Topical Atropine in Retarding Myopic Progression and Axial Length Growth in Children with Moderate to Severe Myopia: A Pilot Study

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1 Jpn J Ophthalmol 2007;51:27 33 Japanese Ophthalmological Society 2007 DOI /s CLINICAL INVESTIGATION Topical Atropine in Retarding Myopic Progression and Axial Length Growth in Children with Moderate to Severe Myopia: A Pilot Study Dorothy S. P. Fan, Dennis S. C. Lam, Carmen K. M. Chan, Alex H. Fan, Eva Y. Y. Cheung, and Srinivas K. Rao Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong Eye Hospital, Kowloon, Hong Kong, People s Republic of China Abstract Purpose: To study the safety and efficacy of topical 1% atropine eye ointment in retarding myopic progression in children with moderate to severe myopia. Methods: This was an interventional control study. Children (aged 5 10 years) with myopia of 3.00 diopters (D) or more were treated with 1% atropine ointment once daily for 1 year. Baseline and regular assessments of refractive errors by cycloplegic autorefraction and of axial length were done by ultrasound biometry, and the results were compared with data of control subjects. Results: Twenty-three children (mean age: 7.4 ± 1.6 years) with moderate to severe myopia, being treated in the Hong Kong Eye Hospital of the Chinese University of Hong Kong, were recruited into the atropine group, and 23 children from the same eye clinic were matched with the study subjects with respect to age, sex, and initial spherical equivalent refraction, as controls. The initial refractive errors were 5.18 ± 2.05 D and 5.12 ± 2.33 D in the atropine and the control groups, respectively (P = 0.934). Myopic progression was significantly less (P = 0.005) in the atropine group (+0.06 ± 0.79 D) than in the control group ( 1.19 ± 2.48 D). Axial length increase was also significantly smaller in the atropine group (0.09 ± 0.19 mm) than in the control group (0.70 ± 0.63 mm) (P = 0.004). One child (4.3%) developed an allergic reaction. No other major adverse effects related to the treatment were noted. Conclusion: Topical 1% atropine ointment is a safe and effective treatment for retarding myopic progression in moderate to severe myopia. Further large-scale randomised controlled study with longer followup seems warranted. Jpn J Ophthalmol 2007;51:27 33 Japanese Ophthalmological Society 2007 Key Words: atropine, myopia, myopic progression Introduction Myopia is one of the most common ocular abnormalities. 1,2 In the United States, 25% of the adult population is myopic, while higher prevalence rates of 90% have been reported Received: March 31, 2006 / Accepted: August 30, 2006 Correspondence and reprint requests to: Dorothy S.P. Fan, Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, 3/F, Hong Kong Eye Hospital, 147K Argyle Street, Kowloon, Hong Kong dorothyfan@cuhk.edu.hk Dorothy S. P. Fan and Dennis S. C. Lam contributed equally to the study. in some Asian populations. 1 4 Higher degrees of myopia are associated with a number of sight-threatening complications, which include macular degeneration, retinal detachment, glaucoma, and cataract. 5 8 All of these myopia-related complications may lead to permanent visual impairment or blindness, and tend to occur in young adults, unlike other blinding disorders, for example, diabetic retinopathy and age-related macular degeneration. At present, the exact mechanism of myopia remains unclear. However, even without a good understanding of the mechanism underlying myopic development, many options for slowing the progression of myopia have already been proposed and evaluated. These include the use of bifocal lenses, 9 11 multifocal lenses, 12,13 contact lenses (e.g.,

2 28 Jpn J Ophthalmol Vol 51: 27 33, 2007 rigid, gas-permeable lenses), 14,15 orthokeratology, 16 and a number of pharmacological agents (e.g., timolol and atropine). Unfortunately, the results have been controversial. 17,18 To date, atropine is the only treatment that has been demonstrated to be consistently effective in slowing myopic progression. 17,18 The first report of atropine treatment for myopia was published by Wells nearly two centuries ago. 18 Since then, a number of clinical studies have evaluated the effects of topical atropine on myopic progression However, most of the previous studies on the effect of atropine on myopic progression were done in children with low degrees of myopia, and information regarding atropine treatment in moderate to high degrees of myopia is scarce. Children with moderate to severe myopia are expected to have greater and more rapid myopic progression. 4 They are also more prone to have complications associated with the myopia, and a safe and effective treatment to retard progression of the refractive error would be very useful in this cohort. It was, therefore, the purpose of the current study to evaluate the safety and efficacy of topical atropine in retarding myopic progression in children with moderate to severe myopia. Subjects and Methods This was an interventional case control study conducted at the Hong Kong Eye Hospital. The study was approved by the institutional review board of the Chinese University of Hong Kong, and parental informed consent was obtained. The study was conducted according to the guidelines of the Helsinki Declaration, and carried out from 2002 to Children aged 5 to 10 years with moderate to severe myopia, defined as spherical equivalent refraction (SER) of more than 3.00 diopters (D) (SER = spherical plus half of the cylinder reading), were recruited from patients being treated at the Hong Kong Eye Hospital of the Chinese University of Hong Kong. According to their history, all subjects had had at least 0.50 D of myopic progression in both eyes in the past year. They also had a best-corrected visual acuity of better than 0.1 by the Early Treatment for Diabetic Retinopathy Study guidelines (equivalent to 20/25 by Snellen chart examination) and had less than 1.50 D per cylinder of astigmatism in each eye. Children who had previously been treated to prevent myopia progression (e.g., with bifocal lenses, multifocal lenses, contact lenses, or atropine) or with a history of having ophthalmic diseases other than refractive errors were excluded from the study. Other exclusion criteria included the presence of systemic disease that required long-term medication, heart disease, allergy to atropine, and anisometropia (>1.00 D). Twenty-three subjects were selected for the study. The same eligibility criteria applied to the control subjects. Both eyes of the 23 subjects were treated by topical 1% atropine ointment (1% atropine sulphate, Alcon, Mississauga, Canada) once daily for 1 year. Atropine ointment was used because of its increased retention time and reduced systemic absorption via the lachrymal system. 28,29 Cycloplegic autorefraction and keratometry (Topcon KR-7100 autorefractometer; Topcon, Tokyo, Japan) were performed before the commencement of the study and at trimonthly intervals thereafter for a total follow-up period of 1 year. Axial length measurement by ultrasonography (Compuscan; Storz Ophthalmic, St. Louis, MO, USA) and intraocular pressure measurement (Tonopen; Mentor, Norwell, MA, USA) were done at the beginning and trimonthly till the end of the study. The repeatability of ultrasound biometry in children was found acceptable in a previous study. 30 The optometrists performing the above efficacy measurement and visual acuity testing were masked regarding the treatment that the children received. To detect any adverse effects, careful and comprehensive examination, including slit-lamp and fundus examination, was performed by a single ophthalmologist for all subjects on a trimonthly basis. Pupil size, blurring of vision, photophobia, and allergic symptoms were evaluated. The children and their parents were asked to return all of the medication tubes, both used and unused ones, during visits in order to assess compliance. Photochromic progressive glasses (+2.50 D lens, Varilux Comfort, Essilor, Charentonle-Pont, France) with ultraviolet filter lens were prescribed for every participant according to their subjective refraction, for the loss of accommodation after cycloplegia, and to protect the eye from ultraviolet light damage after pupil dilatation. All control cases were matched with the study cases in terms of age, sex, and initial SER (±0.50 D). If more than one child matched with a study case, one of these was randomly selected as the control. The control group received the same ophthalmic examinations as the study subjects. All children in the study, both subjects and controls, were examined regularly, with cycloplegic (1% cyclopentolate hydrochloride; Alcon-Couvreur, Puurs, Belgium) autorefraction and axial length measurements. The rate of myopia progression, in terms of diopters per year, and the change in axial length were the two major outcomes measured. The sample size of 23 per group was estimated on the assumption that the difference in myopia progression between the two groups would be 1.0 D per year, providing a power of Adverse effects, if any, were recorded. Data were analysed using the Statistical Package for the Social Sciences for Windows (ver. 11.0; SPSS Science, Chicago, IL, USA). The t test and χ-squared test were used to compare the initial and final refraction between the atropine and control groups. A general linear model was also fitted with age and sex as covariates. The results were regarded as significant if the P value was less than A total of 23 children (46 eyes) were recruited into the atropine group, and all of them completed the 1-year course of atropine treatment and follow-up. Thirteen (56.5%) of the children were girls and 10 (43.5%) were boys, with a mean age of 7.4 years (SD, 1.6 years; range, 5 10 years).

3 D. S. P. FAN ET AL. 29 ATROPINE RETARDS MYOPIC PROGRESSION Results None of the cases was lost to follow-up, and all children completed the examinations. There was a high correlation in initial SER between the right and left eyes (r = 0.935). Therefore, only the data from the right eye of each child was used for analysis. The initial refractive error measured by cycloplegic autorefraction of the atropine group was 5.18 D (SD, 2.05 D; range, 3.00 to 9.75 D), whereas that of the control group was 5.12 D (SD, 2.33 D; range, 3.00 to 9.75 D) (Table 1). There was no statistically significant difference in the mean initial refractive errors between the two groups (t test, P = 0.934). After 1 year of atropine treatment, the cycloplegic refraction of the atropine group was 5.12 D (SD, 2.15 D; range, 3.00 to 9.25 D) and that of the control group was 5.99 D (SD, 2.48 D; range, 3.00 to 9.75 D) (t test, P = 0.305). The final refraction was more myopic compared with the initial refraction in the control group (paired t test, P = 0.002), but not in the atropine group (paired t test, P = 0.759). The 1- year change in refractive error for the atropine and control groups was, therefore, D (SD, 0.79 D; range, 1.50 to 0.75 D) and 1.19 D (SD, 2.48 D; range, 5.00 to 0.00 D) respectively (t test, P = 0.005). Figure 1 shows the change in myopia progression in the atropine and control groups throughout the 1-year study period. The mean keratometric measurement at the initial examination was D (SD, 2.30 D; range, to D) and D (SD, 1.92 D; range, to D) for the atropine and the control groups, respectively (t test, P = 0.991). There was also no significant difference in keratometric measurements between the two groups (atropine, ± 2.07 D; control, ± 1.85 D; t test, P = 0.914) 1 year after the initial examination. The mean intraocular pressure (IOP) at the initial examination was 16.0 mmhg (SD, 2.7 mmhg; range, 11.3 to 20.0 mmhg) and 16.0 mmhg (SD, 2.6 mmhg; range, 12.0 to 20.0 mmhg) for the atropine and the control groups, respectively (t test, P = 0.998). There was also no significant difference in IOP between the two groups (atropine, 15.5 ± 2.1 mmhg; control, 16.1 ± 2.6 mmhg; t test, P = 0.547) 1 year after the initial examination. Fifteen (65.2%) children in the atropine group, in contrast to 2 (8.7%) in the control group, (χ-squared test, P < Table 1. Initial and final cycloplegic autorefraction in atropine and the control groups Atropine Control P value Initial examination 5.18 D 5.12 D (before the start of (SD: 2.05 D) (SD: 2.33 D) atropine) Final examination 5.12 D 5.99 D (1 year after initial (SD: 2.15 D) (SD: 2.48 D) examination) Annual change D 1.19 D (SD: 0.79 D) (SD: 2.48 D) D, diopter ) had no progression or a reduction in myopia (Table 2). Five (21.7%) children in the atropine group, compared with 19 (82.6%) children in the control group, had more than 0.50 D progression in myopia (χ-squared test, P < 0.001). Only three children in the atropine group had rapid myopic progression of greater than 1.00 D, compared with eight out of 23 (34.8%) in the control group, who had rapid myopic progression (χ-squared test, P = 0.084). There were no significant differences in age (no progression group, 6.91 ± 1.51 years; progression group, 7.83 ± 1.55 years; t test, P = 0.109); sex (χ-squared, P = 0.803); initial SER (no progression group, 5.61 ± 2.06 D; progression group, 4.62 ± 2.14 D; t test, P = 0.206); astigmatism (no progression group, 1.14 ± 0.74 D; progression group, 1.14 ± 0.75 D; t test, P = 0.997), keratometry (no progression group, ± 2.00 D; progression group, ± 2.11 D; t test, P = 0.450), axial length (no progression group, ± 1.02 mm; progression group, ± 0.92 mm; t test, P = 0.612); or IOP (no progression group, 14.8 ± 2.4 mmhg; progression group, 16.7 ± 2.5 mmhg; t test, P = 0.091) between the children with no myopia progression and the children with myopia progression. Mean + SD of SER / D Month Figure 1. Change in myopic progression in the atropine and control groups during the 1-year study period., atropine group; , control group. Bars show 1 SD. Table 2. Degrees of myopic progression in the atropine and control groups 9 12 Atropine Control P value No progression in myopia 15/23 (65.2%) 2/23 (8.7%) <0.001 Myopic progression 5/23 (21.7%) 19/23 (82.6%) <0.001 of 0.50 D or more Myopic progression 3/23 (13.0%) 8/23 (34.8%) of 1.0 D or more

4 30 Jpn J Ophthalmol Vol 51: 27 33, 2007 The initial axial length was mm (SD, 1.03 mm; range, mm) in the atropine group and mm (SD, 0.78 mm; range, mm) in the control group (t test, P = 0.719). The final axial length was mm (SD, 0.97 mm; range, mm) in the atropine group and mm (SD, 0.92 mm; range, mm) in the control group (t test, P = 0.253). Children receiving atropine treatment had significantly less increase in annual axial length compared with those in the control group (Table 3, Fig. 2). The change in axial length was 0.09 mm (SD, 0.19 mm; range, mm) in the atropine group and 0.70 mm (SD, 0.63 mm; range, mm) in the control group (t test, P = 0.004). In the initial examination, the right eye distance visual acuity (VA) was 0.0, as measured by the Early Treatment for Diabetic Retinopathy Study method (equivalent to 20/20 by Snellen chart examination) in all children in the atropine group (n = 23) except one whose visual acuity was 0.1 (equivalent to 20/25 by Snellen chart examination). At the end of the study, 21 cases retained 0.0 VA, the child with initial 0.1 VA remained the same, and one child had improvement of VA to 0.9 (equivalent to 20/15 by Snellen chart examination). The near VA of all children in the atropine group was 0.0 throughout the study. Mean + SD of axial length / mm Month Figure 2. Axial length in the atropine and control groups during the 1-year study period., atropine group; , control group. Bars show 1 SD All children in the atropine group tolerated the 1% atropine ointment and completed the whole course of treatment. One child (4.3%) had a mild allergic reaction to the topical atropine ointment initially. The allergic reaction subsided quickly upon cessation of treatment, and the child was able to resume the treatment later without any further reaction. The mean pupil size was 7.2 mm (SD, 0.6 mm; range, mm). Twelve children (52.2%) complained of temporary photophobia. None of the children complained of a near vision problem. No other ocular or systemic adverse effects, including dermatitis, keratitis, and lens opacity, were detected during the 1-year follow-up period. The wearing of progressive glasses was also well tolerated by these children. All of them enjoyed normal daily activities and school life during the treatment period. Discussion The results of our interventional case control study indicated that 1% topical atropine is effective in slowing myopic progression in moderately to severely myopic children (more than 3.00 D) at the end of 1 year of treatment, compared with age-, sex-, and refractive error-matched controls who did not receive any intervention. In our study, the mean myopia progression rate was significantly slower in the 1% atropine group (+0.06 D/year) than in the control group ( 1.19 D/year). The difference in myopic progression rate between the atropine group and the control group was 1.25 D/year, and was higher than that previously reported by other studies (Table 4). A number of clinical reports and trials addressing the efficacy of atropine in retarding myopia progression have been published in the past three decades Most of these studies were able to demonstrate that topical application of atropine is effective in slowing myopic progression. The most common dosage of topical atropine investigated is 1% eye drops or ointment. In 1979, Bedrossian evaluated the effect of 1% atropine ointment in 62 children in a nonrandomized study. 19 The ointment was applied once at night in one eye for 1 year with the fellow eye as control. After 1 year, treatment was switched to the fellow eye. Myopia progression was found to be significantly less in the treated eyes (+0.02 D/year) compared with the control eyes ( 0.85 D/year). Posttreatment data analysis indicated that the effects were long-term. Since then, atropine has been consistently demonstrated to be effective in retarding myopia progression ,31 Shih et al. 26 compared the effects of different dosages of topical atropine (0.5%, 0.25%, and Table 3. Change of axial length in the atropine and control groups Atropine Control P value Initial exam mm (SD: 1.03 mm) mm (SD: 0.78 mm) Final exam mm (SD: 0.97 mm) mm (SD: 0.92 mm) Annual change 0.09 mm (SD: 0.19 mm) 0.70 mm (SD: 0.63 mm) 0.004

5 D. S. P. FAN ET AL. 31 ATROPINE RETARDS MYOPIC PROGRESSION Table 4. Annual myopic progression in the atropine and control groups in the literature Atropine Control Difference Bedrossian (1979) 19 1% ointment D/year 0.85 D/year 0.87 D/year Yen et al. (1989) 27 1% eye drops 0.22 D/year 0.91 D/year 0.69 D/year Shih et al. (1999) 26 1% eye drops 0.04 D/year 1.06 D/year 1.02 D/year Syniuta and Isenberg (2001) 33 1% eye drops 0.05 D/year 0.84 D/year 0.79 D/year Lee et al. (2006) % eye drops 0.28 D/year 0.75 D/year 0.47 D/year Our results 1% ointment D/year 1.19 D/year 1.25 D/year 0.1%). 26 and noted a mean myopia progression of 0.04 D/ year in the 0.5% atropine group (n = 41), 0.45 D/year in the 0.25% atropine group (n = 47), 0.47 D/year in the 0.1% atropine group (n = 49), and 1.06 D/year in the control group (n = 49). This implies that the effect of atropine may be dose-dependent. On the other hand, most of the previous studies concerning the use of atropine for treating myopia were done in children with low degrees of myopia. Since children with moderate to severe myopia in general have more rapid myopic progression, it is logical that they would benefit most from a safe and effective treatment that retards myopia progression. 4 Therefore, if effective, atropine would be very beneficial for these highly myopic children. At present, information concerning the effect of atropine on the refractive error change in children with moderate to severe myopia is limited. In a small case series involving 20 highly myopic children (more than 6.00 D), myopic progression was found to be significantly reduced after the use of 0.5% atropine eyedrops. 32 The results of this case series, though encouraging, were weakened by the lack of controls, no axial length measurement, and the previous use of myopia treatment other than atropine in most of the subjects. Among the limitations of the present study was the lack of randomization of the subjects to the treatment and no treatment groups. There was also no placebo used in the control group. We tried to overcome this limitation by using controls matched for age, sex, and refractive error with the children in the atropine group. With regard to the interpretation of the efficacy of atropine in prevention of myopic progression, 17 27,31 33 the use of different cycloplegic agents for measuring refraction in the atropine and the control groups also may have influenced the difference in refractive errors noted during treatment. In these studies, children in the atropine group were under the influence of atropine throughout the study period. On the other hand, children in the control group received a short-acting, milder cycloplegic agent (1% cyclopentolate) only before each refraction measurement. As atropine is a stronger cycloplegic, it could reveal more hypermetropia. 34 This may account for the reduction in myopia in some children treated with atropine. In order to minimise the possible errors brought about by the use of different cycloplegic agents in measuring refractive errors, another objective parameter reflecting myopia progression is needed. Axial length measurement by ultrasonography is well established as reflecting the severity of myopia and is independent of the effects of cycloplegic agents at the time of measurement. Therefore, change in axial length was used as an indicator of myopia progression in our study. Indeed, the effect of atropine on axial length has not been examined in most of the previous clinical trials. In our study, change in axial length growth was significantly less (P = 0.004) in the atropine group (0.09 mm) than in the control group (0.70 mm). There was also a significant correlation between myopia progression and axial length increase (r = 0.771, P = 0.001). The effect of atropine in retarding the elongation of axial length has been postulated to be due to both local effects (e.g., suppressing dopamine neurotransmitters and retinal growth signals) and systemic effects (e.g., suppressing growth hormone secretion from the pituitary gland). 38,39 Progressive lenses have been proposed to reduce myopia progression in children. 12,13 However, the results from the COMET study showed only a small amount of retardation in myopic progression (0.20 D) over 3 years in the progressive lenses group compared with the single lenses group. 13 In addition, other studies have shown that the use of a progressive lens cannot retard myopic progression in children. 40 Since we noted a more significant change in refractive error progression in the atropine group in our study over 1 year, we are not sure of the relative contribution of atropine and progressive lens use toward reducing myopic progression. A selective antimuscarinic agent (pirenzepine) has been proposed to prevent myopia progression and has fewer side effects than atropine. The mean myopia progression in children using 2% pirenzepine was 0.47 D after 1 year compared to 0.84 D in the control group. 41 The efficacy and the safety of pirenzepine are still under active investigation. Other studies have examined the effect of ocular hypotension in preventing myopic progression, based on the hypothesis that the increase in eye size in myopia may be due to passive stretching of the sclera. 42 However, the results of these studies are not consistent. 43,44 Our study did not find differences in IOP between the atropine-treated children and the controls at the initial examination or 1 year after. In our study, we found that myopic progression was less in children treated with atropine than in controls. This was associated with less increase in axial length. However, no difference was found by keratometry. Therefore, the retardation of myopia progression was attributed to the

6 32 Jpn J Ophthalmol Vol 51: 27 33, 2007 reduction of the increase in axial length. However, further analysis of the exact mechanism is warranted. There are potential hazards associated with atropine treatment. These include potential toxicity to the retina and lens due to long-term dilation of pupils and exposure to ultraviolet light, and also the potential influence on ocular phoria and accommodation. In addition, the medication may also have systemic effects. 17,18 On the other hand, the side effects of atropine treatment have been shown to be easily tolerated by previous studies A study by Kennedy et al. 23 observed no serious adverse effect associated with atropine application in children, after a median follow-up of 3.5 years and a maximum of 11.5 years. According to our experience in the current trial, photophobia is usually shortlived. Loss of accommodation was treated by using progressive glasses. None of the children complained of a near vision problem. The potential damage that may be brought about by excessive ultraviolet light was minimised by adding an ultraviolet filter to the glasses. After taking all these preventive measures, all of our subjects completed the whole course of treatment. In our 1-year study, no serious problem was found among the children. In conclusion, despite the hazards of the use of atropine noted above, our study indicates that the use of 1% atropine ointment has the effect of slowing myopic progression in children with moderate to severe myopia. On the other hand, the long-term effects are still unclear. The effects reported in the present study appear to be mediated by altering axial length changes. It may be warranted to study the long-term effects of atropine on myopic progression, as well as its long-term side effects by a, randomised, placebocontrolled study with a larger sample size and longer followup. 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