Safety and Efficacy of Different Concentrations of Atropine in Retarding the Myopia Progression

Purpose: To evaluate the safety and efficacy of different concentrations of topical atropine in retarding the progression of myopia.

Method. A total of 90 individuals with bilateral myopia ranging between 2-6 diopters (spherical equivalent) with astigmatism of up to 1 diopter and ages ranging between 9-15 years of age were recruited. Patients were randomly assigned to one of three treatment arms i.e. 0.01%, 0.025%, and 0.05% atropine once daily in 1:1:1 ratio. All patients at baseline underwent cycloplegic refraction and axial length measurements. All patients were fully corrected for myopia and given +2.00 Diopters of near add in executive bifocals. Progression in Spherical equivalent and axial length were measured and compared across the three treatment arms was the main outcomes:.

Results: After 1 year the mean [SD] progression of spherical equivalent was 0.48 [0.17] D, 0.38 [0.19] and 0.27[0.16] in 0.01%, 0.025% and 0.05% treatment groups respectively (p=0.00). The mean (SD] axial elongation was 0.16[0.06], 0.13[0.06] and 0.09 [0.05] mm in 0.01%, 0.025% and 0.05% treatment groups (p=0.00). None of the participants from 0.01% and 0.025% group reported any adverse events. However, 10% of patients from 0.05% group reported mild degree of transient photophobia.

Conclusion: Low dose atropine can slow down myopia in a dose dependent manner with relatively fewer side effects. Bifocals with near addition, when worn as standard spectacle during atropine therapy, may help further slowdown the progression.

Key words: Atropine, Myopia, Bifocals, Progression, Pakistan

Received: July’2020                        Accepted: Sep’2020

INTRODUCTION:

Myopia is a refractive condition of the eye wherein the parallel incident rays of light falling on the eye are focussed in front of the retina. Myopia usually develops from a disproportionate increase in the axial length of the eyeball or the corneal curvature. The prevalence of myopia varies remarkably across the globe, from 3% in Sherpa of Nepal[1] to over 90% in Taiwanese[2] and Chinese students[3]. Almost 1/3rd of the population of the U.S.A. is myopic[4], whereas the prevalence of Myopia in Pakistan is 36.5%[5]. Studies have projected that myopia will affect 50% of the world population by 2050, with 10% of people being highly Myopic.[6,7]  A few studies have claimed that the prevalence of myopia is higher in females[8-11], while others show no such gender predilection[12-14]. Typically, Myopia develops in childhood and progresses through the next 15-16 years of age.

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Lower doses of atropine are safe in retarding myopic
progression and to slow down in a dose.

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The usual average rate of progression of myopia is approximately 0.50 D,which settles by the age of 21 years.[15-18]  However, in a subset of patients, the condition continues to progress and thus is termed progressive (or pathological) Myopia that has grave visual consequences.[19,20]  Although genes are the primary determinant of a person’s refractive error,[21,22]  the condition is altered by environmental factors, the most considerable risk factor for the progression of Myopia is excessive near work.[23-] Moreover, the higher the degree of Myopia, the higher is the risk for developing sight-threatening ocular complications like cataract, glaucoma, atrophic changes and detachment of the retina.. Therefore, the researchers have devoted voluminous resources to conduct studies probing the methods to retard myopic progression. The appraised strategies include under-correction of refractive error, use of bifocal and progressive spectacles,15, 16, contact lenses (Gas permeable, orthokeratological]and soft bifocal contact lenses, and topical drugs.. The pioneering trial that documented the definitive role of atropine eye drops in controlling myopic progression was ‘Atropine for the Treatment Of Myopia’ (ATOM) trial. This study demonstrated that 1%atropine eye drops retarded themyopia progression to -0.28±0.92D, as compared to -1.20±0.69D in the placebo group, exhibitinga 77% better control as compared to the control group. Atropine is a non-selective anti-muscarinicagent that paralyzes the ciliary muscles. This paralysis decreases traction on the sclera, (which is a trigger for the lengthening of the eyeball), and thus reduces myopic progression. However, the success was marred by the visually debilitating side-effects like the blurring of near vision and photophobia. ATOM 2 and ‘Low-concentration Atropine for Myopia Progression’ (LAMP) study addressed these issues by using lower concentrations of Atropine. In these studies, the diluted the drug, the fewer were the side effects; however, so was the effectiveness of the drug in reducing myopic progression. As myopia is widely prevalent in Pakistan, and hitherto no treatments are available to stop myopia progression, we proposed this study to assess the combined effect of atropine and executive bifocals on the progression of myopia.

MATERIALS AND METHODS:

The study was adhered to the tenets of Helsinki. After approval from the Ethical Committees Sehhat foundation and Poonch Medical College. The study was conducted as a multicenter, randomized, clinical trial having no placebo or control arm. After taking informed consent, 180 eyes of 90 participants from either gender were included in the study. Children with age from 9 to 15 years, with myopia of 2-6 D Spherical Equivalent (S.E.) and astigmatism of up to 1 D, with a documented progression of at least 1 D in the preceding 12 months were included in the study. There were three arms designed based on the dosage of Atropine given, i.e., 0.01%, 0.025%, and 0.05% atropine. The patients were randomly assigned to one of the three treatment arms in 1:1:1 ratio. All participants were fully corrected for myopia at baseline and given +2.00D of near add in executive bifocals (regardless of degree of myopia). Patients excluded from the study were those having progression of Myopia of more than 1D in preceding 12 months, as were those who had fundus changes suggestive of myopic degeneration, had a history of previous intraocular/refractive surgery, or those who had a history of use of atropine eye drops for more than 3 weeks in the preceding 6 months. The baseline measurements documented were the cycloplegic refraction of the patients and the measurement of their axial lengths. The patients were followed for 1 year. The data was collected on a proforma designed for the study; the primary outcomes were changes in spherical equivalent (S.E.) and axial length form baseline, which were measured and compared across three groups. Moreover, adverse events related to the use of atropine were subjectively assessed. Patients were educated about the possible adverse events associated with the use of topical atropine and given the option to report adverse events. In case of any significant adverse events, they were asked to visit the office for detailed evaluation. The data was analyzed using S.P.S.S. v23. Qualitative data, like gender, were expressed in frequency and percentage while quantitative data like age, refractive error, and axial lengths were expressed as Mean Range and standard deviation. Conisderding the normal distrtibution of data repeated measure ANOVA was used to compare the outcomes across different treatment arms.

RESULTS:

90 Patients were enrolled in the study, among which 40 (44%) were male, while 50 (56%) were female. The mean age of patients was 11.77±1.60, 12.03±1.56, and 12.02±1.54 in 0.01%, 0.25%, and 0.05% arms, respectively. The Baseline SE was -3.45±0.99, -3.45±1.01, and -3.45±1.00%. The baseline axial length was 24.55±0.33%, 24.55±0.33, and 24.56±0.33, 0.01%, 0.25%, and 0.05% arms, respectively. At the end of the study period, the mean progression in Spherical equivalent was -0.48 [0.17] D, -0.38 [0.19] D, and -0.27[0.16] D, in the 0.01%, 0.025% and 0.05%respectively. On comparison between 0.01% and 0.025%, the p-value was 0.005, between 0.01% and 0.05% p-value was 0.000, whereas between the 0.025% and 0.05% group the p-value was 0.002%. The lowest p-value was between 0.01% and 0.05%, indicating the effect was statistically significant for these groups, with 0.05% group being most effective of all. At the end of the study period, the increase in axial length was 0.16mm, 0.13mm, and 0.09mm for the 0.01%, 0.25% and 0.50% arms, indicating that the progression was reduced most in the 0.05% arm. On comparison of change in axial length among the groups, the following were the results. On the comparison between 0.01% and 0.025%, the difference in axial length was -0.03mm, and the p-value was 0.005. The difference between 0.01% and 0.05% group was 0.07mm, with p-value of 0.000, whereas between the 0.025% and 0.05% it was 0.04 group the p-value was 0.002. The lowest p-value was between 0.01% and 0.05%, indicating that the effectiveness was statistically significant for these groups, with 0.05% group being more effective.

Table 2 demonstrates the comparisons between various concentrations in our study over one year. With these findings, it seems reasonable to extrapolate that increasing the dosage frequency of atropine drops or by the usage of higher concentrations, myopia progression is slowed over a period.

DISCUSSION:

Myopia has a very high prevalence affecting approximately one-third of the U.S. population and over 90 % of the population in some East Asian countries. According to a study, myopia affects about 36.5 % of the population in Pakistan, and uncorrected refractive errors are accountable for 11.4 % of the blindness. Other studies reported the prevalence to be 31.5% in Sialkot and as high as 51.5 % in school-going children of Faisalabad, Pakistan. Despite the high prevalence worldwide, very little is known about pathogenesis and the progression of myopia. Both genetic and environmental factors have been found to play a role, with the higher prevalence found in children of myopic parents than in children whose parents did not have any refractive errors themselves.[23-25]Similarly, monozygotic twins have been found to have a significantly higher correlation of development of myopia than dizygotic twins; supporting a strong genetic component towards susceptibility to myopia development. However, to date- no single gene locus has been localized to be consistently associated with myopia development. Among environmental factors, both the time spent on nearwork and time spent outdoors have been studied as potential contributory and protective factors towards myopia development and progression respectively [23-; however, no concrete evidence exists as to what environmental factor can be implicated as a direct causative factor in its development.

It has been documented in numerous studies that higher degrees of myopia are associated with greater risk of sight-threatening problems such as retinal detachment, choroidal degeneration, pre-senile cataracts, glaucoma, macular degeneration, and macular haemorrhage.[9-12]  Therefore, slowing myopia progression has been of great interest, especially in the last decade, when various treatment options such as myopia under- correction, gas-permeable contact lenses, bifocal/ multifocal spectacles, as well as different topical pharmaceutical agents such as atropine have been extensively studied as treatment modalities. Topical pharmaceutical methods such as the use of atropine have been applied for myopia control for some years now. So has the use of bifocal and multifocal spectacles for reducing the need for accommodation, which is a stimulus for an increase in axial length of the eyeball. moreover, they are helpful in situations where near add is required due to loss of accommodation. In our study, we evaluated the efficacy of low concentrations of topical atropine at 0.01 %, 0.25%, and 0.05%, alongwiththe use of standard bifocals with (+2D addition) over one year, by assessing the effect mean S.E. progression and A.L. elongation. Our study shared baseline characteristics in S.E. and A.L. with subjects of LAMP study (except that our subjects were olderby about two years, which was conducted in China from January 2016 to November 2017. The placebo group was only employed in LAMP study and was not part of ATOM2 or our study. Similar to results from the LAMP study, our results suggest that all three concentrations work well in retarding the usual progression of myopia in a concentration-dependent manner. In our study, after a period of one year, the change noticed in mean S.E. progression was found to be 0.48 (+-0.17 )D, 0.38 (+-0.19), and 0.27 (+-0.16) D for atropine concentrations of 0.01 %, 0.025%, and 0.05%, respectively. A meta-analysis that was conducted by Donovan, L. et al. showed estimated myopia progression,at the mean age of 9.3 years, after one year of follow-up to be −0.55 D (95% CI −0.39 to −0.72 D) for populations of European descent and −0.82 D (95% CI −0.71 to −0.93 D) for Asians. Our result values show a significant change from the estimated progression of -0.82D per annum. On one to one comparison with LAMP study for the same concentration of 0.01% atropine, our results showed lesser progression in mean S.E. (-0.48 in our study vs -0.59 in LAMP) which could be attributed to the synergistic effect of standard bifocal executive lenses that were employed across all the subjects in our study group.

The dose-dependent response on retardation of myopia progression is also supported by ATOM2 study showing that Atropine concentrations of 0.5%, 0.1%, and 0.01% slowed myopia progression to -0.43(+-0.52)D, -0.31(+-0.50)D, and -0.17 (+-0.47)D, respectively, afterone year at the end of two year the difference between the three groups with values of_0.49_0.60,_0.38_0.60, and _0.30_0.63 D in the atropine 0.01%, 0.1%, and0.5% groups, respectively (P_0.07), with a significant differenceonly between the 0.01% and 0.5% groups. A concentration dependent response on the slowing of myopia progression with increasing atropine concentrations has also been reported in previous studies. where 0.5%, 0.25%, and 0.1% were studied. Two subsequent meta-analyses that followed ATOM2 also failed to establish any pattern in difference of efficacy across different concentrations. Recently conducted LAMP study attempted to address some of these critical ambiguities in ATOM2 and the meta-analyses-firstly, by assessment of myopia progression in comparison with a placebo group and secondly, by also showing a concentration-dependent response on retardation of progression with increasing atropine concentrations. The subjects in ATOM2 and LAMP study were provided with progressive spectacles as per need. Our results also show similarity with the evidence from the LAMP study comparing the efficacy of exactly similar low doses of atropine, studied over oneyear, as a safe intervention for myopia control. Since our results showed slightly better control with addition of standard bifocal lenses concomitant with atropine treatment(as evidenced by mean progression of - 0.48D vs -0.59D in LAMP) we also propose that the combined treatment may serve as a useful adjunct in slowing progression of myopia. However, further studies are needed to explore the synergistic effect of bifocal lenses in addition to simultaneous atropine treatment. All three concentrations were well-tolerated by our study group in near-vision and best-corrected distant vision, and there were no reports of any treatment-related adverse effects. It should be noted here that in the ATOM 2 study that was conducted over two years, participants in the 0.01 % atropine group progressed by 0.43+-0.52 D during the first year with remarkable reduction in speed of progression occurring in the second year with only an increase of 0.06 D in the second year (Total progression being 0.49 +-0.63mm). As evident in TABLE 4, our results are comparable to ATOM 2 when the lower concentration of 0.01 % is being compared with the same dose of atropine over two years (0.48 D in our study vs. 0.43D in ATOM2). However, in the LAMP study, the efficacy of 0.01% appeared to be lesser than that of ATOM2 or our study results, with an S.E. progression of -0.59 +-0.61 D over one year period. The benefit that our research showed in comparison with LAMP may be attributed to the usage of bifocal lenses in our study population. This observation may be further explored in future trials. In our study, the A.L. progression was 0.16 mm for 0.01 % dosage of atropine forone year and lower for higher concentrations. In ATOM2, AL increased by 0.24 +-0.19 mm in the first year and 0.17 mm during the second year even when myopia progression was slowed itself. Although the difference in S.E. progression of 0.01 % when compared with higher concentrations is smaller,the elongation of A.L. shows significance in ATOM2. Furthermore, AL elongation in 0.01 % group remained significant (0.41+-0.32mm/2 years),which questioned the role of low dose atropine in myopia control Additionally, the difference in A.L. between the 0.01 % atropine and placebo in the LAMP study was also not significant [86]. Various studies have attempted to explain the A.L. elongation in ATOM2, suggesting that it is only secondary to decreased tonic accommodation at rest, causing changes in lens curvature. Some studies have also indicated that the most effective myopia control was, infact, provided by 0.01% atropine, one year after discontinuation] most probably because of the return of accommodative tonus to normal, offsetting the stronger myopia control primarily due to changes in tonic accommodation. Therefore, follow up results from LAMP and other future studies will be important to assess the long-term effect of varying atropine concentrations. Our study was limited in this capacity by lack of a placebo group. The main limiting factor against usage of higher doses of atropine includes blurry vision secondary to pupillary dilatation with higher concentrations of atropine. In our study, none of the patients from 0.01% and 0.025% atropine groups reported any significant adverse events, and 3% of patients on a 0.05% treatment group reported mild photophobia. None of the Patients from any group reported difficulties with near visual tasks. However, there is an additional concern about non-responders to atropine that were brought forward by a retrospective cohort study based on the data from the ATOM1 study. The study showed that there might be a subset of younger children, with higher myopia at baseline or with a vital genetic component towards myopia, who may not be good responders to atropine as a therapeutic modality against myopia progression. Rapid myopia progression was also noted in the first year of ATOM2 study, where a progression of upto 0.5 D was recorded in the first year in all three cohorts. In another study by Shih and associates, it was also noted that 10.6 % of patients progressed by 0.75 D or more in the first 18 months of atropine treatment at a concentration of 0.5 %. In another study. Myopia rebound is another phenomenon that was observed when 1 % atropine was suddenly stopped after two years of use. When the results from ATOM 1 and ATOM2 are combined, it was shown that two years following treatment when atropine was stopped, there was an increase in myopia that was “greater in eyes treated with higher dosages of atropine”. A dose-related response was noticed, showing that the myopic rebound was higher in the eyes treated with 1% atropine than in the eyes that were treated with lower concentrations of 0.5%, 0.1 %, and 0.01 % of atropine. This paradoxically resulted in worsening myopia at 36 months following treatment with 1% atropine compared to eyes that were treated with lower concentrations. It was also noticed that there was a corresponding increase in A.L. in the eyes that were treated with 0.1 % and 0.5% of atropine. The authors subsequently concluded that 0.01 % of atropine resulted in the least myopic rebound with greater sustainability in myopia retardation and overall myopia reduction. Hence, further exploration is needed to evaluate different factors that may contribute towards non-responsiveness to atropine or may result in a myopic rebound, including a deeper understanding of A.L.changes and its potential contribution towards loss of myopic control after cessation of treatment.

CONCLUSION:

Lower doses of atropine are safe in retarding myopia progression and slow down the myopia in a dose depandant manner.

2. Third eyelids of camels

Camels have not one, not two, but three eyelids. Called a nictitating membrane, the transparent lid helps keep out sand and dust; it can even improve vision, like a contact lens. Many animals, including dogs, cats, sharks, and some birds and amphibians, also have third eyelids. Jan 28, 2014

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