Population, Ethics and Legal Issues
The compilation of this cross-sectional, single centre, observational case series was approved by our institutional Ethics Committee (Institutional Review Board Approval University of Freiburg #287/16) and adhered to the tenets of the Declaration of Helsinki. Informed parental consent with regard to the therapy and data capture, as well as the off-label use of low-dose atropine, was obtained at the time of first presentation. This observational investigation was carried out within the clinical routine, and hence did not fall under the auspices of the German drug law.
Between June 2014 and December 2017, we started 56 children on bilateral topical therapy with 0.01% atropine at bedtime. Inclusion criteria were an age between 6 and 17 years and a myopic progression ≥ 0.5 D during the year prior to inclusion. Iris colour was classified as light or dark . Our exclusion criteria were non-European ancestry, myopia acquired before primary school, any organic eye disease, strabismus, prematurity and pre-treatment with atropine. Two children were excluded from analysis during follow-up because they used multifocal contact lenses concurrently; one child was lost to follow-up at the 12-months visit.
Progression in the year prior to therapy was assessed by relying on the current refraction compared to their previous prescription or information provided by the family ophthalmologist or optician. We performed non-cycloplegic automated refraction (RM-8900, Topcon, Tokyo, Japan) followed by subjective refraction whenever possible. Five children who could not comply with this method due to their age received cycloplegic retinoscopy (Beta 200 retinoscope, Heine, Herrsching, Germany). Follow-up examinations for refractive error and visual acuity were performed every 6 months. Each patient’s follow-up refraction was measured as it had been done before. As axial eye length could not be determined prior to treatment and was not documented systematically during treatment, we have no such data to report.
All children were advised to spend about 2 h per day outdoors and to wear their full optical correction. New glasses were prescribed whenever an undercorrection of ≥ 0.5 D was detected. 0.01% custom-made atropine was provided by a pharmacy (Berg Apotheke, Tecklenburg, Germany) as single-dose vials without preservatives. Children were given one drop into each eye at bedtime every day.
At each visit we checked for any potential side effects like glare, reading difficulties, or an enlarged pupil. Answers were classified as “no problem”, “problem, but only mentioned on demand” and “problem and described by patient himself”. Compliance was assessed by history and parental report.
A subset of 20 families agreed to start the therapy in one eye only and to present the next day for an assessment of near vision, accommodation, and pupil size at 08:00, 10:00 and 12:00 a.m. by an orthoptist blinded to the trial. This enabled us to exploit the untreated fellow eye for intraindividual control. Allocation of the treated eye was randomised. From the day thereafter, both eyes were treated with atropine. Pupil size was measured with the cross lines of the eye-piece of a manual Goldmann perimeter (Haag-Streit, Bern, Switzerland) at 10 cd/m2. Near visual acuity was tested with Landolt single optotypes (C test for near and distance vision, according to Haase/Hohmann, Oculus, Wetzlar, Germany) in 30 cm with the distance refraction. Accommodation was estimated via dynamic retinoscopy averaging three measurements: The patients were instructed to read optotypes while being examined with the retinoscope (Beta 200 retinoscope, Heine, Herrsching, Germany), as that was brought continuously closer to the eye. The near point of accommodation was defined as the distance at which the fundus red flickering reflex changed to a “with movement”.
All refraction data are presented as the spherical equivalent in D derived from sphere and cylinder. Data were analysed using the R system (R Foundation for Statistical Computing, Vienna, Austria). Continuous data are presented via mean and standard deviation. Categorial data are aggregated via percentages. To analyse the primary endpoint, we performed linear regression analysis. We plotted the spherical equivalents over time for each patient separately. We extracted the slope of myopia progression before treatment, after treatment until 6 months later and, where possible, after treatment until 1 year later. We used the paired t test to compare the slope before treatment to the slope after treatment until 6 months and/or until 12 months. It was further used to compare younger with older children as well as children with light and dark coloured irides. Data were considered significant at p < 0.05.