Diagnosis and Treatment of Myopic Maculopathy. Tae Yokoi, MD, and Kyoko Ohno-Matsui, MD, PhD

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1 REVIEW ARTICLE Diagnosis and Treatment of Myopic Maculopathy Tae Yokoi, MD, and Kyoko Ohno-Matsui, MD, PhD Abstract: Visual impairment resulting from pathologic myopia is a serious issue worldwide. This is mainly due to the development of different types of myopic maculopathy. Despite being a major cause of visual impairment worldwide, myopic maculopathy was not consistently defined. To overcome this problem, in 2015 the Meta-Analysis for Pathologic Myopia Study Group proposed a simplified, uniform classification system for myopic maculopathy. Among several lesions of myopic maculopathy, myopic choroidal neovascularization (CNV) is one of the most common and severe vision-threatening complications. Recent large clinical trials have reported a good initial efficacy for visual acuity improvement by application of anti vascular endothelial growth factor therapy for myopic CNVs. However, long-term clinical studies demonstrate a gradual decrease in the visual acuity gain and return to the baseline level due to the development of myopic CNV-related macular atrophy. Regarding visual impairment caused by advanced myopic chorioretinal atrophy, the only way to prevent blindness is to prevent myopia from developing or progressing at a young age before the axial length elongates extremely. As peripapillary diffuse atrophy in childhood may be an indicator of more advanced myopic chorioretinal atrophy in later life, some preventive measures should be considered in such children. Key Words: diffuse atrophy, Fuchs spot, lacquer cracks, myopic choroidal neovascularization, myopic maculopathy, patchy atrophy, pathologic myopia (Asia Pac J Ophthalmol (Phila) 2018;7: ) Visual impairment resulting from pathologic myopia is a serious issue worldwide. 1 This is mainly due to the development of different types of myopic maculopathy, such as diffuse atrophy, patchy atrophy, lacquer cracks, myopic choroidal neovascularization (CNV), and CNV-related macular atrophy. In fact, myopic maculopathy is the leading cause of blindness in Japan, 2 the second most common cause of blindness in China 3 and in the elderly urban Danish population, 4 and the third leading cause of blindness in Latinos 40 years and older in the United States. 5 In addition, over the past 50 years, parallel to the increase in the prevalence of myopia in general, the prevalence of high myopia has markedly increased, especially in the East Asian countries, From the Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University, Tokyo, Japan. Received for publication June 19, 2018; accepted August 17, The authors have no funding or conflicts of interest to declare. Reprints: Kyoko Ohno-Matsui, Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo , Japan. k.ohno.oph@med.tmd.ac.jp. Copyright 2018 by Asia-Pacific Academy of Ophthalmology ISSN: DOI: /APO with 80% of 18-year-old high school graduates being myopic and 20% of 18-year-old high school graduates having a severe degree of myopia. 6,7 Moreover, a recent review article estimated that the prevalence of high myopia will increase from 2.7% of the world s population in 2000 to 9.8% by Although not all eyes with high myopia develop vision-threatening macular complications, researchers are now concerned that the recent increase in the prevalence of high myopia may lead to future increases in the incidence of low vision and blindness worldwide because the higher degrees of myopia are associated with an increased risk of severe types of myopic maculopathy. Despite being a major cause of visual impairment worldwide, myopic maculopathy has not been consistently defined until recent years. The lack of a standardized definition of myopic maculopathy has made it difficult to perform direct comparison or to pool data from different studies to evaluate the prevalence, incidence, and pattern of individual lesion subtypes. To overcome this problem, in 2015 an international panel of researchers in myopia (the Meta-Analysis for Pathologic Myopia Study Group; the META-PM Study Group) proposed a simplified, uniform classification system for myopic maculopathy after reaching a consensus among myopia experts supported by intra- and interobserver agreement. 9 In this review article, we describe a novel classification system of myopic maculopathy established by the META-PM Study Group and summarize the current therapeutic strategy for each lesion along with the limitations in managing these conditions. CLASSIFICATION OF MYOPIC MACULOPATHY IN META-PM STUDY In the META-PM classification, lesions of myopic maculopathy are classified into 5 categories (Fig. 1): no myopic retinal lesions (category 0), tessellated fundus only (category 1) (Fig. 1A), diffuse chorioretinal atrophy (category 2) (Fig. 1B), patchy chorioretinal atrophy (category 3) (Fig. 1C), and macular atrophy (category 4) (Fig. 1F). These categories were defined based on long-term clinical observations that tracked the progression patterns and risk of myopic CNV development at each stage. Three additional features were added to these categories and were included as plus signs : (1) lacquer cracks (Fig. 1D), (2) myopic CNV, and (3) Fuchs spot (Fig. 1E). The reason for separately defining these plus signs is that these 3 types of lesions have been shown to be strongly associated with central vision loss, but they do not fit into any particular category and may develop from, or coexist in, eyes with any of the myopic maculopathy categories described above. Based on this new classification, pathologic myopia is defined as myopic maculopathy category 2 or above, the presence of a plus sign, or the presence of posterior staphyloma. Asia-Pacific Journal of Ophthalmology Volume 7, Number 6, November/December

2 Yokoi and Ohno-Matsui Asia-Pacific Journal of Ophthalmology Volume 7, Number 6, November/December 2018 A B C D E F FIGURE 1. META-PM classification of myopic maculopathy by color fundus photographs. A, Category 1, tessellated fundus. Outline of choroidal vessels can be seen throughout the posterior fundus. B, Category 2, diffuse atrophy. Yellowish-white and ill-defined chorioretinal atrophy exists in the entire posterior pole. C, Category 3, patchy atrophy. Multiple lesions of patchy atrophy appear as well-defined, grayish-white lesions on a background of diffuse atrophy. D, Lacquer cracks (plus sign). Yellowish thick linear patterns, which run in branch or crisscross, are observed in the posterior fundus (arrows). E, Fuchs spot (plus sign). In scar phase, myopic CNV can be covered by proliferating pigment cells (Fuchs spot). Afterwards, myopic CNVrelated macular atrophy develops resulting from the enlargement of the Bruch membrane rupture around regressed myopic CNV (arrowheads). F, Category 4, macular atrophy. Multiple lesions of patchy atrophy enlarged and fused. Finally, macular region is involved. FEATURES OF EACH LESION OF MYOPIC MACULOPATHY Tessellated Fundus (Category 1) In eyes with high myopia, axial elongation reduces the retinal pigment epithelium (RPE) and leads to hypoplasia of the pigment, allowing for a clear image of the choroidal vessels. Tessellated fundus, along with the myopic conus around the optic disc, is one of the preliminary signs in eyes with high myopia. Tessellation begins to develop around the optic disc, typically in the region between the optic disc and the central fovea. Compared with the eyes of highly myopic patients with diffuse atrophy, the eyes of patients with tessellated fundus are significantly younger and have less myopia, shorter axial length, and less staphyloma. 10 A large majority (about 90%) of eyes with only tessellated fundus or no chorioretinal atrophy have an axial length less than 26 mm. As axial length elongates, the percentage of tessellation decreases linearly and becomes 0% when the eye stretches more than 31 mm. A decrease in visual acuity does not usually happen in highly myopic eyes with tessellated fundus alone; however, multifocal electroretinogram can detect a reduced amplitude and a delayed latency, even in tessellation alone. 11 Diffuse Chorioretinal Atrophy (Category 2) Diffuse atrophy can be observed as yellowish-white and ill-defined chorioretinal atrophy. The area of atrophy generally first appears around the optic disc. The frequency of diffuse atrophy increases with age or increased axial length. It is possible to calculate the increase in the percentage of the eye with diffuse atrophy by using a simple regression equation. For axial lengths between 27 and 33 mm, the percentage increase is 13.3% per millimeter in the total number of myopic eyes, 9.4% per millimeter in eyes under age 40, and 12.2% per millimeter in eyes over age On fluorescein angiography (FA), diffuse atrophy is demonstrated as mild hyperfluorescence in the late phase because of tissue staining. From indocyanine green angiography (ICGA), within the area of diffuse atrophy, a significant decrease of the choroidal capillary and medium or large choroidal vessels can be seen. As the penetrating site of short posterior ciliary arteries moves to the edge of posterior staphyloma, the density of the choroidal blood vessels in the posterior pole decreases, and the blood vessels in the rear of the eye are sometimes seen through the sclera in the posterior pole. On optical coherence tomography (OCT) scans, significant thinning of the choroidal layer in the area of diffuse atrophy and occasional sporadic large choroidal vessels remaining can be seen. The presence of outer retina and RPE even in the area where most of the choroid is gone might explain relatively preserved vision in eyes with diffuse atrophy. Patchy Chorioretinal Atrophy (Category 3) Patchy atrophy can be seen as well-defined, grayish-white lesions in the macular area or around the optic disc. The area affected could vary among 1 and several choroidal lobules. The pathology of patchy atrophy is a complete loss of choriocapillaris, which can lead to the destruction of the outer retina and RPE. Within patchy atrophy, even though there is a total loss of choriocapillaris, large choroidal vessels still remain. Both FA and ICGA show a choroidal filling defect in the area of patchy atrophy, suggesting that this lesion is a complete closure of choriocapillaris. On OCT, the area of patchy atrophy is characterized Asia-Pacific Academy of Ophthalmology

3 Asia-Pacific Journal of Ophthalmology Volume 7, Number 6, November/December 2018 Myopic Maculopathy by an absence of the entire thickness of the choroid and the RPE along with the outer retina. Hypertransmission through the underlying sclera can be seen. Thus, the inner retina is directly on the sclera within the area of patchy atrophy. Recent swept-source OCT or histologic studies report that the Bruch membrane is discontinuous in the region with patchy atrophy and in the peripapillary gamma zone. Thus, macular Bruch membrane defects are a feature of these lesions. 12 Therefore, patchy atrophy could be renamed as macular Bruch membrane rupture, because it is not an atrophy but a rupture. Patchy atrophy is subdivided into 3 types (Fig. 2): (1) patchy atrophy that develops from lacquer cracks, P(Lc) (Fig. 2A); (2) patchy atrophy that develops within the area of an advanced diffuse atrophy, P(D) (Fig. 2B); and (3) patchy atrophy that can be seen along the border of the posterior staphyloma, P(St) (Fig. 2C). 13 According to the shape of the patchy atrophy, we can identify these 3 types: P(Lc) tends to have a narrow elliptical shape, whereas P(D) tends to be circular or oval. P(St) tends to enlarge toward the macula, whereas patchy atrophy in the macula region enlarges in all directions. Central vision loss is rare for patchy atrophy (Fig. 2D); however, a paracentral absolute scotoma may occur as a result of photoreceptor loss within the atrophic area. Macular Atrophy (Category 4) Although patchy atrophy does not usually involve the fovea center until the end stage of myopic chorioretinal atrophy, in advanced cases, the entire area of posterior fundus is replaced by an enlarged patchy atrophy including the foveal region (macular atrophy) and causes central vision loss. The posterior fundus has a bare sclera appearance with retrobulbar blood vessels observable through the thin transparent retinal tissue. The fundus appearance of patchy atrophy is similar to myopic CNV-related macular atrophy (Fig. 1E) 12 and it is important to differentiate it from patchy atrophy. Myopic CNV-related macular atrophy is a late complication of myopic CNV and it develops around the regressed myopic CNV. The main difference between CNV-related macular atrophy and patchy atrophy is that the former develops in and just around the fovea and enlarges concentrically around the fovea even in the background of tessellated fundus or when there is no chorioretinal atrophy, whereas it is rare for patchy atrophy to involve the fovea center until the end stage of myopic chorioretinal atrophy (Fig. 2D). According to the long-term study on progression patterns of myopic maculopathy by Hayashi et al 14 who analyzed 806 eyes of 429 consecutive patients with high myopia who were followed for 5 to 32 years, the leading causes of the significant decrease in vision were the fusion of patchy atrophy, development of CNV, and macular atrophy. During the follow-up period, due to the fusion of patchy atrophy, the best-corrected visual acuity (BCVA) [logarithm of the minimum angle of resolution (logmar)] was significantly decreased from 0.30 ± 0.18 at the initial visit to 0.62 ± 0.35 at the final visit (P = 0.46). Furthermore, CNV-related macular atrophy after the development of myopic CNV extensively weakened the vision (0.71 ± 0.45 at the initial visit, and 1.07 ± 0.41 at the final visit, P < ). PREVENTION OF ADVANCED MYOPIC CHORIORETINAL ATROPHY Regarding visual impairment resulting from enlargement and fusion of multiple patchy atrophies on the background of severe diffuse atrophy, the only way to prevent blindness is to prevent myopia from developing or progressing at a young age, before the axial length elongates to extremes. In a recent longitudinal study on 35 eyes of adult patients with pathologic myopia and a mean age of 37.0 ± 5.1 years (range, years), 29 of the 35 eyes (83%) showed a peripapillary diffuse choroidal atrophy (PDCA) in childhood (mean age, 10.5 ± 2.6 years; range, 5 15 years), with a mean axial length of 27.8 ± 1.2 mm (range, mm) (Figs. 3A, B). 15 The study suggests that the presence of PDCA in children with high axial myopia might be an indicator of eventual pathologic myopia in adulthood. Therefore, if there are highly myopic children who show an initial development of diffuse atrophy around the optic disc, some preventive measures should be considered before the axial length becomes extremely elongated and the atrophic lesions of myopic maculopathy increase in severity. According to a study using swept-source OCT on 41 eyes of 21 children with PDCA (mean age, 9.4 ± 3.7 years; mean refractive error, 11.5 ± 3.1 diopters), 16 the segmental and abrupt thinning of the choroid in the temporal peripapillary region is a characteristic of PDCA when analyzed with OCT (Figs. 3C, D). This study also showed that a choroidal thickness measurement with cutoff value of less than 60 μm at 2500 μm nasal to the fovea can help detect children with PDCA with 75.6% sensitivity and 100% specificity. As there are large racial differences in choroidal pigmentation caused by melanin pigment within choroidal melanocytes, and as the ophthalmoscopic assessment of PDCA is subjective and depends on the experience of the examiner, the measuring of choroidal thickness in the temporal peripapillary region using OCT may be helpful for the detection and diagnosis of PDCA in highly myopic children. FIGURE 2. Three types of patchy atrophy. A, P(Lc): patchy atrophy that develops from lacquer cracks, which tend to have a narrow elliptical shape. B, P(D): patchy atrophy that develops within the area of advanced diffuse atrophy. P(D) tends to be circular or oval. C, P(St): patchy atrophy that can be seen along the border of the posterior staphyloma. D, Foveal center is rarely affected by the enlargement and fusion of patchy atrophy until the final stage of myopic chorioretinal atrophy. Visual acuity is Asia-Pacific Academy of Ophthalmology 417

4 Yokoi and Ohno-Matsui Asia-Pacific Journal of Ophthalmology Volume 7, Number 6, November/December 2018 FIGURE 3. Comparison of clinical manifestations between simple hemorrhages and myopic CNV. A, Diffuse atrophy had already been observed temporal to the optic disc when the patient was 11 years old. Refractive error is 13.0 diopters (D) and axial length is 27.4 mm. B, When appearing in a 41-year-old patient, the diffuse atrophy has enlarged beyond the macular area and patchy atrophy developed from the temporal side of the fovea. Refractive error is 20.0 D and axial length is 32.3 mm. C, Child s eye with pathologic myopia that shows peripapillary diffuse atrophy around the optic disc. The patient is 12 years old. Refractive error is 20.0 D and axial length is 30.6 mm. D, Peripapillary diffuse choroidal atrophy in children is associated with extreme thinning of the peripapillary choroid (arrowheads). This can be detected on OCT. Lacquer Cracks (Plus Sign) Lacquer cracks are observed as fine, irregular, yellow lines, often branching and crisscrossing, in the posterior fundus of pathologic myopia. Lacquer cracks develop at a relatively early age and the mean age of patients with lacquer cracks was 32 years. 17 With time, lacquer cracks increase in number and also increase their width. In histopathologic studies, the lacquer cracks are characterized by linear ruptures of the Bruch membrane or healed mechanical fissures in the RPE Bruch membrane choriocapillaris complex in the macular area. 18 If the mechanical rupture of the Bruch membrane happens, choriocapillaris is also damaged and subretinal macular hemorrhage without CNV may occur (simple macular hemorrhage) (Fig. 4A). 19 Most patients with simple macular hemorrhage have a good visual prognosis. However, if the bleeding penetrates into the inner retina beyond the external limiting membrane, the ellipsoid defect seen at the onset by OCT remains after the absorption of the hemorrhage, leading to permanent vision impairment. 19 Lacquer cracks are also known as precursor lesions of myopic CNV (Fig. 4D). 20 Myopic CNV is considered to occur when the connective tissue, accompanied by the CNV, grows under the retina as a wound healing response on the scaffold of the lacquer cracks. Lacquer cracks are relatively easy to detect with FA, ICGA, fundus autofluorescence imaging, and infrared reflectance imaging. However, it is difficult to detect such a narrow lesion with OCT, because even if the OCT slice goes across the crack, there is a chance the crack is too narrow to detect as an anomaly on the OCT image. However, if the crack is wide enough and can be detected, OCT is considered to be the most accurate diagnostic tool because only OCT can visualize the discontinuity of the Bruch membrane. On FA, lacquer cracks show a consistent linear hyperfluorescence during the entire angiographic phase. In the early phase, there is a window defect due to RPE atrophy overlying the Bruch membrane defects and in the late phase, a staining of healed scar tissue filling the Bruch membrane defect. On ICGA, lacquer cracks are observed as linear hypofluorescence during the entire angiographic phase. The hypofluorescence in ICGA is more easily recognized in the late phase because, in the early phase, an intense fluorescence of retrobulbar blood vessels or large choroidal vessels impairs the observation of narrow linear hypofluorescence of lacquer cracks. Lacquer cracks also show linear hypoautofluorescence on fundus autofluorescence. Although it is difficult to detect lacquer cracks on OCT, in some cases, the discontinuities of the RPE and Bruch membrane and an increased penetrance into the deeper tissue beyond the RPE are observed at the site of the lacquer cracks. Myopic CNV and Fuchs Spot (Plus Signs) Myopic CNV is one of the most common and severe vision-threatening complications in patients with pathologic myopia. Myopic CNV occurs in 5% to 11% of highly myopic patients, and unfortunately it develops during the most productive periods of their lives. About 35% of the patients who have CNV in one eye eventually develop CNV in the other eye within 8 years, compared with about 6% of patients without a history of preexisting CNV. 21 Most cases of myopic CNV seem to originate from lacquer cracks and are usually fairly small and less likely to show sub- or intra-retinal fluid or proliferation in the subretinal space. Therefore, myopic CNV tends to regress spontaneously. In the scar phase, the CNV is engulfed by proliferating pigment cells and is observed as a dark pigmented spot named the Fuchs spot (plus sign) (Fig. 1E). In the atrophic phase, well-defined chorioretinal atrophy occurs around the Fuchs spot and gradually enlarges affecting the macula region (CNV-related macular atrophy). A recent clinical study using swept-source OCT demonstrates that macular Bruch membrane defect is a feature of CNV-related macular atrophy. 12 The possible mechanism in which CNV-related macular atrophy occurs around regressed CNV is described below: The myopic CNV is invariably type 2, which suggests the CNV has broken through the Bruch membrane. The defect in the Bruch membrane enlarges as it is subjected to forces related to the axial expansion of the eye and local forces generated by the CNV regression. As macular Bruch membrane defects lack photoreceptors and thus represent an absolute scotoma, the long-term visual prognosis of myopic CNV is poor. At 5 and 10 years after onset, visual acuity drops to 20/200 or less in 89% and 96% of cases, respectively. 22 On FA, myopic CNV shows distinct hyperfluorescence throughout the entire angiographic phase (represented as socalled classic CNV) in the active phase, whereas myopic CNV does not show hyperfluorescence on ICGA in most cases because of the low activity of CNV. On OCT, myopic CNV is shown as a hyperreflective, elevated lesion in the subretinal space as type 2 CNV with minimal subretinal fluid or exudate. It is difficult to distinguish subretinal bleeding with or without CNV (myopic CNV or simple macular hemorrhage) in eyes with pathologic myopia only by OCT (Figs. 4B, E); nevertheless, FA helps with differential diagnosis (Figs. 4C, F). Additionally OCT angiography (OCT-A) is a useful tool for detecting myopic CNV. It can Asia-Pacific Academy of Ophthalmology

5 Asia-Pacific Journal of Ophthalmology Volume 7, Number 6, November/December 2018 Myopic Maculopathy FIGURE 4. Fundus appearance of a child s eye with pathologic myopia. A, Simple macular hemorrhage appears as subretinal macular hemorrhage, resulting from damage of the choriocapillaris subsequent to rupture of the Bruch membrane. B, Vertical OCT image showing an elevated lesion in the outer retina due to simple macular bleeding. A defect or irregularity of the ellipsoid is not obvious in the area of the hemorrhage. C, Simple macular hemorrhage demonstrates hypofluorescence of the lesion without accompanying dye leakage. D, Myopic CNV can happen in eyes with lacquer cracks. E, OCT shows myopic CNV as a hyperreflective, elevated lesion in the subretinal space with minimal subretinal fluid or exudate. F, On FA, myopic CNV shows distinct hyperfluorescence throughout the entire angiographic phase. identify myopic CNV with 90.48% sensitivity and 93.75% specificity. 23 However, there are still limitations in using OCT-A to determine the activity of myopic CNV for treatment guidance because it reveals myopic CNV with blood flow even in the scar or atrophic phase, so it is difficult to distinguish among the various phases. In the atrophic phase, fundus autofluorescence is an essential tool for the evaluation of the area of CNV-related macular atrophy, which shows hypoautofluorescence. CURRENT TREATMENT OF MYOPIC CNV Recently, intravitreal injection of an anti vascular endothelial growth factor (anti-vegf) has been demonstrated to be safe and effective in treating myopic CNV. 24,25 Thus, it has become the first-line therapy for myopic CNVs. The initial anti-vegf agent used was off-label intravitreal bevacizumab (Avastin; Genentech Inc., San Francisco, CA). Presently, ranibizumab (Lucentis; Genentech, Inc., South San Francisco, CA) and aflibercept (Eylea; Regeneron, Tarrytown, NY) are also available for intraocular use for myopic CNVs. Relatively short-term favorable outcomes (with 12-month follow-up periods) after intravitreal injections of anti-vegf agents have been reported by large clinical trials. 25,26 The RADIANCE study, which is a first phase III, randomized, double-masked, multicenter, active-controlled trial for myopic CNVs, demonstrates that the use of ranibizumab for myopic CNV leads to a rapid improvement of the BCVA at 3 months after the first injection. 24 The BCVA continues to improve for up to 12 months. This BCVA improvement at 12 months after using ranibizumab is significantly better than that of eyes treated with photodynamic therapy alone. The MYRROR study shows that intravitreal aflibercept results in significantly better BCVA with a gain of 13.5 letters compared with that of the sham control group with a gain of 3.9 letters at 12 months. 25 However, the results after long follow-up periods have not met expectations The results of a study with a follow-up period of 6 years after bevacizumab or ranibizumab for myopic CNV show that early visual acuity improvement is sustained at the 3-year follow-up point, but the improvement is not statistically significant from that of the baseline after 4, 5, or 6 years. 28 Several other longterm studies on anti-vegf agents for myopic CNV show similar clinical results, namely, good initial efficacy for BCVA improvement but a gradual decrease in the BCVA gain and a return to the baseline BCVA on average The results of statistical analyses show that the decreased BCVA in longer follow-up periods after anti-vegf therapy is significantly correlated with the development of CNV-related macular atrophy. According to a study with a follow-up period of 5 years after ranibizumab for 51 eyes with myopic CNV, the decreased BCVA at 5 years after ranibizumab therapy was significantly correlated with the number of ranibizumab injections. 27 One possible explanation for this may be that the more severe recurring cases with poor visual prognosis require more frequent ranibizumab injections. On the other hand, recent experimental research has shown several adverse effects of anti-vegf agents on the retina and choriocapillaris, such as RPE cell death, photoreceptor damage, formation of immune complexes, and thrombotic microangiopathy. 12,21 32 Compared with age-related macular degeneration (AMD), eyes with pathologic myopia differ in having severe degenerative changes in the Bruch membrane RPE complex and an extremely thin choroid. Therefore, repetitive administration of anti-vegf agents can more easily disturb these intraocular tissues, leading to the gradual decrease of BCVA in eyes with longer 2018 Asia-Pacific Academy of Ophthalmology 419

6 Yokoi and Ohno-Matsui Asia-Pacific Journal of Ophthalmology Volume 7, Number 6, November/December 2018 observational periods. According to the study with a follow-up period of 5 years after using ranibizumab for myopic CNV, 27 the average number of ranibizumab injections was 1.6 ± 1.0 during the 5-year follow-up period. Whereas, in the previous study on AMD, the mean number of injections of anti-vegf agents to control 44 eyes with AMD of 37 patients was 12.6 in 5 years. 33 The number of injections needed to control myopic CNV is considered to be much lower than that in eyes with AMD. As most cases of myopic CNV can be controlled with a very small number of injections, the number of additional injections should be considered carefully to avoid potential harm, especially in patients with a large number of injections. CONCLUSIONS Pathologic myopia has become a major cause of visual impairment worldwide and is often caused by the development of different types of myopic maculopathy. Despite its importance, myopic maculopathy has not been consistently defined until recent years. The META-PM classification system will enable researchers to perform direct comparisons or to pool data from future studies to evaluate the prevalence, incidence, and pattern of individual lesion subtypes. Although myopic CNV can be well regulated by application of anti-vegf therapy, further studies evaluating the long-term outcomes of anti-vegf therapy for myopic CNV are warranted. In addition, regarding visual impairment resulting from progression of severe types of myopic chorioretinal atrophy, the only way to prevent blindness is to prevent myopia from developing or progressing at a young age, before the axial length elongates extremely. Thus, if there are highly myopic children who show an initial development of diffuse atrophy around the optic disc, which can be detected by OCT as an extreme thinning of the peripapillary choroid, some preventive measures should be considered before the axial length becomes extremely elongated and the atrophic lesions of myopic maculopathy increase in severity. REFERENCES 1. Morgan IG, Ohno-Matsui K, Saw SM. Myopia. Lancet. 2012;379: Iwase A, Araie M, Tomidokoro A, et al. Prevalence and causes of low vision and blindness in a Japanese adult population: the Tajimi Study. Ophthalmology. 2006;113: Xu L, Wang Y, Li Y, et al. Causes of blindness and visual impairment in urban and rural areas in Beijing: the Beijing Eye Study. Ophthalmology. 2006;113:1134.e1 e Buch H, Vinding T, La Cour M, et al. Prevalence and causes of visual impairment and blindness among 9980 Scandinavian adults: the Copenhagen City Eye Study. Ophthalmology. 2004;111: Cotter SA, Varma R, Ying-Lai M, et al. 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