect on ASL, the AL measured using the Lenstar is actually underestimated compared to the IAL values (i.e. the distance from the anterior cornea to the anterior sclera), which includes the SFChT. In the Ortho-k group, choroidal thickening accounted for approximately 53% of the change in IAL at the one-month visit and 26% of the change at the six-month visit. However, the current study showed that when altered SFChT is considered, the change in IAL length between the two groups at the one- month visit (Table 3, P = 0.218) showed no significant difference, but a significant difference at the sixmonth visit was found (Table 3, P = 0.001), indicating Ortho-k treatment did inhibit ocular growth after six months of lens wear. It should be emphasized that whether ChT would remain unchanged after Orthok treatment is discontinued is still unknown, and further studies are needed for verification. As mentioned above, it is important to ensure the precision of the ChT measurement, as even a small change in ChT after Ortho-k treatment could be detected. Repeat scans were captured with the aid of automatic registration, and the follow-up mode of Spectralis was utilized to ensure the same retinal location. In this study, all procedures were performed at approximately the same time of day to avoid the potentially confounding influence of diurnal ocular variations [27]. In addition, the use of a cycloplegic agent was consistent with previously published routines [28] to avoid the effect of the time elapsed until measurement after drug administration. Moreover, although no manifest refractive error was measured during Ortho- treatment, the mean change in ACP at both one month (−2.60D) and six months (−2.57D) was very closed to the baseline refractive sphere (−2.86D) which suggested a full correction due to the previous report that change in ACP underestimated the change in refractive error by an average of 0.34D [43]. No difference between unaided visual acuity in Ortho-k group and visual acuity with spectacle correction in control group was found at each follow-up visit, indicating similar correction between two groups in this study. However, one of limitations in current study is that the thickness calculations using axial methods in this study may cause an overestimation error, which has been discussed in previous studies [8,44]. However, we only measured the SFChT, and this error tends to be minimal for central locations without retinal tilt [45]. In conclusion, Ortho-k treatment induced significant subfoveal choroidal thickening in myopic children at both 1 and 6 months after commencing lens wear compared to a spectacle wearing control group. LCVL thickness also showed a change similar to but smaller than that of SFChT, which accounted for the majority of subfoveal choroidal thickening observed. The underlying mechanism of the thickening in LCVL induced by Ortho-k remains unclear and further research is required.

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Supporting funding This work was supported by grants from National Natural Science Foundation of China, China (grant no.: 81200716).

Financial disclosure None for all authors.

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