Abstract
Purpose:
To explore the effect of topical atropine on axial eye growth and emmetropization in infant marmosets.
Methods:
Atropine was applied to one eye from the age of 7 to 56 days in two dose regimens, High (0.1–1% twice daily, increasing with age) or moderate (Mod) (0.1% once daily). Both eyes of the marmosets were refracted, and axial dimensions were measured ultrasonically, at 14, 28, 42, 49, 56, 70, 105, 168, and 279 days of age. The time course of each measured variable was analyzed using multilevel mixed-effects modeling realized in R.
Results:
The logistic growth curves fitted to anterior segment depth (ASD) did not differ significantly between the dose regimens, but xmid, the age at which growth was half-maximal, and scal, the time constant of the exponential term in the logistic growth curve equation, differed significantly between the ASD of atropinized and untreated eyes (P = 0.03 and P < 0.0001, respectively), with the ASD of atropinized eyes shorter than that of untreated eyes. The splines fitted to lens thickness did not vary significantly with dose, but differed significantly (P < 0.0001) between the atropinized and untreated eyes, with the atropinized lenses thicker. Vitreous chamber depth (VCD) was not significantly different, but the variance of VCD was significantly greater (P < 0.001) in the atropinized compared with the untreated eyes. Refractive error (RE) became relatively myopic in atropinized eyes. The variance of RE in atropinized eyes was significantly greater (P < 0.0001) than in untreated eyes.
Conclusions:
Atropine caused the infant marmoset lens to move forward and thicken, a relative myopia, and increases in the between-animals variance in VCD, which could be considered a failure of emmetropization.
There has been longstanding interest in whether daily topical atropine is effective in reducing myopia progression in eyes of children either already myopic or at risk of becoming so.
1 Systematic reviews of clinical trials
2–4 have concluded that atropine, combined with optical correction, reduces progression of myopia by approximately 0.5 diopter (D)/year. Recent studies
5–7 claim (and others contest
8) that very low-dose atropine (0.01%), which does not affect accommodation, is as effective as moderate or higher doses, and its effect is maintained for some time after cessation of treatment, unlike with higher doses where a rebound myopia occurs. Interim results of the latest study
9 show a graded effect of atropine doses of 0.05%, 0.25%, and 0.01% on myopic progression and axial length increase, with 0.05% being the most effective, but 0.01% not having a statistically significant effect on axial length at 1 year. The mechanism by which atropine, a nonspecific muscarinic anticholinergic, is effective is unidentified.
Studies in animals have shown that atropine prevents the development of myopia caused by visual deprivation in chicks,
10–13 some macaques,
14–16 squirrels,
17 and tree shrews
18,19-notably in chicks, whose ciliary muscle innervation is nicotinic rather than muscarinic, suggesting that the antimyopic effect of atropine must depend on factors other than its attenuation of accommodation. It has also been shown that atropine prevents “lens-induced myopia,”
20,21 perhaps more accurately described as the compensatory response to wearing negative-powered spectacle lenses, and that 1% atropine disrupts eye growth in mice.
22 For practical reasons (eyes grow more quickly and by larger amounts in infancy), most animal experiments have been carried out in infant animals. It is thought that atropine probably affects the development of myopia through a retinal action. Of the five classes of known muscarinic receptors in the retina (M1–M5), the M1 and M4 receptors have been most heavily implicated,
23–25 though there is a view that atropine may exert its effects through mechanisms other than action on muscarinic receptors.
26
The motivation for these experiments was to examine the effect of atropine on the early phase of eye growth and emmetropization in nonhuman primates. While we should stress that our experiments were not intended to address directly the mechanism by which atropine may reduce the rate of increase of myopia in school-age children (due to the age differences), we feel they provide important insights into how atropine can influence eye growth.
Throughout the period of atropinization, the amplitude of accommodation of the untreated fellow eyes of the two marmosets was greater than 30 D.
The mean accommodative amplitude for the atropinized eye of the marmoset in the High group was 6.5 and 11 D at 34 and 48 days of age, respectively (i.e., after 26 and 41 days of atropine treatment). The range of measures throughout the day at each of the three ages for this animal was not greater than 2 D.
In contrast, the amplitude of accommodation in the atropinized eye of the infant in the Mod group varied considerably during the day. At 26 days of age the amplitude of accommodation of the atropinized eye was 6 D 1 hour after and 10 D 9 hours after the atropine dose. At 44 days of age the amplitude had increased to 10 D 1 hour after and 31 D (i.e., approximately normal) 9 hours after the atropine dose.
These experiments are not directly comparable with studies of the effectiveness of atropine in preventing or reducing myopia progression in juvenile humans. Atropine was applied earlier in life in our studies, without refractive correction, and in subjects that were hyperopic rather than myopic or at risk of becoming myopic.
We have shown that early in life, doses of atropine in the same range as those used in human treatment of myopia have effects on the growth of the anterior eye. This suggests that one may want to be cautious about using atropine in human infants during early emmetropization. It is worth noting that 1% atropine is also used clinically for protracted periods to treat amblyopia as an alternative to patching. Strabismic and anisometropic amblyopia generally develops at a younger age than myopia. Amblyopia treatment associated with unilateral congenital cataracts occurs at even younger ages that are comparable to the developmental stage of the animals in this study. Careful monitoring of anterior segment development should be considered in clinical application of topical atropine for prolonged periods in human infants and young children.
The authors thank the Animal House staff for their dedicated care for the animals. We thank Daniel I. Flitcroft and two anonymous reviewers for helpful suggestions on the paper.
Supported by the McDonnell-Pew Centre, Oxford, UK.
Disclosure: A.R. Whatham, None; D. Lunn, None; S.J. Judge, None