Myopia has become one of the most common ocular disorders worldwide. The prevalence of myopia is about 20 to 50% in Europe and the United States and is up to 70% or even higher than 80% for young adults in some parts of East Asia.1–5 High myopia is a risk factor for cataract, glaucoma, myopic retinopathy, and retinal detachment.6–9 Therefore, it is very important to slow or even stop the progression of myopia in children.
Many researchers are investigating ways to control myopia progression. Several medical treatments have been considered to suppress myopia progression, including topical application of tropicamide,10 atropine,11 and pirenzepine.12 Nevertheless, there have been no ideal therapeutic modalities to effectively prevent myopic progression in light of efficacy, safety, economic feasibility, and ease of application.2,13 Orthokeratology, an optical correction mainly for correcting low-to-moderate myopia, is showing a potential to reduce the progression of myopia.14–20 It is reversible and if the patient is unhappy with the treatment, he or she can simply discontinue wearing the lenses.
Axial length (AL) elongation is the most important factor in myopia progression.21 A number of nonrandomized controlled trials (non-RCTs) have reported that AL elongation in subjects wearing orthokeratology lenses were 36 to 56% slower when compared with that of subjects wearing spectacles.14,16,17,20 Two recent randomized single-masked studies also reported the efficacy of orthokeratology for slowing axial growth in high and low myopic children.18,19 These studies suggest that orthokeratology may suppress myopia progression in children, but in general, the sample sizes of these studies were relatively small. Therefore, it would be valuable to conduct a quantitative and systematic summary of the evidence using rigorous methods. In the present study, a meta-analysis was conducted to assess the results from published studies on the efficacy of orthokeratology in myopia control.
To find the relevant literature, PubMed, Embase, and the Cochrane Library were searched. Reference lists of included trials were also searched. There were no language or data restrictions in searching trials. The date of searching databases ended November 16, 2013. The search strategy was based on combinations of medical subject headings and free text words and the search terms used were “orthokeratology,” “ortho-k,” “corneal reshaping contact lens,” and “myopia,” “nearsight,” and “shortsight” in various combinations. Retrieved articles were imported into EndNote X6 (Thomson Reuters, New York, NY) where duplicate articles were manually removed.
Inclusion and Exclusion Criteria
Published studies, regardless of sample size, were included if they (1) were controlled clinical trials, including RCTs and non-RCTs; (2) included myopic patients aged 18 years and younger; (3) compared orthokeratology with control subjects (single-vision spectacles or soft contact lenses); and (4) reported AL elongation or more information relevant to myopia progression, for example, vitreous chamber depth (VCD) elongation. The major reasons for exclusion of studies were (1) review papers, (2) having no control groups, and (3) having no relevant data. We also excluded conference abstracts that had not been published. If duplicated data were presented in several studies, only the largest study was included. Article titles were screened for eligibility by two reviewers (SJK and TK) independently, and abstracts or full texts were reviewed as necessary.
Two review authors (SJK and TK) independently extracted the data from articles that met this study’s inclusion criteria. Two authors resolved inconsistencies by discussion and consensus. The following data were extracted from articles that met this study’s inclusion criteria: name of first author, the year of publication and location of the study, various intervention groups, number of subjects, patient age, sex, duration of follow-up, and the baseline refractive error. The outcome measures were AL elongation and VCD elongation.
Missing SDs were derived from other statistics, such as p values or confidence intervals (CIs) if needed.22 When a p value was reported as, for example, p ≤ 0.001, p = 0.001 was assumed.23 The missing SDs were able to be captured from figures using GetData Graph Digitizer 2.24 (available at http://getdata-graph-digitizer.com/index.php).
The methodological quality of the articles was evaluated using the Jadad scale.24 This validated approach assesses randomization (0 to 2 points), blinding (0 to 2 points), and withdrawals (0 to 1 point) on a five-point scale. This study followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement.25
Statistical analysis was performed with RevMan 5.2.6 software (Cochrane Collaboration, Oxford, UK). In the present meta-analysis, the effect sizes of each study were presented as weighted mean difference (WMD) with 95% CIs for continuous outcome measures (AL, VCD). The continuous outcome measures were calculated by the inverse variance statistical method of random-effects model. In the inverse variance method, the weight given to each study is chosen to be the inverse of the variance of the effect estimate and is expressed as the percentage of every weight in the overall weight.23 The statistical heterogeneity was tested by using the I2 statistic. The statistical heterogeneity was considered significant when the I2 statistic was greater than or equal to 50%. Because patient characteristics, region, the baseline refraction error, and other confounding factors were not consistent between studies, we further performed sensitivity analysis to examine the influence of various exclusion criteria on the overall pooled estimate. We also investigated the influence of a single study on the overall pooled estimate by omitting each study in turn. The sensitivity analysis was only performed for changes in AL because of the small number of studies reporting changes in VCD. The pooled effect sizes were considered significant when the 95% CI of WMD did not cross zero. We did not analyze publication bias because of the limited number of studies.
A total of 461 studies were identified by the initial database search, of which 439 studies were excluded because they were duplicates or irrelevant to our subject. The remaining 22 full-text studies were carefully reviewed for more detailed evaluation, and 15 of them were excluded. Thus, two RCTs18,19 and five non-RCTs14–17,20 published from 2005 to 2013 were included in the final meta-analysis. Fig. 1 shows the process of filtering articles to determine their appropriate value for inclusion in the meta-analysis.
Characteristics and Quality of Trials
A total of 435 subjects (orthokeratology group, 218; control group, 217) aged 6 to 16 years were included in the present meta-analysis. The basic characteristics of the included studies are described in Table 1. Among these seven studies, five studies14,16,18–20 were performed in East Asia, one study was performed in Europe,17 and one study was performed in America.15 All studies included reported the AL, and two studies also reported VCD. The follow-up time was 2 years for the seven studies. The quality assessment of studies included in this meta-analysis is presented in Table 1.
The gold standard for determining myopic progression is the elongation of AL26; hence, we selected the AL changes as the first outcome measure. As the SDs in the article by Walline et al.15 were missing, we derived the SDs from the p values using the method reported by Wiebe et al.22 We also captured missing SDs from the study by Santodomingo-Rubido et al.17 from published figures using GetData Graph Digitizer 2.24. The results showed that AL increased with time in both orthokeratology and control subjects. At 2 years follow-up, the AL elongation of the orthokeratology group was significantly slower than that of the control group (WMD, −0.26 mm; 95% CI, −0.31 to −0.21; p < 0.001) (Fig. 2). We performed sensitivity analysis to test the robustness of the results. Table 2 shows the results of sensitivity analysis based on various exclusion criteria for AL. All groups in Table 2 showed insignificant heterogeneity: I2 ≤ 50%, p ≥ 0.10. We also assessed the influence of individual studies on the combined risk estimate by sequentially excluding each study in turn to test the stability of the main results. The exclusion of any single study did not materially alter the overall combined WMD, which ranged from −0.25 mm (95% CI, −0.31 to −0.20; p < 0.001) to −0.27 mm (95% CI, −0.33 to −0.22; p < 0.001).
Two studies reported VCD,14,15 which increased with time in both groups of subjects. The VCD changes in the orthokeratology group were significantly slower than those in the control group (WMD, −0.18 mm; 95% CI, −0.33 to −0.03; p = 0.02) (Fig. 3).
The major purpose of the present meta-analysis was to evaluate the efficacy of orthokeratology in myopia control. Our meta-analysis suggests that compared with control, orthokeratology may effectively reduce the elongation of AL to a certain extent, with mean differences of −0.26 mm in 2 years. Moreover, the difference between orthokeratology and control in VCD elongation was −0.18 mm in 2 years. Exclusion of any single study and sensitivity analysis based on various exclusion criteria did not materially alter the pooled results, which added robustness to our main result.
Some early reports27–29 described apparent effectiveness of overnight orthokeratology for arresting the progression of myopia. Subsequently, retrospective and prospective studies provided further evidence in support of the effectiveness of treatment. These results indicated that orthokeratology could suppress myopia progression with mean difference for AL elongation between orthokeratology and control ranging from −0.22 to −0.33 mm in 2 years.14–20 In our study, the meta-analysis that combined seven studies with 435 subjects (orthokeratology group, 218; control group, 217) indicated a similar result and confirmed the efficacy of orthokeratology for myopia control.
The mechanism by which orthokeratology might control myopic eye growth is still debatable. It has been proposed that relative peripheral hyperopic defocus in myopes may trigger axial elongation.30,31 Recent animal studies indicate that form deprivation that is limited to the peripheral retina can produce myopic eye growth in monkeys, despite ablation of the fovea with an argon laser.32 In human studies, myopic eyes experience more relative hyperopia in the periphery, on average, than hyperopic and emmetropic eyes.33 Furthermore, results from the CLEERE (Collaborative Longitudinal Evaluation of Ethnicity and Refractive Error) study indicated that children who become myopic have more relative hyperopic peripheral refractive error than emmetropic children 2 years before the onset of myopia.34 Therefore, peripheral hyperopia may act as a signal for increased eye growth. The correction of peripheral hyperopia may be the mechanism of orthokeratology in the suppressing of myopic eye growth. In orthokeratology, the central cornea is flattened, reducing the axial myopia, whereas the midperipheral cornea remains relatively steeper, leading to relative peripheral myopia in myopic eyes. The peripheral myopia created by orthokeratology reduces peripheral hyperopic defocus, and this may reduce the visual feedback for eye elongation, leading to slower myopic progression.35–37 In contrast, the CLEERE group’s later study38 found that hyperopic relative peripheral refractive error was not a significant risk factor for the onset of myopia as a whole. However, the association between more hyperopic relative peripheral refractive error and the risk of the onset of myopia varied by ethnic group, with Asian American children having the highest risk. Thus, whether relative peripheral hyperopic defocus acts as an important mechanism by which orthokeratology might control myopia progression is still uncertain. Furthermore, researchers have found that many other factors may influence the effectiveness of myopia control with orthokeratology, including corneal relative peripheral power change,39 levels of parental myopia,40 and pupil sizes.41 All factors mentioned above serve to remind us that the mechanism by which orthokeratology might control myopic eye growth may be complex.
This study has several limitations. First, our analysis was based on only seven studies (two RCTs and five non-RCTs) with relatively small sample sizes, thus limiting the reliability of the results. Second, the targeted population varied greatly, and study protocols and designs differed. These factors may have potential effects on our results. Third, the study by Walline et al.15 was included in this meta-analysis, although soft contact lenses were used as control. Moreover, most trials included in the present meta-analysis were performed in Asia, and only two studies15,17 were conducted outside this region in America and Spain.
Further studies should focus on the following two points. First, although RCTs for orthokeratology are difficult to carry out, using RCTs can leave little room for bias, and the results of RCTs are more convincing. Therefore, future large-scale RCTs to investigate the effects of orthokeratology on myopia progression are still important. Second, because the mechanism of myopia progression is still debatable, additional animal and human studies will be needed to further elucidate the potential biological mechanisms that are involved.
In conclusion, our meta-analysis suggests that orthokeratology can reduce the progression of myopia to a certain extent. The results of this meta-analysis should be interpreted with caution because of the limitations discussed above. Further large-scale studies are needed to substantiate the current results and to investigate the long-term effects of orthokeratology in myopia control.
Department of Ophthalmology
Affiliated Eye Hospital of Shandong
University of Traditional Chinese Medicine
48 Yingxiongshan Rd
e-mail: [email protected]
This study was supported by the National Natural Science Foundation of China (81173440) and the Shandong Traditional Chinese Medicine Science and Technology Development Plans Project (2011-130). Jun-Kang Si and Kai Tang contributed equally to this work.
Received February 17, 2014; accepted October 10, 2014.
1. Pan CW, Klein BE, Cotch MF, Shrager S, Klein R, Folsom A, Kronmal R, Shea SJ, Burke GL, Saw SM, Wong TY. Racial variations in the prevalence of refractive errors in the United States: the multi-ethnic study of atherosclerosis. Am J Ophthalmol 2013; 155: 1129–38.
2. Koffler BH, Sears JJ. Myopia control in children through refractive therapy gas permeable contact lenses: is it for real? Am J Ophthalmol 2013; 156: 1076–81 e1.
3. You QS, Wu LJ, Duan JL, Luo YX, Liu LJ, Li X, Gao Q, Wang W, Xu L, Jonas JB, Guo XH. Prevalence of myopia in school children in greater Beijing: the Beijing Childhood Eye Study. Acta Ophthalmol 2014; 92: e398–406.
4. Foster PJ, Jiang Y. Epidemiology of myopia. Eye (Lond) 2014; 28: 202–8.
5. Wu JF, Bi HS, Wang SM, Hu YY, Wu H, Sun W, Lu TL, Wang XR, Jonas JB. Refractive error, visual acuity and causes of vision loss in children in Shandong, China. The Shandong Children Eye Study. PLoS One 2013; 8: e82763.
6. Kanthan GL, Mitchell P, Rochtchina E, Cumming RG, Wang JJ. Myopia and the long-term incidence of cataract and cataract surgery: the Blue Mountains Eye Study. Clin Experiment Ophthalmol 2014; 42: 347–53.
7. Mitchell P, Hourihan F, Sandbach J, Wang JJ. The relationship between glaucoma and myopia: the Blue Mountains Eye Study. Ophthalmology 1999; 106: 2010–5.
8. Hochman MA, Seery CM, Zarbin MA. Pathophysiology and management of subretinal hemorrhage. Surv Ophthalmol 1997; 42: 195–213.
9. Kang HM, Lee CS, Park HJ, Lee KH, Byeon SH, Koh HJ, Lee SC. Characteristics of rhegmatogenous retinal detachment after refractive surgery: comparison with myopic eyes with retinal detachment. Am J Ophthalmol 2014; 157: 666–72 e1–2.
10. Iribarren R. Tropicamide and myopia progression. Ophthalmology 2008; 115: 1103–4.
11. Chua WH, Balakrishnan V, Chan YH, Tong L, Ling Y, Quah BL, Tan D. Atropine for the treatment of childhood myopia. Ophthalmology 2006; 113: 2285–91.
12. Tan DT, Lam DS, Chua WH, Shu-Ping DF, Crockett RS. One-year multicenter, double-masked, placebo-controlled, parallel safety and efficacy study of 2% pirenzepine ophthalmic gel in children with myopia. Ophthalmology 2005; 112: 84–91.
13. Walline JJ, Lindsley K, Vedula SS, Cotter SA, Mutti DO, Twelker JD. Interventions to slow progression of myopia in children. Cochrane Database Syst Rev 2011:CD004916.
14. Cho P, Cheung SW, Edwards M. The longitudinal orthokeratology research in children (LORIC) in Hong Kong: a pilot study on refractive changes and myopic control. Curr Eye Res 2005; 30: 71–80.
15. Walline JJ, Jones LA, Sinnott LT. Corneal reshaping and myopia progression. Br J Ophthalmol 2009; 93: 1181–5.
16. Kakita T, Hiraoka T, Oshika T. Influence of overnight orthokeratology on axial elongation in childhood myopia. Invest Ophthalmol Vis Sci 2011; 52: 2170–4.
17. Santodomingo-Rubido J, Villa-Collar C, Gilmartin B, Gutierrez-Ortega R. Myopia control with orthokeratology contact lenses in Spain: refractive and biometric changes. Invest Ophthalmol Vis Sci 2012; 53: 5060–5.
18. Cho P, Cheung SW. Retardation of Myopia in Orthokeratology (ROMIO) study: a 2-year randomized clinical trial. Invest Ophthalmol Vis Sci 2012; 53: 7077–85.
19. Charm J, Cho P. High myopia-partial reduction ortho-k: a 2-year randomized study. Optom Vis Sci 2013; 90: 530–9.
20. Chen C, Cheung SW, Cho P. Myopia control using toric orthokeratology (TO-SEE study). Invest Ophthalmol Vis Sci 2013; 54: 6510–7.
21. Lam CS, Edwards M, Millodot M, Goh WS. A 2-year longitudinal study of myopia progression and optical component changes among Hong Kong schoolchildren. Optom Vis Sci 1999; 76: 370–80.
22. Wiebe N, Vandermeer B, Platt RW, Klassen TP, Moher D, Barrowman NJ. A systematic review identifies a lack of standardization in methods for handling missing variance data. J Clin Epidemiol 2006; 59: 342–53.
23. Higgins JP, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions. Cochrane Collaboration; Version 5.1.0 [updated March 2011]. Available at: www.cochrane-handbook.org
. Accessed September 3, 2014.
24. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996; 17: 1–12.
25. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 2009; 339: b2700.
26. Cheung SW, Cho P. Validity of axial length measurements for monitoring myopic progression in orthokeratology. Invest Ophthalmol Vis Sci 2013; 54: 1613–5.
27. Cheung SW, Cho P, Fan D. Asymmetrical increase in axial length in the two eyes of a monocular orthokeratology patient. Optom Vis Sci 2004; 81: 653–6.
28. Lee TT, Cho P. Discontinuation of orthokeratology and myopic progression. Optom Vis Sci 2010; 87: 1053–6.
29. Reim TR, Lund M, Wu R. Orthokeratology and adolescent myopia control. Contact Lens Spectrum 2003; 18: 40–2.
30. Norton TT, Siegwart JT Jr. Animal models of emmetropization: matching axial length to the focal plane. J Am Optom Assoc 1995; 66: 405–14.
31. Smith EL 3rd, Ramamirtham R, Qiao-Grider Y, Hung LF, Huang J, Kee CS, Coats D, Paysse E. Effects of foveal ablation on emmetropization and form-deprivation myopia. Invest Ophthalmol Vis Sci 2007; 48: 3914–22.
32. Smith EL 3rd, Kee CS, Ramamirtham R, Qiao-Grider Y, Hung LF. Peripheral vision can influence eye growth and refractive development in infant monkeys. Invest Ophthalmol Vis Sci 2005; 46: 3965–72.
33. Mutti DO, Sholtz RI, Friedman NE, Zadnik K. Peripheral refraction and ocular shape in children. Invest Ophthalmol Vis Sci 2000; 41: 1022–30.
34. Mutti DO, Hayes JR, Mitchell GL, Jones LA, Moeschberger ML, Cotter SA, Kleinstein RN, Manny RE, Twelker JD, Zadnik K. Refractive error, axial length, and relative peripheral refractive error before and after the onset of myopia. Invest Ophthalmol Vis Sci 2007; 48: 2510–9.
35. Queirós A, González-Méijome JM, Jorge J, Villa-Collar C, Gutiérrez AR. Peripheral refraction in myopic patients after orthokeratology. Optom Vis Sci 2010; 87: 323–9.
36. Mathur A, Atchison DA. Effect of orthokeratology on peripheral aberrations of the eye. Optom Vis Sci 2009; 86: 476–84.
37. Kang P, Swarbrick H. Peripheral refraction in myopic children wearing orthokeratology and gas-permeable lenses. Optom Vis Sci 2011; 88: 476–82.
38. Mutti DO, Sinnott LT, Mitchell GL, Jones-Jordan LA, Moeschberger ML, Cotter SA, Kleinstein RN, Manny RE, Twelker JD, Zadnik K. Relative peripheral refractive error and the risk of onset and progression of myopia in children. CLEERE Study Group. Invest Ophthalmol Vis Sci 2011; 52: 199–205.
39. Zhong Y, Chen Z, Xue F, Zhou J, Niu L, Zhou X. Corneal power change is predictive of myopia progression in orthokeratology. Optom Vis Sci 2014; 91: 404–11.
40. Santodomingo-Rubido J, Villa-Collar C, Gilmartin B, Gutierrez-Ortega R. Factors preventing myopia progression with orthokeratology correction. Optom Vis Sci 2013; 90: 1225–36.
41. Chen Z, Niu L, Xue F, Qu X, Zhou Z, Zhou X, Chu R. Impact of pupil diameter on axial growth in orthokeratology. Optom Vis Sci 2012; 89: 1636–40.