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Two-year add-on effect of using low concentration atropine in poor responders of orthokeratology in myopic children
  1. Zhi Chen,
  2. Jiaqi Zhou,
  3. Feng Xue,
  4. Xiaomei Qu,
  5. Xingtao Zhou
  1. Ophthalmology and Visual Science, Fudan University Eye Ear Nose and Throat Hospital, Shanghai, Shanghai, China
  1. Correspondence to Dr Xingtao Zhou, Ophthalmology and Visual Science, Fudan University Eye Ear Nose and Throat Hospital, Shanghai, Shanghai, China; xingtaozhou{at}163.com

Abstract

Methods Axial elongation in 73 eyes of 73 subjects who completed 3 years of orthokeratology (ortho-k) treatment was retrospectively reviewed. During their first year of ortho-k treatment (phase 1), they all demonstrated an axial elongation of 0.30 mm or greater. They were then divided into two groups: orthokeratology and atropine (OKA) group (n=37) being treated with nightly 0.01% atropine in addition to ortho-k treatment for another 2 years and orthokeratology (OK) group (n=36) continued to be treated with ortho-k without atropine (phase 2). Axial elongation over time and between groups was compared.

Results Baseline biometrics was similar between the two groups in phase 1 (all p>0.05). The mean axial elongation was 0.47±0.15, 0.21±0.15, 0.23±0.13 mm for the OKA group and 0.41±0.09, 0.30±0.11, 0.20±0.13 mm for the OK group during the first, second and third year, respectively. The cumulative axial elongation over 3 years was 0.91±0.30 mm for the OKA group and 0.91±0.24 mm for the OK group. The overall AL change was not significantly different between the two groups (p=0.262). Baseline myopic refractive error had a significant impact on axial elongation over 3 years of treatment (p<0.001). None of baseline age (p=0.129), lens design (p=0.890) or treatment modality (p=0.579) had a significant impact on axial elongation.

Conclusions For fast myopia progressors and poor responders of ortho-k, combining 0.01% nightly atropine did not significantly change the3-year axial elongation outcome as compared to ortho-k mono-therapy.

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Myopia is an optical disorder featured by an overelongated eye and decreased unaided distance visual acuity. Among Eastern Asian children, myopia typically starts at early school year and progresses in severity until adulthood.1 The prevalence of myopia has reached unprecedented levels around the globe, especially in Eastern Asia.2 The disturbing aspects of myopia include, not only the inconvenience of wearing optical correction lenses, but also the possibility of becoming high myopia, a condition associated with a high risk of developing serious complications in later life,3 hence justifying the necessity for interventions to slow the progression of myopia in children.

Multiple interventional methods, including pharmaceutical and optical treatments, have been attempted to retard myopia progression in children and adolescents.4 Among all the myopia control modalities, orthokeratology (ortho-k) has gained popularity in China in the last decade, with the current number of ortho-k lens wearers estimated to be over 1.5 million.5 Modern ortho-k contact lenses are specially designed rigid gas-permeable lenses worn overnight to correct mild to moderate refractive error during sleep. It has been shown to effectively slow myopia progression in children and adolescents, with an average control effect of approximately 41.7% across different studies.6 This effect, however, is accompanied with significant individual variability. The patient’s age,7–9 initial refractive error8 10 11 and pupil size12 have all been proposed to be influencing factors, with younger children being most likely to experience faster axial elongation during ortho-k treatment.

On the pharmaceutical arm, atropine, a non-selective muscarinic receptor antagonist, revealed a significant effect against myopia progression and axial elongation in a concentration-related manner.13 While low concentration (eg, 0.01%) atropine may not be potent enough to control myopia when used as a single treatment, it has shown promising control effects when used in combination with ortho-k.14–16 In a preliminary study, low concentration atropine was used in addition to ortho-k in order to enhance the myopia control effect in fast myopia progressors.17 The authors found that the annual axial elongation rate dropped significantly when 0.01% atropine eye drop was added. That study, however, lasted for 2 years with only 1 year of combined treatment, raising the question whether this myopia control effect is sustainable through a longer term.

The current study was aimed at investigating the 2-year add-on effect of using low concentration atropine in poor responders of ortho-k in myopic children

Methods

Study design

Chinese children who visited the Fudan University Eye and Ear, Nose and Throat (ENT) Hospital (Shanghai, China) between April 2016 and June 2019 and who met the following criteria were consecutively enrolled in this retrospective study: (1) aged under 12 years when starting ortho-k treatment; (2) initial myopic refractive error between −5.75 D and −0.75 D; (3) anisometropia no greater than 1.00 D; (4) annual axial elongation of 0.30 mm or greater in the first year of ortho-k treatment (fast progressors); (5) have had axial length (AL) values to be collected every half year (±1 month) over a period of 3 years without missing values. All data were retrieved from the patients’ clinical records.

Study protocol

Phase 1

All subjects had received comprehensive screening tests before being fitted with either spherical or toric designed 4-zone ortho-k lenses (Euclid, USA) in both eyes. A trial lens fitting strategy has been applied in all cases and lenses were ordered targeting full correction. Follow-up visits were scheduled at 1 day, 1 week, 1 month, 3 months and every 3 months after ortho-k lens wear as a clinical routine. During regular follow-up visits at 1 month or later, if daily visual acuity was lower than 20/25, overrefraction would be performed and new lens ordered accordingly, otherwise lenses were replaced routinely every 12–18 months.

AL measurement using the IOLMaster 5.5 (Carl Zeiss Meditec, Dublin, USA) was performed in both eyes at baseline and every 6 months after commencing ortho-k lens wear (AL measurement was taken every 3 months as a clinical routine in this research setting). Subjects who showed axial elongation of 0.30 mm or greater in the first year of ortho-k treatment were given the option to apply one drop of 0.01% atropine nightly before ortho-k lens wear. Those who were willing to use atropine were assigned to the test (orthokeratology and atropine, OKA) group and the rest were assigned to the control (orthokeratology, OK) group for phase 2.

Phase 2

Subjects in the OKA group were prescribed 0.01% concentration atropine eye drop at the end of first year. The 0.01% atropine ophthalmic solution was prepared by the pharmaceutical department of Fudan University Eye and Ear, Nose and Throat (ENT) Hospital by diluting atropine sulfate injection 0.05% (Hubei Xinghua Pharmaceutical, Wuhan, China) with sodium hyaluronate eye-drops 0.3% (Santen Pharmaceutical) at a ratio of 1:4 in a sterile manner. The 0.01% atropine solution was then stored in a 5 mL polypropylene container refrigerated at 5°C and the shelf life for an unopened product was 3 months. Since the benzalkonium chloride preservative was also diluted, the solution was used within a month after opening. Subjects in the combination group were instructed to instil the 0.01% atropine eye drop into both eyes without their eyelids or eyelashes touching the tip of the bottle, once daily at night, at least 10 min before inserting the ortho-k lenses.

Subjects were requested to log any visual disturbances associated with atropine use, for example, photophobia, reading difficulties during the follow-up visits. AL measurement was made every 6 months after atropine use. The subjects were followed for 2 years in phase 2.

Statistical analysis

Baseline spherical equivalent refractive error (SERE), AL and age were compared between the two study groups using independent samples t-test. AL elongation over time and between groups was compared using repeated measures analysis of variance. Generalised estimating equation was conducted to flexibly assess the impact of various factors including baseline age, refractive error, lens design and treatment (OK vs OKA) on axial elongation over 3 years of treatment. All statistical analyses in this study were performed in software R (V.3.2.0.).

Results

Data of the right eyes of 73 patients (37 OKA, 36 OK) were retrieved from clinic files. Baseline age (8.8±1.2 yo vs 8.9±1.4 years, t=−0.535, p=0.594), spherical refractive error (2.61±1.10 D vs 2.17±0.99 D, t=1.805, p=0.075), SERE (−2.85±1.08 D vs −2.38±1.10 D, t=1.767, p=0.082) or AL (24.49±0.95 mm vs 24.26±0.90 mm, t=1.083, p=0.283) did not differ significantly between the two study groups (OKA vs OK). Toric lens design was used in six patients in the OKA group and 10 patients in the OK group. All subjects underwent uneventful ortho-k treatment in both phases and no subjects reported photophobia or near vision difficulties.

AL change was 0.47±0.15 mm, 0.21±0.15 mm, 0.23±0.13 mm and 0.41±0.09 mm, 0.30±0.11 mm, 0.20±0.13 mm for the OKA and OK group during the first, second and third year, respectively. The cumulative axial elongation over a total of 3 years was 0.91±0.30 mm in the OKA group and 0.91±0.24 mm in the OK group (figure 1).

Figure 1

Annual and cumulative axial length change in the combined treatment (OKA) group and the orthokeratology (OK) group.

Because Mauchly’s test showed that the sphericity of data is not assumed, Greenhouse-Geisser correction was used to compare axial elongation within groups (over time) and between groups (OK vs OKA). AL significantly changed over time (p<0.001), showing increase in both study groups (figure 2). However, AL change was not statistically significantly different between the two study groups (p=0.262), neither was there a significant interaction between time*group (p=0.362).

Figure 2

Axial growth in the combined treatment (OKA) group and the orthokeratology (OK) group.

Generalised estimating equation model showed that baseline myopic refractive error had a significant impact on axial elongation over 3 years of treatment (p<0.001), with higher baseline myopia associated with faster axial elongation. None of baseline age (p=0.129), lens design (p=0.890), or treatment modality (p=0.579) had a significant impact on axial elongation.

Discussion

In this retrospective study, we found that for fast myopia progressors and poor responders of ortho-k, combining 0.01% nightly atropine did not significantly change the 3 years (phase 1 and 2) axial elongation outcome as compared with ortho-k mono-therapy.

In a previous study, we retrospectively assessed the data of patients who had completed 1 year of ortho-k treatment and another year of combined (ortho-k +0.01% atropine) therapy.17 The subjects in the test group had a mean axial elongation of 0.46 mm in the first year. When nightly dose of 0.01% atropine eye drop was added, annual axial elongation slowed dramatically to a mean of 0.14 mm. In agreement with that study,17 the addition of atropine significantly slowed axial elongation rate in children undergoing ortho-k therapy in the first year of combined treatment (from 0.47 to 0.21 mm) in the current study. However, the axial elongation in the second year of combined treatment (0.23 mm) did not show a further decrease in rate compared with the previous year or any advantage over the OK group in the same study year (0.20 mm). Therefore, the mean cumulative axial elongation over 3 years of study did not differ between the two study groups (0.91 mm in both groups).

In concordance with the findings in this study, Kinoshita et al14 revealed a better control effect of combined treatment over ortho-k monotherapy (0.09 mm vs 0.19 mm) in the first year. When the authors extended the study to 2 years, the OKA group revealed no consistent advantage in myopia control over the OK group in the second year (0.20 mm vs 0.21 mm).16 Although Kinoshita et al’s study and the current study had similar findings that myopia control efficacy decreases over time in the combined treatment,16 it should be noted that the two studies vary in a few aspects. The mean age of subjects was 10.3 years old in Kinoshita et al’s study16 as compared with 8.8 years old in the current study. The subjects in Kinoshita et al’s study were randomly allocated to OKA or OK group and were not necessarily fast myopia progressors.16 The subjects in the current study were all fast myopia progressors who had over 0.30 mm annual axial elongation even undergoing ortho-k therapy, meaning that all the subjects enrolled were all poor responders of ortho-k at least in the first year. Despite these significant discrepancies, the two studies resemble in results and both raise questions as to whether the combined treatment effect is sustainable and whether the addition of 0.01% atropine is beneficial over using ortho-k mono-therapy in the long term.

There are two possible explanations for the 3 years’ negative results. First, the dramatic decrease in axial elongation rate in the first year of combined treatment could be due to a temporary choroidal thickening after atropine use. Studies have shown that topical 1% atropine can lead to choroidal thickening and AL shortening.18 By the same token, 0.01% atropine may have caused choroidal thickening when added to ortho-k treatment, exaggerating the axial elongation control effect during the first year of combined treatment. Second, it has been proposed that atropine exerts its myopia control effect as a non-selective muscarinic antagonist.19 Based on this assumption, continuous exposure to this pharmacological antagonist may have ‘exhausted’ the receptors and lead to a reduction in myopia control efficacy over time.

It should be noted that the axial elongation rate in the ortho-k control group showed a consistent decrease over time, which agrees with the evidence that myopia progression slows down with age in normal Chinese children.20 Hiraoka et al21 compared 5-year axial elongation between subjects wearing ortho-k lenses and single-vision lenses and reported a consistent annual axial elongation of approximately 0.20 mm in the ortho-k group throughout the study period. Noteworthy is that the baseline age for their subjects was on average 10 years, as compared with 8.8 years old in the current study. Therefore, it is not surprising that the axial elongation in the third year (when subjects became 2 years older) of the current study (0.23 mm in OKA group and 0.20 mm in OK group) was similar to that of Hiraoka et al’s study (0.20 mm). Should axial elongation after ortho-k treatment slow down with age and plateau after a few years of treatment, for example, yielding a consistent 0.20 mm annual axial elongation, then using combined atropine would not bring additional benefit over using ortho-k alone in the long-term.

It is found in the current study that there was a significant individual variability in the 3 years of treatment, with subjects of higher initial myopia showing faster axial elongation. The studies conducted by Kakita et al and Hiraoka et al have found that ortho-k is less effective in slowing axial elongation in lower compared with higher degrees of myopia.10 21 In Cho and Cheung and Zhong et al’s study, axial elongation is not correlated to initial refractive error in ortho-k subjects.8 22 Wan et al found that the combination treatment of lower concentration (0.025%) atropine and ortho-k slows axial elongation in lower myopic patients (<6 D) but not in high myopic patients (≥6 D) when compared with ortho-k mono-therapy.23 Caution should be taken when comparing these above-mentioned studies with the current study as they have applied different analytical methods. Wan et al divided the patients into different refractive error groups.23 Kakita et al did simple correlation test.10 The rest of the above-mentioned studies used linear regression analysis, taking into account various factors including initial refractive error and age.8 21 22 In the current study, generalised estimating equation was conducted to assess the impact of baseline age, refractive error, lens design and treatment (OK vs OKA) on axial elongation over 3 years of treatment and showed different results from the above-mentioned studies. Therefore, it can be argued that the addition of atropine may be more effective in controlling axial elongation in ortho-k subjects with lower initial degree of myopia, which agrees with the finding of Kinoshita et al’s study16 and Wan et al’s study.23 Further studies are needed to illustrate the mechanisms underlying this correlation.

This study has a few limitations. First, although the two study groups were well matched at baseline, the study design was retrospective in nature and was therefore subject to selection bias. Those who were willing to use atropine might be due to the fact that they were having higher educational stress and less time outdoors. Second, since all the subjects included in this study were fast myopia progressors and poor responders of ortho-k, the conclusion cannot be readily extrapolated to general myopic patients who are undergoing ortho-k therapy. Third, we proposed that the dramatic change in axial elongation rate in the first year of combined treatment was partly caused by choroidal thickening after atropine use. Evidence, however, is lacking as we did not measure the choroidal thickness using optical coherence tomography, which should always be considered in future study designs. Lastly, this study did not address the question whether higher concentration, for example, 0.02%, atropine has a stronger myopia control effect when used in combination with ortho-k, because higher concentrations of atropine may have a more potent myopia control effect than 0.01% concentration, as indicated by a 2-year randomised clinical trial published recently.13

In conclusion, we found in the current study that for fast myopia progressors and poor responders of ortho-k, combining 0.01% nightly atropine did not significantly change the 3 years axial elongation outcome as compared with ortho-k mono-therapy. Therefore, caution should be exercised when determining whether to use atropine, especially of 0.01% concentration, in fast myopia progressors and poor responders of ortho-k.

References

Footnotes

  • Contributors ZC, JZ, FX conducted the study, collected and analysed the data, and wrote the manuscript. XQ and XZ designed the study, provided critical supervision, did the proofreading and revised the manuscript.

  • Funding This work was supported by the National Natural Science Foundation of China grant number 81700870.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available on reasonable request. The deidentified patient data were retrieved from clinic files.

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