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Torres , Christine F. Spherical equivalent refractive error SER and axial length AL data, as well as retinal and choroidal thickness data were collected weekly. The treated eyes of the control group showed relatively more axial elongation and myopia progression than both the Atr-QD and Atr-Q3D groups. Choroidal blood vessel area also decreased over time in the treated eyes of the control group, coupled with choroidal thinning overall, with these changes being attenuated by atropine. Retinal thickness showed a developmental decrease over the treatment period but was unaffected by atropine. Translational Relevance : The results from this study suggest that the frequency of dosing for topical atropine may be reduced from the widely used daily dosing regimen without loss of myopia control efficacy. Purchase this article with an account. Jump To Open Access. Torres ; Christine F. Correspondence: Christine F. Alerts User Alerts. You will receive an email whenever this article is corrected, updated, or cited in the literature. You can manage this and all other alerts in My Account. This feature is available to authenticated users only. Get Citation Citation. Get Permissions. Myopia, or near-sightedness, reflects a mismatch between the axial length of the eye and its refractive power, typically due to excessive ocular elongation. This causes parallel light rays from distant objects to focus in front of the retina, resulting in blurred vision without correction. Myopia is now the most common refractive error worldwide. Among the currently used myopia control treatments, two anti-muscarinic pharmaceutical agents, atropine and pirenzepine, applied topically, have been shown to be effective in slowing myopia progression. Although topical ophthalmic atropine is now used widely clinically for slowing myopia progression, either as an approved or off-label treatment, several studies have reported dose-dependent side-effects, including photophobia, glare, blur, and allergic reactions, which have proved to be intolerable for some participants. For example, in the ATOM studies, more than 0. Given the well-recognized long duration of action of topical atropine, when applied to the eye for diagnostic purposes, the possibility of reducing exposure through less frequent dosing, while maintaining treatment efficacy, as examined in the study reported here, was deemed plausible. Animal model studies have provided critical insights into the mechanisms underlying refractive error development and myopia, and have also provided valuable data on various therapeutic interventions. The guinea pig has become an important and widely used mammalian myopia model for this purpose, offering a number of advantages, including its relatively large eye size and cooperative nature. Muscarinic receptors are present throughout its ocular tissues, including the retina, choroid, and sclera. The study design made use of our recently described contact lens model for myopia. As detailed in the following sections, reducing the atropine dosing frequency to once every 3 days had minimal effect on treatment efficacy. Two-week-old New Zealand strain pigmented guinea pigs were used in this study and bred on-site. Pups were weaned at 5 days of age and reared as single-sex pairs in transparent plastic tubs. They had free access to water and vitamin C-supplemented food, and received fresh vegetables and fruits three times a week as dietary enrichment. Details concerning lens wear and monitoring schedules are described in a previous publication. Topical treatments were confined to the contact lens-wearing eyes of the guinea pigs, delivered at AM, when the contact lenses were also replaced. The fellow untreated eyes of all animals served as contralateral controls for their respective groups. Baseline refractive error and axial length data, as well as anterior corneal curvature, retinal thickness, and choroidal thickness data were collected and then at weekly intervals after initiation of treatments. From collected high resolution choroidal images, various structural parameters were also derived. Measurements on individual animals were performed at the same time of day, around PM, to avoid possible confounding effects of circadian rhythms in eye growth. Both refractive error and axial length data were collected on awake animals. For these measurements, the Lenstar chin rest was replaced with a platform on which the guinea pigs were seated for measurements. Each measurement comprised an average of at least three readings. For optimal imaging, the position of each guinea pig was adjusted to ensure the images to be scanned were clear and in the center of the screen. Observation of a bright white line running perpendicular to the corneal apex was used as an indicator of good alignment and high-quality imaging. In brief, both the right and left limbal margins boundary between white sclera and grainy cornea were first identified and a circle connecting these two points and the anterior corneal apex generated, the latter being identified automatically by the software. The radius of the circle was taken as the anterior corneal radius of curvature CRC. Choroidal analyses were restricted to the visual streak region, which is approximately 2. The use of the ONH as a reference landmark allowed capture of cross-sectional images from the same ocular fundus area at each measurement time point. The cornea was massaged through the eyelids, at approximately 5-minute intervals during imaging, to maintain the integrity of the tear film, in the interest of good quality images. The built-in calipers in the Bioptgen instrument were used to measure ChT and RT from captured cross-sectional images. The middle third of the cross-sectional images was selected for analysis to avoid optical distortions affecting more peripheral off-axis parts of images. Luminal areas were determined using the Threshold Tool after image manipulations aimed at reducing the noise in images. In addition to total luminal areas, total interstitial and choroidal areas were calculated, and the ratio of total vessel area to total choroidal area subsequently derived. Adult guinea pigs were used in this study, because of the difficulty in reliably identifying the iris pupil boundary in young guinea pigs. Measurements were made on awake animals under a room illumination of to lux. Mixed-model repeated measures ANOVAs with a Bonferroni post hoc test were used to compare treated eyes and control eyes within each group, as well as changes over time in interocular differences across the three groups, for various ocular parameters. Any P values less than 0. Regression analyses were performed to evaluate the relationship between interocular differences in AL and VCD at the end of the study, for each of the three groups. Thus statistically, there were no significant differences between treated and fellow contralateral control eyes within each group at this time. View Table. Refractive errors SERs : As expected, the contact lens-wearing eyes of the control group elongated significantly more than their fellows over the treatment period, to become myopic by the end of the study. Figure 1. View Original Download Slide. The control group showed the largest increase in AL in lens-wearing eyes. For this group, the interocular difference in AL had reached 0. Figure 2. Other axial ocular parameters and corneal curvature: To verify that interocular differences in AL reflected increases in VCD, as characteristic of myopia, correlations between the interocular differences in VCD and AL recorded at the end of week 6 were examined for each group Fig. Interocular differences in VCD at the end of the 6-week treatment period for guinea pigs treated with atropine daily or every 3 days were also significantly smaller 0. None of the other measured axial parameters CCT, ACD, and axial lens thickness , showed significant changes in interocular differences over time, nor were there significant differences between the groups in terms of changes in interocular differences. Likewise, the central corneal radius of curvature showed no treatment-related changes Supplementary Fig. Figure 3. Retinal thickness RT : Lens-wearing eyes and their fellows showed similar decreases in RT over the treatment period. Thus, for each group, interocular differences in RT at the end of the experiment were close to that recorded at baseline and there were also no significant differences in interocular differences in RT between the groups Supplementary Fig. Choroidal thickness ChT : In contrast to the lack of treatment effects on RT, the myopia induced in the lens-wearing eyes of the control group was linked to decreases in ChT, whereas the fellow eyes of the group recorded slight increases over the same period. The changes over time in interocular differences in ChT for this group reflect these contrasting patterns of change, becoming significantly more negative, from 1. On the other hand, the two atropine groups recorded only small interocular differences in ChT that were relatively stable over the treatment period 1. Figure 4. The ChT data just described imply that atropine, either directly or indirectly inhibited myopia-related choroidal thinning. For the lens-wearing eyes of the control group, the ratio of blood vessel area to total choroidal area gradually decreased over time, while that of their fellows remained almost unchanged. By comparison, the equivalent ratios derived for both the lens-wearing and fellow eyes of the two atropine groups remained relatively stable over the course of the experiment. This difference between the control and atropine groups is also reflected in the interocular differences in this ratio, which changed significantly for the control group from 1. Figure 5. Customized negative RGP lenses were used to induce myopia in this guinea pig study. Although the more commonly used approach to myopia induction in guinea pigs involves spectacle lenses, they can become detached as the animals move around in their cages, interrupting the myopia-inducing visual experience, in this case hyperopic defocus. The contact lenses used in the current study largely avoided this problem, being rarely dislodged and so providing a continuous defocus experience. The left eyes of all animals were left untreated, thereby serving as contralateral controls. Over the 6-week monitoring period, these eyes showed a gradual reduction in their hyperopic refractive errors, flattening of their corneas, and increases in all axial dimensions, with the exception of retinal thickness, which decreased. These changes are consistent with normal ocular development and emmetropization, as reported by others, 26 , 27 also implying minimal treatment-related interocular yoking. This study represents the first to demonstrate the efficacy of topical atropine sulfate solution in the guinea pig defocus model of myopia, whereas the finding that atropine inhibits myopia progression is not in of itself new. The only other published study into the efficacy of atropine in controlling myopia in guinea pigs involving form deprived myopia FDM animals, which received a daily peribulbar injection of atropine sulfate monohydrate over a 2-week period. Although the latter changes are much larger in percentage terms than those reported here i. That two different myopia inductions method were used form deprivation versus hyperopic defocus , may also be significant, given the evidence that different underlying retinal mechanisms are involved. On the other hand, the same growth changes serve to progressively compensate for imposed hyperopic defocus. We incremented the power of the contact lenses mid-way through the treatment period in our study in an attempt to minimize the decrease in imposed defocus. The power of the latter is also expected to change over time, due to developmental corneal flattening. Finally, although no significant contact lens-induced changes in corneal curvature were recorded, it is possible that subtle changes in the latter may also partly account for the apparent mismatch in inhibitory effects on myopia progression versus axial elongation. These results suggest an enduring action of topical atropine and are consistent with observed sustained pupil dilation with topical atropine in our adult guinea pigs see Supplementary Fig. Although the ocular site of action for the anti-myopia effect of atropine remains under debate, it is reasonable to assume a similar or longer duration of action in young guinea pigs, given the smaller size of their eyes and hence likely higher intraocular concentrations. With repeated dosing, it is also likely that atropine accumulated over time in pigmented ocular tissues iris, ciliary body choroid, and retinal pigment epithelium , bound to melanin, thereby creating local intraocular depots. Slow release from such depots allows for sustained receptor blockade. In relation to the above speculation, parallels may be drawn between reports from human clinical and animal studies. For example, in one study, delayed but longer lasting cycloplegia and mydriasis have been reported in human individuals with more heavily pigmented eyes. Although as already indicated, there is no general agreement on the ocular site of action of atropine's anti-myopia action, there is accumulating evidence that it can prevent, directly or indirectly, the choroidal thinning that typifies myopic eyes. The choroid lies between the retinal pigment epithelium and the sclera, and is the main source of nutrients to the outer retina and sclera. Specifically, choroidal thinning and reductions in blood flow have been reported in myopic human eyes, as well as animal eyes with experimentally induced myopia, with the opposite effects seen under conditions that slow eye elongation and so slow or reverse myopic changes. For example, exposure to myopic defocus, either imposed optically with positive lenses, or after myopia-inducing treatments are terminated, has been linked to increased blood flow and choroidal thickening, at least in animal model studies. The mechanism underlying the effects of atropine on choroidal thickness and blood vessel area remains unclear. In the current study, the observed decrease in choroidal blood vessel ratio in the lens-wearing eyes in the control group largely reflected decreases in blood vessel areas from 27, Of potential relevance to the inhibitory effect of atropine on the above changes is a study in chickens, which linked the inhibitory effect of atropine on form deprivation myopia to increased nitric oxide NO synthesis. In the current study, the fellow, untreated eyes of all three groups appeared unaffected by the applied treatments, be it imposed hyperopic defocus combined with artificial tears, or hyperopic defocus combined with topical atropine. In the case that atropine was able to reach the fellow eyes intact, this result would indicate that atropine does not interfere with normal emmetropization, a potentially important observation with respect to atropine's clinical use for myopia control in that it allows for its use prior to the onset of myopia in high-risk children. As alluded to above, previous studies investigating the anti-myopia effects of atropine in animal models have used a variety of routes of administration, with ocular pharmacokinetics expected to vary, depending on the choice. Both intravitreal and peribulbar injection have been widely used in animal model studies. As examples, intravitreal injections of 2. On the other hand, the results from the current study, which used topical delivery, are potentially translatable to clinical practice. Although the mechanism s underlying atropine's myopia control effect remains to be fully resolved, our results add to accumulating evidence pointing to involvement of the choroid. Disclosure: Q. Zhu , None; S. Goto , None; S. Singh , None; J. Torres , None; C. Wildsoet , None. Dolgin E. The myopia boom. The epidemics of myopia: Aetiology and prevention. Prog Retin Eye Res. Increased prevalence of myopia in the United States between and Arch Ophthalmol. Increasing prevalence of myopia in europe and the impact of education. Global prevalence of myopia and high myopia and temporal trends from through Myopia and associated pathological complications. Ophthalmic Physiol Opt. Efficacy comparison of 16 Interventions for myopia control in children: A Network Meta-analysis. Interventions to slow progression of myopia in children. Cochrane Database Syst Rev. Bedrossian RH. The effect of atropine on myopia. Ann Ophthalmol. Atropine for the treatment of childhood myopia. Atropine for the treatment of childhood myopia: safety and efficacy of 0. Differential effects on ocular biometrics by 0. Efficacy and adverse effects of atropine in childhood myopia: A Meta-analysis. JAMA Ophthalmol. Marron J. Cycloplegia and mydriasis by use of atropine, scopolamine and homatropine-paredrine. Dynamic retinoscopy. Curr Opin Ophthalmol. Schaeffel F, Feldkaemper M. Animal models in myopia research. Clin Exp Optom. Spectacle lens compensation in the pigmented guinea pig. Vision Res. Form-deprivation myopia in the guinea pig Cavia porcellus. Changes in muscarinic acetylcholine receptor expression in form deprivation myopia in guinea pigs. Mol Vis. Pharmacologically stimulated pupil and accommodative changes in Guinea pigs. Invest Ophthalmol Vis Sci. Muscarinic and nicotinic synaptic activation of the developing chicken iris. J Neurosci. The role of the iris in chick accommodation. Kochik S, Wildsoet CF. Topical atropine prevents contact lens-induced myopia in guinea pigs. Strain-dependent differences in sensitivity to myopia-inducing stimuli in guinea pigs and role of choroid. Choroidal structure in normal eyes and after photodynamic therapy determined by binarization of optical coherence tomographic images. Emmetropization and schematic eye models in developing pigmented guinea pigs. Normal development of refractive state and ocular dimensions in guinea pigs. Increased choroidal blood perfusion can inhibit form deprivation myopia in guinea pigs. Form deprivation and lens-induced myopia: are they different? Int Ophthalmol. Iris pigmentation and atropine mydriasis. J Pharmacol Exp Ther. Racial differences in mydriatic action of cocaine, euphthalmine, and ephedrine. Am J Phys Anthropol. Peiffer RL, Jr. Chapter 19 — Models in ophthalmology and vision research. Variations in eyeball diameters of the healthy adults. J Ophthalmol. The penetration and distribution of topical atropine in animal ocular tissues. Acta Ophthalmol. Nickla DL, Wallman J. The multifunctional choroid. Short-term effect of low-dose atropine and hyperopic defocus on choroidal thickness and axial length in young myopic adults. PLoS One. Additive effect of atropine eye drops and short-term retinal defocus on choroidal thickness in children with myopia. Sci Rep. Changes in choroidal thickness and choroidal blood perfusion in guinea pig myopia. Vision-dependent changes in the choroidal thickness of macaque monkeys. Moving the retina: choroidal modulation of refractive state. Temporal relationship of choroidal blood flow and thickness changes during recovery from form deprivation myopia in chicks. Exp Eye Res. Effect of atropine eye drops on choroidal thinning induced by hyperopic retinal defocus. Nitric oxide NO mediates the inhibition of form-deprivation myopia by atropine in chicks. The effect of the nonspecific nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester on the choroidal compensatory response to myopic defocus in chickens. Optom Vis Sci. Effects of intravitreally and intraperitoneally injected atropine on two types of experimental myopia in chicken. Atropine reduces experimental myopia and eye enlargement via a nonaccommodative mechanism. Studies on retinal mechanisms possibly related to myopia inhibition by atropine in the chicken. Graefes Arch Clin Exp Ophthalmol. Inhibitory effects of apomorphine and atropine and their combination on myopia in chicks. Optom and Vis Sci. Principles of pharmacology in the eye. Br J Pharmacol. Pharmacokinetic aspects of retinal drug delivery. Supplement 1. Copyright The Authors. View Metrics. Forgot password? To View More Create an Account or Subscribe Now. You must be signed into an individual account to use this feature. This site uses cookies. By continuing to use our website, you are agreeing to our privacy policy.

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