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[64]
cascade by cleaving C3b and C4b . Leveziel hypothesized that the specific genetic effects related to the
inflammatory pathway would increase the risk of mCNV.

[65]
In another large case-control study conducted by Miyake et al. in Japan, rs10033900 was not found in
mCNV patients, but rs12603825 in PEDF gene is possibly associated with mCNV patients whose AL is ≥ 29
mm. Pigment epithelium-derived factor (PEDF) is a member of the serine protease inhibitor superfamily .
[66]
[67]
It was first identified as a potent inducer of neuronal differentiation in cultured retinoblastoma cells . In
ocular tissue, PEDF is secreted by photoreceptors and RPE cells and released into the interphotoreceptor
matrix between RPE and photoreceptors as well as in the inner retina [68,69] . It is also expressed in cornea and
ciliary epithelium and can be detected in the vitreous body and aqueous humor. PEDF is a
[70]
[73]
[72]
multifunctional protein with antiangiogenic , neurotrophic , and antioxidant properties in ocular
[71]
tissue. PEDF exerts its antiangiogenic effect by inducing apoptosis of endothelial cells and interfering with
[74]
VEGF-induced angiogenesis . In a laser-induced CNV rat model, decreased expression of PEDF was
observed at the injury sites, suggesting permission on the formation of CNV . In addition, PEDF protects
[75]
RPE monolayer and pericytes from oxidant stress [76,77] , as well as protects photoreceptors by suppression of
[78]
[53]
apoptotic and inflammatory pathways . According to Costagliola et al. , after anti-VEGF therapy, the
level of VEGF decreases, while the PEDF level increases in the aqueous humor of patients with mCNV. It is
known that the development of CNV is an imbalance between angiogenic and antiangiogenic factors.
Therefore, the SNP in the PEDF gene could be a biological marker associated with mCNV.
The ATN classification
Compared with the META-PM classification, the atrophy-traction-neovascularization (ATN) classification
[79]
proposed by Ruiz-Medrano et al. in 2019 takes tractional and neovascular components into
consideration. ATN represents three key factors in myopic maculopathy: atrophy (A), traction (T), and
neovascularization (N). The ATN classification is based on both fundus photography and OCT to assess
myopic maculopathy. In 2021, Ruiz-Medrano et al. updated the ATN system [Table 2]. Based on longer
[80]
AL and worse BCVA, they defined severe pathologic myopia as eyes graded ≥ A3, ≥ T3, and/or ≥ N2, which
indicate a significant myopic macular complication. The atrophic and neovascular classifications in ATN
system are the same as META-PM system. Both systems have five classifications on the aspect of atrophy
and three statuses of mCNV. The ATN system includes the tractional component, which is closely related to
[79]
visual acuity .
CURRENT INTERVENTIONS TO MYOPIC MACULOPATHY
Currently, no available treatment has been found for myopic maculopathy except for mCNV. Management
of mCNV is the same as other types of CNV by laser photocoagulation, verteporfin photodynamic therapy,
and anti-VEGF therapy. Approaches have been proposed to retard myopic progression including
pharmacologic, surgical, and optical intervention.

Non-surgical interventions
Pharmacologic intervention (e.g., low concentration atropine) and optical intervention (e.g.,
orthokeratology) are used to slow down myopic progression before the development of myopic
maculopathy.

Low concentration atropine
The Atropine in the Treatment of Myopia (ATOM1) study in 2006 suggested that 1% of atropine can slow
down the progression of childhood myopia . This study recruited 400 children (6-12 years old) with low to
[81]
moderate myopia (spherical equivalent of -1.00 to -6.00 D and astigmatism of ≤ -1.5 D). Participants were