1040-5488/13/9012-1486/0 VOL. 90, NO. 12, PP. 1486Y1492 OPTOMETRY AND VISION SCIENCE Copyright * 2013 American Academy of Optometry
ORIGINAL ARTICLE
Treatment Outcomes of Myopic Anisometropia with 1% Atropine: A Pilot Study Lin Lixia*, Lan Weizhong*, Liao Yunru*, Zhao Feng*, Chen Can*, and Yang Zhikuan†
ABSTRACT Purpose. To investigate the safety and efficacy of the treatment of myopic anisometropia with 1% atropine. Methods. Twenty-two children with myopic anisometropia were prescribed 1% solution of atropine sulfate to the more myopic eye, one drop before sleep every 3 days. Children were visited every 3 to 4 months until the degree of anisometropia was no more than 0.5 diopters (D) (‘‘Success’’) or unchanged after 9 months of treatment (‘‘No effect’’). The treatment effect was assessed by comparing the interocular imbalance in refraction and axial length before and after the treatment. A detailed questionnaire about subjective symptoms in each visit and an electroretinogram in the end were administered to evaluate the side effects of this treatment. Results. The subjects were followed for 7 to 16 months. Six subjects withdrew participation on their own accord, and three were excluded because of inconstant usage of drug. Of the 13 remaining subjects, the refraction of the treated eyes decreased by 0.63 T 0.59 D (p = 0.007), whereas that of the untreated eyes increased by j0.72 T 0.65 D (p G 0.001). A corresponding trend was also found in the change of the axial length. Accordingly, the level of anisometropia was reduced from 1.82 T 0.73 D to 0.47 T 0.65 D (p G 0.001) and 10 (76.9%) of the 13 subjects were designated a ‘‘Success.’’ One percent atropine was well tolerated by the children, and no electroretinogram abnormality was detected. Conclusions. The results from this pilot study indicate that monocular usage of a solution of 1% atropine sulfate is an effective treatment to reduce anisometropia, although with some tolerable side effects. Nevertheless, an attenuated benefit was observed after cessation of atropine treatment. Thus, participants should be informed of a possible rebound effect before the administration of atropine for myopic anisometropia. (Optom Vis Sci 2013;90:1486Y1492) Key Words: atropine, myopia, anisometropia, clinical trial, ERG
A
nisometropia is an ophthalmic condition in which refractive errors are different in both eyes. Refractive errors can be either refractive or caused by differences in axial length, with the latter by far the more frequent cause. Axial anisometropia influences binocular visual function caused by the interocular difference in retinal image sizes. For example, every 0.25 diopters (D) of difference in refraction between the two eyes results in approximately a 0.5% difference between the sizes of the
*MD † MD, PhD State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong, China (LL, LW, ZF, YZ); Section of Neurobiology of the Eye, Center for Ophthalmology, University of Tuebingen, Tuebingen, Germany (LW); Graduate School of Cellular and Molecular Neuroscience, University of Tuebingen, Tuebingen, Germany (LW); Ophthalmic Department, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China (LY); and Aier Eye Hospital Group, Changsha, Hunan, China (CC, YZ).
retinal images. Generally, the visual cortex can cope with a size difference of about 5%, and a maximum interocular difference of approximately 2.50 D or less is usually tolerated by the visual system and seldom causes any symptoms. If anisometropia exceeds this limit, the difference in the visual inputs from the two eyes exceeds the tolerance of the visual cortex and frequently leads to symptoms and complaints. When this happens in infancy and early childhood, it can result in the development of amblyopia because the input from the more ametropic eye tends to be suppressed, and binocular vision is excluded. When this occurs later, even in the absence of amblyopia, the subject may experience visual fatigue syndrome and subnormal binocular function, which interrupts continuous reading and has a remarkable impact on the child’s achievement in school. It may also lead to reduced stereopsis, which has a more important effect than visual acuity on the quality of life.1 In addition, reduced stereopsis induced by significant anisometropia substantially limits the types of occupation an individual can select and the working performance of adults.
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Myopic Anisometropia Treatment with 1% AtropineVLixia et al.
Depending on the type of refractive errors in the eyes, anisometropia can be divided into hyperopic anisometropia, myopic anisometropia, astigmatic anisometropia, combined spherical and astigmatic anisometropia, and mixed anisometropia (hyperopia in one eye and myopia in the other eye).2 In a 3-year cohort of 71 anisometropic children, Tong et al.3 found that almost all subjects (n = 69) developed an increased level of anisometropia over time. This indicates that anisometropia is unlikely to regress spontaneously. Furthermore, Larsson and Holmstrom4 studied the natural history of anisometropia for 10 years and found that, although there was no change in the prevalence of anisometropia from 2.5 to 10 years, its magnitude increased significantly. Likewise, Parssinen5 followed 238 binocular myopic schoolchildren for 3 years and found that the level of anisometropia increased because of an increase in myopia in the more myopic eye. From a clinical point of view, if the progression of mild and asymptomatic anisometropia could be retarded, this would markedly decrease the risk of the aforementioned symptoms of gross anisometropia. Given that the prevalence of myopia, of which the majority is axial, has increased dramatically in most areas of the world in recent decades6Y10 and that atropine has been shown to reduce the progression of axial myopia in several studies,11Y15 it is of great interest to investigate whether myopic anisometropia could benefit from the application of atropine. Here, we report treatment outcomes in myopic anisometropia with a solution of 1% atropine from a prospective pilot study.
METHODS This prospective contra-lateral control study was carried out at Zhongshan Ophthalmic Center during 2009 to 2011. All the experimental protocols and procedures complied with the tenets of the Declaration of Helsinki and were approved by the local institutional review board. Informed consent was obtained from each enrolled child and the child’s parents after a verbal and a written explanation of the potential advantages and risks of the study. This study was registered at: http://www.chictr.org/cn/ website (registration no: ChiCTR-ONC-12001931).
Enrollment Examination We enrolled 22 subjects from an ophthalmic clinic for a longitudinal study, including eight males and 14 females (mean age, 11.4 years). ‘‘Anisometropia’’ was defined as interocular differences in the spherical equivalent refractive error ([SER] i.e., spherical power plus half of cylindrical power). The inclusion criteria were as follows: (1) aged 8 to 15 years (2) both eyes having refractions no more than j4.00 D and astigmatism no more than j1.00 D as determined by subjective refraction (3) anisometropia higher than 0.50 D (4) binocular best-corrected vision acuity (BCVA) of at least 1.0 (decimal scale, Snellen chart) (5) both eyes having normal intraocular pressure (between 11 and 21 mm Hg), as measured by a noncontact tonometer
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(6) no known other general pathologies (7) consent to nonapplication of additional antimyopia treatment
Refraction and Axial Length Measurement Autorefraction and axial length measurements were both done 30 minutes after application of a cycloplegic agent (one drop of 0.5% tropicamide along with 0.5% phenylephrine hydrochloride [Sinqi Pharmaceutical Co. Ltd., Shenyang, China] every 5 minutes, with three drops in total administered).16 The mean of three consecutive autorefraction readings was taken as the objective refractive error (RM 8800; Topcon Corp., Tokyo, Japan). Axial length was measured with an IOL Master (Carl Zeiss, Germany), which has been reported to have high reliability in ocular biometry. Detailed operation procedures have been described in other studies.17,18
Intervention Protocol All the children were prescribed a solution of 1% atropine sulfate (Zhongshan Ophthalmic Center, Guangzhou, China). They were required to instill one drop of the solution to the more myopic eye before sleep every 3 days. To minimize systemic atropine absorption, the children were advised to press the nasolacrimal duct for at least 5 minutes after the application of the solution. Compliance was assessed by comparing the interocular difference in the size of the pupil and the pupillary light reflex at each follow-up visit. The children were followed up every 3 or 4 months until the degree of anisometropia was no more than 0.5 D (designated as ‘‘success’’) or unchanged after 9 months of treatment (designated as ‘‘no effect’’). They were advised to wear glasses constantly during the treatment, and a new lens was prescribed once the change of refraction was more than 0.5 D in either eye.
Safety Assurance To ensure the safety of this intervention, the parents and the children were also advised about the need to wear spectacles with UV protection lenses to minimize potential retinal damage. In addition, we advised the children not to play under the sun or go to the seaside without wearing sunglasses. In addition to the previously described measurements, BCVA, a slit lamp examination after mydriasis, and a fundus examination were included in each follow-up visit to detect possible adverse events (e.g., decreased visual acuity, lens opacity, and retinal toxicity). Furthermore, a detailed questionnaire was developed to record possible side effects of the atropine utilization. Details are shown in the Appendix. Answer ‘‘A’’ scored 1 point, ‘‘B’’ scored 2 points, and ‘‘C’’ scored 3 points. The children and their parents were required to fill in the questionnaires at every visit in accordance with the instructions of the researchers. If a subject scored 12 points or less or answered ‘‘A’’ in one questionnaire on two occasions in a row, the subject was considered intolerant to the treatment and was dropped from the study. More importantly, at the end of the final follow-up visit, all the subjects were required to undergo an ISCEV standard scotopic electroretinogram (ERG) (Diagnosys ESPION suite, MA) to determine whether there were any retinal abnormalities.
Optometry and Vision Science, Vol. 90, No. 12, December 2013
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1488 Myopic Anisometropia Treatment with 1% AtropineVLixia et al. TABLE 1.
Frequencies of complaints during the trial Grades of complaints
Photophobia
Near work difficulty
Fever
Facial flushing
Dry mouth
Abdominal disorder
A B C A B C A B C
0 40 8 0 15 2 0 55 10
0 24 24 0 11 6 0 30 35
0 34 14 0 15 2 0 49 16
0 27 21 0 13 4 0 40 25
3 27 18 2 9 6 5 36 24
0 0 48 0 0 17 0 0 65
Retained subjects (n = 13)
Lost and excluded subjects (n = 9)
Total frequencies
Grade A, intolerable or happens constantly; grade B, have difficulty but still tolerable or happens only once in a while; grade C, no discomfort or never happens.
Analysis and Statistics All the analyses were performed with commercial SPSS version 16.0 software (SPSS, Chicago, IL). Data are presented as mean T SD, if not indicated otherwise. Tests of significance were two-tailed, and the level of significance was set at 0.05. The change in the anisometropia, the refraction, and the axial length for each eye were compared with the paired t test, and the correlation between the change in refraction and axial length for each eye was evaluated with Pearson correlation test and linear regression. The change in the BCVA between the pretreatment and posttreatment was evaluated with the Wilcoxon signed rank test.
RESULTS Twenty-two subjects were enrolled in the study initially. During the follow-up visits, six subjects withdrew of their own accord, and three were excluded because of inconsistent usage of the atropine sulfate solution. In total, 65 questionnaires regarding possible complaints associated with the atropine treatment were collected. Details on the frequencies of the complaints are shown in Table 1. No subject was dropped from the study because of
having total points of less than 12 or selecting more than one ‘‘A’’ in one questionnaire, indicating that the tolerance of the intervention was good on average. The BCVA results for the subjects throughout the study were either 1.0 or 1.2. There was no significant change in the BCVA for the treated eyes or the contralateral eyes (Wilcoxon signed rank test, both p = 0.66). No lens opacities were found in our subjects after pharmacological mydriasis throughout the entire study. For the remaining 13 subjects, the duration of the atropine treatment ranged from 7 to 16 months, with an average of 11.5 months. Table 2 shows their baseline characteristics. At the end of the treatment, ERG recordings showed that all the photopic and scotopic response parameters were in the normal range. There were no interocular differences in any of the subjects (Table 3). Fig. 1 shows the change in the refraction over time for each eye. The refraction of the treated eyes was j1.92 T 0.91 D at baseline and decreased by 0.63 T 0.59 D (p = 0.007) after the treatment. By contrast, the refraction of the untreated eyes changed from j0.08 T 0.99 D to j0.81 T 1.07 D and increased by j0.72 D T 0.65 D (p G 0.001). At the end of the treatment, the level of anisometropia was reduced from 1.82 T 0.73 D to 0.47 T 0.65 D (p G 0.001). Fig. 2 shows the pretreatment and posttreatment anisometropia. All the
TABLE 2.
Baseline characteristics of the retained subjects Treated eye Subjects No. 1 2 3 4 5 6 7 8 9 10 11 12 13
Sex
Age, y
Medication duration, mo
SER, D
AL, mm
F F F M F F F M M M M F M
10 15 10 10 12 12 10 8 12 16 10 12 10
16 11 12 11 16 13 10 13 9 13 10 9 7
j2.50 j2.25 j1.00 j1.13 j0.38 j3.25 j2.00 j1.75 j1.25 j2.13 j2.75 j3.38 j1.00
23.93 24.30 22.84 24.68 23.37 24.54 22.97 24.12 23.79 24.67 24.81 24.54 24.90
Untreated eye SER, D j0.50 0.00 0.75 j0.63 2.25 j0.25 0.50 j0.25 j0.25 0.25 j1.00 j2.00 0.00
AL, axial length; F, female; M, male; SER, spherical equivalent refractive error. Optometry and Vision Science, Vol. 90, No. 12, December 2013
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AL, mm 23.11 23.40 22.27 24.56 22.16 23.61 22.03 23.56 23.30 23.44 23.97 23.94 24.50
Myopic Anisometropia Treatment with 1% AtropineVLixia et al.
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TABLE 3.
Electroretinographic parameters Responses Cone
Rod
Parameters
Treated eyes
Untreated eyes
p
a wave implicit time, ms a wave amplitude, KV b wave implicit time, ms b wave amplitude, KV a wave implicit time, ms a wave amplitude, KV b wave implicit time, ms b wave amplitude, KV
14.23 T 0.60 j70.06 T 15.23 33.61 T 2.26 186.75 T 42.69 39.85 T 2.76 j3.97 T 9.94 93.69 T 3.68 340.47 T 41.10
14.38 T 0.51 j68.44 T 12.92 33.77 T 2.62 173.1 T 37.42 39.46 T 2.60 j4.98 T 10.98 91.69 T 5.66 333.19 T 43.09
0.34 0.76 0.85 0.13 0.75 0.83 0.34 0.68
subjects showed reduced anisometropia after the treatment, except one who had the same amount of anisometropia. The success (defined as G0.5 D of anisometropia at the final visit) was 76.9% (i.e., 10 of 13 subjects had significantly improved). Concomitantly, the axial length of the treated eyes decreased from 24.11 T 0.69 mm to 24.00 T 0.78 mm (p = 0.035), whereas that of the untreated eyes increased from 23.3 T 0.82 mm to 23.71 T 0.84 mm (p G 0.001) (Fig. 3). The differences in the axial length between both eyes dropped significantly from 0.74 T 0.32 mm to 0.29 T 0.32 mm (p G 0.001). Fig. 4 shows there is a strong correlation between the changes 2 in refraction and axial lengths for all eyes (R = 0.9175, p G 0.0001). The correlation remains when the contralateral eyes and the treated eyes are plotted separately. This clearly shows that all changes in refraction were axial in origin. The slopes of the regression lines in the plots of refraction versus axial length were similar for the pooled data from both eyes, for only the control eyes, and only the treated eyes: j2.919, j2.699, and j2.794, respectively. These numbers indicate that an axial elongation of 1 mm was equivalent to an increase in myopia of about 2.7 to 3.0 D.
well tolerated by the children. No deficits in visual function were observed. This treatment was effective in eliminating juvenile myopic anisometropia. The overall rate of success was 76.9%, and the anisometropia was reduced, on average, by about 74% after the treatment.
Safety Assessment In previous studies, practitioners found that atropine treatment has some short-term side effects, resulting not only from cycloplegia and mydriasis but also from parasympathetic disorders caused by systemic absorption via the lacrimal system.12Y14,19 Interestingly, during a similar intervention (unilateral atropine usage), Chua et al.12 did not find any severe adverse events. The most common reason for withdrawal in their study was hypersensitivity, which did not occur in our study. Although they did not report specific details, they noted that the remaining subjects had good tolerance to monocular usage of topical atropine. According to our questionnaires, the intervention was tolerated well in both the lost and the retained patients. The most common complaint in our study was mydriasis-induced photophobia, but
DISCUSSION The results of our pilot study indicate that monocular usage of 1% atropine eye drops every 3 days for up to 16 months was
FIGURE 1. Change in the refraction over time for each eye. The refraction of the treated eyes changed from j1.92 T 0.91 D to j1.28 T 1.09 D (p G 0.001) after the treatment. The refraction of the untreated eyes changed from j0.08 T 0.99 D to j0.81 T 1.07 D (p G 0.001). At the end of the treatment, the level of anisometropia was reduced from 1.82 T 0.73 D to 0.47 T 0.65 D (p G 0.001). *p G 0.05. Error bars represent SDs.
FIGURE 2. Comparison between the baseline anisometropia and anisometropia at the end of the treatment period. Data points within the gray area denote those with no more than 0.5 D anisometropia at the last visit, indicating ‘‘success’’ of the treatment. According to this criterion, 10 (76.9%) of the 13 subjects fell into this category.
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1490 Myopic Anisometropia Treatment with 1% AtropineVLixia et al.
FIGURE 3. Changes in axial length over time. The axial length of the treated eyes decreased from 24.11 T 0.69 mm to 24.00 T 0.78 mm (p = 0.035), whereas that of the untreated eye increased from 23.37 T 0.82 mm to 23.71 T 0.84 mm (p G 0.001). The differences in the axial length between two eyes dropped significantly from 0.74 T 0.32 mm to 0.29 T 0.32 mm (p G 0.001). *p G 0.05. Error bars represent SDs.
no one withdrew from the study because of intolerance. In about 85% of the questionnaires, the subjects complained of mydriasis on sunny days. Near-vision difficulty induced by cycloplegia was not particularly common in these subjects. With regard to atropine-related parasympathetic symptoms, five of 65 subjects reported a persistently dry mouth in the questionnaires (three of the subjects remained in the study, and two were lost). Other than that, facial flushing, fever-like allergic symptoms, and abdominal distention were also present occasionally in some subjects, but these symptoms were well tolerated. Taken together,
the frequency of complaints recorded in our study was similar to that from another study performed in Chinese children. Besides the short-term effects outlined above, the long-term effects of the application of atropine are also concerns in clinical practice. Retinal toxicity is one major potential risk with this intervention because of the possibility of overexposure to UV light. In this respect, the subjects in the study were prescribed UVfiltering lenses and informed of other necessary measures to protect against UV light. The current study showed that none of the subjects manifested detectable functional retinal impairment, at least as indicated by the results of the ERG. This is consistent with a previous study in which atropine eye drops were administered once daily for a 2-year period.20 Another potential risk might be crystalline opacity.21 In the present study, however, we did not observe any changes in crystalline transparency after a careful examination even under pharmacological mydriasis with a pupil size of no less than 7 mm. We speculate that the risk of opacity formation depends on the concentration of atropine, the frequency of administration, and the total duration of the treatment. Thus, it is suggested that additional attention should be paid to avoid this unwanted side effect.
Anisometropia Efficiency After the treatment, the treated eyes showed reduced progression of myopia, and the refraction decreased by an average of 0.64 D, thereby diminishing the degree of anisometropia. Myopia in the untreated eyes progressed by an average of j0.72 D. Interestingly, the reduction of myopia observed in the atropinetreated eyes was the result of a shorter axial length. Although shortening of the axial length during development is unexpected, it is possible under atropine treatment, as already shown by Shih
FIGURE 4. Regression analysis of the changes in refraction and axial length for all eyes. Linear regression showed a high correlation coefficient (R2 = 0.9175, p G 0.0001; slope of the regression line, j2.919). The line represents the least square fit through all data. If the untreated and atropine-treated eyes were separately analyzed, the slopes were similar (j2.699 and j2.794, respectively). Optometry and Vision Science, Vol. 90, No. 12, December 2013
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Myopic Anisometropia Treatment with 1% AtropineVLixia et al. TABLE 4.
Change of refraction after cessation of atropine Previously treated Previously untreated Duration eyes eyes after cessation (m) $SERa (D) D/annum $SERa (D) D/annum Subjects 1 4 6 8 9 11 12 14
16 29 7 12 11 15 9 3
j1.00 j2.75 j0.75 j1.25 j1.63 j0.75 j0.63 j0.25
j0.75 j1.14 j1.29 j1.25 j1.78 j0.60 j0.84 j1.00
j0.50 j2.50 j0.75 j0.25 j0.75 j0.50 j0.50 j0.25
j0.38 j1.03 j1.29 j0.25 j0.82 j0.40 j0.67 j1.00
‘‘a’’ SER= spherical equivalent refractive error.
et al.22 Research has also shown that axial shortening can occur in eyes of chicks, tree shrews, marmosets, and rhesus macaques in response to myopic defocus when wearing positive lenses or when they recover from induced myopia or myopia produced by wearing negative lens.23 As this finding is consistent across species, it is likely that the mechanism is conserved in evolution.23 Furthermore, adult human eyes were also found to be capable of shortening axially, possibly in response to the increased refractive power of the cornea and the lens caused by increasing age.24 More direct evidence to support our finding is that a recent study administering atropine to myopic children also reported a reduction in axial length, with a similar magnitude (j0.14 T 0.28 mm) after 1 year of treatment.12 Consistent with the reduced axial length, we found that there was a corresponding reversed myopic change in the treated eyes. As the regression coefficients are approximately the same in the contralateral and in the treated eyes (j2.699 and j2.794, respectively), the primary mechanism of myopia inhibition by atropine seems to be axial in origin. Myopia progression in the untreated eyes was j0.72 T 0.65 D in the present study, with a range from +0.25 to j1.75 D. As every subject had a different treatment period, the adjusted myopia progression was j0.71 T 0.58 D per year after adjustment. This is almost the same rate as that reported previously from subjects in the same city (j0.72 T 0.37 D per year),25 indicating that the administration of atropine in one eye does not affect the progression of myopia in the fellow eye.
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and strabismus) caused blurred vision during intermediate and near tasks, leading to blurred vision in the treated eye for a considerable time of the day. Although we did not observe significant impairment in the subjects’ visual acuity, it should be kept in mind that such impairment could have a detrimental effect on binocular vision. Therefore, we suggest that, in clinical practice, children undergoing monocular atropine therapy for anisometropia should, at least, have spectacles to provide intermediate and near correction in the treated eye. In addition, their binocular function should be closely monitored during the treatment to avoid any possible breakdown in fusion.
Rebound Effects of Atropine Treatment Recently, a Singapore group observed a rebound phenomenon after cessation of atropine treatment.31 They found that the mean progression of myopia in an atropine-treated group was significantly faster 1 year after the cessation of atropine treatment than in a vehicle-treated group.31 To test whether this phenomenon also occurred in the present study, we recently measured the refractive error of the participants. Although only eight of the 13 subjects were available, all eyes showed a myopic shift compared with the results of the last visit (Table 4). Furthermore, we observed that, after the cessation of atropine, all the previously atropine-treated eyes exhibited faster myopia progression than the fellow untreated eyes (j1.08 T 0.37 D per year vs. j0.73 T 0.37 D per year; p = 0.04). As a consequence, the preceding benefit of atropine for anisometropia in these eight subjects was attenuated from 1.45 T 0.65 D to 1.02 T 0.70 D (p = 0.004). A recent study reported that the rates of myopia progression in the second half of the year after stopping atropine treatment dropped to approximately 50% of those in the previous 6 months, with the rates being only slightly higher than those of control eyes.31 However, it remains to be seen whether a longer period of drug-free treatment will cancel out the earlier benefit.
CONCLUSIONS In conclusion, the results from this pilot study demonstrate that monocular usage of a solution of 1% atropine sulfate is an effective treatment to reduce anisometropia. There are some tolerable side effects associated with the treatment. An attenuated benefit was observed after the cessation of atropine treatment. Thus, patients need to be informed about a possible rebound effect before the administration of atropine. Future studies are needed to determine the long-term benefit of atropine treatment.
Limitations and Future Studies In the present study, we did not measure the subjects’ binocular function (e.g., accommodation balance and fusion). Thus, we do not know whether the prolonged monocular usage of atropine affected their binocular function. Several studies reported that binocular visual function improved when better visual acuity was achieved after refractive or strabismus amblyopia was cured by either monocular atropine penalization or occlusion therapy.26Y29 Another study showed that binocularity partially recovered after the elimination of anisometropia by refractive surgery.30 Nevertheless, in our study, applying monocular atropine treatment in the more myopic eye in normal subjects (i.e., without amblyopia
ACKNOWLEDGMENTS This study was supported by the National Natural Science Foundation of China, Beijing, China (grant no. 81170871; grant no. 81200714) and the Foundation for Distinguished Young Talents in Higher Education of Guangdong, Guangdong Province, China (grant no. LYM 11009). The authors thank Prof. Frank Schaeffel for his helpful advice in the preparation of the manuscript and for his critical review of the manuscript. The first two authors contributed equally to this work and are considered co-first authors. The authors have no proprietary or commercial interest in any materials discussed in this article. Received April 1, 2013; accepted August 28, 2013.
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1492 Myopic Anisometropia Treatment with 1% AtropineVLixia et al.
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18. Kimura S, Hasebe S, Miyata M, Hamasaki I, Ohtsuki H. Axial length measurement using partial coherence interferometry in myopic children: repeatability of the measurement and comparison with refractive components. Jpn J Ophthalmol 2007;51:105Y10. 19. Shih YF, Chen CH, Chou AC, Ho TC, Lin LL, Hung PT. Effects of different concentrations of atropine on controlling myopia in myopic children. J Ocul Pharmacol Ther 1999;15:85Y90. 20. Luu CD, Lau AM, Koh AH, Tan D. Multifocal electroretinogram in children on atropine treatment for myopia. Br J Ophthalmol 2005; 89:151Y3. 21. Saw SM, Gazzard G, Au EKG, Tan DT. Myopia: attempts to arrest progression. Br J Ophthalmol 2002;86:1306Y11. 22. Shih YF, Chen CH, Chou AC, Ho TC, Lin LL, Hung PT. Effects of different concentrations of atropine on controlling myopia in myopic children. J Ocul Pharmacol Ther 1999;15:85Y90. 23. Zhu X, McBrien NA, Smith EL 3rd, Troilo D, Wallman J. Eyes in various species can shorten to compensate for myopic defocus. Invest Ophthalmol Vis Sci 2013;54:2634Y44. 24. Grosvenor T. Reduction in axial length with age: an emmetropizing mechanism for the adult eye? Am J Optom Physiol Opt 1987;64: 657Y63. 25. Weizhong L, Zhikuan Y, Wen L, Xiang C, Jian G. A longitudinal study on the relationship between myopia development and near accommodation lag in myopic children. Ophthalmic Physiol Opt 2008;28:57Y61. 26. Cleary M, Houston CA, McFadzean RM, Dutton GN. Recovery in microtropia: implications for aetiology and neurophysiology. Br J Ophthalmol 1998;82:225Y31. 27. Houston CA, Cleary M, Dutton GN, McFadzean RM. Clinical characteristics of microtropiaYis microtropia a fixed phenomenon? Br J Ophthalmol 1998;82:219Y24. 28. Lee SY, Isenberg SJ. The relationship between stereopsis and visual acuity after occlusion therapy for amblyopia. Ophthalmology 2003;110:2088Y92. 29. Simons K, Stein L, Sener EC, Vitale S, Guyton DL. Full-time atropine, intermittent atropine, and optical penalization and binocular outcome in treatment of strabismic amblyopia. Ophthalmology 1997;104:2143Y55. 30. Autrata R, Rehurek J. Clinical results of excimer laser photorefractive keratectomy for high myopic anisometropia in children: four-year follow-up. J Cataract Refract Surg 2003;29:694Y702. 31. Tong L, Huang XL, Koh AL, Zhang X, Tan DT, Chua WH. Atropine for the treatment of childhood myopia: effect on myopia progression after cessation of atropine. Ophthalmology 2009;116: 572Y9.
Yang Zhikuan State Key Laboratory of Ophthalmology Zhongshan Ophthalmic Center Sun Yat-sen University Guangzhou, Guangdong China e-mail: [email protected]
Optometry and Vision Science, Vol. 90, No. 12, December 2013
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ORIGINAL ARTICLE
Treatment Outcomes of Myopic Anisometropia with 1% Atropine: A Pilot Study Lin Lixia*, Lan Weizhong*, Liao Yunru*, Zhao Feng*, Chen Can*, and Yang Zhikuan†
ABSTRACT Purpose. To investigate the safety and efficacy of the treatment of myopic anisometropia with 1% atropine. Methods. Twenty-two children with myopic anisometropia were prescribed 1% solution of atropine sulfate to the more myopic eye, one drop before sleep every 3 days. Children were visited every 3 to 4 months until the degree of anisometropia was no more than 0.5 diopters (D) (‘‘Success’’) or unchanged after 9 months of treatment (‘‘No effect’’). The treatment effect was assessed by comparing the interocular imbalance in refraction and axial length before and after the treatment. A detailed questionnaire about subjective symptoms in each visit and an electroretinogram in the end were administered to evaluate the side effects of this treatment. Results. The subjects were followed for 7 to 16 months. Six subjects withdrew participation on their own accord, and three were excluded because of inconstant usage of drug. Of the 13 remaining subjects, the refraction of the treated eyes decreased by 0.63 T 0.59 D (p = 0.007), whereas that of the untreated eyes increased by j0.72 T 0.65 D (p G 0.001). A corresponding trend was also found in the change of the axial length. Accordingly, the level of anisometropia was reduced from 1.82 T 0.73 D to 0.47 T 0.65 D (p G 0.001) and 10 (76.9%) of the 13 subjects were designated a ‘‘Success.’’ One percent atropine was well tolerated by the children, and no electroretinogram abnormality was detected. Conclusions. The results from this pilot study indicate that monocular usage of a solution of 1% atropine sulfate is an effective treatment to reduce anisometropia, although with some tolerable side effects. Nevertheless, an attenuated benefit was observed after cessation of atropine treatment. Thus, participants should be informed of a possible rebound effect before the administration of atropine for myopic anisometropia. (Optom Vis Sci 2013;90:1486Y1492) Key Words: atropine, myopia, anisometropia, clinical trial, ERG
A
nisometropia is an ophthalmic condition in which refractive errors are different in both eyes. Refractive errors can be either refractive or caused by differences in axial length, with the latter by far the more frequent cause. Axial anisometropia influences binocular visual function caused by the interocular difference in retinal image sizes. For example, every 0.25 diopters (D) of difference in refraction between the two eyes results in approximately a 0.5% difference between the sizes of the
*MD † MD, PhD State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong, China (LL, LW, ZF, YZ); Section of Neurobiology of the Eye, Center for Ophthalmology, University of Tuebingen, Tuebingen, Germany (LW); Graduate School of Cellular and Molecular Neuroscience, University of Tuebingen, Tuebingen, Germany (LW); Ophthalmic Department, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China (LY); and Aier Eye Hospital Group, Changsha, Hunan, China (CC, YZ).
retinal images. Generally, the visual cortex can cope with a size difference of about 5%, and a maximum interocular difference of approximately 2.50 D or less is usually tolerated by the visual system and seldom causes any symptoms. If anisometropia exceeds this limit, the difference in the visual inputs from the two eyes exceeds the tolerance of the visual cortex and frequently leads to symptoms and complaints. When this happens in infancy and early childhood, it can result in the development of amblyopia because the input from the more ametropic eye tends to be suppressed, and binocular vision is excluded. When this occurs later, even in the absence of amblyopia, the subject may experience visual fatigue syndrome and subnormal binocular function, which interrupts continuous reading and has a remarkable impact on the child’s achievement in school. It may also lead to reduced stereopsis, which has a more important effect than visual acuity on the quality of life.1 In addition, reduced stereopsis induced by significant anisometropia substantially limits the types of occupation an individual can select and the working performance of adults.
Optometry and Vision Science, Vol. 90, No. 12, December 2013
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Myopic Anisometropia Treatment with 1% AtropineVLixia et al.
Depending on the type of refractive errors in the eyes, anisometropia can be divided into hyperopic anisometropia, myopic anisometropia, astigmatic anisometropia, combined spherical and astigmatic anisometropia, and mixed anisometropia (hyperopia in one eye and myopia in the other eye).2 In a 3-year cohort of 71 anisometropic children, Tong et al.3 found that almost all subjects (n = 69) developed an increased level of anisometropia over time. This indicates that anisometropia is unlikely to regress spontaneously. Furthermore, Larsson and Holmstrom4 studied the natural history of anisometropia for 10 years and found that, although there was no change in the prevalence of anisometropia from 2.5 to 10 years, its magnitude increased significantly. Likewise, Parssinen5 followed 238 binocular myopic schoolchildren for 3 years and found that the level of anisometropia increased because of an increase in myopia in the more myopic eye. From a clinical point of view, if the progression of mild and asymptomatic anisometropia could be retarded, this would markedly decrease the risk of the aforementioned symptoms of gross anisometropia. Given that the prevalence of myopia, of which the majority is axial, has increased dramatically in most areas of the world in recent decades6Y10 and that atropine has been shown to reduce the progression of axial myopia in several studies,11Y15 it is of great interest to investigate whether myopic anisometropia could benefit from the application of atropine. Here, we report treatment outcomes in myopic anisometropia with a solution of 1% atropine from a prospective pilot study.
METHODS This prospective contra-lateral control study was carried out at Zhongshan Ophthalmic Center during 2009 to 2011. All the experimental protocols and procedures complied with the tenets of the Declaration of Helsinki and were approved by the local institutional review board. Informed consent was obtained from each enrolled child and the child’s parents after a verbal and a written explanation of the potential advantages and risks of the study. This study was registered at: http://www.chictr.org/cn/ website (registration no: ChiCTR-ONC-12001931).
Enrollment Examination We enrolled 22 subjects from an ophthalmic clinic for a longitudinal study, including eight males and 14 females (mean age, 11.4 years). ‘‘Anisometropia’’ was defined as interocular differences in the spherical equivalent refractive error ([SER] i.e., spherical power plus half of cylindrical power). The inclusion criteria were as follows: (1) aged 8 to 15 years (2) both eyes having refractions no more than j4.00 D and astigmatism no more than j1.00 D as determined by subjective refraction (3) anisometropia higher than 0.50 D (4) binocular best-corrected vision acuity (BCVA) of at least 1.0 (decimal scale, Snellen chart) (5) both eyes having normal intraocular pressure (between 11 and 21 mm Hg), as measured by a noncontact tonometer
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(6) no known other general pathologies (7) consent to nonapplication of additional antimyopia treatment
Refraction and Axial Length Measurement Autorefraction and axial length measurements were both done 30 minutes after application of a cycloplegic agent (one drop of 0.5% tropicamide along with 0.5% phenylephrine hydrochloride [Sinqi Pharmaceutical Co. Ltd., Shenyang, China] every 5 minutes, with three drops in total administered).16 The mean of three consecutive autorefraction readings was taken as the objective refractive error (RM 8800; Topcon Corp., Tokyo, Japan). Axial length was measured with an IOL Master (Carl Zeiss, Germany), which has been reported to have high reliability in ocular biometry. Detailed operation procedures have been described in other studies.17,18
Intervention Protocol All the children were prescribed a solution of 1% atropine sulfate (Zhongshan Ophthalmic Center, Guangzhou, China). They were required to instill one drop of the solution to the more myopic eye before sleep every 3 days. To minimize systemic atropine absorption, the children were advised to press the nasolacrimal duct for at least 5 minutes after the application of the solution. Compliance was assessed by comparing the interocular difference in the size of the pupil and the pupillary light reflex at each follow-up visit. The children were followed up every 3 or 4 months until the degree of anisometropia was no more than 0.5 D (designated as ‘‘success’’) or unchanged after 9 months of treatment (designated as ‘‘no effect’’). They were advised to wear glasses constantly during the treatment, and a new lens was prescribed once the change of refraction was more than 0.5 D in either eye.
Safety Assurance To ensure the safety of this intervention, the parents and the children were also advised about the need to wear spectacles with UV protection lenses to minimize potential retinal damage. In addition, we advised the children not to play under the sun or go to the seaside without wearing sunglasses. In addition to the previously described measurements, BCVA, a slit lamp examination after mydriasis, and a fundus examination were included in each follow-up visit to detect possible adverse events (e.g., decreased visual acuity, lens opacity, and retinal toxicity). Furthermore, a detailed questionnaire was developed to record possible side effects of the atropine utilization. Details are shown in the Appendix. Answer ‘‘A’’ scored 1 point, ‘‘B’’ scored 2 points, and ‘‘C’’ scored 3 points. The children and their parents were required to fill in the questionnaires at every visit in accordance with the instructions of the researchers. If a subject scored 12 points or less or answered ‘‘A’’ in one questionnaire on two occasions in a row, the subject was considered intolerant to the treatment and was dropped from the study. More importantly, at the end of the final follow-up visit, all the subjects were required to undergo an ISCEV standard scotopic electroretinogram (ERG) (Diagnosys ESPION suite, MA) to determine whether there were any retinal abnormalities.
Optometry and Vision Science, Vol. 90, No. 12, December 2013
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1488 Myopic Anisometropia Treatment with 1% AtropineVLixia et al. TABLE 1.
Frequencies of complaints during the trial Grades of complaints
Photophobia
Near work difficulty
Fever
Facial flushing
Dry mouth
Abdominal disorder
A B C A B C A B C
0 40 8 0 15 2 0 55 10
0 24 24 0 11 6 0 30 35
0 34 14 0 15 2 0 49 16
0 27 21 0 13 4 0 40 25
3 27 18 2 9 6 5 36 24
0 0 48 0 0 17 0 0 65
Retained subjects (n = 13)
Lost and excluded subjects (n = 9)
Total frequencies
Grade A, intolerable or happens constantly; grade B, have difficulty but still tolerable or happens only once in a while; grade C, no discomfort or never happens.
Analysis and Statistics All the analyses were performed with commercial SPSS version 16.0 software (SPSS, Chicago, IL). Data are presented as mean T SD, if not indicated otherwise. Tests of significance were two-tailed, and the level of significance was set at 0.05. The change in the anisometropia, the refraction, and the axial length for each eye were compared with the paired t test, and the correlation between the change in refraction and axial length for each eye was evaluated with Pearson correlation test and linear regression. The change in the BCVA between the pretreatment and posttreatment was evaluated with the Wilcoxon signed rank test.
RESULTS Twenty-two subjects were enrolled in the study initially. During the follow-up visits, six subjects withdrew of their own accord, and three were excluded because of inconsistent usage of the atropine sulfate solution. In total, 65 questionnaires regarding possible complaints associated with the atropine treatment were collected. Details on the frequencies of the complaints are shown in Table 1. No subject was dropped from the study because of
having total points of less than 12 or selecting more than one ‘‘A’’ in one questionnaire, indicating that the tolerance of the intervention was good on average. The BCVA results for the subjects throughout the study were either 1.0 or 1.2. There was no significant change in the BCVA for the treated eyes or the contralateral eyes (Wilcoxon signed rank test, both p = 0.66). No lens opacities were found in our subjects after pharmacological mydriasis throughout the entire study. For the remaining 13 subjects, the duration of the atropine treatment ranged from 7 to 16 months, with an average of 11.5 months. Table 2 shows their baseline characteristics. At the end of the treatment, ERG recordings showed that all the photopic and scotopic response parameters were in the normal range. There were no interocular differences in any of the subjects (Table 3). Fig. 1 shows the change in the refraction over time for each eye. The refraction of the treated eyes was j1.92 T 0.91 D at baseline and decreased by 0.63 T 0.59 D (p = 0.007) after the treatment. By contrast, the refraction of the untreated eyes changed from j0.08 T 0.99 D to j0.81 T 1.07 D and increased by j0.72 D T 0.65 D (p G 0.001). At the end of the treatment, the level of anisometropia was reduced from 1.82 T 0.73 D to 0.47 T 0.65 D (p G 0.001). Fig. 2 shows the pretreatment and posttreatment anisometropia. All the
TABLE 2.
Baseline characteristics of the retained subjects Treated eye Subjects No. 1 2 3 4 5 6 7 8 9 10 11 12 13
Sex
Age, y
Medication duration, mo
SER, D
AL, mm
F F F M F F F M M M M F M
10 15 10 10 12 12 10 8 12 16 10 12 10
16 11 12 11 16 13 10 13 9 13 10 9 7
j2.50 j2.25 j1.00 j1.13 j0.38 j3.25 j2.00 j1.75 j1.25 j2.13 j2.75 j3.38 j1.00
23.93 24.30 22.84 24.68 23.37 24.54 22.97 24.12 23.79 24.67 24.81 24.54 24.90
Untreated eye SER, D j0.50 0.00 0.75 j0.63 2.25 j0.25 0.50 j0.25 j0.25 0.25 j1.00 j2.00 0.00
AL, axial length; F, female; M, male; SER, spherical equivalent refractive error. Optometry and Vision Science, Vol. 90, No. 12, December 2013
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AL, mm 23.11 23.40 22.27 24.56 22.16 23.61 22.03 23.56 23.30 23.44 23.97 23.94 24.50
Myopic Anisometropia Treatment with 1% AtropineVLixia et al.
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TABLE 3.
Electroretinographic parameters Responses Cone
Rod
Parameters
Treated eyes
Untreated eyes
p
a wave implicit time, ms a wave amplitude, KV b wave implicit time, ms b wave amplitude, KV a wave implicit time, ms a wave amplitude, KV b wave implicit time, ms b wave amplitude, KV
14.23 T 0.60 j70.06 T 15.23 33.61 T 2.26 186.75 T 42.69 39.85 T 2.76 j3.97 T 9.94 93.69 T 3.68 340.47 T 41.10
14.38 T 0.51 j68.44 T 12.92 33.77 T 2.62 173.1 T 37.42 39.46 T 2.60 j4.98 T 10.98 91.69 T 5.66 333.19 T 43.09
0.34 0.76 0.85 0.13 0.75 0.83 0.34 0.68
subjects showed reduced anisometropia after the treatment, except one who had the same amount of anisometropia. The success (defined as G0.5 D of anisometropia at the final visit) was 76.9% (i.e., 10 of 13 subjects had significantly improved). Concomitantly, the axial length of the treated eyes decreased from 24.11 T 0.69 mm to 24.00 T 0.78 mm (p = 0.035), whereas that of the untreated eyes increased from 23.3 T 0.82 mm to 23.71 T 0.84 mm (p G 0.001) (Fig. 3). The differences in the axial length between both eyes dropped significantly from 0.74 T 0.32 mm to 0.29 T 0.32 mm (p G 0.001). Fig. 4 shows there is a strong correlation between the changes 2 in refraction and axial lengths for all eyes (R = 0.9175, p G 0.0001). The correlation remains when the contralateral eyes and the treated eyes are plotted separately. This clearly shows that all changes in refraction were axial in origin. The slopes of the regression lines in the plots of refraction versus axial length were similar for the pooled data from both eyes, for only the control eyes, and only the treated eyes: j2.919, j2.699, and j2.794, respectively. These numbers indicate that an axial elongation of 1 mm was equivalent to an increase in myopia of about 2.7 to 3.0 D.
well tolerated by the children. No deficits in visual function were observed. This treatment was effective in eliminating juvenile myopic anisometropia. The overall rate of success was 76.9%, and the anisometropia was reduced, on average, by about 74% after the treatment.
Safety Assessment In previous studies, practitioners found that atropine treatment has some short-term side effects, resulting not only from cycloplegia and mydriasis but also from parasympathetic disorders caused by systemic absorption via the lacrimal system.12Y14,19 Interestingly, during a similar intervention (unilateral atropine usage), Chua et al.12 did not find any severe adverse events. The most common reason for withdrawal in their study was hypersensitivity, which did not occur in our study. Although they did not report specific details, they noted that the remaining subjects had good tolerance to monocular usage of topical atropine. According to our questionnaires, the intervention was tolerated well in both the lost and the retained patients. The most common complaint in our study was mydriasis-induced photophobia, but
DISCUSSION The results of our pilot study indicate that monocular usage of 1% atropine eye drops every 3 days for up to 16 months was
FIGURE 1. Change in the refraction over time for each eye. The refraction of the treated eyes changed from j1.92 T 0.91 D to j1.28 T 1.09 D (p G 0.001) after the treatment. The refraction of the untreated eyes changed from j0.08 T 0.99 D to j0.81 T 1.07 D (p G 0.001). At the end of the treatment, the level of anisometropia was reduced from 1.82 T 0.73 D to 0.47 T 0.65 D (p G 0.001). *p G 0.05. Error bars represent SDs.
FIGURE 2. Comparison between the baseline anisometropia and anisometropia at the end of the treatment period. Data points within the gray area denote those with no more than 0.5 D anisometropia at the last visit, indicating ‘‘success’’ of the treatment. According to this criterion, 10 (76.9%) of the 13 subjects fell into this category.
Optometry and Vision Science, Vol. 90, No. 12, December 2013
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1490 Myopic Anisometropia Treatment with 1% AtropineVLixia et al.
FIGURE 3. Changes in axial length over time. The axial length of the treated eyes decreased from 24.11 T 0.69 mm to 24.00 T 0.78 mm (p = 0.035), whereas that of the untreated eye increased from 23.37 T 0.82 mm to 23.71 T 0.84 mm (p G 0.001). The differences in the axial length between two eyes dropped significantly from 0.74 T 0.32 mm to 0.29 T 0.32 mm (p G 0.001). *p G 0.05. Error bars represent SDs.
no one withdrew from the study because of intolerance. In about 85% of the questionnaires, the subjects complained of mydriasis on sunny days. Near-vision difficulty induced by cycloplegia was not particularly common in these subjects. With regard to atropine-related parasympathetic symptoms, five of 65 subjects reported a persistently dry mouth in the questionnaires (three of the subjects remained in the study, and two were lost). Other than that, facial flushing, fever-like allergic symptoms, and abdominal distention were also present occasionally in some subjects, but these symptoms were well tolerated. Taken together,
the frequency of complaints recorded in our study was similar to that from another study performed in Chinese children. Besides the short-term effects outlined above, the long-term effects of the application of atropine are also concerns in clinical practice. Retinal toxicity is one major potential risk with this intervention because of the possibility of overexposure to UV light. In this respect, the subjects in the study were prescribed UVfiltering lenses and informed of other necessary measures to protect against UV light. The current study showed that none of the subjects manifested detectable functional retinal impairment, at least as indicated by the results of the ERG. This is consistent with a previous study in which atropine eye drops were administered once daily for a 2-year period.20 Another potential risk might be crystalline opacity.21 In the present study, however, we did not observe any changes in crystalline transparency after a careful examination even under pharmacological mydriasis with a pupil size of no less than 7 mm. We speculate that the risk of opacity formation depends on the concentration of atropine, the frequency of administration, and the total duration of the treatment. Thus, it is suggested that additional attention should be paid to avoid this unwanted side effect.
Anisometropia Efficiency After the treatment, the treated eyes showed reduced progression of myopia, and the refraction decreased by an average of 0.64 D, thereby diminishing the degree of anisometropia. Myopia in the untreated eyes progressed by an average of j0.72 D. Interestingly, the reduction of myopia observed in the atropinetreated eyes was the result of a shorter axial length. Although shortening of the axial length during development is unexpected, it is possible under atropine treatment, as already shown by Shih
FIGURE 4. Regression analysis of the changes in refraction and axial length for all eyes. Linear regression showed a high correlation coefficient (R2 = 0.9175, p G 0.0001; slope of the regression line, j2.919). The line represents the least square fit through all data. If the untreated and atropine-treated eyes were separately analyzed, the slopes were similar (j2.699 and j2.794, respectively). Optometry and Vision Science, Vol. 90, No. 12, December 2013
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Myopic Anisometropia Treatment with 1% AtropineVLixia et al. TABLE 4.
Change of refraction after cessation of atropine Previously treated Previously untreated Duration eyes eyes after cessation (m) $SERa (D) D/annum $SERa (D) D/annum Subjects 1 4 6 8 9 11 12 14
16 29 7 12 11 15 9 3
j1.00 j2.75 j0.75 j1.25 j1.63 j0.75 j0.63 j0.25
j0.75 j1.14 j1.29 j1.25 j1.78 j0.60 j0.84 j1.00
j0.50 j2.50 j0.75 j0.25 j0.75 j0.50 j0.50 j0.25
j0.38 j1.03 j1.29 j0.25 j0.82 j0.40 j0.67 j1.00
‘‘a’’ SER= spherical equivalent refractive error.
et al.22 Research has also shown that axial shortening can occur in eyes of chicks, tree shrews, marmosets, and rhesus macaques in response to myopic defocus when wearing positive lenses or when they recover from induced myopia or myopia produced by wearing negative lens.23 As this finding is consistent across species, it is likely that the mechanism is conserved in evolution.23 Furthermore, adult human eyes were also found to be capable of shortening axially, possibly in response to the increased refractive power of the cornea and the lens caused by increasing age.24 More direct evidence to support our finding is that a recent study administering atropine to myopic children also reported a reduction in axial length, with a similar magnitude (j0.14 T 0.28 mm) after 1 year of treatment.12 Consistent with the reduced axial length, we found that there was a corresponding reversed myopic change in the treated eyes. As the regression coefficients are approximately the same in the contralateral and in the treated eyes (j2.699 and j2.794, respectively), the primary mechanism of myopia inhibition by atropine seems to be axial in origin. Myopia progression in the untreated eyes was j0.72 T 0.65 D in the present study, with a range from +0.25 to j1.75 D. As every subject had a different treatment period, the adjusted myopia progression was j0.71 T 0.58 D per year after adjustment. This is almost the same rate as that reported previously from subjects in the same city (j0.72 T 0.37 D per year),25 indicating that the administration of atropine in one eye does not affect the progression of myopia in the fellow eye.
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and strabismus) caused blurred vision during intermediate and near tasks, leading to blurred vision in the treated eye for a considerable time of the day. Although we did not observe significant impairment in the subjects’ visual acuity, it should be kept in mind that such impairment could have a detrimental effect on binocular vision. Therefore, we suggest that, in clinical practice, children undergoing monocular atropine therapy for anisometropia should, at least, have spectacles to provide intermediate and near correction in the treated eye. In addition, their binocular function should be closely monitored during the treatment to avoid any possible breakdown in fusion.
Rebound Effects of Atropine Treatment Recently, a Singapore group observed a rebound phenomenon after cessation of atropine treatment.31 They found that the mean progression of myopia in an atropine-treated group was significantly faster 1 year after the cessation of atropine treatment than in a vehicle-treated group.31 To test whether this phenomenon also occurred in the present study, we recently measured the refractive error of the participants. Although only eight of the 13 subjects were available, all eyes showed a myopic shift compared with the results of the last visit (Table 4). Furthermore, we observed that, after the cessation of atropine, all the previously atropine-treated eyes exhibited faster myopia progression than the fellow untreated eyes (j1.08 T 0.37 D per year vs. j0.73 T 0.37 D per year; p = 0.04). As a consequence, the preceding benefit of atropine for anisometropia in these eight subjects was attenuated from 1.45 T 0.65 D to 1.02 T 0.70 D (p = 0.004). A recent study reported that the rates of myopia progression in the second half of the year after stopping atropine treatment dropped to approximately 50% of those in the previous 6 months, with the rates being only slightly higher than those of control eyes.31 However, it remains to be seen whether a longer period of drug-free treatment will cancel out the earlier benefit.
CONCLUSIONS In conclusion, the results from this pilot study demonstrate that monocular usage of a solution of 1% atropine sulfate is an effective treatment to reduce anisometropia. There are some tolerable side effects associated with the treatment. An attenuated benefit was observed after the cessation of atropine treatment. Thus, patients need to be informed about a possible rebound effect before the administration of atropine. Future studies are needed to determine the long-term benefit of atropine treatment.
Limitations and Future Studies In the present study, we did not measure the subjects’ binocular function (e.g., accommodation balance and fusion). Thus, we do not know whether the prolonged monocular usage of atropine affected their binocular function. Several studies reported that binocular visual function improved when better visual acuity was achieved after refractive or strabismus amblyopia was cured by either monocular atropine penalization or occlusion therapy.26Y29 Another study showed that binocularity partially recovered after the elimination of anisometropia by refractive surgery.30 Nevertheless, in our study, applying monocular atropine treatment in the more myopic eye in normal subjects (i.e., without amblyopia
ACKNOWLEDGMENTS This study was supported by the National Natural Science Foundation of China, Beijing, China (grant no. 81170871; grant no. 81200714) and the Foundation for Distinguished Young Talents in Higher Education of Guangdong, Guangdong Province, China (grant no. LYM 11009). The authors thank Prof. Frank Schaeffel for his helpful advice in the preparation of the manuscript and for his critical review of the manuscript. The first two authors contributed equally to this work and are considered co-first authors. The authors have no proprietary or commercial interest in any materials discussed in this article. Received April 1, 2013; accepted August 28, 2013.
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1492 Myopic Anisometropia Treatment with 1% AtropineVLixia et al.
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Yang Zhikuan State Key Laboratory of Ophthalmology Zhongshan Ophthalmic Center Sun Yat-sen University Guangzhou, Guangdong China e-mail: [email protected]
Optometry and Vision Science, Vol. 90, No. 12, December 2013
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