Myopia has become a worldwide public health issue. In

REVIEW ARTICLE A Review of the Potential Factors Influencing Myopia Progression in Children Using Orthokeratology Xiao Yang, MD, Zhouyue Li, MD, and Junwen Zeng, PhD Abstract: Myopia has become a worldwide public health issue. Recent studies have consistently reported that orthokeratology (Ortho-K) significantly inhibits the progression of myopia by slowing the elongation of axial length. It has been hypothesized that this effect results from the induction of peripheral myopic defocus, which is a result of the effects of the Ortho-K lenses on the midperipheral corneal topography. Previous studies have investigated the relationship between predicting factors and the inhibitory effect of Ortho-K for slowing childhood myopic progression and found some meaningful results; however, some of the findings are controversial. To enhance the understanding of the underlying mechanism of Ortho-K in slowing childhood myopic progression, the factors affecting this process were reviewed. Key Words: myopia, orthokeratology lenses (Asia Pac J Ophthalmol 2016;5: 429 433) Myopia has become a worldwide public health issue. In countries in East and Southeast Asia, such as China, Singapore, Japan, and Korea, myopia now affects 80% to 90% of children completing high school, whereas high myopia occurs in 10% to 20% of school children. 1 These changes are not restricted to East and Southeast Asia; the prevalence of myopia is also increasing in Western countries such as the United States, 2 Australia, 3 and Barbados, 4 with approximately one third of the US population, 15% of Australian adults, and 21.9% of Barbados adults now affected by myopia. The World Health Organization recently launched a global initiative for the elimination of avoidable blindness, which includes the correction of refractive errors. 5 The mechanism for the onset and development of myopia is not clear. However, the high prevalence and increase in myopia have brought about increased risk of ocular complications, such as retinal detachment and atrophy, 6,7 glaucoma, 8,9 and cataracts. 10,11 Thus, scientists have considered many methods aiming to reduce the progression of myopia, 12 including undercorrection of myopic refractive error, 13 gas-permeable contact lenses, 14,15 bifocal or multifocal spectacles, 16,17 soft bifocal contact lenses, 18,19 and topical pharmaceutical agents. 20 23 To date, no treatment modality has been shown to completely eliminate the progression of myopia, although in children, Ortho-K shows promise as a potential method for slowing childhood myopic progression. The Ortho-K lens, which is a rigid, gas-permeable contact lens with a reverse geometry design to temporarily reshape the cornea during sleep, was designed several decades ago. 24 Recent studies reported that Ortho-K lenses significantly reduced the axial growth rate in childhood by 32% to 55% compared with From the State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, China. Received for publication August 8, 2016; accepted October 15, 2016. Supported by the National Natural Science Foundation of China (Grant Number: 81200716) and Science and Technology Program of Guangzhou, China (11BPP2Xaa2060017). The authors have no conflicts of interest to declare. Reprints: Junwen Zeng, Zhongshan Ophthalmic Center, 54 S Xianlie Rd, Guangzhou 510060, China. E-mail: 1394392659@qq.com. Copyright 2016 by Asia Pacific Academy of Ophthalmology ISSN: 2162-0989 DOI: 10.1097/APO.0000000000000242 wearing single-vision spectacles or soft contact lenses for 1- to 5-year periods. 25 29 It is surprising that the results of axial length (AL) inhibition with Ortho-K treatment vary in these studies. Moreover, an important clinical issue that remains to be resolved is the identification of children in whom Ortho-K is likely to be most effective. The development of effective treatment strategies for control of the onset and/or progression of myopia requires a clear understanding of what governs its underlying physiological and biological processes. In the current review, the factors potentially affecting the efficacy of Ortho-K for slowing childhood myopia progression are reviewed with the aim of summarizing current understanding of the underlying mechanism of Ortho-K lenses on modulating axial elongation. INITIAL AGE Many previous studies have demonstrated that myopic progression in children was negatively associated with age. 30 33 To evaluate the relationship between axial elongation and initial age in Ortho-K subjects, subjects were further divided into younger and older subjects to study the effect of age on the percentage of rapid progression in some studies. 26,27,29 In 2012, Cho et al 26 reported that 65% of younger subjects had rapid myopic progression in the spectacle group compared with 20% in the Ortho-K group. Furthermore, stepwise multiple linear regression analysis conducted by Cho et al 29 in 2013 showed that among the predicting factors, axial elongation was significantly correlated with the initial age of the subjects (standardized β = 0.30, P = 0.02). At the end of the 24-month follow-up, the odds of exhibiting rapid progression [myopic progression exceeding 1.00 diopter (D) per year or axial elongation > 0.36 mm/y] were 14.9 times greater in children wearing single-vision spectacles than in those wearing Ortho-K lenses (95% confidence interval, 1.7 131.3; Fisher exact test, P = 0.005). Hiraoka et al 27 found that the slope of the linear regression line comparing the relationship between axial elongation for 5 years and age was significantly flatter in the Ortho-K group ( 0.178) than in the control group ( 0.359). It seems that younger children tend to experience faster axial elongation and may benefit from early Ortho-K treatment. Therefore, early initiation of Ortho-K treatment may be necessary to reduce the prevalence of high myopia. BASELINE MYOPIA Cho et al 34 took the baseline severity of myopia into account in their studies using Ortho-K. They found that eye elongation is faster in those with higher baseline myopia wearing spectacles and in those with lower baseline myopia wearing Ortho-K, respectively. Similarly, Hiraoka et al 27 also found a positive relationship between AL progression and baseline myopia in subjects with Ortho-K treatment but no association between AL progression and baseline myopia in subjects wearing spectacles. Moreover, Kakita et al 35 also found a similar association between AL progression and baseline myopia in the Ortho-K group, whereas this relationship only existed in the higher myopic Ortho-K subjects. Although they did not define high myopia in their study, the AL elongation was similar and no relationship was found in low baseline myopes Asia-Pacific Journal of Ophthalmology Volume 5, Number 6, November/December 2016 www.apjo.org 429

Yang et al Asia-Pacific Journal of Ophthalmology Volume 5, Number 6, November/December 2016 in both Ortho-K and control groups. In contrast, the results of more recent studies carried out by Cho and Cheung, 26 Chen et al, 29 and Santodomingo-Rubido et al 36 showed that axial elongation was not significantly correlated with initial myopia. According to previous studies, 37,38 correcting not only central refractive error but also peripheral defocus and image quality may be a potentially effective method to control axial elongation in myopic children. From this viewpoint, Ortho-K seems to be a promising method because it induces central epithelial thinning and midperipheral thickening to yield a flatter central area. 39,40 The midperipheral annulus of corneal steepening created on the corneal surface leads to an induction of peripheral myopic defocus, and this may reduce the visual feedback for axial elongation, leading to slower myopic progression. 30,37 In the study of high myopia-partial reduction Ortho-K, 28 although subjects in the high myopia study were all treated for 4.00 D of myopia, the average refractive change was greater than that in low and moderate myopia studies. Thus, it seems that the average target for myopia treatment may well be important. When it is restricted within a certain range, the baseline myopia is higher and the average target for myopia control will be higher. It is reasonable to speculate that when more severe myopia is corrected by Ortho-K, the central cornea becomes flatter and the power toward the periphery becomes greater; this may lead to a greater decrease of hyperopic defocus in the peripheral retina, thereby exerting a greater suppressive effect on axial growth. However, the ethnic populations, sample size, the kind of Ortho-K, and so on in the previously mentioned studies 26,27,29,34 36 were different; thus, further studies with the same ethnic populations, large sample size, and the same kind of Ortho-K are warranted. CORNEAL REFRACTIVE POWER CHANGES Several animal experiments have shown that peripheral hyperopic defocus can promote central myopic shift, 41,42 and increasing evidence suggests that childhood myopia progression is slower with optical strategies that reduce the peripheral hyperopic defocus. 16 19 In addition, it has been demonstrated that Ortho-K can decrease central corneal refractive power and increase peripheral corneal refractive power. 43 Moreover, it also has been demonstrated that the midperipheral annulus of corneal steepening created on the corneal surface can lead to an induction of peripheral myopic defocus. 30,37 It seems that the change in corneal refractive power distribution caused by Ortho-K may be one of the crucial factors slowing AL progression. A 2-year study was conducted by Zhong et al 44 in 2014 to investigate the relationship between corneal power change along 3 axes (nasal, temporal, and inferior) after Ortho-K treatment and 2-year axial growth in children. In their study, the maximum power change along each axis over an 8-mm diameter ring in 1-mm steps, depending on whether the value was below or above the mean value, was divided into 2 categories called level 1 and level 2. The relationship between the maximum power change and axial elongation at the end of the 2-year period was analyzed. The results showed that the 2-year axial elongation in patients with larger corneal power changes (level 2) was reduced by 54% to 69% compared with patients with smaller corneal power changes (level 1). In addition, the maximum power changes along the 3 axes were negatively correlated with 2-year axial growth (P < 0.05). This indicates that corneal power change could be used to represent the peripheral myopic defocus shift, which may be protective against the progression of myopia in children. 44 In 2015, Zhong et al 45 found that axial elongation was significantly correlated with summed corneal power change (standardized β = 0.573, P < 0.001). According to the hypothesis by Kang et al, 46 reducing optic zone diameter would decrease the area of the central treatment zone and tighten the peripheral curve, thus inducing myopic shifts in peripheral refraction closer to the visual axis and increasing the amount of midperipheral corneal steepening, respectively. This change of lens design may correspondingly cause an increase in myopic defocus induced onto the peripheral retina. Optimizing the lens designs that induce a properly increasing corneal power change seems to be a good choice for childhood myopic control, but according to the final study results, it was challenging and unlikely to be successful to individualize myopia control through manipulation of Ortho-K lens parameters. PUPIL SIZE Pupil size determines how much light actually enters the eye, and it predominantly blocks peripheral light beams when its size is small. Previous studies showed that Ortho-K lenses induce more peripheral myopic shift in the farther periphery (ie, ±30 degrees vs ±10 degrees). 47 49 From this viewpoint, pupil size may have an influence on the relative contribution of peripheral myopic defocus in Ortho-K therapy, resulting in the progression of myopia in children undergoing Ortho-K treatment. Chen et al 50 demonstrated that large pupil diameters promote the effect of Ortho-K to slow axial growth in myopia; they speculated that this is because of enhancement of the myopic shift in the peripheral retina. In their study, baseline pupil area was negatively correlated with axial growth at the 24-month visit in the Ortho-K group (r 2 = 0.405, P < 0.001), but there was no significant correlation between axial growth and baseline pupil area in the single-vision spectacle lens group (r 2 = 0.171, P = 0.056). To be more specific, at the end of the 24-month period, AL change (from baseline) in the Ortho-K subjects with above-average pupil size was approximately half that of the Ortho-K subjects with below-average pupil size (F = 25.04, P<0.001). However, in the study by Chen et al, 50 subjects were not randomly assigned into different treatment groups. Randomized clinical trials are still warranted in future study designs. Moreover, Downie and Lowe 51 found that there was no significant association between pupil size and the degree of attenuation in myopic progression in children undergoing Ortho-K from a long-term retrospective analysis. After careful analysis, the study methods, measured time, ethnic populations, sample size, method of pupil diameter measurement, and so on were different in the 2 studies. For example, Downie and Lowe 51 investigated the relationship between myopia progression and the other parameters in Australian children in 2-year intervals up to 8 years, whereas Chen et al 50 divided subjects into 2 subcategories according to their baseline scotopic pupil diameters and then investigated the myopia progression at baseline and at every 6-month visit through to 24 months. We hypothesize that as pupil diameter increases, the retinal area exposed to myopic defocus increases and that larger pupils may enhance the suppressive effect of Ortho-K on axial elongation in children. Further randomized studies with larger sample sizes are warranted to confirm or refute this hypothesis. ABERRATIONS Corneal morphology, with the annular ring of steepened area in the midperiphery surrounding the central flattened cornea (oblate-shaped cornea) induced by Ortho-K, has been demonstrated to produce large amounts of higher-order aberrations, notably positive spherical aberration. 52,53 It seems that the inhibitory effect of Ortho-K on axial progression in myopic children is associated with the changes in optical quality, particularly positive spherical aberration. Hiraoka et al 54 conducted a 1-year prospective clinical study to determine the association between ocular 430 www.apjo.org 2016 Asia Pacific Academy of Ophthalmology

Asia-Pacific Journal of Ophthalmology Volume 5, Number 6, November/December 2016 Myopia Progression in Children Using Ortho-K optical parameters and axial elongation in myopic children undergoing overnight Ortho-K. Multivariate analysis showed that after 1 year of Ortho-K treatment, the change in coma-like aberration was the most relevant variable that was negatively related to axial elongation (r = 0.461, P = 0.0003), followed by the change in defocus (C 2 0 ; r = 0.427, P = 0.001). However, neither the change in spherical aberration (C 4 0 ) nor the posttreatment value of C 4 0 showed significant correlations with axial elongation (P = 0.6187 and 0.7941, respectively). It is reasonable to speculate that asymmetric corneal shapes, rather than concentric and radially symmetric shapes, have a considerable effect on the retardation of axial elongation. However, Downie and Lowe 51 found that nonprogressing Ortho-K eyes had a lower degree of vertical asymmetry on baseline corneal topography. However, they only measured the baseline vertical diopteric difference between the superior and inferior cornea by topography. It is particularly important that the cornea is significantly flattened after Ortho-K treatment. Downie and Lowe 51 investigated baseline corneal asymmetry, whereas Hiraoka et al 54 investigated corneal asymmetry at baseline and after Ortho-K treatment. Moreover, it is known that when asymmetry of the cornea is increased excessively because of a larger increase in coma-like aberration by Ortho-K, the contrast sensitivity deteriorates. 55 Thus, an appropriate balance between quality of vision and the effect of myopia control by Ortho-K should be maintained, and further studies to determine the appropriate level are warranted. LENS OXYGEN TRANSMISSIBILITY The Ortho-K lens is designed to reshape the corneal contour to temporarily modify or eliminate refractive error using specially designed and fitted rigid contact lenses. When Ortho-K lenses are worn overnight, the cornea undergoes a certain amount of edema, which is related to the lens oxygen transmissibility (Dk/t). The Dk/t values may affect corneal health and the refractive effect of the Ortho-K lens. Alharbi et al 56 demonstrated that wearing low Dk/t Ortho-K lenses for a single night was unsuccessful in correcting any refractive error, suggesting that the cornea requires a certain level of oxygen to produce a corneal reshaping effect. Lum and Swarbrick 57 demonstrated that Ortho-K lenses with a moderately low Dk/t were able to produce clinically significant reductions in myopia, whereas Ortho-K lenses with a higher Dk/t produced greater changes in unaided visual acuity and refractive error. Flattening and increases in asphericity were greater with the higher Dk/t lens than the lower Dk/t lens. Moreover, the higher Dk/t lens produced less overnight edema compared with the lower Dk/t lens. These results were consistent with those reported by Haque et al. 58 In contrast, Lu et al 59 found no difference in the reduction in myopia, central corneal flattening, and unaided visual acuity when comparing 2 lenses with different Dk/t values; however in their study, the lenses had a different design (Paragon Corneal Refractive Technology), and they were fabricated using different materials (Equalens II: Dk/t 47 units vs Menicon Z: Dk/t 91 units). According to the opinion of Lum et al, 57 higher Dk material would help improve the cellular metabolism rate by increasing the oxygen available to corneal epithelium cells, which may result in more rapid central epithelial thinning and possibly midperipheral epithelial thickening. It would be significant, practical, and meaningful for both patients and clinicians to reach the target refractive change in a shorter period. Most of the previously mentioned findings add further support to the recommendation that high Dk materials should be used for overnight Ortho-K not only to provide physiological advantages but also to optimize clinical outcomes. OTHER FACTORS Beyond the factors mentioned previously, there are other elements that may affect Ortho-K s ability to slow childhood myopic progression. In 2013, Santodomingo et al 60 showed that female sex, a lower rate of myopia progression before baseline, longer anterior chamber depth, larger iris diameter, and lower levels of parental myopia may play an important role in enhancing the inhibitory effect of myopia progression in myopic children with Ortho-K treatment compared with spectacle treatment. However, it was shown by Cho et al 26,27 in 2012 and 2013 that among all of the predicting factors, sex, initial myopia, initial refractive cylinder, and initial corneal toricity were not correlated with the inhibitory effect of Ortho-K treatment on axial elongation. Thus, further clinical studies to demonstrate a clear relationship between these factors and myopic control with Ortho-K are warranted. CONCLUSIONS In summary, it can be stated that the following characteristics may allow children to benefit more from Ortho-K treatment for controlling myopia progression: higher baseline myopia, younger age, larger pupil size, asymmetric corneal shapes, larger corneal power changes, female sex, lower rate of myopia progression before baseline, and lenses with high Dk/t. However, perspective clinical studies researching the factors mentioned above in specific ethnic populations with large sample sizes are still needed. 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Asia-Pacific Journal of Ophthalmology Volume 5, Number 6, November/December 2016 Myopia Progression in Children Using Ortho-K 55. Hiraoka T, Okamoto C, Ishii Y, et al. Contrast sensitivity function and ocular higher-order aberrations following overnight orthokeratology. Invest Ophthalmol Vis Sci. 2007;48:550 556. 56. Alharbi A, La Hood D, Swarbrick HA. Overnight orthokeratology lens wear can inhibit the central stromal edema response. Invest Ophthalmol Vis Sci. 2005;46:2334 2340. 57. Lum E, Swarbrick HA. Lens Dk/t influences the clinical response in overnight orthokeratology. Optom Vis Sci. 2011;88: 469 475. 58. Haque S, Fonn D, Simpson T, et al. Corneal refractive therapy with different lens materials, part 1: corneal, stromal, and epithelial thickness changes. Optom Vis Sci. 2007;84:343 348. 59. Lu F, Simpson T, Sorbara L, et al. Corneal refractive therapy with different lens materials, part 2: effect of oxygen transmissibility on corneal shape and optical characteristics. Optom Vis Sci. 2007;84:349 356. 60. Santodomingo-Rubido J, Villa-Collar C, Gilmartin B, et al. Factors preventing myopia progression with orthokeratology correction. Optom Vis Sci. 2013;90:1225 1236. Put your heart, mind and soul into even your smallest acts. This is the secret of success. Swami Sivananda 2016 Asia Pacific Academy of Ophthalmology www.apjo.org 433