Does controlling myopia in childhood prevent the development of pathologic myopia in adulthood?

PM is a sight-threatening condition that includes myopic macular degeneration (MMD), myopic traction maculopathy, myopic choroidal neovascularisation (mCNV) and myopia-associated optic neuropathy.^{8 10} Posterior staphyloma (PS), an outward protrusion of all layers of the posterior eye globe, is a hallmark lesion of PM.¹¹ The prevalence of PM is closely correlated with the severity of myopia.¹² The Guangzhou twin eye study demonstrated that earlier age at myopia onset was associated with a higher myopic refractive error at the age of 18 years.¹³ Current myopia control options can reduce progression by 50%, and specifically among children at the onset of age 8 years, myopia control would reduce their mean refractive error from −6D to −3D. This level of myopia control would significantly reduce the risk of PM from 30% to 5%.¹⁴

Conversely, PM is a complex condition with multiple non-modifiable risk factors other than axial length (AL), such as age, gender and genetics.¹⁰ With pharmaceutical treatments, AL reduction may be limited. Specifically in the atropine in the treatment of myopia (ATOM) and low-concentration atropine for myopia progression (LAMP) studies, AL increased by +0.41 mm and +0.36 mm in the 0.01% atropine groups, respectively, compared to +0.38 mm and +0.4 mm with placebo.^15–18 In the LAMP study, a greater reduction in axial elongation was seen with higher doses of atropine (+0.20 mm and +0.29 mm in the 0.05% and 0.025% groups, respectively). In addition, the second year follow-up of LAMP study reported significant reduction in axial elongation when children on placebo were switched to 0.05% atropine in the second year (0.15 vs 0.43 mm, p<0.001 in years 2 and year 1, respectively).¹⁹ Furthermore, eyes with shallow PS may have a higher frequency of mCNV,²⁰ suggesting that the risk of mCNV may not be closely correlated with AL. Age is another important risk factor. PM and PS commonly occur in older individuals, but have also been observed in children with high myopia.^21–23 Men in general have longer AL than women,²⁴ but a higher prevalence of MMD and mCNV is observed in women in multivariable analyses.^{25 26} Lastly, genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) for refractive error,²⁷ while the SNPs specific for PM are still unknown.²⁸ However, it remains unclear if slowing myopia progression in individuals with high genetic risk will be effective in preventing PM.

A potential treatment target: is the sclera and choroid, or Bruch’s membrane a primary site of pathogenesis in pathologic myopia?

Ophthalmoscopic features of axial myopia suggest a significant contribution of the Bruch’s membrane (BM) to several pathologic features including lacquer cracks (cracks in the BM), patchy/macular atrophy (both are BM defects), mCNV (which arise from a break of the BM) and parapapillary gamma zone (a result of the temporal shift and widening of the optic nerve head–related BM opening). Histologically, BM defects in congenital colobomata and toxoplasmotic scars are associated with scleral staphyloma.²⁹ Both choroidal and scleral volume are not associated with AL, but BM increases in volume with AL.³⁰ This suggests that BM may have an active role in the process of axial elongation. A hypothesis for the role of BM in the process of myopisation states that axial elongation occurs by the production of the BM and elongation of the BM in the equatorial region.³¹ This explains the decrease in retinal pigment epithelium density and retinal thinning at the equator.^{32 33} Also, the compression of the choroid against the sclera by the expanding BM results in choroidal thinning.³¹ Enlargement of the BM opening and development of macular BM defects may be explained by the tension in BM in the coronal direction.³¹ Thus, BM may be more than just an almost invisible double basal membrane with some collagen and elastin in between. Further evidence to support this hypothesis was demonstrated in a guinea pig model of myopia, in which intraocular injection of antibodies to amphiregulin, a member of the epithelial growth factor family that regulates the production of BM, was shown to decrease axial elongation in a dose-dependent manner.^{34 35}

There is equally strong evidence for the sclera and choroid as the primary sites of pathology in PM. In both mammalian models and human studies, myopia development is associated with rapid scleral thinning and tissue loss.^36–38 Remodelling of the sclera is a major feature in the guinea pig model of myopia in particular.³⁹ In terms of biomechanics, scleral biomechanical properties vary with the severity of myopia, and focal areas of weakness in the sclera can be found in the myopic eye.⁴⁰ Choroidal thinning is closely associated with increasing levels of myopia and MMD.^{41 42} In the chicken myopia model, choroid thickness is negatively correlated with myopia.⁴³ Scleral crosslinking as a means to stop scleral growth has been extensively investigated, but clinical application has been limited by a lack of safe and effective methods for applying ultraviolet A radiation and chemicals to the posterior sclera.^{44 45} Lastly, scleral regenerative therapy is an approach whereby human fibroblasts transplanted onto the posterior sclera may strengthen the sclera by producing type I collagen and has been shown to significantly reduce axial elongation in a rat myopia model.⁴⁶

Conclusion

There is currently no definitive evidence to suggest that myopia control in childhood could prevent PM development later in life, and as such, long-term prospective studies are needed to answer this question. Research in myopia treatment would benefit from a shift in focus towards devising clinical therapies targeted at preventing AL elongation and resultant PM. However, there is currently insufficient evidence to support a primary site of pathology in PM. Thus, research into possible strategic targets for therapies may require focus on multiple sites, as current evidence suggest the possibility of BM, choroid and sclera playing a role in PM development.

Should orthokeratology be the treatment of choice for controlling myopia progression in children?

Ortho-K has been reported to be effective in controlling myopia progression (30–56% reduction).^53–58 Ortho-K may have different treatment effects depending on the age and degree of myopia. In the Retardation of Myopia in Orthokeratology study, the effectiveness of Ortho-K on myopia control was observed to be better in younger children less than 9 years than in older subjects.⁵⁸ In another retrospective study, AL elongation was slower by 49%, 59% and 46% in the low, moderate and high myopia subgroups, respectively. While significant differences between Ortho-K and control groups were observed in both the first and second years of follow-up in the low and moderate myopia groups, a significant difference was only observed in the first year within the high myopia group.⁵⁹ In comparison, atropine’s efficacy depending on concentration ranges between 60% and 80% reduction.^{15–17 60} However, higher doses are associated with increased side effects such as photophobia and a decrease in accommodation amplitude which may result in the need for photochromic, progressive or bifocal addition spectacles. Furthermore, there is a need for concurrent spectacle or contact lens usage.⁶¹ On the other hand, the main risk associated with Ortho-K would be infectious keratitis. While the estimated incidence of infectious keratitis in Ortho-K wearers is rare at 7.7/10 000 patient eye years, this increases to 13.9/10 000 patient-years in children, which make up the brunt of Ortho-K wear for myopia progression treatment.^{63 64} A 10-year retrospective study of 104 eyes of 53 children who underwent Ortho-K treatment observed adverse events in 53 eyes (51%). Of these, conjunctival complications such as allergic conjunctivitis were the most frequent, while corneal infiltration and keratitis occurred in eight eyes (7.7%).⁶⁵ To put the figures in perspective, the estimated incidence of infectious keratitis in daily-wear rigid-gas-permeable lens wearers is 1.2/10 000, while in extended wear soft lens wearers, the incidence ranges from 13.3 to 19.5/10 000. This suggests that Ortho-K wear risk in children is essentially similar to that of extended wear soft contact lens wear.⁶⁶ Risk factors for infectious keratitis include overnight wear, insufficient training of practitioners and wearers, non-professional fitting procedures, poor compliance with lens hygiene or inadequate follow-up.⁶⁷ These infections can be severe and may result in visual loss or the need for corneal transplantation. Importantly, parents should be counselled as to the risk of infectious keratitis and eye care professionals should undergo rigorous training and accreditation before prescribing Ortho-K to ensure quality control. Besides microbial keratitis, other side effects of Ortho-K include induced astigmatism, third-order and fourth-order spherical aberrations, recurrent corneal erosion, corneal staining, oedema and haze.^{63 64}

Rebound upon discontinuation is an important issue emphasised in atropine, but this has been less widely studied in Ortho-K.^{16 60 68} In terms of vision, Ortho-K provides the best uncorrected visual acuity, whereas atropine may cause poor near visual acuity especially with higher doses and spectacles are still required. Quality of life and subjective ratings from multiple studies show an improvement with Ortho-K compared to wearing single-vision spectacles.^69–71 The cost-effectiveness of Ortho-K requires further study. Ortho-K lenses in general are more expensive than other optical interventions, costing annually on an average US$1000–2000,⁷² requiring individualised design and fitting, and intensive review to detect complications. Additionally, they are usually not covered by most health reimbursement or insurance plans.⁷²

Should atropine eye-drops be used in children with low or no myopia to prevent myopia progression?

Both the Meta-analysis of Interventions for Myopia Control (30 randomised controlled trials, 5422 eyes) and the Meta-analysis of Atropine Studies for Myopia Control (19 studies, 3137 children) concluded that atropine markedly slowed myopia progression.⁶² While there is currently only one small study providing evidence for the effectiveness of atropine in children with no myopia,⁷³ it is known that younger age of myopia onset is associated with high myopia. It can be safely predicted that 5-year-old children, whose refractions are between +0.75D and −0.49D will soon develop myopia.⁷⁴ These may be the at-risk group (pre-myopes) that is likely to benefit from low-dose atropine use. ATOM3 is an ongoing double-blind randomised placebo-controlled clinical trial initiated in June 2017 designed to evaluate the use of atropine 0.01% in the prevention and control of myopia in pre-myopes⁷⁵

The main concern against using atropine in children with no myopia is the risk of side effects. In the LAMP study, 30–34% of children on atropine required photochromatic glasses and 2.8–6.4% developed allergic conjunctivitis.¹⁸ A 70% and 61% of subjects receiving 0.5% and 0.1% atropine, respectively, required progressive glasses for reading in the ATOM 2 study.¹⁶ In the LAMP study, even 0.01% atropine was associated with accommodation paralysis in 1.8% of subjects.¹⁸ Hence, some children may paradoxically require spectacles after commencing atropine. Although extremely rare, there is a risk of more severe systemic side effects such as palpitations, confusion, dry mouth and high fever. In addition, the long-term side effects of atropine eye-drops are still unclear. In children, a rebound effect was observed upon abrupt cessation of treatment, where the rate of myopia progression increased. When higher dose atropine was stopped for 12 months after 24 months of treatment (phase 2 of ATOM2), there was a rapid increase in myopia in children originally treated with higher concentrations of atropine, whereas those receiving the lowest concentration of 0.01% showed minimal change.^{16 68} This rebound phenomenon can significantly reduce the effectiveness of atropine eye-drops for myopia control, compared to optical treatments. Importantly, atropine is largely used as an off-label treatment for myopia in most countries. Where low-dose atropine eye-drops are unavailable commercially, the use of low-dose atropine may bear significant risks from patients diluting down higher doses and inconsistencies from compounding pharmacies.

Conclusion

Overall, optimising the clinical management of myopia would benefit from an alignment of best practice patterns, with a tailored approach that can only be achieved with close collaboration among eye care practitioners. While current evidence suggests that low-dose atropine is a good option, potential side effects and the lack of availability in certain healthcare settings need to be considered. However, the use of atropine in children with low or no myopia requires further evidence from clinical trials prior to any recommendation. Ortho-K can be an effective option for myopia control but requires close clinical monitoring to avoid sight-threatening complications. There are other emerging treatment options that are effective such as defocus multizone soft contact lens, and DIMS spectacles, which could be considered in the holistic management pathway of myopia. Finally, there is growing interest in combining interventions,⁵¹ such as atropine and Ortho-K, which may have a synergistic effect while balancing the risks and benefits of both therapies.⁵²

Is optical coherence tomographic angiography (OCTA) adequate for the evaluation of myopic choroidal neovascularisation?

OCTA is a relatively new imaging technology that has emerged as a potential alternative to more invasive imaging modalities, namely fundus fluorescein angiography for the evaluation of mCNV. The pooled diagnostic accuracy of OCTA was reported in two separate meta-analyses to have a sensitivity of 0.87–0.90, specificity of 0.97 and an area under the curve of 0.96 for detecting CNV.^{78 79} OCTA, in conjunction with optical coherence tomography (OCT), can be used for the monitoring of treatment response and activity. On OCT, the resolution of subretinal hyper-reflective material, subretinal fluid and a well-defined border to the mCNV lesion are reliable signs of inactivity. On OCTA, the mCNV lesion typically decreases in size although the vascular network persists, regular monitoring of the vascular network size on OCTA is useful for assessing for recurrence.⁷⁷

However, several limitations of OCTA remain. First, OCTA informs of perfusion through the vascular complex but offers no information on vascular leakage, which is a key treatment indicator. Relying on OCTA alone may result in over-treatment of inactive mCNV. Second, artefacts and poor scan quality are common in patients with poor vision and who are thus unable to sustain fixation long enough for scan acquisition. Third, segmentation errors are particularly prevalent in highly myopic eyes with long AL, steep retinal contours and PS. Moreover, poor fixation and motion artefacts are common causes of uninterpretable scans (figure 2).

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Figure 2

Swept-source optical coherence tomographic angiography scans (12×12 mm) of the choroid in a patient with good fixation (A) and a patient with poor fixation (B). Note the presence of motion artefacts (white arrowheads) and artefactual dropout of vascular flow signal due to segmentation error (white arrow).

Can current diagnostics adequately diagnose and monitor glaucoma or myopia-associated optic neuropathy in high myopes?

There are several challenges for the adequate diagnosis and monitoring of glaucoma or myopia-associated optic neuropathy in high myopes. Anatomically, the three layers of the optic nerve head, namely the BM opening, the choroidal opening and the opening in the peripapillary scleral flange covered by the lamina cribrosa are misaligned by a shift of the BM opening usually into the temporal inferior direction.⁸⁰ This leads to an overhanging of BM into the intrapapillary region at the nasal disc border, and an absence of BM in the temporal parapapillary region, that is, the temporal gamma zone.^{80 81} With an AL of more than 26.5 mm, the BM opening additionally enlarges, eventually leading to a circular gamma zone. In addition, the colour contrast and the spatial contrast between the optic cup and neuroretinal rim decrease with longer AL. This complicates the assessment of cup-to-disc ratio and measurements of retinal nerve fibre layer (RNFL) thickness with OCT. Functionally, these eyes often have macular pathology and these may confuse the assessment of glaucomatous visual field defects on perimetry. The decreased scleral rigidity in highly myopic eyes may also result in underestimation of the intraocular pressure in these eyes.^{82 83}

Regardless, there are clinical indicators and clues that can aid a physician in diagnosing and monitoring glaucoma in these patients. First, glaucoma is a progressive disease in which longitudinal analysis is key. By comparing the same eye over time, the impact of ambiguous anatomy on diagnosis and monitoring will be reduced. Second, assessing the macular ganglion cell-inner plexiform layer (GC-IPL) thickness measurements in areas without BM defects for vertical asymmetry is also a useful method for diagnosis and monitoring glaucoma because most eyes with MMD tend to have preservation of the inner retinal thickness, at least in the earlier stages.⁸⁴

However, none of the current imaging modalities currently used for glaucoma assessment has been optimised for use in high myopes. RNFL measurements with OCT are problematic due to an indistinct BM edge which tends to shift temporally in high myopes. The superior and inferior RNFL converge more temporally than in a non-highly myopic eye, and signal loss around optic disc can occur in the presence of a PS. GC-IPL measurements can be inaccurate when there is coexisting myopic traction maculopathy (figure 3) or underlying BM defects. An overarching limitation of structural analysis is the lack of a normative database for the highly myopic population, which is likely to differ significantly from a database of non-highly myopic eyes due to the above-mentioned anatomical differences. Lastly, objective visual field assessment such as the Humphrey visual field is often unable to differentiate between deterioration due to glaucoma or myopic maculopathy.^{82 85}

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Figure 3

Ganglion cell-inner plexiform layer (GC-IPL) thickness analysis using spectral-domain optical coherence tomography in a patient with high myopia and normal-tension glaucoma. Red and yellow lines on the optical coherence tomography (OCT) B scan image define the anterior and posterior boundaries of the GC-IPL layer, respectively. Segmentation error is seen on the OCT B scan in the right eye (white arrow) due to myopic traction maculopathy. OD, right eye; OS, left eye; OU, both eyes.

Conclusion

The structure of the myopic eye adds complexity to the evaluation and early detection of sight-threatening complications, such as MMD and myopia-associated optic neuropathy, that cannot be bridged with current diagnostics. Collaboration between clinicians, researchers and industry is needed to optimise diagnostic and imaging technologies specifically for the myopic eye. Currently, OCTA imaging alone may be inadequate for evaluating mCNV, while the evaluation of myopia-associated optic neuropathy requires further research to accurately evaluate optic nerve damage in PM. Overall, there is an unmet need to explore and develop new imaging modalities for both structural and functional analyses and to establish normative databases for myopia in the long term.