Follow these considerations when deciding to use combination treatments

Despite consistent evidence demonstrating the safety and efficacy of myopia control options such as novel contact lenses and low dose atropine eyedrops, none of the treatment modalities can halt myopia progression or demonstrate good homogeneity of efficacy outcome, both within and across different trials.¹ In other words, myopic children participating in the trials responded to the same treatment very differently, with a wide distribution of efficacy measures. The lack of consistency in the efficacy performance of varying interventions hence limited generalizability of clinical trial outcomes, adding challenges in predicting the long-term efficacy of such interventions in real world patient populations.

One of the major factors associated with reduced efficacy is the younger age of myopia onset, which is usually accompanied by a faster progression. The poor prognosis related to the early onset is not surprising, as it implies a stronger genetic predisposition, hence less responsiveness to the interventions. Nonetheless, more aggressive treatments, such as higher concentrations of atropine or a treatment regimen combining atropine with novel CLs or spectacles, have been attempted in those younger myopes both in research and clinical settings to hopefully benefit from the potential synergy of the combination treatments. Here, we discuss some important clinical considerations in prescribing such combo treatments.

Research evidence behind the combination treatment

Evidence from animal models suggest that atropine and defocus may work independently in regulating axial growth, for which atropine blocks the choroidal thinning (a potential precursor for accelerated axial elongation) mediated by parasympathetic pathway; while myopic defocus enhances choroidal thickening mediated by dopaminergic pathway.² As a result, combining atropine with any novel optical myopia-controlling treatment could potentially work synergistically for better axial inhibiting effect.³

Another alternative hypothesis behind such synergy is that the pupil dilation from low dose atropine potentiates the induced “stop signals” generated from the novel optical treatments so the interaction from atropine is primarily attributable to its mydriatic effect. While the exact mechanism of such synergy is not fully understood, retrospective studies investigating the additive benefit of atropine have shown promising results when combined with overnight ortho-k,^4,5,6 or with novel spectacles.⁷ Although randomized clinical trials with larger sample size are necessary to confirm these promising results, it seems justifiable to consider such options for the younger, fast progressive myopes, when weighing the minimally added risks but significant benefit of improved efficacy from the combo modalities.

Separate starts

While it is understandable from both the practitioners’ and the parents’ perspective to initiate both (i.e. the optical and the pharmaceutical) components of the combo treatments concurrently as early as possible to achieve the highest possible efficacy, prescribing the combo treatment in a sequential manner offers some unique advantages. First, starting with a single treatment allows a more reliable efficacy evaluation of the first treatment independently, as well as the additive benefit from the second modality, which provides critical information for adjusting the “dosage” for each treatment.

Secondly, adding a second treatment after sufficient time for the adaptation to the first option provides better opportunity for the patient to quantify the severity of the treatment-related side effects, hence more tailored decisions on the lens designs or concentrations of atropine to minimize such side effects. For example, for someone who experiences significant glare and halo with a combo treatment of overnight ortho-k and low dose atropine, it is difficult to weigh the relative contribution of each modality to the side effects if started concurrently since both treatments induce halo and glare as common complications, though under different mechanisms. As a result, it would be very difficult to troubleshoot the case to best balance the efficacy and tolerability of the treatment regimen.

Finally, it is not uncommon to see a complete halt of the myopia progression just with multi-focal soft contact lenses (MFSCL) or ortho-k, and adding atropine to the management of those cases provide no additional benefit but increased cost and side effects.

Concentration of atropine

While the myopia-controlling efficacy of atropine as a standalone treatment has shown a dose dependent effect, the exact dose-response relationship when used as an adjunct therapy has not been fully established. Considering the significant worsening of visual performance due to dramatically increased high-order aberrations by MFSCL or ortho-k under dilated pupil condition, it is recommended to start with a lower concentration of atropine such as 0.01% or 0.025% for combo treatments to allow reasonable tolerability of the regimen, especially considering the long-term nature of the modality. Additionally, dynamic pupillometry is highly recommended as a routine measure at each follow-up visit to allow better understanding of the underlying interactions of the combo treatments in both myopia control and visual side effects.

Additionally, caution needs to be exercised when starting a higher concentration of atropine as adjunct therapy, due to its significant interactions with the optical treatments in induced visual side effects. Photophobia, halo, and glare are common visual complaints that can result from such combo treatments.

Bringing the treatments together

In summary, treatments combining low-dose atropine and novel optical designs are commonly prescribed to myopic children with younger age of onset and/or faster progression. Initiating the combo treatments sequentially allows more reliable evaluation of the myopia-controlling efficacy of each treatment separately, as well as better understanding of the relative contribution to the side effects. OM

References

1. Lawrenson JG, Shah R, Huntjens B, et al. Interventions for myopia control in children: a living systematic review and network meta-analysis. Cochrane Database Syst Rev. 2023;2(2):CD014758. doi: 10.1002/14651858.
2. Nickla DL, Zhu X, Wallman J. Effects of muscarinic agents on chick choroids in intact eyes and eyecups: evidence for a muscarinic mechanism in choroidal thinning. Ophthalmic Physiol Opt. 2013;33(3):245–256. doi: 10.1111/opo.12054.
3. Chiang ST, Turnbull PRK, Phillips JR. Additive effect of atropine eye drops and short-term retinal defocus on choroidal thickness in children with myopia. Sci Rep. 2020;10(1):18310. doi: 10.1038/s41598-020-75342-9.
4. Chen Z, Huang S, Zhou J, et al. Adjunctive effect of orthokeratology and low dose atropine on axial elongation in fast-progressing myopic children-A preliminary retrospective study. Cont Lens Anterior Eye. 2019;42:439–442. doi: 10.1016/j.clae.2018.10.026.
5. Kinoshita N, Konno Y, Hamada Y, et al. Additive effects of orthokeratology and atropine 0.01% ophthalmic solution in slowing axial elongation in children with myopia: first year results. Jpn J Ophthalmol. 2018;62(5):544–553. doi: 10.1007/s10384-018-0608-3.
6. Wan L, Wei C-C, Chen CS, et al. The synergistic effects of orthokeratology and atropine in slowing the progression of Myopia. J Clin Med. 2018;7(9):259. doi: 10.3390/jcm7090259.
7. Yu M, Jiang L, Chen M. Effect of atropine 0.01% on myopia control in children aged 6–13 years during the 2022 lockdown in Shanghai. Front Public Health. 2023;11:1074272. doi: 10.3389/fpubh.2023.1074272.

DR. LIU is an associate professor at Herbert Wertheim School of Optometry & Vision Science, University of California Berkeley. She is also the founder of the Myopia Control Clinic, UC Berkeley Eye Center. She received her bachelor’s degree of Clinical Medicine from Peking University, her OD from Pacific University, and her PhD and MPH from UC Berkeley. She is a world-recognized clinical researcher in myopia. Dr. Liu is a consultant for Coopervision and Essilor China.