The Effects of Low Dose Atropine on Choroidal Thickness

Atropine eye drops are considered to be an effective form of myopia control in human eyes. However, the mechanism by which it exerts it effects are not fully understood. Thickening of the choroid subsequent to atropine administration may play an important role in the mechanisms by which atropine induces myopia control. Literature also notes that choroidal thickness undergoes diurnal variations, which is a variable that will be controlled in this study in order to examine atropine's effects on different baseline choroidal thicknesses. The purpose of the proposed study is to characterize better the influence of atropine on choroid thickness. The study aims are to: Determine the effect of low dose concentration of topical atropine (0.1% and 0.01%) on choroid thickness Determine the effect of topical atropine on choroid thickness in relationship to baseline thickness throughout the day and after one week of daily instillation Hypothesis: Atropine's effect on choroidal thickness will be dependent on the subject's baseline thickness measurements, at a designated time of the day when the choroid is at its thinnest.

Atropine eye drops are an effective form of myopia control in children with progressive myopia1, but the mechanism in which this occurs is still not fully understood. The choroid has been established to play a significant role in the modulation of ocular growth in the chick eye;2 eyes with thicker choroids grow slower than eyes with thinner choroids.3 Choroidal compensation has also been discovered in other animal species including tree shrews,4 marmosets,5 rhesus macaques,6 guinea pigs,7, 8 and even in humans.9, 10 A study in humans demonstrated how the thickening of the choroid subsequent to atropine use may contribute to the mechanisms by which atropine induces myopia control.11 These results are supported by another study where children with less choroidal thickening over time exhibited faster axial growth.12 Furthermore, diurnal variation in choroidal thickness has been documented13, 14 and individuals with thinner choroids exhibited less variation in thickness across the day. 13 Currently, atropine is prescribed by eye care providers on a daily basis and administered at night for convenience. However, choroidal thickness undergoes diurnal variations13, and the efficacy of atropine on myopia control in relationship to the patient's baseline choroidal thickness is unknown. A preliminary study shows that atropine 1% has an effect on reducing choroidal thinning throughout the day, but how this translates to low concentration atropine as is commonly prescribed in myopia control treatment is unknown. Specifically, preliminary results reveal that the maximal pharmaceutical effects on choroidal thickening occurred one hour after atropine 1% instillation in the morning, but its relative efficacy during specific time points and duration of the day is still unclear. Also, baseline diurnal measurements demonstrate that the choroid thins in the morning, is thinnest at noon, and gradually thickens in the evening and overnight. The effects of atropine on the choroid from noon to the afternoon were not explicitly measured in our previous study, and therefore, are measurements of interest. While it is critical to understand the effects of low dose atropine on choroidal thickness throughout the evening as commonly prescribed clinically, it is important to also understand its effects when the choroid is shown to thin during the day. Additionally, the study measured changes in choroidal thickness after one instillation of atropine, but did not explore the effects of daily instillation on choroidal thickness and whether there is further minimization of choroidal thinning. Thus, the objective of this study is to provide data to characterize the influence of low dose atropine on choroid thickness. The study aims are: To determine the effect of low dose topical atropine (0.1% and 0.01%) on choroid thickness To determine the effect of topical atropine on choroid thickness in relationship to baseline thickness throughout the day and after one week of daily instillation. It is hypothesized that atropine's effect on choroidal thickness will be dependent on the subject's baseline thickness measurements, at a designated time of the day when the choroid is at its thinnest. Potential risks of this study are related to the use of atropine eye drops. Atropine 0.1% and 0.01% eye drops may cause dilation of the pupil (mydriasis) and paralysis of accommodation (cycloplegia).15 There are also rare ocular and systemic adverse effects associated with the use of atropine eye drops as described in section C3 below.15 However, using the minimum dosage in combination with low concentrations of the drug will minimize these adverse effects associated with atropine.16 Participants will be asked if they have experienced any reactions to eye drops in the past. The puncta can be occluded as a preventative measure against systemic absorption. Risks can be further minimized by preparing for adverse systemic side effects and by immediate recognition of the signs and appropriate monitoring. The participant will also be educated to report any unforeseen side effects from instillation of the atropine according to the instructions detailed in consent form. All participants will be trained to promptly report any side effects to the investigators. Medline and Pubmed databases were used for literature review.

Participants will be on topical atropine 0.01% ophthalmic solution QD OU for 1 week (7 days) and then topical atropine 0.1% ophthalmic solution QD OU for 1 week (7 days) with a washout period of 4 weeks in between each intervention

Participants will be on topical atropine 0.1% ophthalmic solution QD OU for 1 week (7 days) and then topical atropine 0.01% ophthalmic solution QD OU for 1 week (7 days) with a washout period of 4 weeks in between each intervention

Measure choroidal thickness changes at baseline and compare to choroidal thickness after intervention of atropine 0.01% and atropine 0.1%

Measure distance and near visual acuity at baseline and re-measure after intervention of atropine 0.01% and atropine 0.1% for any changes

Measure axial length at baseline and compare to changes after intervention of atropine 0.01% and atropine 0.1%

Measure lens thickness at baseline and compare to changes after intervention of atropine 0.01% and atropine 0.1%

Measure anterior chamber depth at baseline and compare to changes after intervention of atropine 0.01% and atropine 0.1%

The questionnaire is a Rasch-tested, linear-scaled, 30-item instrument on three scales providing a QoV score in terms of symptom frequency, severity, and bothersome. There are four options of increasing severity of symptoms from none, mild, moderate, and to severe for each item. The use of Rasch analysis turns the original questionnaire responses (raw ordinal data) into continuous interval data, providing a linear measurement; it is on a linear interval scale.

Sodium fluorescein dye is added to the eye and the tear film is observed under the slit lamp while the patient avoids blinking until tiny dry spots develop; compare any differences between baseline and after one week of atropine use

Measure amount of tear production; compare value at baseline to values after 1 week of atropine use to determine if tear production is affected with atropine use

This is a 12-item questionnaire with 5 options from 0 to 5 (with 0 indicating none of the time, and increases to 5 indicating all of the time). The sum of the scores across the 12 items are totaled, and inputted into a formula to generate a sliding scale of the disease condition. The scale ranges from 0 to 100, with higher scores representing greater disability of the disease condition. This questionnaire will be completed at baseline and after 1 week of atropine use to compare for any differences.

Inclusion Criteria: Aged between 18 - 35 years Good general and ocular health Soft contact lens wearers to cease lens wear for at least 24 hours No previous rigid gas permeable lens wear Not taking monoamine oxidase inhibitors (MAOIs) and are not pregnant Exclusion Criteria: History of ocular surgery, including refractive surgery Use of ocular medications Amblyopia Conditions where topical atropine is contraindicated Any eye or systemic disease that affect vision or refractive error

Chia A, Lu QS, Tan D. Five-Year Clinical Trial on Atropine for the Treatment of Myopia 2: Myopia Control with Atropine 0.01% Eyedrops. Ophthalmology. 2016 Feb;123(2):391-399. doi: 10.1016/j.ophtha.2015.07.004. Epub 2015 Aug 11.

Wallman J, Winawer J. Homeostasis of eye growth and the question of myopia. Neuron. 2004 Aug 19;43(4):447-68. doi: 10.1016/j.neuron.2004.08.008. Erratum In: Neuron. 2012 Apr 12;74(1):207.

Nickla DL, Totonelly K. Choroidal thickness predicts ocular growth in normal chicks but not in eyes with experimentally altered growth. Clin Exp Optom. 2015 Nov;98(6):564-70. doi: 10.1111/cxo.12317.

Siegwart JT Jr, Norton TT. The susceptible period for deprivation-induced myopia in tree shrew. Vision Res. 1998 Nov;38(22):3505-15. doi: 10.1016/s0042-6989(98)00053-4.

Troilo D, Nickla DL, Wildsoet CF. Choroidal thickness changes during altered eye growth and refractive state in a primate. Invest Ophthalmol Vis Sci. 2000 May;41(6):1249-58.

Hung LF, Wallman J, Smith EL 3rd. Vision-dependent changes in the choroidal thickness of macaque monkeys. Invest Ophthalmol Vis Sci. 2000 May;41(6):1259-69.

Howlett MH, McFadden SA. Form-deprivation myopia in the guinea pig (Cavia porcellus). Vision Res. 2006 Jan;46(1-2):267-83. doi: 10.1016/j.visres.2005.06.036. Epub 2005 Aug 31.

Howlett MH, McFadden SA. Spectacle lens compensation in the pigmented guinea pig. Vision Res. 2009 Jan;49(2):219-27. doi: 10.1016/j.visres.2008.10.008. Epub 2008 Dec 4.

Woodman EC, Read SA, Collins MJ. Axial length and choroidal thickness changes accompanying prolonged accommodation in myopes and emmetropes. Vision Res. 2012 Nov 1;72:34-41. doi: 10.1016/j.visres.2012.09.009. Epub 2012 Sep 24.

Chakraborty R, Read SA, Collins MJ. Monocular myopic defocus and daily changes in axial length and choroidal thickness of human eyes. Exp Eye Res. 2012 Oct;103:47-54. doi: 10.1016/j.exer.2012.08.002. Epub 2012 Aug 16.

Zhang Z, Zhou Y, Xie Z, Chen T, Gu Y, Lu S, Wu Z. The effect of topical atropine on the choroidal thickness of healthy children. Sci Rep. 2016 Oct 7;6:34936. doi: 10.1038/srep34936.

Read SA, Alonso-Caneiro D, Vincent SJ, Collins MJ. Longitudinal changes in choroidal thickness and eye growth in childhood. Invest Ophthalmol Vis Sci. 2015 May;56(5):3103-12. doi: 10.1167/iovs.15-16446.

Tan CS, Ouyang Y, Ruiz H, Sadda SR. Diurnal variation of choroidal thickness in normal, healthy subjects measured by spectral domain optical coherence tomography. Invest Ophthalmol Vis Sci. 2012 Jan 25;53(1):261-6. doi: 10.1167/iovs.11-8782.

Chakraborty R, Read SA, Collins MJ. Diurnal variations in axial length, choroidal thickness, intraocular pressure, and ocular biometrics. Invest Ophthalmol Vis Sci. 2011 Jul 11;52(8):5121-9. doi: 10.1167/iovs.11-7364.

North RV, Kelly ME. A review of the uses and adverse effects of topical administration of atropine. Ophthalmic Physiol Opt. 1987;7(2):109-14. doi: 10.1111/j.1475-1313.1987.tb01004.x.

Gong Q, Janowski M, Luo M, Wei H, Chen B, Yang G, Liu L. Efficacy and Adverse Effects of Atropine in Childhood Myopia: A Meta-analysis. JAMA Ophthalmol. 2017 Jun 1;135(6):624-630. doi: 10.1001/jamaophthalmol.2017.1091.

Pediatric Eye Disease Investigator Group.. A randomized trial of atropine vs. patching for treatment of moderate amblyopia in children. Arch Ophthalmol. 2002 Mar;120(3):268-78. doi: 10.1001/archopht.120.3.268.

McAlinden C, Pesudovs K, Moore JE. The development of an instrument to measure quality of vision: the Quality of Vision (QoV) questionnaire. Invest Ophthalmol Vis Sci. 2010 Nov;51(11):5537-45. doi: 10.1167/iovs.10-5341. Epub 2010 May 26.

Rahman W, Chen FK, Yeoh J, Patel P, Tufail A, Da Cruz L. Repeatability of manual subfoveal choroidal thickness measurements in healthy subjects using the technique of enhanced depth imaging optical coherence tomography. Invest Ophthalmol Vis Sci. 2011 Apr 8;52(5):2267-71. doi: 10.1167/iovs.10-6024. Print 2011 Apr.