The Treatment Zone Size and Its Decentration Inuence Axial Length Grow in Children With Orthokeratology Treatment

Background: To investigate whether the treatment zone size (TZS) and treatment zone decentration (TZD) will affect the axial length growth in myopic children undergoing orthokeratology treatment. Methods: A self-controlled retrospective study was conducted on 352 children who met the inclusion criteria. Axial length was measured before and at 12 months after the initial lens wear. Corneal topography was measured at baseline and at each follow-up after lens wear. The Corneal topography obtained from the 12-month visit was used to quantify TZS and TZD for each subject. Cycloplegic refraction was required for all subjects before tting the orthokeratology lenses. Results: Axial length growth was signicantly associated with age, baseline spherical equivalent (SE), TZS, and TZD with univariate linear regression. In groups with both small and large TZS, axial length growth was signicantly decreased with large TZD (both P < 0.001). In groups with both small and large TZD, axial length growth was signicantly decreased with small TZS (P = 0.027 for small TZD, P = 0.011 for large TZD). Age, SE, and TZD were signicantly associated with axial length growth in multiple regression (all P < 0.001). Conclusion: and


Background
Myopia has become a serious public health issue due to its increased prevalence and severity over the past decades . 1, 2 Myopia has increased in prevalence to 20-30% in western countries and 40-70% in Asian populations. 3,4 In East Asian countries, 80% of 18-year-olds are myopic. 5 Progression of myopia, with axial growth and eyeball expansion, increased the risk of a series of myopia pathological changes, such as macular degeneration, posterior scleral staphyloma, and choroidal neovascularization. 6, 7 Therefore, prevention and control of myopia in teenagers has become a topic of signi cant interest.
A variety of methods have been used for controlling the progress of myopia, including orthokeratology, which has an effectiveness supported by several studies. 8-10 An orthokeratology lens is a rigid contact lens with a reverse geometry on its back surface. 11 Through overnight wearing, the central portion of the cornea is attened to correct refractive errors for good daytime vision. Relative corneal refractive power in the mid-peripheral cornea is increased, inducing myopic defocus on the peripheral retina. Animal studies have demonstrated strong inhibitory effects of peripheral myopic defocus on axial length elongation or myopia development. [12][13][14] It has been proposed that changes in peripheral retina defocus may be responsible for the reduced myopia progression reported with orthokeratology. [15][16][17] A series of factors have been proposed to be associated with the individual variation in axial growth with orthokeratology, such as age, baseline spherical equivalent (SE), corneal shape, and pupil size. 18, growth. 20 However, it is not clear how decentration contributes to the slowing of myopia progression, but factors such as increased corneal coma 21 , 22 and increased corneal asymmetry 19 have been suggested.
Another factor, treatment zone size (TZS), was also suggested to be associated with slowing myopia progression. 23 The mechanism by which TZS and TZD affect myopia control may be associated with the distribution of the corneal power shift or the conditions of the retinal peripheral defocus. To our knowledge, no study to date has combined these two factors in an orthokeratology study. The purpose of this current study was to explore the effect of TZS combined with TZD on slowing myopia progression in patients using orthokeratology. This will enhance our understanding of the effects of orthokeratology in slowing myopia progression over a topography pro le.

Subjects
This retrospective study was conducted at the Tianjin Medical University Eye Hospital (Tianjin, China) between May 2018 and July 2019. This study adhered to the tenets of the Declaration of Helsinki and was approved by the Ethics Committee of Tianjin Medical University Eye Hospital. In total, 352 subjects were deemed suitable for this study and included for analysis according to the inclusion criteria below.
The subjects were recruited from the children who visited the myopia control clinic. The initial inclusion criteria for orthokeratology lens tting were: aged between 8 and 14 years; SE of cycloplegic refraction from -0.75 D to -6.00 D; corneal astigmatism ≤ 1.50 D; best-corrected monocular visual acuity no less than 20/20; cycloplegic refraction with compound tropicamide eye drops (5 mg/mL, one drop every 5 minutes for four times) before tting orthokeratology lenses. Exclusion criteria were: strabismus or ocular surface disease; any history of surgery or contact lens use; binocular vision dysfunction.
Orthokeratology lens tting and follow up plan Subjects were tted with spherical four-zone orthokeratology lenses (Euclid Systems Corporation, Herndon, USA) composed of oprifocon A (Boston EQUALENS II) with an oxygen permeability of 127× 10 −11 (cm 2 /s) (mL O 2 /mL · mm Hg). Total lens diameter had a range of 10.2-11.0 mm. Lens tting procedures strictly followed the guidelines provided by the lens manufacturer. Subjects received instructions for contact lens wearing and cleaning at tting. Lenses were required to be worn for more than 8 hours per night, for at least 6 days per week. Follow-up visits were scheduled at one day, one week and one month after the initial lens wear, and at least once every 3 months afterward. All subjects included were continuously worn the lenses and do topographic map examination within four hours after removing the lenses. A total of 352 subjects meet the above conditions. Determination of treatment zone size and treatment zone decentration Corneal topography was rst obtained with a Medmont Corneal Topographer (Medmont Pty Ltd, Camberwell, Victoria, Australia) at baseline ( Figure 1A). Corneal topography was performed at each follow-up visit and topography parameters were computed based on the topography obtained 12 months after the initial lens wear ( Figure 1B). To determine the central treatment zone, a difference map was calculated by subtracting the post-treatment tangential curvature map from the baseline map. The area containing locations reduced by more than 0.00 D was de ned as the treatment zone, and its boundary was tted to a circle using a custom Matlab function (MathWorks, Natick, WA) ( Figure 1C). The center of the circle was de ned as the center of the treatment zone (white cross, Figure 1C). The distance between the center of the circle and the geometric center of the corneal (red cross, Figure 1C) was de ned as the TZD (r, Figure 1C). The area of the tted circle (s = π * R 2 ) was de ned as the TZS (white circle, Figure  1C).

Axial length measurement
Axial length was measured before lens tting (baseline) and at 12 months after lens treatment using noncontact optical biometry (Lenstar 900; Haag-Streit AG, Switzerland). All measurements were done by the same experienced technician, and the results meet the quality control requirements of the instrument.

Statistical analysis
For descriptive purposes, the means and standard deviations were calculated for baseline SE, ages, axial growth and corneal parameters ( at-K, steep-K). The normality of the data was tested with a Schapiro-Wilk test. Univariate linear regression was used to analyze the relationships between axial growth and age, baseline SE, TZS, TZD. Stepwise multiple linear regression was used to analyze the relationships between axial growth and age, baseline SE, TZS, TZD and corneal parameters. All statistical analyses were performed using R software (version 3.2.2 http://www.R-project.org/). A P < 0.05 value was de ned as statistically signi cant.

Measurements
Corneal topography data were retrospectively collected from the clinical records of the 352 subjects; only the right eye data (352 eyes) was used for statistical analysis. The mean age of the subjects was 10.28 ± 1.88 years (range 8-14 years). At baseline, the mean SE was -3.25 ± 1.28 D (range -6 to -0.75 D), the mean axial length was 24.92 ± 1.36 mm, the mean corneal at-K was 42.65 ± 3.88 D, the mean corneal steep-K was 43.88 ± 3.96 D. After treatment, the mean axial length growth was 0.16 ± 0.23 mm per year, the mean TZD was 0.52 ± 0.22 mm (range 0.05 to 1.24mm), and the mean TZS was 11.22 ± 1.43 mm 2 (range 6.89 to15.7 mm 2 ).

Association between axial growth and parameters
The association between axial growth and the parameters was rst analyzed by univariate linear regression. Axial growth was signi cantly associated with age and baseline SE (Figure 2A, B). Axial growth became slower in older children (P < 0.001) and children with greater baseline SE (P < 0.001).
Axial growth was signi cantly associated with TZS ( Figure 2D) and TZD ( Figure 2C). Axial growth became slower in children with a smaller TZS (P < 0.001) or a larger TZD (P < 0.001). The corneal at-K and steep-K were not associated with axial growth (both p>0.05).

Classi cation based on decentration and treatment zone size
There was no signi cant correlation between TZD and TZS (r = -0.05, P = 0.37, Figure 3A). Overall, the TZS was normally distributed (grey dotted line in Figure 3B). The subjects were divided into two groups at the mean of the normal distribution (red vertical line in Figure 3B): small TZS (≤ 11.22 mm 2 ) and large TZS (r >11.22 mm 2 ). The TZD data also followed a normal distribution ( Figure 3C), and subjects were divided at the mean of the normal distribution into two groups: small TZD (≤ 0.52 mm) and large TZD (> 0.52 mm). All subjects were categorized using these four combinations of TZS and TZD.
Axial growth versus treatment zone decentration and treatment zone size In groups with either small TZS or large TZS, the axial growth was signi cantly negatively associated with TZD ( Figure 4A, P < 0.001). In groups with either small TZD or large TZD, myopia control was improved with a decrease in TZS ( Figure 4B, P = 0.027, P = 0.011). However, there was no signi cant difference in axial growth between subjects who had both small TZS and small TZD and those who had both large TZS and large TZD ( Figure 4A, P = 0.3212).
To explore the association of axial growth with the factors age, baseline SE, at-K, steep-K, TZD, and TZS, a multiple regression analysis was applied in a stepwise manner. Multiple regression analysis revealed that axial growth was signi cantly correlated with age, SE, and TZD (Table).
Table1: Multivariable regression analysis showing the association between axial length growth and age, spherical equivalent, treatment zone decentration.

Discussion
In current study, subjects with smaller TZS and larger TZD bene ted from a greater slowing of myopia progression with 12 months orthokeratology. Multiple regression showed that initial age, baseline SE and TZD were signi cantly associated with axial growth.

Initial age and baseline spherical equivalent
Many studies have examined factors that in uence axial growth during orthokeratology treatment, and initial age and baseline SE have been reported to be critical factors in affecting axial growth. In our study, both initial age and baseline SE were signi cantly correlated with axial growth in multiple linear regression (Table), with older children and greater baseline SE associated with smaller axial growth. Other studies have reported differing associations. Zhong et al. reported that initial age did not affect axial length growth on 32 children aged 9-14 years old in a 24-month follow-up study. 24 In contrast, Rubido et al. reported that initial age is signi cantly negatively correlated with axial length growth, 25  The association between axial growth and baseline SE has also been debated. In studies that reported a signi cant negative correlation between axial growth and baseline SE, the subjects had a wider baseline SE range, typically between -6.0 and -1.0 D. 26,27 In studies that reported a lack of association between baseline SE and axial length growth, the subject's baseline SE was in a limited middle range, mostly between -4.0 and -1.0 D. 8, 28 In our current study, we found that older initial age and greater baseline SE were bene cial in slowing the progression of myopia in children receiving orthokeratology treatment for twelve months follow up.
Treatment zone decentration TZD is a common phenomenon in orthokeratology clinical practice and is di cult to avoid. Many factors may contribute to TZD, such as corneal asymmetry, lens tting, lens diameter, corneal astigmatism. [29][30][31] Smaller lens diameter and greater corneal astigmatism are more likely to result in lens offset and TZD. 31 Traditional orthokeratology guidelines encourage clinicians to pursue perfect centering with a bull's-eye pattern during orthokeratology lens tting. In traditional orthokeratology practice, there is no clear guideline on how much TZD should be allowed and how hard one should push for perfect centering.
In the current study, the mean TZD was 0.52 ± 0.22 mm (range 0.05-1. . 31 In the current study where 352 subjects were analyzed, we found that the TZD was signi cantly negatively correlated with axial growth ( Figure 2C, P < 0.001), and our study, therefore, provides evidence to clarify the relationship between TZD and the slowing of myopia progression with orthokeratology treatment for twelve months follow-up. subjects increased TZD was bene cial in controlling myopia, with relatively larger TZD associated with smaller axial growth ( Figure 4A). Nevertheless, we state that the trends between TZD and axial growth would need a longer period of study to con rm. We do not suggest deliberate decentration of the orthokeratology lens, as large TZD can cause visual discomfort, such as ghosting and visual fatigue. 32,33 It is important to identify subjective sensations caused by TZD and then decide whether it is necessary to adjust the lens parameters.
Treatment zone size combined with treatment zone decentration TZS and TZD were two previously neglected factors for myopia control effectiveness, compared with the known factors such as initial age and SE at baseline. We found that in subjects with smaller TZS, larger TZD was associated with the smallest axial growth (0.06 mm per year, Figure 4A). In subjects with larger TZS, smaller TZD was associated with the largest axial growth (0.23 mm per year, Figure 4A). There was no axial growth difference between subjects with both smaller TZS and smaller TZD and those with both larger TZS and larger TZD (P = 0.3212, Figure 4A). When multiple linear regression was used to control for the contribution from initial age and baseline SE, only TZD was signi cantly associated with axial growth. The reason for TZS being excluded by multiple regression may be that only one design of orthokeratology lens was used in the current study (Euclid, back optic zone diameter is 6.2mm), which may result in a large range of TZS (6.89-15.7 mm 2 , radius 1.48 to 2.24mm) with continuous boundary. Two different orthokeratology lens designs (different in TZ diameter and same total lens diameter) should be included in further research. Multiple linear regression is necessary to identify the factors that independently in uence axial growth.

The potential mechanism
Page 8/15 The mechanism of orthokeratology in control of myopia progression is still not clear. We hypothesized that orthokeratology induces myopia defocus in relative peripheral refractive error interfering the axial length growth pattern as "peripheral refraction theory", which has been recognized by most researchers. [34][35][36] Cho et al. 37 hypothesized that the greater the corneal reshaping effect, the greater peripheral myopic defocus, the higher the regulation e cacy in retarding myopia progression. Yang et al. 38 suggested that areal summed corneal power shift (ASCPS) in a 4 mm area was a potential predictor of axial elongation in orthokeratology treatment. Wang et al. 19 agreed that a maximum value of posttreatment corneal relative power (PCRP) resulted in a higher probability of effective axial elongation control. Zhong measured the relative corneal refractive power shift (RCRPS) in the nasal, temporal, and inferior axes and found that the maximum changes were negatively correlated with 2-year axial growth. 24 With a decentered treatment zone or a smaller treatment size, the reverse zone which has positive RCRPS moves closer to the apex. This could lead to a larger summed RCRPS within a 4 mm area, which agrees with the study by Yang et al. 38 Given the same pupil size, TZD, and a smaller TZS, the summed RCRPS within the pupillary zone would be much greater in corneal power pro les, which would agree with the larger pupil size often associated with smaller axial growth. 18 We speculate that a smaller TZ and a higher decentered one will move the mid-peripheral ring inside the pupil if it is of the appropriate size, inducing higher optical changes that may be bene cial for myopia control in the subjects receiving orthokeratology treatment. However, in current retrospective study we did not measure the pupil size and RCRPS directly, we will incorporate these factors in the further prospective study. Another potential mechanism may be that corneal shape asymmetry is increased with orthokeratology TZD. Corneal shape asymmetry increases higher-order corneal aberrations. 18, 39 Hiraoka et al. found that increased corneal coma was signi cantly associated with decreased axial growth in orthokeratology treatment. 22

Limitations Of The Current Study
There are several limitations to the current study. First, we suggest that TZS and TZD bene t the retinal myopic defocus, but we did not directly measure peripheral retinal defocus in this study. Second, we speculate that the myopic control with TZD might shift more PCRP into the pupillary area as a potential mechanism for orthokeratology, but we did not measure the subject's pupil. Third, we speculated that higher-order corneal aberrations were associated with myopia control, but we did not directly measure higher-order aberrations.

Conclusion
Subjects with relatively smaller TZS and larger TZD after Orthokeratology experienced slower axial elongation by the end of 12 months. This effect might be mediated by the induction of a greater amount of relative myopic defocus on the peripheral retina. Further studies are needed to assess whether change on lens designs increase e cacy for slowing progression of myopia.

Declarations
Ethics approval and consent to participate This study was approved by the Human Research Ethics Committee of Tianjin Medical University Eye Hospital and was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all enrolled participants.

Consent for publication
We obtained written informed consent for publication from the patients related to details and images.

Availability of data and materials
The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.
Methods to determine the treatment zone decentration and treatment zone size. (A) Axial map at baseline; (B) tangential curvature map at the twelve-month visit; (C) difference map used to determine treatment zone decentration and treatment zone size. The red cross indicates the corneal apex, the white circle represents the tted treatment zone, and the white cross indicates the center of the treatment zone.
The distance between the white cross and red cross was de ned as the decentration of the treatment zone. The area of the white circle was de ned as the treatment zone size. R: radius of treatment zone circle; r: the distance of treatment zone decentration.