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Special Issue
IMI Pathologic Myopia
Kyoko Ohno-Matsui,1Pei-Chang Wu,2Kenji Yamashiro,3,4Kritchai Vutipongsatorn,5
Yuxin Fang,1Chui Ming Gemmy Cheung,6Timothy Y. Y. Lai,7Yasushi Ikuno,8–10
Salomon Yves Cohen,11 ,12 Alain Gaudric,11,13 and Jost B. Jonas14
1Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University, Tokyo, Japan
2Department of Ophthalmology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of
Medicine, Kaohsiung, Taiwan
3Department of Ophthalmology and Visual Sciences, University Graduate School of Medicine, Kyoto, Japan
4Department of Ophthalmology, Otsu Red-Cross Hospital, Otsu, Japan
5School of Medicine, Imperial College London, London, United Kingdom
6Singapore Eye Research Institute, Singapore National Eye Center, Singapore
7Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong Eye Hospital,
Hong Kong
8Ikuno Eye Center, 2-9-10-3F Juso-Higashi, Yodogawa-Ku, Osaka 532-0023, Japan
9Department of Ophthalmology, Osaka University Graduate School of Medicine, Osaka, Japan
10Department of Ophthalmology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
11Centre Ophtalmologique d’Imagerie et de Laser, Paris, France
12Department of Ophthalmology and University Paris Est, Creteil, France
13Department of Ophthalmology, APHP, Hôpital Lariboisière and Université de Paris, Paris, France
14Department of Ophthalmology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
Correspondence: Kyoko
Ohno-Matsui, Department of
Ophthalmology and Visual Science,
Tokyo Medical and Dental
University, Tokyo, Japan;
k.ohno.oph@tmd.ac.jp.
Received: January 6, 2021
Accepted: January 8, 2021
Published: April 28, 2021
Citation: Ohno-Matsui K, Wu P-C,
Yamashiro K, et al. IMI Pathologic
myopia. Invest Ophthalmol Vis
Sci. 2021;62(5):5.
https://doi.org/10.1167/iovs.62.5.5
Pathologic myopia is a major cause of visual impairment worldwide. Pathologic myopia is
distinctly different from high myopia. High myopia is a high degree of myopic refractive
error, whereas pathologic myopia is dened by a presence of typical complications in
the fundus (posterior staphyloma or myopic maculopathy equal to or more serious than
diffuse choroidal atrophy). Pathologic myopia often occurs in eyes with high myopia,
however its complications especially posterior staphyloma can also occur in eyes without
high myopia.
Owing to a recent advance in ocular imaging, an objective and accurate diagnosis of
pathologic myopia has become possible. Especially, optical coherence tomography has
revealed novel lesions like dome-shaped macula and myopic traction maculopathy. Wide-
eld optical coherence tomography has succeeded in visualizing the entire extent of large
staphylomas. The effectiveness of new therapies for complications have been shown, such
as anti-VEGF therapies for myopic macular neovascularization and vitreoretinal surgery
for myopic traction maculopathy.
Myopia, especially childhood myopia, has been increasing rapidly in the world. In
parallel with an increase in myopia, the prevalence of high myopia has also been increas-
ing. However, it remains unclear whether or not pathologic myopia will increase in
parallel with an increase of myopia itself. In addition, it has remained unclear whether
genes responsible for pathologic myopia are the same as those for myopia in general, or
whether pathologic myopia is genetically different from other myopia.
Keywords: pathologic myopia, myopic maculopathy, optical coherence tomography, gene
analyses, myopic macular neovascularization,myopic foveoschisis,myopic traction macu-
lopathy, dome-shaped macula
DEFINITION OF PATH OL OG IC MYOPIA
According to the IMI,1pathologic myopia is an exces-
sive axial elongation associated with myopia that leads
to structural changes in the posterior segment of the eye
(including posterior staphyloma, myopic maculopathy, and
high myopia-associated optic neuropathy) and that can lead
to loss of best-corrected visual acuity. The term “pathologic
myopia” is often confused with “high myopia.” These two
entities are distinctly different; high myopia is dened as a
high degree of myopic refractive error, whereas “pathologic
myopia” is characterized by the presence of typical myopic
lesions in the posterior fundus. Duke-Elder2dened patho-
logic myopia as “that type of myopia which is accompanied
by degenerative changes occurring especially in the poste-
rior pole of the globe.”
Characteristic myopic lesions in the posterior fundus
include myopic maculopathy equal to or more serious than
Copyright 2021 The Authors
iovs.arvojournals.org | ISSN: 1552-5783 1
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
IMI Pathologic Myopia IOVS | Special Issue | Vol. 62 | No. 5 | Article 5 | 2
diffuse chorioretinal atrophy (equal to category 2 in the
META-analysis for Pathologic Myopia [META-PM] classica-
tion3) and/or the presence of a posterior staphyloma.4The
cut-off values of the myopic refractive error and axial length
were not set for the denition of pathologic myopia because
a posterior staphyloma has been reported to occur in eyes
with normal axial length5or in eyes with an axial length of
less than 26.5 mm,6although long axial length is one of the
risk factors for fundus complications.
Because progressive choroidal thinning and formation
of Bruch’s membrane defects in the macular region are
key phenomena associated with myopic maculopathy, the
lesions of myopic maculopathy are better classied by their
appearance in the optical coherence tomography (OCT)
images than by the morphology as detected on fundus
photographs.7
BASIC ASPECTS OF PATH OL OG IC MYOPIA
Epidemiology of Pathologic Myopia
Prevalence and Its Impact on Vision. It has been
reported that pathologic myopia affects up to 3% of the
world’s population, with racial differences regarding the
prevalence of the disease.8Approximately 1% to 3% of
Asians and 1% of Caucasians have pathologic myopia.
However, the denition of pathologic myopia used in earlier
studies was not consistent and pathologic myopia was
confused with high myopia. Thus, an accurate prevalence
needs to be determined based on the new standard deni-
tion of pathologic myopia.
Pathologic myopia causes vision impairment or blindness
in 0.2% to 1.5% of Asians and 0.1% to 0.5% of Caucasians.8
Particularly, it is one of the major causes of low vision in
working-aged populations, as well as in the elderly popula-
tion. In Asia, pathologic myopia is the leading cause of irre-
versible blindness in Taiwan, Japan, and China. In Taiwan,
pathologic myopia is the second leading cause of vision
impairment in individuals aged 65 years or older.9In Japan,
pathologic myopia is the third leading cause of bilateral low
vision and the leading cause of monocular blindness in indi-
viduals aged 40 years or older.10 In China, pathologic myopia
is the leading cause of blindness and low vision in indi-
viduals aged 40 to 49 years.11 In Western countries, patho-
logic myopia is the third cause of blindness according to the
Rotterdam Study, the Copenhagen City Eye Study, and the
Los Angeles Latino Eye Study.12–14
High Myopia and Myopia. Recently, owing to
changes in environmental and lifestyle factors, the preva-
lence of myopia and high myopia has increased rapidly.
Therefore, the associated prevalence of pathologic myopia
may also increase dramatically in the near future.
High myopia can be dened as a refractive error of at least
–5.00 diopters (D).15 High myopia is linked to pathologic
myopia. Most pathologic myopia occurs in eyes with high
myopia, although low myopia and some individuals with
emmetropia will also develop pathologic myopia. Approx-
imately 28.7%, 44.4%, 45.9%, 47.6%, 58.31%, 72.7%, and
65% of high myopia cases in adult or elderly populations
have pathologic myopia in Singapore, Australia, Japan, rural
China, South China, Taiwan, and Beijing, respectively.9,16 –21
This means that approximately one-half of subjects with high
myopia in the adult population would develop pathologic
myopia.
The prevalence of high myopia is linked to the over-
all prevalence of myopia. In Taiwan, the prevalence of
myopia is as high as 84% in 18-year-old individuals and
the prevalence of high myopia is about 21%.22 Approxi-
mately 22.9% of the world population were diagnosed with
myopia in 2000, and 11.6% had high myopia among the
myopia population. It is estimated that by 2050, approxi-
mately one-half of the world’s population will have myopia
and up to one-fth of the myopia population will be
highly myopic.23 Thus, areas with high prevalence rates of
myopia would have increased rates of high myopia and
pathologic myopia. Pathologic myopia will be associated
with a high number of individuals suffering from vision
impairment and will have a signicant negative impact on
society.
The degree of myopia is associated with the risk of patho-
logic myopia. The prevalence of pathologic myopia is only
1% to 19% in the low-to-moderate myopia (–3 D) popula-
tion, but its prevalence is as high as 50% to 70% in the high
myopia population.17,18,24 A 1-D increase in myopia is asso-
ciated with a 67% increase in the prevalence of pathologic
myopia.25 A linear trend is observed for increasing myopia
diopters until −7.00 D, followed by an exponential trend in
the prevalence rates of pathologic myopia.26
Age. In addition to the degree of myopia, age is an
important factor in the development of pathologic myopia.
The prevalence of myopic maculopathy increased and expo-
nentially with increasing spherical equivalent and age in
Singapore.19 The prevalence of pathologic myopia is low
in children and adolescents, but increases with advanc-
ing age. In individuals with high myopia aged 40 years or
older, a progressive increase was noted in the prevalence
and severity of maculopathy. Pathologic myopia changes
with chorioretinal atrophy were found in 52.9% and 19.3%
of the Chinese and Singaporean adult groups with high
myopia, respectively.27 ,28 In the Taiwanese elderly popu-
lation, myopic maculopathy increased from 2.2% in indi-
viduals aged 65 years to 14.8% in relatively older adults.
Myopic maculopathy is rare in children with high myopia.29
However, a long-term follow-up study showed that 83% of
adults with pathologic myopia and myopic maculopathy had
already had diffuse choroidal atrophy around the optic disc
in their childhood.30 This nding suggested the possibil-
ity that children who eventually develop pathologic myopia
may be different, even at an early age.
Genetic or Acquired. There are two types of
myopia—congenital myopia or infantile myopia and
acquired myopia or school myopia. Congenital myopia has
family aggregation and is strongly inuenced by genetic
factors. However, the prevalence of congenital myopia is
low, less than 1% among Caucasian population.31 The initial
degree of infantile myopia is often high and progression
of myopia is also observed.32 A longer life span with high
myopia may be linked to the high prevalence of pathologic
myopia.
Acquired or school myopia occurs in children who
develop myopia in the primary school or early secondary
school years, with the exclusion of congenital myopia of
strong familial inheritance.33 It should be noted that, from
age 6, the annual progression rate for children with myopia
is approximately 1 D until the end of adolescence, with the
development of high myopia between the ages of 11 and
13 years.34 Considering the myopia boom in children
worldwide, the severity of pathologic myopia associated
with vision impairment is predictable.
IMI Pathologic Myopia IOVS |SpecialIssue|Vol.62|No.5|Article5|3
Environmental Factors. In the case of acquired
myopia, there might be a genetic susceptibility owing to
a variation in the prevalence observed in different areas.
Although more than 200 gene variants have been found to
be associated with myopia, none predominately contribute
to acquired myopia.35 Therefore, environmental factors play
a more important role in the development of myopia and
high myopia. Risk factors include educational stress, near-
work time and intensity, and lack of outdoor time.36,37 In
addition, increased digital screen time because of the smart-
phone era and the popularity of online education owing to
the coronavirus disease 2019 pandemic may aggravate the
prevalence of myopia in the near future.38
Genetics
Genome-wide association studies (GWASs) have identied
more than hundreds susceptibility genes for myopia.39–44
However, the genetic background for pathologic myopia has
not been elucidated fully. For example, little is known about
whether all subjects with high myopia have the same risk of
developing pathologic myopia or if the risk of developing
pathologic myopia depends on the patient’s genetic back-
ground.
Candidate Gene Analysis for Pathologic Myopia.
Several studies have examined the association between
myopic macular neovascularization (MNV) and susceptibil-
ity genes for myopia, high myopia, and AMD. Among the
susceptibility genes for AMD and their related genes, ARMS2,
CFH, C2/CFB, C3, CFI, ABCA1, APOE, LIPC, CETP, TIMP3,
COL8A1, COL10A1, VEGFA, and PEDF were evaluated for
their association with MNV.45 –50 CFI, COL8A1, and PEDF
were suggested as susceptibility genes for MNV,48–50 and
it has been reported that VEGFA is associated with the
size of MNV and the visual prognosis after treatment for
MNV.47 ,51 However, these associations were not conrmed
in later studies. Among the susceptibility genes for myopia
and high myopia, GJD2, RASGRF1, TOX, RDH5, and SHISA6
were evaluated for association with MNV, but no association
was found.52,53
In 2015, a photographic classication and grading system
for myopic maculopathy was proposed.3Since then, the
Myopic Maculopathy Classication System (META-PM clas-
sication) has been used to study pathologic myopia. In
2019, the genotype distribution of 50 susceptibility genes for
myopia were compared between 348 highly myopic cases
with myopic maculopathy and 898 highly myopic controls
without myopic maculopathy, but none of the genes showed
a signicant association with myopic maculopathy in the
highly myopic eyes.54
GWAS for Pathologic Myopia. In 2018, a GWAS on
myopic maculopathy in a Japanese population identied
CCDC102B as a susceptibility gene for myopic maculopa-
thy.55 The genotype distribution of CCDC102B was signi-
cantly different between the 1381 highly myopic cases with
myopic maculopathy and the 936 highly myopic controls
without myopic maculopathy. In contrast, CCDC102B was
not signicantly associated with axial length, and previ-
ous GWASs on myopia have not reported any association
between CCDC102B and myopia. CCDC102B is a suscep-
tibility gene for myopic maculopathy, but not for myopia.
Given that the genetic background for developing myopia
and the genetic background for developing myopic macu-
lopathy are different, we would be able to develop preven-
tive methods for myopic maculopathy, even for patients who
have already developed myopia or high myopia. The role
of CCDC102B in the development of myopic maculopathy
should be elucidated.
The discovery of CCDC102B suggests that we might be
able to prevent the development of myopic maculopathy,
even after the development of high myopia. To control
the development of pathologic myopia in highly myopic
patients, further studies need to discover more susceptibil-
ity genes for myopic maculopathy that are not associated
with high myopia. Because posterior staphyloma is associ-
ated with myopic maculopathy in highly myopic eyes, the
identication of susceptibility genes for posterior staphy-
loma and/or posterior eye shape would also contribute to
future control of the development of pathologic myopia. The
posterior fundus shape can be quantitatively evaluated using
OCT.56 GWASs on fundus shape might be able to discover
genes associated with fundus shape and/or staphyloma and
contribute to future control of the development of patho-
logic myopia.
Animal Models of Pathologic Myopia
Since Wiesel and Raviola57 discovered in 1977 that lid-
sutured monkeys developed axial elongation, animal models
have been a vital tool to understand and develop treatments
for myopia. This section summarizes animals that sponta-
neously, or via monocular deprivation, developed features
of pathologic myopia.
A search on Embase database using the following
keywords: “animal model” with “posterior staphyloma,”
“lacquer cracks,” “myopic maculopathy,” “choroidal neovas-
cularization,” and “Fuchs spot” one feature at a time revealed
1502 results. There were 1466 entries from “choroidal
neovascularization,” which were almost entirely induced
articially through laser photocoagulation and, hence, were
excluded. A summary of screened studies is found in Table 1 ,
which included retinopathy, globe enlarged (rge)chicks,
normal chicks, and LRP2 knockout mice.
The murine model is widely used because its genet-
ics and physiology are well-understood.58 Similar to in
humans, murine sclera and broblasts contain ve types
of muscarinic receptors.59,60 However, they are nocturnal
animals that lack a fovea and ability to accommodate.61
Additionally, their lenses are more spherical compared with
human lenses and occupy most of the vitreal cavity.62
Chick eyes are relatively larger and make up 50% of the
cranial volume compared with 5% in adult human.63 Addi-
tionally, they contain pecten, a comb-like structure of blood
vessels that provides nutrition and oxygenation to the retina.
Crucially, chick sclera has a cartilaginous layer and ossi-
cles, unlike any mammals.64,65 Nonetheless, there is a rod-
free region called the area centralis in the chick retina that
contains a greater concentration of cone photoreceptors,
resembling the macula in human.66 Similar to mice, chicks
have no fovea.
Animal Models of Lacquer Cracks. Lacquer cracks
are the yellowish linear lesions in the macular region
and seem to lack choriocapillaris under OCT angiogra-
phy (OCTA). They are seen in 4.3% to 15.7% of patients
with pathologic myopia.67–70 These lesions are believed to
represent mechanical breaks in the Bruch’s membrane–RPE–
choriocapillaris complex. In pathologic myopia, lacquer
cracks are commonly found temporal to the fovea in a
horizontal direction.71 One may discuss that because a hori-
zontal tension within Bruch’s membrane may be relieved
IMI Pathologic Myopia IOVS | Special Issue | Vol. 62 | No. 5 | Article 5 | 4
TABLE 1. Summary of Animal Models That Demonstrated Features of Pathologic Myopia Spontaneously or Induced Through Monocular Deprivation
Authors Animal nRelevant Phenotypes Method
Time of First
Intervention
Degree of Induced
Myopia Other Features
Cases et al.,95 2015 Mouse 20 Peripapillary
staphyloma after 21
days, chorioretinal
atrophy after 60
days
Spontaneous in LRP2
knockout model.
Mutation associated
with Stickler
syndrome and
Donnai-Barrow or
facio-acoustico-
renal syndrome
(DBS/FOAR), which
present with ocular
defect
Day 0 Day 90: About 40%
increase in axial
length
Increase in vitreous
chamber, retina
thinning (owing to
increased cell
death), scleral
thinning at the
posterior pole, and
collagen brils
formed fewer
lamellae
Wen e t al .,295 2006 Chick 45 Lacquer cracks after
12 weeks
Form-deprivation via
lid suturing
Day 2 Week 4: –10.23 ±2.15
D, Week 8: –15.57 ±
2.52 D, Week 12:
–17.01 ±3.29 D.
Axial length
increases by 13.5%,
11.4% and 11.1%
respectively
—
Hirata and Negi,72 1998 Chick 40 Lacquer cracks after 8
weeks, chorioretinal
atrophy
(choriocapillaris
signicantly less
dense) after 4
weeks
Form deprivation via
lid suturing
Day 1 Week 8: 28.3%
increase in axial
length
—
Montiani-Ferreira et al.,76 2004 Chick 9 rge/rge,
12 rge/+,
5+/+
Lacquer cracks after
6.4 weeks, patchy
chorioretinal
atrophy and scleral
displacement after
134 weeks
Spontaneous in
congenital
stationary night
blindness model
(mutation in GNB3
gene), animals
known as
retinopathy globe
enlarged (rge)
chicks
Day 0 Hyperopia. At Day 92,
rge/rge shows 9.8 ±
7.4 D, rge/+shows
4.3 ±0.57 D. Axial
length increases by
14.8%
Areas of ruptured
Bruch’s membrane
with focal absence
of RPE Fibroblasts
covered the
interface of the
abnormal Bruch’s
membrane and
choriocapillaris
Mao et al.,296 2006 Chick 32 Chorioretinal atrophy
after 12 weeks
Form deprivation via
lid suturing
Day 1 Week 12: –18.0 ±2.25
D, 23.1% increase in
axial length
TUNEL-positive cells
in ONL and INL of
myopic chick eyes
INL, inner nuclear layer; ONL, outer nuclear layer.
IMI Pathologic Myopia IOVS |SpecialIssue|Vol.62|No.5|Article5|5
FIGURE 1. Images taken from 8-week-old lid-sutured chick. (A) Macroscopic appearance of the eyecup of a lid-sutured eye. Horizontal lacquer
cracks could be seen running perpendicularly to the pecten. (B) Vascular cast at site of the LC and showing a central gap surrounded by
areas of decreased choriocapillaris density and some large choroidal bridging vessels between the gap. (C) Histology image at the site of
the LC. The white arrow depicts the proliferation and accumulation of RPE while the red arrows indicates both ends of Bruch’s membrane.
FIGURE 2. Images taken from rge chick. (A, Left) Macroscopic appearance of an eyecup taken from a 7-week-old rge chick showing lacquer
cracks as white linear lesions. Reprinted with permission from Montiani-Ferreira F, Kiupel M, Petersen-Jones SM. Spontaneous lacquer
crack lesions in the retinopathy, globe enlarged (rge)chick.JCompPathol. 2004;131(2-3):105-11. Copyright © 2004 Elsevier Ltd. (B, Right)
Histology image taken from 48-week-old rge chick showing Bruch’s membrane rupture and absence of RPE (Toluidine blue. Bar, 20 mm).
by a temporally located parapapillary gamma zone, lacquer
cracks may be orientated in a horizontal direction to relieve
the remaining excess tension in the vertical direction.
Lid-sutured Chick. Chicks that undergo monocular depri-
vation through lid suturing on the rst day after hatching
develop lesions that resemble lacquer cracks after 8 weeks72
(Fig. 1A). Similar to human, these lesions are frequently
orientated horizontally, which may be due to the verti-
cally orientated pectin in its retina. Vascular casts show that
lacquer cracks are not sharply demarcated. There is a central
gap that is void of Bruch’s membrane and choriocapillaris.
This gap is surrounded by an area with reduced chorio-
capillaris density, possibly owing to atrophy from increased
tension on the vessel bed (Fig. 1B). Large choroidal vessels
bridging the gap could also be seen. Proliferation and accu-
mulation of RPE, seen as a white arrow in Figure 1C, suggest
that this lacquer crack has developed over a period of time
and the RPE had sufcient time to respond.
Retinopathy, Globe Enlarged (rge) Chick. Rge chicks
have a progressive, early onset visual loss and a deletion
in GNB3, a gene that encodes guanine nucleotide binding
protein b3 (Gbeta3),73 resulting in a nonfunctional protein.
Physiologically, Gbeta3 forms a part of phototransduction
cascade and is an integral part of the G-protein signaling
within ON-bipolar cells.74 In humans, GNB3 mutation is seen
in patients with congenital stationary night blindness with
normal retinal thickness.75
Lacquer cracks in rge chicks are seen as early as 45 days
after hatching76 (Fig. 2A). Histologic images show a rupture
of Bruch’s membrane and a lack of RPE compared with
the surrounding area where these structures are intact
(Fig. 2B).
Long-term Follow-up Observation of Lacquer Cracks in
Humans and Chicks. Studies show that lacquer cracks in
patients with pathologic myopia tend to deteriorate by elon-
gating, increasing in number, or progressing to patchy atro-
phy.71 ,77,78 Interestingly, the chick models also develop simi-
lar progression patterns. In Figure 3, a 50-week-old lid-
sutured chick eye developed a greater number of lacquer
cracks and a marked elongation as compared with an 8-
week-old eye shown in Figure 2. Although there was no
obvious formation of a patchy atrophy during the long-term
observation of lid-sutured chicks, 134-week-old rge chicks
developed circular lesions that resembled a patchy atrophy
(Fig. 3). OCT images at the lesions showed areas of tissue
thinning and posterior bowing of sclera, which were consis-
tent with a patchy chorioretinal atrophy in patients with
pathologic myopia. This nding suggests that both features
IMI Pathologic Myopia IOVS | Special Issue | Vol. 62 | No. 5 | Article 5 | 6
FIGURE 3. Images of older lid-sutured (A)andrge chicks (B–D). (A) Eyecup of 50-week-old lid-sutured chick. There are more orientations
and a higher number of lacquer cracks compared with an 8-week-old lid-sutured eyecup with two lesions crisscrossing each other (red
arrow) (B) Confocal scanning laser ophthalmoscopy (cSLO) FA of 134-week-old rge chicks showing three circular lesions near the pecten.
(C) Spectral domain OCT (SD-OCT) image of a circular lesion illustrating the marked loss of tissue and the posterior bowing of sclera at the
lesion site. (D) A 3D image of the circular lesion showing similar ndings.
may share a similar pathophysiology and that rge chicks
might be a suitable animal model to study the disease.
Animal Models of Posterior Staphyloma. Poste-
rior staphyloma is a localized, outpouching of the eye wall
with a radius of curvature that is less than the surround-
ing curvature of the eye wall.79 It is present in approxi-
mately 50% of patients with pathologic myopia and little is
known about its etiology.5Scleral weakness secondary to
tissue loss and change in collagen brils have been impli-
cated in some studies.80–82 However, scleral re-enforcement
treatments have yielded mixed results.83–86 Choroidal thin-
ning has also been proposed because it is strongly asso-
ciated with posterior staphylomas.87 However, patients
with an acquired choroidal thinning still demonstrate axial
elongation without developing posterior staphylomas.88
Furthermore, patients with retinitis pigmentosa can develop
posterior staphylomas in areas where the choroid was
intact.89
Bruch’s membrane is an acellular, ve-layered extracellu-
lar matrix located between the RPE and choroid.90 With a
thickness of 2 to 4 μm, it facilitates the transport of nutri-
ents and metabolic byproducts between the choriocapil-
laris and the RPE, as well as providing structural support
to the globe. Bruch’s membrane and its surrounding struc-
tures are markedly thinned or absent along the staphy-
loma edges.91 Additionally, eyes with a secondary Bruch’s
membrane defect, such as in toxoplasmotic macular scars,
can show a collateral scleral staphyloma.92 Furthermore,
because its thickness remains constant while other layers
thin out in axially elongated globes, Jonas et al.93 proposed
that Bruch’s membrane may play an active role in the process
of emmetropization, myopization and potentially staphy-
loma development as well.
Rge Chicks. As seen in Figure 3C, the OCT images of
134-week-old rge chicks show an outward bowing of the
sclera in the regions of a Bruch’s membrane defect. Because
the extent of scleral displacement is limited, it is difcult to
conclude if these scleral deformations were certainly staphy-
lomas. However, it seems reasonable to suggest that this may
be an early stage of a transition toward a staphyloma forma-
tion. A longer observation period may be necessary to moni-
tor the development of scleral deformation.
IMI Pathologic Myopia IOVS |SpecialIssue|Vol.62|No.5|Article5|7
FIGURE 4. Images taken from 134-week-old rge chicks. (A) Confocal scanning laser ophthalmoscopy (cSLO) FA showing three circular
lesions near the pecten. (B) Spectral domain OCT (SD-OCT) image of a circular lesion illustrating the marked loss of tissue and the posterior
bowing of sclera at the lesion site. (C) A 3D image of the circular lesion showing similar ndings.
LRP2 Knockout Mouse. Currently, there is one animal
model that denitively develops posterior staphyloma,
which is the LRP2 knockout mouse.94 LRP2 (low-density
lipoprotein receptor–related protein 2) encodes megalin—a
transmembrane receptor found on the apical side of absorp-
tive epithelia. It regulates the level of certain circulating
compounds such as lipoproteins, sterols, vitamin-binding
proteins, and hormones.95 Its mutation is associated with
rare genetic conditions such as Donnai–Barrow syndrome
and Stickler syndrome, both of which present with facial
dysmorphology, hearing loss, ocular defects and chorioreti-
nal atrophy.96
Histologic sections and magnetic resonance imaging
(MRI) show evidence of axial elongation and posterior
staphyloma from days 15 and 21, respectively (Figs. 4A
and 4B). A separation of the choroid and RPE began at the
edge of the staphyloma. Both layers became progressively
thinner before disappearing at the optic nerve head. Bruch’s
membrane could not be identied clearly on these images.
Furthermore, there was a marked thinning of the retina and
pycnotic cell bodies were detected throughout the excavated
region. This nding indicated an area of peripapillary atro-
phy apparently corresponding with the region with peripap-
illary staphyloma in this model. This formation is compatible
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FIGURE 5. Proposed nomenclature for staphylomas. (A) Normal eye shape. (B) Axial elongation occurring in the equatorial region that
does not induce altered curvature in the posterior aspect of the eye. This eye has axial myopia but no staphyloma. (C) A second curvature
occurs in the posterior portion of the eye with a small radius (r2) than the surrounding eye wall (r1). This secondary curve is staphyloma,
Reproduced with permission from Spaide RF. Staphyloma: part 1. Pathologic Myopia: Springer; 2014:167-176.
FIGURE 6. Three-dimensional MRI of the eye with posterior staphyloma. A clear outpouching of a part of the posterior segment of the eye
is observed in the image viewed from the side (left) as well as in the image viewed from the inferior (right).
with a posterior bowing of the area of peripapillary gamma
zone in patients with pathologic myopia.97 Figure 4Cshows
a posterior bowing of the area of gamma zone.
Apart from posterior staphyloma, mutant mice also devel-
oped retinal and scleral thinning and chorioretinal atrophy,
similar to patients with pathologic myopia. Furthermore,
they maintained a similar IOP throughout their lifespan,
which is consistent with the ndings from patients with
pathologic myopia as well. Thus, LRP2 knockout mouse may
serve as an animal model to study the etiology of pathologic
myopia.
CLINICAL ASPECTS OF PATH OL OG IC MYOPIA
Posterior Staphyloma
Posterior staphylomas are hallmarks of pathologic myopia
and are among other major causes or sequels of developing
myopic maculopathy.3,18,77,98 –100 The presence of a poste-
rior staphyloma is part of a recently updated denition of
pathologic myopia that was characterized by the occurrence
of myopic choroidal atrophy equal to or more serious than
diffuse choroidal atrophy or by the presence of a posterior
staphyloma.3,4
As described by Spaide,79 a posterior staphyloma is an
outpouching of a circumscribed posterior fundus region and
has a curvature radius that is smaller than the curvature
radius of the adjacent eye wall (Fig. 5).4,5Posterior staphylo-
mas should be differentiated from a simple scleral backward
bowing which is commonly seen on OCT images of highly
myopic eyes.
Applying three-dimensional (3D)-MRI, Moriyama et al.
recently analyzed the shape of the whole eye,5,101,102 so that
even large posterior staphylomas could be imaged entirely
(Fig. 6). Based on 3D-MRI images of the eye, they showed
that the difference in the ocular shape is correlated with the
development of vision-threatening conditions in eyes with
pathologic myopia.5Applying 3D-MRI and wide-eld fundus
imaging, Ohno-Matsui102 recently classied posterior staphy-
lomas into six types: the wide macular type, the narrow
macular type, the peripapillary type, the nasal type, the infe-
rior type, and other congurations (Fig. 7). This classica-
tion was based on the previous categorization of staphylo-
mas by Curtin103 into 10 types, among which the types I
to V were primary staphylomas and the types VI to X were
compound staphylomas. The most predominant staphyloma
type was the wide, macular type (74% of eyes with staphy-
loma), followed by the narrow, macular type of staphyloma
(14% of eyes with staphyloma). However, 3D-MRI was not
feasible as a screening technique and, owing to a relatively
low spatial resolution, subtle changes of shallow staphylo-
mas were difcult to detect.
A new prototype of a wide-eld swept source OCT
system has recently been developed and uses not one but
IMI Pathologic Myopia IOVS |SpecialIssue|Vol.62|No.5|Article5|9
FIGURE 7. Classication of staphyloma. A new classication of posterior staphyloma according to its location and extent. The staphyloma
type is renamed according to its location and distribution. Type I →wide, macular staphyloma, Type II →narrow, macular staphyloma,
Type III →peripapillary staphyloma, Type IV →nasal staphyloma, Type V →inferior staphyloma, Others →staphylomas other than type
I to V. Reprinted with permission from Ohno-Matsui K. Proposed classication of posterior staphylomas based on analyses of eye shape by
3D-MRI. Ophthalmology. 2014;121:1798-1809. © 2014 American Academy of Ophthalmology. Published by Elsevier Inc.
FIGURE 8. Ultra-wide-eld optical coherence tomographic image of staphyloma. (A) In a horizontal OCT section across the fovea, the edge
of the staphyloma (arrow) shows consistent features with a gradual thinning of the choroid from the periphery toward the staphyloma edge
as well as a gradual re-thickening of the choroid from the staphyloma edge in direction to the posterior pole, accompanied by a change
in the curvature of the sclera at the staphyloma edge. The staphylomatous region shows a posterior outpouching of the sclera nasal to the
staphyloma edge. (B) Three-dimensionally reconstructed image shows the staphyloma edge clearly (outlined by arrowheads). Reprinted
with permission from Shinohara K, Shimada N, Moriyama M, et al. Posterior staphylomas in pathologic myopia imaged by wideeld optical
coherence tomography. Invest Ophthalmol Vis Sci. 2017;58:3750-3758. Licensed under a Creative Commons Attribution 4.0 International
License (CC BY).
multiple scan lines and generates scan maps allowing the
3D reconstruction of posterior staphylomas in a region of
interest of 23 ×20 mm and a depth of 5 mm. Shinohara et
al.104 showed that wide-eld OCT can provide tomographic
images of posterior staphylomas in a resolution and size
that have been unachievable so far and that may replace
3D-MRI in assessing posterior staphylomas. Using wide-eld
OCT, the edge of staphylomas showed consistent features
with a gradual thinning of the choroid from the periphery
toward the staphyloma edge and a gradual rethickening of
the choroid from the staphyloma edge in direction to the
posterior pole, accompanied by a change in the curvature
radius of the sclera at the staphyloma edge (Fig. 8).
In a study by Tanaka et al.,105 55 eyes of 30 patients with
a mean age of 12.3 years and a mean axial length of 27.9 mm
were studied. Seven of the 55 eyes (12.7%) had a posterior
displacement of the sclera and were diagnosed as having
a staphyloma. Although staphylomas are generally consid-
ered to be pathological changes that develop in later life, the
results showed that posterior staphylomas can be present at
a much younger age than they had been believed.
Ultra-wide-eld OCT is considered to be a useful method
to identify children with pathologic myopia. One of the
strengths of ultra-wide-eld OCT is that structures of the
neural retina can be visualized and a relationship between
staphylomas and chorioretinal complications can be exam-
ined. Shinohara et al.106 showed that, in eyes with staphylo-
mas, myopic macular retinoschisis is observed only within
the area of staphylomas. Myopic macular retinoschisis is also
seen in eyes without staphyloma, in which cases myopic
macular retinoschisis is seen in a diffuse fashion. Takahashi
et al.107 analyzed a relationship between vitreous adhesion
and staphylomas.
Finally, therapies targeting staphylomas are eagerly
expected. Before vision-threatening complications occur,
preventing and treating staphylomas are considered to be
ideal treatments.
Myopic Choroidal Atrophy
Myopic maculopathy, also known as myopic macular degen-
eration, is a key feature of pathologic myopia. Curtin and
Karlin70 rst described ve myopic fundus changes that are
associated with an increase of axial length, including optic
nerve crescent, chorioretinal atrophy, central pigment spot,
lacquer cracks, and posterior staphyloma. Later, Avila et
al.108 developed a grading system of myopic maculopathy
on a scale of increasing severity from 0 to 5 as follows: M0,
normal-appearing posterior pole; M1, choroidal pallor and
tessellation; M2,M
1plus posterior staphyloma; M3,M
2plus
lacquer cracks; M4,M
3plus focal areas of deep choroidal
atrophy; and M5, large geographic areas of deep chorioreti-
nal atrophy shown as “bare sclera.” In an atlas of patho-
logic myopia,109 Tokoro updated and organized the lesions
of myopic maculopathy. Tokoro109 classied myopic macular
lesions into four categories based on ophthalmoscopic nd-
ings: (1) tessellated fundus, (2) diffuse choroidal atrophy,
(3) patchy choroidal atrophy, and (4) macular hemorrhage.
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TABLE 2. META-PM Classication and an Impact on Vision
META-PM Classication*Visual Impairment
Pathologic
Myopia
Category
Tessellated fundus (category 1) None –
Diffuse chorioretinal atrophy (category 2) Mild +
Patchy chorioretinal atrophy (category 3) Parafoveal scotoma +
Macular atrophy (category 4) Central scotoma +
Plus lesions
Myopic MNV (including Fuchs’ spots) Central scotoma, distorted vision +
Lacquer cracks Temporal scotoma owing to simple hemorrhage, distorted vision (in some cases) +
*Modied from Ohno-Matsui K, Kawasaki R, Jonas JB, et al. International photographic classication and grading system for myopic
maculopathy. Am J Ophthalmol. 2015;159:877e883.
Pathologic myopia is dened as equal or greater than myopic maculopathy category 2, or presence of “plus lesion,” or the presence of
posterior staphyloma.
Lacquer cracks were included in the diffuse atrophy category
and macular hemorrhage was subclassied into two types
of lesions—myopic MNV and simple macular hemorrhage.
Later, Hayashi et al.98 investigated the natural course of 806
eyes of 429 consecutive patients with high myopia (myopic
refractive error of >8 D or an axial length of ≥26.5 mm)
who had follow-up for 5 to 32 years. Hayashi et al.98 made
some modications to Tokoro’s classication based on clini-
cal impression; they categorized lacquer cracks and myopic
MNV as independent lesions. This longitudinal observation
of all myopic maculopathy lesions has made a great contri-
bution to the subsequent establishment of universal classi-
cation (META-PM classication).3
The META-PM Classication of Myopic Macu-
lopathy. Recently an international panel of researchers in
myopia reviewed previous studies and proposed a simpli-
ed, uniform classication system for pathologic myopia
(Table 2). In this simplied system (the META-PM classi-
cation), myopic maculopathy lesions are categorized into
ve categories from no myopic retinal lesions (category 0),
tessellated fundus only (category 1), diffuse chorioretinal
atrophy (category 2), patchy chorioretinal atrophy (category
3), to macular atrophy (category 4). Three additional features
were added to these categories and were included as “plus
signs”: (1) lacquer cracks, (2) myopic MNV, and (3) Fuchs
spot. The reason for separating these plus signs from the
categories is that these three plus lesions affect or potentially
affect central visual acuity and may develop from, or coex-
ist, in eyes with any categories of the myopic maculopathy.
Based on this classication, pathologic myopia is dened
as equal to or greater than myopic maculopathy category 2,
or presence of plus lesion, or the presence of a posterior
staphyloma.
Features of Each Lesion of Myopic Maculo-
pathy.
Tessellated (or Tigroid) Fundus (Category 1). Tessellated
fundus is dened by the increased visibility of large choroid
vessels owing to axial elongation (Fig. 9). Tessellation begins
to develop around the optic disc, especially in the area
between the optic disc and the central fovea. A tessellated
fundus alone does not affect the central vision, unlike the
other lesions of myopic maculopathy (Tabl e 2). A tessellated
fundus, along with the myopic conus, is one of the prelimi-
nary visible signs in eyes with myopia in general and often
observed in children with high myopia.110 Wong et al.111 also
reported that a tessellated fundus and peripapillary atrophy
were the most common ndings in highly myopic Chinese
adolescents (aged 12–16 years).
Highly myopic patients with a tessellated fundus are
signicantly younger than the patients with other lesions
of myopic maculopathy.21,77,98 ,112 Fang et al.77 and Xiao et
al.21 both showed that highly myopic eyes with a tessellated
fundus had less myopia and a shorter axial length than those
in the category 2 or above. Tokoro109 reported that approx-
imately 90% of eyes with only a tessellated fundus had an
axial length of less than 26 mm. The proportion of tessella-
tion decreases linearly with longer axial length and tessel-
lation is not seen in eyes with an axial length of more than
31 mm. In other words, almost all eyes with axial length
of more than 31 mm would have progressed to advanced
myopic maculopathy (i.e., diffuse atrophy or patchy
atrophy).
The mean (or median) subfoveal choroidal thickness in
eyes with tessellated fundus in high myopia varies from
80 to 166 μm,7,112–114 and is decreased almost by one-half
compared with those with no myopic maculopathy in high
myopia.7,113 The distribution pattern of the choroidal thick-
ness in eyes with tessellation was different with those in
eyes with no maculopathy, but was similar to greater myopic
maculopathy categories (e.g., diffuse atrophy and patchy
atrophy). This nding suggested that the tessellation might
be the rst sign for myopic eyes to become pathologic.
Hayashi et al.98 showed that only 13.4% of eyes with a
tessellated fundus showed a progression after a follow-up
period of 5 to 32 years; 10.1% developed diffuse chorioreti-
nal atrophy, 2.9% developed lacquer cracks, and 0.4% devel-
oped a MNV in the rst time progression. In the population-
based Beijing Eye Study, progression was observed in 19%
eyes with tessellation with 10 years of follow-up.100 Another
large series of 810 highly myopic eyes that were followed
for more than 10 years (mean follow-up, 18 years) showed
a higher progression rate (27%).77 Because the eyes with
greater myopic maculopathy categories showed a greater
progression rate, it is suggested that myopic maculopathy
tends to progress more quickly after the tessellated fundus
stage. A tessellated fundus might be a relatively stable condi-
tion, and highly myopic eyes might stay in this condition for
a relatively long period.
Diffuse Choroidal Atrophy (Category 2). Diffuse
choroidal atrophy is observed as an ill-dened yellowish
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FIGURE 9. Fundus photographs showing different type of myopic maculopathy. (A) Right fundus showing a tessellated fundus with an
axial length of 28.1 mm in a 37-year-old woman. The best-corrected visual acuity (BCVA) is 1.2. (B) Right fundus showing PDCA with an
axial length of 29.76 mm in a 45-year-old woman. The BCVA is 0.8. (C) Right fundus showing MDCA with an axial length of 31.77 mm in
a 76-year-old man. The BCVA is 0.5. (D) Left fundus showing patchy atrophy (arrows) with an axial length of 30.46 mm in a 60-year-old
woman. The BCVA is 0.9. (E) Left fundus showing myopic MNV-related macular atrophy with an axial length of 33.16 mm in a 74-year-old
woman. The BCVA is 0.15. (F) Left fundus showing patchy atrophy-related macular atrophy with an axial length of 32.95 mm in a 61-year-old
woman. The BCVA is 0.2.
FIGURE 10. Diagram showing the progression patterns of high myopia to the different categories of pathologic myopia. Bruch’s membrane,
Bruch’s membrane. Reproduced and modied with permission from Fang Y, Yokoi T, Nagaoka N, et al. Progression of myopic maculopathy
during 18-year follow-up. Ophthalmology. 2018;125(6):863-877. © 2018 by the American Academy of Ophthalmology.
IMI Pathologic Myopia IOVS | Special Issue | Vol. 62 | No. 5 | Article 5 | 12
lesion in the posterior fundus of highly myopic eyes.
The lesion is not uniformly yellow, but shows a granular
appearance. However, the fundus color may look different
according to the degree of fundus pigmentation among
races. Diffuse choroidal atrophy primarily appear around
the optic disc and increases with age and nally covers
the entire posterior pole.109 Thus, diffuse choroidal atrophy
is subclassied to peripapillary diffuse choroidal atrophy
(PDCA)30 and macular diffuse choroidal atrophy (MDCA).77
The frequency of diffuse atrophy increases with age as well
as with an increase of axial length.28,115 Tokoro el al.115
found that diffuse atrophy usually occurred at around the
age 40 and was observed in about 30% to 40% of patients
after age 40. Recently, Liu et al.28 adopted the META-PM
classication to evaluate the frequency and distribution of
the diffuse choroidal atrophy according to the age, axial
length and the best-corrected visual acuity. In this large
Chinese highly myopic cohort, the proportion of diffuse
choroidal atrophy in age groups of 7 to 11, 12 to 18, 19 to
39, and more than 40 years old was 20.9%, 9.2%, 23.1%,
and 52.9%, respectively. The incidence of diffuse choroidal
atrophy increased with longer axial length, from 3.6% in
eyes with an axial length of less than 26.50 mm to 62.8% in
eyes with an axial length of 28.50 mm or greater.
Fluorescein angiography (FA) revealed a mild hyperu-
orescence owing to tissue staining in the late phase of the
angiogram.109 On indocyanine green angiography (ICGA),
a pronounced decrease of the choroidal capillaries and
medium and large-size choroidal vessels can be seen in the
area of diffuse atrophy. OCT shows a marked thinning of
the choroid in the area of diffuse atrophy. The subfoveal
choroidal thickness in eyes with macular diffuse atrophy is
usually less than 100 μm and the mean choroidal thickness
is 50 μm based on a clinic-based study.7In most cases, the
choroid is almost absent, although it is sporadically present
large choroidal vessels. Larger choroidal blood vessels can
be observed to protrude to the retina. However, even in
the area where most of the choroidal layer is absent, the
RPE layer and outer retina are present. It might explain
the relatively preserved vision in eyes with diffuse atrophy.
With the use of OCTA, choriocapillaris ow impairment can
be detected, even though the visualization of the choroidal
circulation remains a challenge for interpretation in eyes
with pathologic myopia. The OCTA in eyes with diffuse atro-
phy shows the low-density choriocapillaris, with the pres-
ence of medium and large choroidal vessels.111,116 Although
the choroid becomes thinned in eyes with a tessellated
fundus, the degree of choroidal thinning is much more seri-
ous in eyes with diffuse atrophy7and such disproportionate
thinning of choroid compared with the surrounding tissue
(RPE, outer retina, and sclera) might be a key phenomenon
in diffuse atrophy as well as pathologic myopia.
Patchy Choroidal Atrophy (Category 3). Patchy choroidal
atrophy can be seen as a grayish-white, well-dened atro-
phy.109 Owing to an absence of RPE and most of the
choroid, the sclera can be observed through transparent
retinal tissue. The median size of patchy atrophy was 1.73
mm2, varying from 0.03 to 101.3 mm2,117 with the diame-
ter of less than one or more lobules of the choriocapillaris.
Pigment clumping is observed within the area of patchy atro-
phy, especially along the margin of the atrophy or along
the large choroidal vessels. Abruptly emerging vessels are
commonly observed within or near the edge of patchy atro-
phy, especially for those with large size.118 Patchy atrophy
was found in 10.5% of patients in a clinic-based Japanese
highly myopic cohort.117 The percentage of patchy atrophy
increases linearly with age and reaches 32.5% after age 60
years.115 The prevalence of patchy atrophy is 3.3% in eyes
with an axial length from 27.0 to 27.9 mm, and exceeds 25%
and 50% if the axial length is longer than 31 mm and 32 mm,
respectively.115 With time, the patchy atrophy enlarges and
coalesces with each other.77,98 ,119
FA as well as ICGA show a choroidal lling defect in
the area of patchy atrophy suggesting that this lesion is
a complete closure of choriocapillaris.109 Fundus autouo-
rescence shows hypoautouorescence with distinct border
owing to a loss of RPE in the area of patchy atrophy. Using
OCT, patchy atrophy is characterized by the lack of RPE
and outer retina with loss of most of choroid. Thus, the
inner retinal layers have direct contact with the inner scleral
surface. Swept source OCT also showed that discontinuities
of Bruch’s membrane in the area of patchy atrophy.117 ,120
The RPE terminates outside of the margin of the macular
Bruch membrane defect. Patchy atrophy could be regarded
as a Bruch’s membrane rupture, not solely an atrophy.
Patchy atrophy is subclassied into three types: patchy
atrophy that develops from lacquer cracks P(Lc); patchy atro-
phy that develops within the area of an advanced diffuse
chorioretinal atrophy P(D); and patchy atrophy which can
be seen along the border of the posterior staphyloma.98
The shape of patchy atrophy may help to differentiate these
types, because P(D) is usually circular or elliptical and P(Lc)
is often longitudinally oval. P(Lc) is considered an enlarge-
ment of Bruch’s membrane defect owing to lacquer cracks,
and P(D) might also represent a Bruch’s membrane hole121
developing within the area of advanced stage of diffuse
atrophy.
Almost all eyes (95%) with patchy atrophy progressed
after a mean follow-up of 18 years, in which an enlarge-
ment of the original patchy atrophy was found predomi-
nantly in 98% and new patchy atrophy was found in 47%
followed by development of myopic MNV in 21.7% and
patchy-related macular atrophy in 8.3%.77 Miere et al.122 also
reported that all patchy atrophies had signicantly enlarged
over at least 12 months using quantitative measurement.
Such high percentages of progression of eyes with patchy
atrophy could be explained by the biomechanical proper-
ties of Bruch’s membrane so that as soon as a defect is
created, the Bruch’s membrane defect would enlarge over
time with ongoing axial elongation. However, it is uncom-
mon for extrafoveal patchy atrophy to later involve the
central fovea. This means that it is rare for patchy atrophy to
cause the central vision loss although this lesion leads to a
paracentral absolute scotoma123 owing to a loss of photore-
ceptors within the atrophic area (Table 3).
Macular Atrophy (Category 4). Macular atrophy is a
well-demarcated, grayish-white or whitish, atrophic lesion
centered on the fovea. The imaging features are similar to
those of patchy chorioretinal atrophy. The main difference
between patchy atrophy and macular atrophy is its location
relative to the central fovea. Based on the long-term follow-
up observation, it is suggested that macular atrophy could be
subclassied into MNV-related macular atrophy and patchy
atrophy-related macular atrophy. MNV-related macular atro-
phy develops centered in the central fovea and enlarges
toward the periphery, and patchy atrophy-related macular
atrophy develops outside of the foveal area and enlarging,
or coalescing with other patchy atrophies, into the foveal
center.77 The differentiation is mainly based on its morpho-
logic features or is assisted by the history of MNV. The
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TABLE 3. Summary of Phase III Clinical Trials Using Anti-VEGF Agents for Myopic Choroidal Neovascularization
Study Treatment Groups
No. of
Eyes
Mean BCVA Change at
Study Primary End Point
Mean BCVA Change at Study
Final Visit
Mean No. of Anti-VEGF
Injections Over Study Period
RADIANCE158 Ranibizumab 0.5 mg guided by
BCVA stabilization
106 +10.5 letters at month 3 +13.8 letters at month 12 month 4.6 ranibizumab injections over
12 months
Ranibizumab 0.5 mg guided by
disease activity
116 +10.6 letters at month 3 +14.4 letters at month 12 month 3.5 ranibizumab injections over
12 months
vPDT then eligible to add
ranibizumab 0.5 mg after
month 3
55 +2.2 letters at month 3 +9.3 letters at month 12 2.4 ranibizumab injections from
month 3 to 12
BRILLANCE160 Ranibizumab 0.5 mg guided by
visual stabilization
182 +9.5 letters at month 3 +12.0 letters at month 12 4.6 ranibizumab injections over
12 months
Ranibizumab 0.5 mg guided by
disease activity
184 +9.8 letters at month 3 +13.1 letters at month 12 3.0 ranibizumab injections over
12 months
vPDT then eligible to add
ranibizumab after month 3
91 +4.5 letters at month 3 +10.3 letters at month 12 3.2 ranibizumab injections from
month 3 to 12
MYRROR161 Aibercept 2 mg 91 +12.1 letters at week 24 +13.5 letters at week 48 4.2 aibercept injections over
48 weeks
Sham followed by aibercept 2
mg after week 24
31 –2.0 letters at week 24 +3.9 letters at week 48 3.0 aibercept injections from
week 24 to 48
SHINY162 Conbercept 0.5 mg 132 +12.0 letters at month 3 +13.3 letters at month 9 4.8 conbercept injections over
9months
Sham followed by conbercept 0.5
mg after month 3
44 +0.6 letters at month 3 +11.3 letters at month 9 3.6 conbercept injections from
month 3 to 9
BCVA, best-corrected visual acuity.
IMI Pathologic Myopia IOVS | Special Issue | Vol. 62 | No. 5 | Article 5 | 14
majority of macular atrophy is an atrophic stage of MNV, with
a very few percentages related to secondary foveal involve-
ment by enlargement of patchy atrophy.
During an 18-year follow-up, loss of best-corrected visual
acuity was associated with the development of MNV, MNV-
related macular atrophy, and enlargement of MNV-related
macular atrophy.77 At the last visit, most of eyes with a best-
corrected visual acuity of less than 0.1 (20/200) had macular
atrophy.
Lacquer Cracks (Plus Lesion). Lacquer cracks can be
detected as ne, irregular, yellow lines in and around
the macula. They are considered to represent healed and
mechanical breaks of the RPE, Bruch’s membrane, and the
choriocapillaris complex.67,68 Multiple lacquer cracks can
often be seen in branching and crisscrossing patterns. The
prevalence of lacquer cracks ranged from 4.2% to 15.7%
in highly myopic eyes in several cohorts.27,67 –69,124 Lacquer
cracks can develop at a relatively early age in patients with
pathologic myopia. Klein and Curtin68 reported that the
mean age of patients with lacquer cracks was 32 years with
a range of 14 to 52 years. Previous studies also indicated that
lacquer cracks occur most often in eyes with an axial length
between 29.0 mm and 32.0 mm.27,67–69 ,71,124–127
The diagnosis of lacquer cracks is made based on multi-
modal imaging. ICGA is considered the gold standard for
lacquer crack detection, observed as linear hypouores-
cence in the late phase.126 On FA, lacquer cracks show a
consistent linear hyperuorescence during the entire angio-
graphic phase, a window defect owing to RPE atrophy over-
lying the defects of Bruch’s membrane in the early phase and
a staining of healed scar tissue lling the Bruch’s membrane
defect in the late phase. Fundus autouorescence shows
hypoautouorescence, which is due to the atrophied RPE
overlying the rupture. Lacquer cracks are easily overlooked
on OCT because they are too narrow to detect. However,
when the lesions are within the OCT scans, lacquer cracks
appear as discontinuities of the RPE and increased trans-
mission into the deeper tissue beyond the RPE.71,127 OCTA
shows partial defect of choriocapillaris in the region of
lacquer cracks.116
Xu et al.71 reported that 53.7% of eyes with lacquer
cracks progressed during a mean follow-up of 3.5 years.
Three progression patterns were found: increase in number
(43.9%), elongation (9.8%), and progression to patchy atro-
phy (14.6%). The most common pattern was an increase in
number of lacquer cracks. New lacquer cracks tend to occur
perpendicularly from the existing lacquer cracks (branch-
ing) or in parallel with the existing lacquer cracks. An elon-
gation of an existing lacquer crack is also seen in a small
percentage of eyes. Lacquer cracks increase their width and
progress to patchy atrophy. In some eyes, this progression is
not a uniform widening of a pre-existing lacquer cracks, but
small circular areas of patchy atrophy rst develop along the
lines of lacquer cracks, and then these circular areas enlarge
and fuse with each other.
Although lacquer cracks are often observed in the vicin-
ity of MNV,108 it is unusual for MNV to develop secondarily
from the existing lacquer cracks. This nding suggests that
the lacquer cracks that are seen as yellowish linear lesions
represent healed scar tissue. When lacquer cracks are newly
formed, MNV might develop through the Bruch’s membrane
rupture. However, once the Bruch’s membrane rupture is
healed with scar tissue, a secondary MNV rarely occurs.
It is rare for lacquer cracks to develop across the central
fovea itself. Thus, lacquer cracks themselves do not gener-
ally impair the central vision; however, the subretinal bleed-
ing that develops at the onset of the rupture of Bruch’s
membrane could cause the impairment of central vision even
after absorption of the hemorrhage (Table 2).
Myopic MNV (Plus Sign). MNV is a major cause of
central vision impairment in pathologic myopia. It has been
included as a plus sign in the META-PM classication. MNV
included three phases: the active phase with proliferation
of a brovascular membrane including MNV, exudation, and
hemorrhage; the scar phase exemplied by a Fuchs spot;
and the atrophic phase represented by MNV-related macu-
lar atrophy. Thus, Fuchs spots were not considered to be
independent lesions and they were a scar phase of MNV.
Further details are discussed in the section on Myopic MNV.
New Classication and Grading System. Although
the META-PM classication is well-suited to identify vari-
ous stages of myopic maculopathy, this classication is only
based on fundus photographs that could lead to an accu-
rate diagnosis of atrophic lesions because of the differ-
ent visual presentations according to the degree of fundus
pigmentation among races. In addition, other myopic macu-
lar lesions such as myopic traction maculopathy and dome-
shaped macula were not included. Thus, an OCT-based clas-
sication has been developed.7Further details are discussed
under the section on OCT-based Classication of Myopic
Maculopathy.
Recently, Ruiz-Medrano et al.128 also published a
comprehensive review summarizing the main features of
pathologic myopia and proposed a new classication
system based on three key factors—atrophy, traction, and
neovascularization—or the ATN classication system. This
proposed classication system does not make any changes
to the current atrophy classication (ve categories in the
META-PM classication). Tractional component is newly
included containing ve stages of inner or/and outer
foveoschisis, foveal detachment, macular hole, and retinal
detachment. Three plus signs in the META-PM classication
are considered as neovascular components.
Progression of Myopic Maculopathy. Based on the
META-PM classication, Fang et al.77 conducted a retrospec-
tive case series study including 810 eyes of 432 highly
myopic patients who had been followed for 10 or more
years. After a mean follow-up of 18 years, the progres-
sion of myopic maculopathy was observed in 58.6% for all
eyes, with 74.3% for eyes with pathologic myopia at base-
line. The three most frequent progression patterns were
(1) an extension of peripapillary diffuse atrophy to macu-
lar diffuse atrophy in diffuse atrophy, (2) an enlargement
of the original atrophic lesion in patchy atrophy, and (3)
the development of patchy atrophy in lacquer cracks. From
two Chinese population-based longitudinal studies, the 10-
year progression rate of myopic maculopathy was 35.5% in
elderly Chinese (aged ≥40 years) (the Beijing Eye Study)100
and the 5-year progression rate was also 35.3% in rural
Chinese adult population (aged ≥30 years) (the Handan Eye
Study).129 In another large highly myopic Chinese cohort
(the Zhongshan Ophthalmic Center-Brien Holden Vision
Institute High Myopia Cohort Study), approximately 15% of
657 highly myopic eyes had progression of myopic macu-
lopathy over 2 years.130 Older age, longer axial length, and
the presence of posterior staphyloma are the main factors
associated with the development and progression of myopic
maculopathy.
A Scheme Depicting the Progression Patterns of
Myopic Maculopathy (Fig. 10). First, the progression
IMI Pathologic Myopia IOVS |SpecialIssue|Vol.62|No.5|Article5|15
from category 0 (no myopic maculopathy) to
category 1 (fundus tessellation) was not associated with a
decrease in visual acuity. Although tessellation is not consid-
ered as pathologic myopia, a remarkable thinning of the
choroid begins with the appearance of tessellation, which
is the rst sign of the progression of myopic maculopathy.
Second, diffuse atrophy (category 2) primarily occurs in the
peripapillary region (PDCA) and eventually extends into the
macula (MDCA). Third, the eyes with patchy atrophy have a
hole in the macular Bruch’s membrane that either forms by
an enlargement of lacquer cracks or develops in regions of
advanced diffuse atrophy with a more vulnerable Bruch’s
membrane. Fourth, both patchy atrophy and macular atro-
phy (MNV related and patchy related) tend to enlarge with
time. Fifth, macular atrophy is almost always MNV related,
although patchy-related macular atrophy can occasionally
occur.
Conclusion. The characteristics of each lesion of
myopic maculopathy have been claried by multimodal
imaging with advanced technique. The wide use of
the META-PM classication system allows researchers to
perform direct comparisons across studies and provides a
common tool for clinical trials and epidemiologic studies.
Further studies targeting the pathogenesis of myopic macu-
lopathy will be of benet to nd an effective treatment and
nally impede the progression of myopic maculopathy.
Myopic MNV
Pathogenesis of Myopic MNV. The pathogenesis of
myopic MNV is not understood fully, and several theories,
such as the mechanical theory and the heredodegenera-
tive theory have been proposed to explain the development
of myopic MNV.108,131 –133 The background changes in an
eye with pathologic myopia are believed to contribute to
the pathogenesis of myopic MNV. These structural changes
involve multiple layers of the eye, including the RPE, Bruch’s
membrane, choriocapillaris, and choroid, as well as the
sclera, and are mostly driven by axial elongation. These
changes can be observed clinically as an increasing sever-
ity of myopic macular degeneration. Specic lesions partic-
ularly associated with myopic MNV include lacquer cracks,
patchy atrophy, and large myopic conus. Marked thinning of
the choroid and loss of large choroidal vessels suggest that
impaired choroidal perfusion may contribute to the devel-
opment of progressive atrophy in a myopic macula.134–136
Lacquer cracks are present in many eyes with myopic MNV
and have been proposed to be an important predisposing
lesion.69 Lacquer cracks are believed to represent ruptures
in Bruch’s membrane and therefore mechanical stretching
has been proposed as a potential underlying factor.137 Alter-
ations in the cytokine levels have also been described in eyes
with pathologic myopia and may contribute to the patho-
genesis of myopic MNV.138 In eyes with myopic MNV, an
increased VEGF level has been found in the aqueous humor
compared with eyes undergoing cataract surgery.139 There
have also been a suggestion that genetic or hereditary factors
may play a role in the development of myopic MNV.48 Single
nucleotide polymorphism in the complement factor I gene
has been associated with myopic MNV.48
Diagnosis of Myopic MNV. The diagnosis of myopic
MNV is based on clinical ndings. Patients may present with
blurring, scotoma, or distortion of vision. Upon ophthal-
moscopy, features of pathologic myopia such as diffuse
or patchy choroidal atrophy or myopic conus are usually
present.69,140 The myopic MNV typically appears as a at,
small, greyish subretinal lesion beneath, or in close prox-
imity to, the fovea with or without hemorrhage.4,108,131 –133
SD-OCT is a useful screening tool because it is noninvasive
and can be performed rapidly. On SD-OCT, myopic MNV
presents as a highly reective area contiguous above the
RPE (type 2 MNV), usually with minimal subretinal uid
(SRF).
A clinical diagnosis of myopic MNV is usually conrmed
by FA, which demonstrates the presence of the neovascular-
ization, which appears as a well-dened hyperuorescence
in the early phase with leakage in the late phase in a classic
MNV pattern. More recently, OCTA has been shown to detect
myopic MNV noninvasively with high sensitivity and speci-
city.141 –143 The key advantage of OCTA lies in its noninva-
sive nature, which allows repeated scans to be performed at
each visit. As such, some centers now accept the diagnosis
of myopic MNV to be made by either form of angiography.
However, because OCTA is a relatively new technology, users
need to be aware of limitations including various artefacts
and segmentation error.144 A key limitation of OCTA is that
activity cannot be assessed reliably based on OCTA alone.
Interpreting OCTA together with structural OCT is therefore
recommended to fully assess the presence, type, area, and
activity of the MNV.
Assessment of Myopic MNV Activity. An accurate
assessment of activity of MNV is important in determining
when to start treatment and whether further treatment is
no longer warranted. A demonstration of leakage in FA has
been the gold standard for evaluating the activity of MNV.133
However, FA cannot be repeated frequently owing to its inva-
siveness. Increasingly, SD-OCT has overtaken FA as the main
modality for assessing activity, particularly during follow-up.
During the active phase, myopic MNV typically appears as a
dome-shaped, hyperreective elevation above the RPE with
ill-dened borders.145 In addition, a lack of RPE coverage
may also help to differentiate an active MNV from an inactive
or scarred MNV.146 SD-OCT is extremely useful in assessing
features of coexisting myopic tractional maculopathy, which
may be exacerbated by the treatment of MNV by anti-VEGF
therapy.147 Although OCTA may detect the area of neovascu-
larization, it does not reect the level of activity. Flow signal
within the MNV often persists in the scar or atrophic phase
of myopic MNV.
Differential Diagnoses. Differential diagnoses to
consider for myopic MNV include a simple macular bleed
in a highly myopic eye, which is often associated with
lacquer cracks. Using FA, simple macular bleeding appears
as blocked uorescence only and high ow signal is absent
in OCTA. On SD-OCT, simple bleeds appear as a projection
of the hemorrhage along the Henle’s ber layer.148 The late
phase of ICGA is also useful to conrm the absence of MNV
and for detecting coexisting lacquer cracks as linear hypou-
orescences. Several inammatory conditions may present
with signs that can be confused with myopic MNV. The
most common conditions are acute multifocal choroiditis
and panuveitis, as well as punctate inner choroidopathy
with or without secondary MNV.4,133 In myopic individu-
als greater than 50 years of age, neovascular AMD may be
confused with myopic MNV. Polypoidal lesions may arise at
the edge of staphyloma or in eyes with tilted disc syndrome.
Idiopathic MNV is diagnosed by excluding other causes; that
is, it is a diagnosis of exclusion. Finally, serous detachment
with or without neovascularization may occur in eyes with
a dome-shaped maculopathy.
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Treatment of Myopic MNV. The natural history of
myopic MNV is generally poor without treatment.149–151 In a
10-year follow-up study that evaluated the long-term visual
outcome of myopic MNV without treatment, visual acuity
was decreased signicantly at 10 years, with the proportion
of eyes having a visual acuity of 20/200 or less increas-
ing from 29.6% to 88.9% and 96.3% at 5 and 10 years,
respecrtively.150 Therefore, the treatment of myopic MNV is
warranted to prevent progressive visual loss.
Based on the Verteporn in Photodynamic Therapy
(VIP) Study,152 verteporn photodynamic therapy (vPDT)
became the rst approved treatment for myopic MNV as
vPDT treated eyes had better mean best-corrected visual
acuity compared with sham treatment. However, vPDT was
unable to result in a gain in mean visual acuity at 2
years.152 Moreover, vPDT also resulted in a signicantly more
frequent development of chorioretinal atrophy and signi-
cantly worse visual acuity compared with intravitreal anti-
VEGF therapy.153 Therefore in the era of anti-VEGF therapy,
the standard-of-care treatment for myopic MNV is the use
of intravitreal anti-VEGF therapy and vPDT is not recom-
mended.133,154–157
The efcacy and safety of intravitreal anti-VEGF ther-
apy for the treatment of myopic MNV has been evalu-
ated in a number of large, phase III, multicenter, random-
ized, controlled clinical trials, including RADIANCE,158,159
BRILLIANCE,160 MYRROR,161 and SHINY (Table 3 ).162,163
Both the RADIANCE and BRILLIANCE studies evaluated the
use of intravitreal ranibizumab 0.5 mg versus vPDT,158–160
whereas MYRROR and SHINY compared the use of intrav-
itreal aibercept 2 mg and intravitreal conbercept 0.5 mg
versus sham treatment, respectively.161,162 Results from these
randomized controlled trials have all demonstrated conclu-
sively that intravitreal ranibizumab, aibercept, and conber-
cept resulted in signicant mean visual acuity gains in
patients with myopic MNV at their primary end points with
an excellent safety prole. These positive ndings have led
to approval of these anti-VEGF agents for the treatment of
myopic MNV by various health authorities. The off-label
use of intravitreal bevacizumab and ziv-aibercept, which
were originally designed to treat systemic neoplasia, have
also been evaluated for treating myopic MNV and both
agents have resulted in favorable visual acuity gains after
treatment.164–167 However, robust clinical trial data in using
intravitreal bevacizumab or ziv-aibercept for myopic MNV
are lacking. The use of these anti-VEGF agents for myopic
MNV should therefore be limited to patients with a lack of
access to the on-label approved anti-VEGF agents.
In comparison with anti-VEGF treatment for MNV owing
to neovascular AMD, the treatment burden in using anti-
VEGF therapy for myopic MNV is considerably lower. The
recommended treatment strategy in using intravitreal anti-
VEGF therapy for myopic MNV is with a single initial injec-
tion followed by as-needed injection with regular monitor-
ing using SD-OCT to assess for disease activity.155,156 This
strategy is based on the treatment protocols used in the
ranibizumab disease activity-guided arms of the RADIANCE
and BRILLIANCE studies158,160 and in the aibercept arm of
the MYRROR study.161 The effectiveness of this as-needed
treatment approach has been evaluated in various real-world
studies.168,169 The prospective LUMINOUS study demon-
strated in the real-world setting that ranibizumab for myopic
MNV resulted in a mean visual improvement of 9.7 letters
and 1.5 letters at 1 year in treatment-naïve and previously
treated eyes, with a low mean number of ranibizumab injec-
tions of 3.0 and 2.6 injections over 12 months respectively.168
Another large-scale prospective real-world study evaluat-
ing the use of ranibizumab for myopic MNV in Japan also
demonstrated similar ndings, with a mean improvement in
the logMAR best-corrected visual acuity of 0.19 unit and a
low mean number of 2.0 injections over 12 months.169 The
long-term results of the RADIANCE study also conrmed the
favorable visual outcomes and low number of retreatment,
with a mean visual acuity gain of 16.3 letters and 83% of
patients required no further treatment for myopic MNV after
up to 48 months of follow-up.170
Several studies have evaluated the prognostic factors
associated with various treatment outcomes in using anti-
VEGF therapy for myopic MNV.159,171 ,172 A subgroup analysis
of the RADIANCE study showed that ranibizumab treatment
resulted in a signicant visual acuity gain, regardless of the
level of baseline age, ethnicity, lesion area, MNV location,
severity of myopia, axial length, and presence or absence of
SRF.159 It was found that eyes with a larger baseline MNV
lesion area required more injections over the study period
compared with those with a smaller area.159 A post hoc anal-
ysis of eyes in the MYRROR study also showed that the sever-
ity of myopic macular degeneration severity did not seem to
inuence the visual or anatomical outcomes after intravit-
real aibercept treatment for myopic MNV.171 Another study
showed that better visual acuity outcomes after ranibizumab
or bevacizumab treatment might be associated with a shorter
duration of symptoms, better baseline best-corrected visual
acuity, and fundus autouorescence pattern.172
One of the main issues concerning the long-term visual
outcomes of myopic MNV after anti-VEGF therapy is the
development of myopic MNV-related macular atrophy, which
can result in a gradual loss of the visual acuity initially gained
over the long run.157,165 Because the current anti-VEGF ther-
apy for myopic MNV only targets the angiogenesis process,
future research efforts should therefore consider investi-
gating methods to target macular atrophy associated with
myopic MNV to achieve better long-term visual outcomes.
Myopic Traction Maculopathy
Pathogenesis. Myopic traction maculopathy includes
a variety of pathologies secondary to tractional force on
the retina in highly myopic eyes. Epiretinal membrane,
lamellar hole, and many other conditions generating trac-
tion to the retina are included. Among myopic traction
maculopathies, myopic foveoschisis is unique to patholog-
ical myopia and worth to learn as a specic complication.
Because of the space limitation, this article will shed a
light on this pathology. Myopic foveoschisis is referred to
as a posterior retinal detachment without a macular hole
in highly myopic eyes, rst documented as a case report by
Phillips in 1958.173 Almost 40 years later, Takano and Kishi174
found that retinoschisis and foveal detachment are common
in highly myopic eyes in OCT. Myopic foveoschisis is charac-
terized by various foveal architectural abnormalities, includ-
ing a foveal cyst, a lamellar hole, and a foveal detachment.175
Typical OCT images of this disease showing split between
inner and outer retina within posterior staphyloma have led
to the hypothesis that the inner retina is less exible than the
outer retina.176 Factors limiting the inner retinal exibility
include the vitreous cortex adhering to the retina, epiretinal
membranes, internal limiting membrane (ILM), and retinal
vessels. Preretinal membranes are often hard to recognize
in high myopia, however it is present at the microscopic
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FIGURE 11. Typical appearance of myopic foveoschisis. The fundus photograph (inset) shows a slightly elevated retina at the posterior pole,
although it is not clearly identiable. A horizontal OCT scan involving the macula shows retinoschisis in multiple retinal layers and a retinal
detachment at the fovea (asterisk). There is glial tissue bridging the inner and outer layers of the retinoschisis (a so-called column, arrow).
level.177 Any or all of these factors can deteriorate the retinal
exibility.
Retinal detachment arising from a macular hole is a
typical complication in highly myopic eyes. The vitreous
cortex adhering to the retinal surface around the hole causes
tangential traction that generates an inward vector compo-
nent in deep staphyloma in highly myopic eyes, resulting in
a retinal detachment.178
Assessment.
Symptoms. Patients are normally aware of central visual
distortion corresponding with the involved area for
retinoschisis and a relative scotoma for retinal detachment.
Patients may be aware of an absolute scotoma at the center
of the relative scotoma when a macular hole opens within
a retinal detachment. Patients also report visual eld loss
at the involved area if an extensive retinal detachment is
complicated. The Watzke–Allen test is usually negative for
macular hole within the area of retinal detachment.
Fundus and OCT Appearance. Myopic foveoschisis can
be recognized as a slight elevation of the posterior retina in
highly myopic eyes; however, OCT is essential for accurate
diagnosis especially in an atrophic fundus. OCT are essential
not only for complete assessment of the retinal status but
for surgical decision-making. Myopic foveoschisis presents
with retinoschisis in multiple retinal layers (Fig. 11). The
split retinal layers normally have a bridge between them, the
so-called column, which is presumed to be residual Müller
cells.179 ILM separation from the other retinal layers can also
be observed, a so-called ILM detachment (Fig. 12A), and
is a good indicator of the tractional force from the ILM.180
The tent-like peak of the inner retina is observed on the
OCT image. This nding is coincident with retinal vessels
and the so-called retinal microvascular traction, and more
clearly observed after vitreous surgery with ILM peeling
(Fig. 12B).181 This tractional force to the retinal vessels are
also observed as a paravascular microhole in highly myopic
eyes.182 The ellipsoid zone line of the photoreceptors some-
times disappears in the area of the retinal detachment;183
however, the ellipsoid zone line is typically well preserved
in the area of retinoschisis. This nding suggests that the
photoreceptor function is well-preserved in this subtype.
Based on OCT appearance, there are two stages
before macular hole formation associated with retinoschisis
(Fig. 13). The rst stage is the development of the retinoschi-
sis type, in which only retinoschisis is present and not a
retinal detachment (Fig. 13A).176 Several months (sometimes
several years) later, a retinal detachment begins around the
FIGURE 12. Representative OCT images specic high myopia. (A)
an ILM detachment (arrows) shows that the ILM layer is detached
from the other retinal layers owing to inexibility of this layer.
(B) Retinal microfolds (arrow) is associated with the retinal vessels
showing microvascular traction on the retina.
fovea. This stage is the so-called foveal detachment type
(Fig. 13B). After a while, the inner retina above the detach-
ment is stretched and torn. This is how a macular hole
appears as a consequence of retinoschisis with a retinal
detachment.
There are two types of macular holes in highly myopic
eyes. (Fig. 14)184 One is the type with the edge of the hole
thickened with retinal cysts (Fig. 14A). There is no reti-
nal detachment around the hole clinically, and this type
usually does not change for months or years. The other
has surrounding retinoschisis instead of retinal cysts around
the hole (Fig. 14B). This type of macular hole results
from myopic foveoschisis and typically progresses rapidly
because of underlying traction.
Treatment.
Surgical Indications and Results. Investigators have
reported that the vision decreased in 69% of patients, a
macular hole developed in 31% after 3 years of follow-
up,185 and in 50% of patients with retinoschisis a macular
hole or retinal detachment developed after 2 years.186 These
IMI Pathologic Myopia IOVS | Special Issue | Vol. 62 | No. 5 | Article 5 | 18
FIGURE 13. Time course and two distinct subtypes of myopic
foveoschisis of the same patient shown in Fig 11.(A)TheOCT
image at the initial visit showing the retinoschisis type character-
ized by only retinoschisis without a retinal detachment. (B)Oneyear
later, the foveal detachment type occurs, which is characterized by
a small localized retinal detachment (asterisk). The photoreceptors
are separated from the RPE.
FIGURE 14. OCT appearance of two distinct subtypes in highly
myopic macular holes. (A) A macular hole without retinoschisis has
only retinal cysts and is normally stable, whereas (B)amacularhole
with surrounding retinoschisis usually presents a higher likelihood
of consequent retinal detachment.
observations encourage surgery on myopic foveoschisis to
prevent more serious condition, namely, macular holes.
Asymptomatic myopic foveoschisis is not a good surgi-
cal indication because of a signicant number of patients
who suffer surgically induced visual decrease. The chance
of visual improvement after surgery is much greater in cases
with a foveal detachment than retinoschisis alone.187,188 The
chance of visual improvement is substantially smaller if a
macular hole is present preoperatively.187
The mean visual acuity after vitrectomy for macular hole
with retinal detachment was less than 20/200, and the initial
reattachment rate was about 50% to 70% after vitrectomy.189
Once a macular hole develops, the hole is difcult to close
after vitrectomy in highly myopic eyes.190 The macular hole
closure rate with retinoschisis or retinal detachment is about
40% to 50% based on OCT images.191 This difculty probably
arises because of the presence of posterior staphyloma for
which the retina is extremely stretched. In fact, a longer axial
length is generally a poor prognostic factor.192
Vitrectomy. The vitreous plays an important role; there-
fore, creating a posterior vitreous detachment is critical.
To create posterior vitreous separation, a vitreous cutter
and silicone-tipped backush needle with active suction are
normally used. Because multiple components such as vitre-
ous cortex, epiretinal membrane, and ILMs are tightly adher-
ing to the retinal surface,193 a diamond-dusted membrane
scraper facilitates to peel these extremely thin membranes.
Importantly, great care is needed to separate the vitreous at
the macula because of the risk of macular hole formation.
The necessity for ILM peeling remains controversial in
myopic foveoschisis. However, the ILM is separated from the
other retinal layers on OCT images in most eyes,180 suggest-
ing that the rigidity of the ILM plays a signicant role. ILM
peeling also can enhance macular hole closure and remove
any traction on the retina in myopic macular holes with a
retinal detachment and raises the success rate.194 Indocya-
nine green or brilliant blue G are commonly used to stain
the ILM selectively.
It is hypothesized that traumatic damage at the fovea
induced by ILM peeling may cause full-thickness tissue loss
at the fovea in myopic foveoschisis. This idea led to an
attempt for surgeons to leave the foveal ILM. Recently, a
nonfoveal ILM peeling technique was introduced to avoid
macular holes.195 So far, studies reported a signicant
reduction of the incidence of postoperative macular holes;
however, the visual acuity level was similar even with a
higher anatomic success rate.196
Macular holes in eyes with high myopia are much
less likely to close. The inverted ILM ap technique was
applied for highly myopic cases. The visual benet has
not been proven, especially in cases with retinal detach-
ment; however, the macular hole closure rate seems to be
higher than with the conventional ILM peeling technique.197
A study using this inverted ILM ap technique has shown
a signicantly higher success rate than conventional peel-
ing technique.198 Autologous ILM199 or partial thickness or
full-thickness retinal transplants200,201 have been reported
recently to enhance the closure of myopic macular holes.
Because there is no coagulation maneuver around the
macula, it is critical to support the retina for a long time to
recover the integrity between the RPE and photoreceptors.
It is preferred to use long-acting gas tamponade (i.e., peru-
oropropane) to attain a greater anatomic success rate.202 Sili-
cone oil tamponade is also an effective option.203
Postoperative Complications. The opening of a macular
hole occurs in between 10% and 20% of patients who under-
went vitrectomy for myopic foveoschisis.187 Cases in which
ILM peeling was performed in the presence of an extremely
thin, stretched fovea are at risk of developing this complica-
tion. We investigated the incidence of postoperative macular
hole formation and looked for the risk factors.204 Apreoper-
ative discontinuity of the ellipsoid zone line defect seen on
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OCT was a predictor of macular hole development. Other
factors, such as age, gender, and visual acuity, did not affect
the rate of macular hole formation.
The recurrence of a retinal detachment is a major post-
operative complication after vitrectomy for a macular hole
with a retinal detachment. Removing residual vitreous cortex
and epiretinal membranes is critical during a reoperation.
However, it is sometimes difcult to identify the apparent
cause of a re-detachment. In those cases, persistent traction,
such as microvascular traction, might be responsible. Macu-
lar buckling can be considered in these cases. Macular buck-
ling can compensate for any tractional force and showed a
slightly higher initial reattachment rate than vitrectomy in
eyes with a macular hole with a retinal detachment.205,206
Conclusion. With the advancement in ocular imag-
ing technologies, the pathophysiology of myopic macular
diseases has become better understood. A number of inter-
esting ndings have suggested the presence of underlying
traction in highly myopic eyes. The preoperative features
of these pathologies should be evaluated carefully, as these
are important for decision-making and for assessing more
effective surgical procedures in patients with myopic macu-
lar complications.
Dome-Shaped Macula
Denition and Clinical Features. In 2008, a French
team reported a previously undescribed cause of visual
loss in myopic patients that they have called dome-shaped
macula.207 It was characterized by an inward bulge of the
macula within the chorioretinal posterior concavity of the
eye. This macular bulge was hardly detectable on fundus
biomicroscopy, and was mainly visualized by OCT. They
have reported ve unilateral and ve bilateral cases, corre-
sponding with 15 of the 140 myopic eyes in their database.
The degree of refractive changes ranged between –2 D and
–15 D. A visual loss was found in 11 eyes, with a median
visual acuity of 20/50. The authors have also reported vari-
ous degrees of changes in the RPE, including atrophy and
pigment clumping, observed in all eyes. A focal uores-
cein leakage was found in seven eyes, but MNV could be
ruled out in all cases.207 The nding has been conrmed by
other authors in various countries and continents, allowing
a better characterization of the condition. The prevalence of
dome-shaped macula has been estimated at between 10.7%
and 14.6% in the Chinese myopic population.208,209 Most
reported cases are adult patients, but the condition has
also been reported in children and adolescents.210 Mild-to-
moderate myopia is usually reported, but the condition may
also be observed in highly myopic eyes, in emmetropic eyes,
and, less often, in hyperopic eyes.211,212 Subtypes of dome-
shaped macula have been identied depending on the dome
shape: round (Fig. 15) or oval with a vertical (Fig. 16) or hori-
zontal axis (Figs. 17 and 18).213–215 In these studies, horizon-
tal dome-shaped macula accounted for two-thirds to three-
quarters of the cases. It is thus recommended to perform
OCT B-scans along different axes to make the diagnosis of
dome-shaped macula.
Multimodal Imaging. In the rst descriptions, time-
domain OCT was used and it was unable to demonstrate if
the bulge was due to the sclera or not.207,212 OCT has shown
that the sclera was signicantly thicker in the macular area
in myopic eyes with dome-shaped macula compared with
myopic eyes without dome-shaped macula,216 whereas there
was no difference in the scleral thickness outside the macu-
lar area. Thus, the authors have concluded that dome-shaped
macula could be the result of a relatively localized change
in the scleral thickness beneath the macula in their highly
myopic patients. In another study, dome-shaped macula has
been found to correspond to a ridge between two outward
concavities within the posterior staphyloma.217 Recently, 3D-
MRI has allowed the reconstruction of the entire posterior
pole in these eyes and has shown the presence of morpho-
logical changes in the entire posterior pole, with a band-
shaped inward convexity that extended horizontally from
the optic disc through the fovea in most eyes with a horizon-
tal oval dome-shaped macula, and a round inward convexity
of the macular area in most eyes with a round dome-shaped
macula. This MRI study has also shown a high diversity in
convexities that could be the border of a single staphyloma
or multiple staphyloma areas.209 The results from studies
assessing the choroidal thickness are more controversial. A
relatively thick choroid has been reported in some stud-
ies,211,212 whereas other studies have reported a relatively
thin choroid,218 and a similar choroidal thickness has been
found between eyes with and without dome-shaped macula
with the same axial length in a comparative case study.219
However, the mean central choroidal thickness seemed to
be thicker than the choroid in the surrounding staphyloma,
and the mean central choroidal thickness-to-mean perimac-
ular choroidal thickness ratio seemed to be greater in dome-
shaped macula eyes than in other myopic eyes with the same
axial length.220 Thus, a dome-shaped macula seems to be
associated with a relatively thicker sclera and choroid at the
bulge apex.
Pathogenesis. Dome-shaped macula has been
suggested to be a possible compensatory mechanism
in myopic anisometropia, after comparing the two eyes of
a 49-year-old woman with mild myopic anisometropia.221
However, little is known about the occurrence of the condi-
tion, which may be unilateral or bilateral. Ohno-Matsui
et al.222 have observed a peri dome choroidal deepening.
Based on this nding, they have assumed that there might
be a dome-induced inward push of the Bruch’s membrane
at the dome-shaped macula apex, leading to a compression
of the subfoveal choroid. They have also observed Bruch’s
membrane defects in 20% of their studied eyes, suggesting
the presence of Bruch’s membrane strains on the dome’s
slopes.222
Course and Complications of a Dome-shaped
Macula. Long-term studies have shown that the bulge
height increases moderately over time.218,219 This increased
height has been shown to be associated with the extension
of macular atrophic changes.219 The scleral thickness slightly
decreases over time, both in the fovea and in parafoveal
areas.218
The main complication of dome-shaped macula is the
occurrence of a macular serous retinal detachment (SRD).
A macular SRD has been observed in all studies, but its inci-
dence varies from 1.8% of cases in a Japanese cohort to
54% of cases in a French cumulative study.214,220 Adome-
shaped macula is considered a vision-threatening condi-
tion, accounting for most cases of visual loss. A SRD is
more commonly observed when the bulge height is greater
than 350 microns and in eyes with vertical oval dome-
shaped macula.213,223 The pathogenesis of SRD remains
unknown but, it has recently been shown that the submac-
ular choroidal blood ow measured on the OCTA B-
scan is greater in eyes with SRF than in eyes without
SRF.220 Thus, the changes in the choroidal thickness at the
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FIGURE 15. Round dome-shaped macula (DSM). The diagnosis of DSM may be challenging based on fundus examination (A, —). The border
of the staphyloma (yellow line) appears on the wide-eld color photo (C). FA (B) only shows a slight hyperuorescence in the macula.
The DSM is visible on both SD-OCT horizontal (D) and vertical (E) B-scans, which also reveal a serous macular detachment. The choroid is
relatively thick in the subfoveal area. The 3D reconstruction of the macula (F,G) clearly shows the round inward bulge of the macula.
transition between the bulge and the staphyloma observed
by different teams217,224 may correspond with abrupt
changes in choroidal blood ow, leading to outer blood–
retina barrier failure and resulting in the occurrence of SRF.
The spontaneous course of SRF is characterized by major
changes in SRF height that may sometimes result in the
complete resolution of the uid.225 The uid resolution may
also correspond with the development of RPE and outer
retina atrophy in the macula.219 Most studies of SRF associ-
ated with dome-shaped macula have shown a poorer visual
acuity at baseline or during the follow-up219,226 but in one
study, a similar prognosis has been reported between eyes
with and without SRF after a 2-year follow-up.227
Other reported complications include pigment epithe-
lial detachment at the dome apex,228 polypoidal choroidal
vasculopathy,229 and MNV that is more easily detected on
OCTA.228 ,230 A similar response of MNV to ranibizumab has
been reported between eyes with and without dome-shaped
macula in a comparative series231 and in the RADIANCE
trial.232
Differential Diagnosis. Dome-shaped macula and its
complications are very similar to the inferior staphyloma
commonly observed in eyes with tilted disc syndrome.
Indeed, both conditions include a change in the eyeball
curvature233 that may lead to complications such as pigmen-
tary changes, MNV, polypoidal choroidal vasculopathy, and
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FIGURE 16. Vertical dome-shaped macula (DSM). Fundus examination (A) is not contributive. Fundus autouorescence (B) shows a hypoaut-
ouorescence revealing RPE atrophy in the macula, surrounded by hyperautouorescent areas. FA shows an uneven hyperuorescence with
leaking points (C). The difference in curvature is obvious when comparing the OCT horizontal (D) and vertical (E) B-scans, or on the 3D
reconstruction of the posterior pole (F). A SRD is present. MRI shows a macular focal thickening of the eye wall in the right eye (G,arrow).
SRF.234 –236 Similarities between these conditions have been
highlighted in different studies,237–239 and similar hypothe-
ses have been suggested to explain the occurrence of SRF.240
A condition close to dome-shaped macula called ridge-
shaped macula has been recently described in younger
patients (<20 years of age). It is characterized by a macular
elevation in only one meridian across the fovea, observed in
the horizontal direction across the vertical scan of OCT. In
this study, no staphyloma and no Bruch’s membrane defect
were associated.241
Therapeutic Attempts. No treatment for dome-
shaped macula is available currently. Its complications such
as MNV or polypoidal choroidal vasculopathy should be
treated promptly with anti-VEGF agents. Different thera-
pies have been proposed for SRF complicating dome-shaped
macula, including photodynamic therapy,242,243 spirono-
lactone,244 aibercept,245 and topical carbonic anhydrase
inhibitors.246 A transient improvement has been observed
after surgery for epiretinal membrane.247 However, all stud-
ies were case reports or small series and no comparison with
a control group was performed. To date, no effective treat-
ment is available for SRF complicating dome-shaped macula.
Glaucoma
The denition of pathologic myopia as suggested by the
META-PM Study Group describes the morphological abnor-
malities in the macular region of highly myopic eyes, while
coexisting changes in the optic nerve head have been mostly
omitted.3Optic nerve damage, however, relatively often
coexists with maculopathy in eyes with pathologic myopia,
and not quite rarely, it is an additional cause for visual
eld defects and vision impairment.248–250 In population-
based studies of various ethnicities, the increase in the
prevalence of glaucomatous or glaucoma-like optic neuropa-
thy occurred beyond a myopic refractive error of –8 D or an
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FIGURE 17. Horizontal dome-shaped macula (DSM). Fundus photography (A) and fundus autouorescence (B) show a horizontal band of
RPE atrophy. The horizontal (C)andvertical(D) B-scans show a horizontal DSM associated with a shallow SRD.
axial length of more than 26.5 mm.248,250 It suggested that
the prevalence of glaucoma in eyes with low to moderate
levels of myopia or in eyes with an axial length shorter than
26.5 mm was similar to that for emmetropic eyes. The same
values of a myopic refractive error of –8 D or an axial length
of 26.5 mm were the cut-off values for the denition of high
myopia, when an enlargement of the optic disc and para-
papillary regions was used as biomarker for the presence of
high myopia.251,252
For the diagnosis and for a better understanding of glau-
coma in myopic eyes, the appearance of the optic nerve head
is of great importance. The optic nerve head changes can be
divided into those occurring in non–highly myopic eyes, and
those in highly myopic eyes. In non–highly myopic eyes, the
major change associated with axial elongation is the shift-
ing of Bruch’s membrane opening in spatial relationship to
the lamina cribrosa, usually in direction to the macula.253
Considering the optic nerve head being composed of three
layers, the Bruch’s membrane opening as the inner layer,
the choroidal opening as the middle layer, and the opening
in the peripapillary scleral ange with the lamina cribrosa
as the outer layer, the Bruch’s membrane opening shift into
the temporal direction leads to an overhanging of Bruch’s
membrane into the intrapapillary region at the nasal optic
disc margin, and to a lack of Bruch’s membrane in the
temporal parapapillary region. It explains the development
of the parapapillary gamma zone that is usually located in
the temporal to temporal inferior parapapillary region and
that is dened by the absence of Bruch’s membrane.254–258 A
hypothetical cause for the Bruch’s membrane opening shift
backward in direction to the macula may be a production
of new Bruch’s membrane in the equatorial region for axial
elongation in the process of emmetropization and myopiza-
tion.93 As a sequel of the Bruch’s membrane opening
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FIGURE 18. Horizontal dome-shaped macula (DSM). Fundus photography (A) and fundus autouorescence (B) show RPE atrophy in the
macula. The vertical (C) scan shows a horizontally oriented bulge. The sclera is thicker beneath the macula than at its periphery.
shift, occurring usually in the horizontal plane, the optic
disc shape, as assessed on ophthalmoscopy, changes from a
mostly circular shape to a vertical oval form. Another reason
for the ophthalmoscopic change to a vertical optic disc shape
is a perspective distortion of the ophthalmoscopic image
of the optic disc, owing to the lateralization of the optic
disc.259 In non–highly myopic eyes, the size of the optic disc
is not correlated signicantly with the axial length of the
refractive error.260 Correspondingly, the size of the Bruch’s
membrane opening is not related to the axial length in non–
highly myopic eyes.253
In high myopia, the size of the Bruch’s membrane open-
ing and of the optic disc (dened as the region with the
lamina cribrosa as its bottom), and consequently the size of
the lamina cribrosa, increase with longer axial length.253,260
The enlargement of the Bruch’s membrane opening leads
to the development of a circular gamma zone, that is, the
Bruch’s membrane opening enlargement is more marked
than the enlargement of the optic disc (and lamina cribrosa)
is. In association with the enlargement of the optic disc
and lamina cribrosa, the latter gets elongated and thinned.
The lamina cribrosa thinning deceases the distance between
the intraocular compartment with the IOP and the retrobul-
bar compartment with the orbital cerebrospinal uid pres-
sure.261,262 Both pressures form the translaminar cribrosa
pressure difference which is of high importance for glau-
comatous optic neuropathy.263 ,264 The decreased distance
between both compartments leads to a steepening of the
translaminar cribrosa pressure gradient what may be one
of the reasons for the increased glaucoma susceptibil-
ity in highly myopic eyes.248–250 Another reason for the
increased glaucoma susceptibility may be morphological
changes inside of the lamina cribrosa in association with
its stretching.
In the parapapillary region, highly myopic eyes show,
in addition to the gamma zone, the development and
enlargement of the parapapillary delta zone.258 The delta
zone is the equivalent of an elongated (stretched) and
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thinned peripapillary scleral ange (within the gamma
zone).265 The latter is the continuation of the inner portion
of the posterior scleral into the lamina cribrosa, with the
collagen bers of the peripapillary border tissue of the scle-
ral ange crisscrossing at the border of the scleral ange
to the lamina cribrosa.266 The peripapillary scleral ange
forms the anterior border of the orbital cerebrospinal uid
space and is covered only by the peripapillary retinal nerve
ber layer.265 It forms the biomechanical anchor for the
lamina cribrosa.267 The outer portion of the posterior sclera
merges with the optic nerve dura mater, with the circular
arterial circle of Zinn–Haller usually located at the merg-
ing line.265 The arterial circle serves roughly as a ophthal-
moscopic peripheral demarcation line of delta zone.267 The
axial elongation-associated lengthening of the peripapillary
scleral ange thus leads to an increased distance between
the arterial circle and the lamina cribrosa that is nourished
by the branches of the arterial circle. The increased distance
between the arterial circle and the lamina cribrosa may be
a further reason for an increased vulnerability of the optic
nerve head in high myopia.248–250 Fitting with the role of
the peripapillary scleral ange as the biomechanical anchor
of the lamina cribrosa, a clinical study has suggested that a
larger delta zone is associated with a higher prevalence of
glaucomatous optic neuropathy in highly myopic eyes.249 In
a parallel manner, a larger optic disc was correlated with a
higher glaucoma susceptibility, whereas in contrast the size
of gamma zone was not signicantly related to the preva-
lence of glaucoma.249
The importance of the peripapillary border tissues for
the biomechanics of the optic nerve head and the glaucoma
susceptibility has remained elusive so far. The peripapillary
border tissue are differentiated into the peripapillary border
tissue of the scleral ange (Elschnig) and the peripapillary
border tissue of the choroid (Jacoby).266 The rst one is the
continuation of the optic nerve pia mater and, as mentioned
elsewhere in this article, crisscrosses with the bers of the
scleral ange when the ange continues into the lamina
cribrosa. The second one is interposed between the peripap-
illary border tissue of the scleral ange (Elschnig) and the
end of Bruch’s membrane. It forms the border between the
choroidal space and the intrapapillary prelaminar compart-
ment.266 Because the inner shells of the eye, that is, the
uvea, Bruch’s membrane, and the retina, are directly or indi-
rectly connected to the outer ocular shell, that is, the sclera,
only at the scleral spur anteriorly and through the peripapil-
lary choroidal border tissue posteriorly, the latter may have
biomechanical importance for the whole globe in general,
and in particular for the connection between the inner ocular
shells bearing the IOP and the lamina cribrosa. Owing to the
development of the gamma zone, the distance between the
end of Bruch’s membrane and the optic border elongates.266
It leads to a thinning of the peripapillary choroidal border
tissue. It has been discussed that, in some highly myopic
eyes, the choroidal border tissue may rupture, leading to a
free Bruch’s membrane end and a corrugation of Bruch’s
membrane in its vicinity.268 The peripapillary border tissues
may, thus, be of some importance for the increased glau-
coma susceptibility in high myopia.
In agreement with the histologic ndings and with obser-
vations made in population-based investigations, a recent
clinical study revealed that the prevalence of glaucomatous
optic neuropathy increased from approximately 12.0% in
eyes with an axial length of less than 26.5 mm to 28.5%
in eyes with an axial length of 26.5 mm or greater and less
than 28.0 mm, to 32.6% in eyes with an axial length of 28
mm or greater and less than 29 mm, to 36.0% in eyes with an
axial length of 29 mm or greater and less than 30 mm, and
to 42.1% in eyes with an axial length of 30 mm or greater.252
After adjusting for axial length, a higher glaucoma preva-
lence was correlated with a larger delta zone and a larger
optic disc. These ndings indicate that clinically a large optic
disc and/or large delta zone should arouse the suspicion
of a coexisting glaucomatous optic nerve damage in highly
myopic eyes.
From a practical point of view, the detection of glaucoma-
tous optic nerve damage gets more difcult with longer axial
length. Axial elongation leads to a attening of the physio-
logical cup, so that the difference between the height of the
neuroretinal rim and the bottom of the optic cup decreases,
and makes the outlining of the cup/rim border more dif-
cult.269,270 In addition, the pinkish color of the neuroreti-
nal rim is reduced, so that the color contrast between the
rim and cup is decreased. The increased brightness of the
parapapillary region, mainly owing to the gamma zone and
delta zone, decreased the detectability of the retinal nerve
ber layer, and the occurrence of both zones make the
detection of glaucoma-associated beta zone difcult. Also,
highly myopic eyes with glaucomatous optic neuropathy
tend to have an IOP within the normal range, and peri-
metric defects are often unspecic, because they may be
caused by refractive abnormalities, myopic macular changes,
and/or nonglaucomatous optic nerve damage.271 The most
important sign for the presence of glaucomatous optic nerve
damage in highly myopic eyes may be the ophthalmoscopi-
cally detected intrapapillary vessel kinking relatively close to
the disc border so that the inferior–superior–nasal–temporal
rule of the shape of the neuroretinal rim is no longer
fullled.252,260
The detection of glaucoma progression as compared with
the detection of the presence of glaucoma is even more
difcult, in particular in highly myopic eyes. Observation
of changes in the outer visual eld may perhaps help for
the detection of glaucoma progression since most other
psychophysical and morphometric techniques may fail.
Although glaucomatous optic neuropathy in highly
myopic eyes can be dened by the intrapapillary vessel kink-
ing relatively close to the optic disc border, studies are lack-
ing that show the dependence of the effect of this optic
nerve damage on the IOP.271 One may therefore speak of
glaucomatous or glaucoma-like optic neuropathy.252 In addi-
tion, there may be a nonglaucomatous optic nerve damage
in eyes with a large gamma zone on the temporal side.
In a recent population-based study, a higher prevalence of
high myopia or myopic maculopathy was correlated with a
thinner retinal nerve ber layer after exclusion of glauco-
matous eyes.250 It ts with clinical observations that highly
myopic eyes without myopic maculopathy category III or
IV and without a glaucoma-like optic nerve head could
show a deep central scotoma. One may discuss that the
elongated distance between the disc and fovea, caused by
the enlargement of gamma zone, led to a stretching of the
macular retinal ganglion cell axons and to their loss. Such
a mechanism may mimic glaucomatous optic nerve damage.
It has remained unclear whether a myopic traction macu-
lopathy, with the inner limiting membrane lifting the reti-
nal ganglion cell layer and thus relatively shortening the
distance between the retinal ganglion cells and the optic
disc, may be partially protective against such a nonglauco-
matous optic nerve damage in highly myopic eyes. If that
IMI Pathologic Myopia IOVS |SpecialIssue|Vol.62|No.5|Article5|25
concept is valid, it may be taken into account, if surgery of
myopic maculopathy is considered.
In conclusion, the prevalence of glaucomatous optic
neuropathy increases with a longer axial length in highly
myopic eyes and can reach values of more than 50%. Glau-
coma should therefore be ruled in for any highly myopic
eye, in particular in those with a secondarily enlarged optic
disc and a large parapapillary delta zone.
OCT-Based Classication of Myopic Maculopathy
OCT has dramatically improved our understanding of vari-
ous retinal pathologies in last two decades. Recent advances
in OCT technology, including enhanced depth imaging OCT
and swept source OCT, provided the high-resolution images
and highly reliable measurements of choroid in highly
myopic eyes. It has been well-known that the choroid in
high myopia is markedly thin.7,87,112,113 ,136,272–286 All of the
previous studies supported the theory that choroidal atten-
uation may have a great contribution to the pathogene-
sis of myopic maculopathy. In addition, swept source OCT
revealed that patchy atrophy and myopic MNV-related macu-
lar atrophy were not simply an atrophy, but were a macu-
lar Bruch’s membrane defect.117,120,287 Furthermore, OCT
enables to detect new macular lesions which were not iden-
tied by fundus photographs, such as myopic traction macu-
lopathy and dome-shaped macula.
Although the META-PM classication is very useful, the
diagnosis of diffuse atrophy relies solely on its yellow-
ish appearance on ophthalmoscopy. However, the fundus
color may look different according to the degree of fundus
pigmentation among races, which could impact the accu-
rate diagnosis of atrophic lesions. Earlier studies showed
that diffuse atrophy was characterized by an extreme thin-
ning of the choroid (almost absence of the entire choroid) in
OCT images.7,112,113,288 Thus, adding the choroidal thickness
into the classication makes the diagnosis possible, objec-
tive, and more accurate. In addition, other myopic macu-
lar lesions that can only be diagnosed with OCT, such as
myopic traction maculopathy and dome-shaped macula, can
be included in the OCT-based classication of myopic macu-
lopathy (Table 4).
Key OCT Features Determining Pathologic
Myopia.
Extreme Choroidal Thinning. It is well-known that the
choroid in highly myopic eyes is thinner compared with
normal eyes.7,87,112,113 ,136,272 –286 In eyes with pathologic
myopia (dened as myopic eyes equal to or more seri-
ous than diffuse atrophy), the thinning of the choroid is
extreme. In many cases, almost the entire thickness of
the choroid disappears with sporadically remaining large
choroidal vessels.7,288
A marked thinning of the choroid starts temporal to the
optic disc in childhood, as PDCA.30 ThepresenceofPDCA
in children with high myopia is considered to be an indica-
tor for the eventual development of advanced myopic macu-
lopathy in later life.30 On OCT images, PDCA in children
is characterized by a profound and abrupt thinning of the
choroid in the temporal parapapillary region.289 The thin-
ning of the choroid is abrupt and local; thus, it is critically
different from a generalized impairment of choroidal circu-
lation. Subsequently, Yokoi et al.289 also compared the OCT
nding between a hospital-based group of highly myopic
children with PDCA and a population-based control group
of children. It was shown that 76% of the PDCA group
had a choroidal thickness at 2500 μm nasal to the foveola
that was thinner than 60 μm, which was not found in the
control group.289 It indicated that this potential cut-off value
of choroidal thickness may be helpful for the detection and
diagnosis of PDCA in myopic children. With time, the area
of extreme choroidal thinning enlarges and it is recognized
as MDCA.77
Bruch’s Membrane Holes. The defects of Bruch’s
membrane in the macular region were reported in a
histologic study of highly myopic eyes.121 These macular
Bruch’s membrane defects were accompanied by a complete
loss of RPE and choriocapillaris and an almost complete
loss of the outer and middle retinal layers and of the middle-
sized choroidal vascular layer. Later, by using swept source
OCT, Bruch’s membrane defects were found in association
with two different macular lesions specic to pathologic
myopia, that is, with myopic MNV-related macular atrophy
and with patchy atrophy.117 ,120,287 These studies showed
that patchy atrophy and MNV-related macular atrophy
which had previously been considered to be chorioretinal
atrophies were not simply an atrophy, but were a hole of
Bruch’s membrane.
Lacquer cracks are also considered to be breaks of
Bruch’s membrane; however, the defect is difcult to detect
by OCT because the lesions tend to be too narrow. In some
cases, lacquer cracks are observed as discontinuities of the
RPE and increased hypertransmission into the deeper tissue
beyond the RPE.71,127
Other Myopic Lesions (Myopic Traction Maculopathy and
Dome-shaped Macula). Myopic traction maculopathy290,291
and dome-shaped macula207 are the most common complica-
tions related to pathologic myopia. OCT is an indispensable
tool to diagnose both entities, although their presence can be
suspected ophthalmoscopically in a few cases. Myopic trac-
tion maculopathy is generally dened by OCT examinations,
including schisis-like inner retinal uid, schisis-like outer
retina uid, foveal detachment, lamellar or full-thickness
macular hole, and/or macular detachment.292 Dome-shaped
macula was initially described by Gaucher et al. using OCT
as an inward bulge in the macular area within a staphy-
loma, which may be responsible for visual loss in myopic
patients.207 According to the following expanded denition,
it can be diagnosed quantitatively as macular bulge height of
greater than 50 μm in the most convex scan in either vertical
or horizontal scan.217
Establishment of an OCT-Based Classication.
The Choroidal Thickness Prole in Myopic Maculopa-
thy Is Different From Normal Fundus in Highly Myopic
Eyes. There are three studies illustrating the relationship
between the choroidal thickness and different lesions
of myopic maculopathy based on META-PM classication
(Fig. 19).7,113,136 A clinic-based cross-sectional study was
conducted for 1487 highly myopic eyes which were exam-
ined by swept source OCT.7In this study, the subfoveal
choroid was the thickest in the horizontal scan in highly
myopic eyes with normal fundus, which was the same
pattern with non–highly myopic eyes.293 In contrast, in eyes
with myopic maculopathy, that is, being equal or more
severe than a tessellated fundus, the temporal choroid was
the thickest. In the vertical scan, the inferior choroid was the
thinnest in the normal fundus, whereas in eyes with myopic
maculopathy, the subfoveal choroid was the thinnest. This
observation was also conrmed in vertical scan by another
study comparing choroidal thickness in eyes with tessellated
and normal fundus.114 What is more, the distribution pattern
IMI Pathologic Myopia IOVS | Special Issue | Vol. 62 | No. 5 | Article 5 | 26
TABLE 4. OCT-based Classication of Myopic Maculopathy
Stage of MM New Terminology Details Old Terminology
Ia Peripapillary choroidal thinning CT of <56.5 μm at 3000 μm nasal from the fovea, outside of gamma zone. PDCA
Ib Macular choroidal thinning CT of <62 μm subfoveally. MDCA
Plus sign Linear Bruch’s membrane defects Yellowish linear lesions. Discontinuities of the RPE and increased
hypertransmission into deeper tissues beyond the RPE in OCT image.
Lacquer cracks
II Extrafoveal Bruch’s membrane defects Well-dened, grayish white, round lesion(s) in the macular, extrafoveal area. The
Bruch’s membrane defect is usually surrounded by a slightly wider RPE defect
the size and shape of which determines the ophthalmoscopic size and shape of
the lesion. In the region of the Bruch’s membrane defect, the outer retinal layer,
the RPE, the choriocapillaris and most of the medium-sized choroidal vessel layer
are absent, and a medium-sized or large choroidal vessel may occasionally be
present. The middle and inner retinal layers, more or less thinned, are in direct
contact with the inner scleral surface
Patchy atrophy
Plus sign Myopic CNV CNV occurring in eyes with at least peripapillary or macular choroidal thinning CNV
III Foveal Bruch’s membrane defect The OCT-based histology is similar to the histology of extrafoveal Bruch’s
membrane defects.
Macular atrophy
IIIb Foveal Bruch’s membrane defect,
CNV-related
Well-dened, round lesion including the fovea and expanding centrifugally around
the fovea. The edges of the macular Bruch’s membrane defect are often upturned.
In the center, remnants of Bruch’s membrane can be present, folded up in the
process of the RPE-associated scar formation.
CNV-MA
IIIa Foveal Bruch’s membrane defects,
patchy related
Develops outside of the foveal area and enlarges in direction to the fovea or
coalesces with other extrafoveal Bruch’s membrane defects in direction to the
fovea.
Patchy MA
Plus sign Macular traction maculopathy Schisis-like inner retinal splitting, schisis-like outer retina splitting, foveal
detachment, lamellar or full-thickness macular hole and/or macular detachment.
—
Plus sign Dome-shaped macula and macular
ridge
Dome-like, inward bulge of the RPE line in all meridians with a height of >50 um
above a base line connecting the RPE lines on both side outside the dome.Macula
ridge: Inward bulge of the RPE line in either horizontal or vertical scan with a
height of >50 um above a base line connecting the RPE lines.
CT, choroidal thickness; CNV, choroidal neovascularization; CNV-MA=choroidal neovascularization-related macular atrophy; Patchy MA, patchy atrophy-related macular atrophy.
IMI Pathologic Myopia IOVS |SpecialIssue|Vol.62|No.5|Article5|27
FIGURE 19. Graph showing the pattern of distribution of choroidal thickness (CT) at different locations for each type of myopic maculopathy
in the horizontal (A) and in the vertical direction (B). The CT was measured at the subfoveal region and at 3 mm nasal, temporal, superior,
and inferior to the fovea. MA =macular atrophy.
FIGURE 20. The subfoveal CT (mean with standard deviation) in each myopic maculopathy are shown. The CT decreased signicantly from
normal fundus to tessellated fundus, to PDCA, and to MDCA in all locations. There is no signicant difference in choroidal thickness between
eyes with MDCA and patchy atrophy. *P<0.05. CT =choroidal thickness; MA =macular atrophy; NS =not signicant.
of choroidal thickness in eyes with a tessellation was simi-
lar to the eyes with other myopic maculopathy in greater
categories, such as, PDCA, MDCA, and patchy atrophy. This
nding suggested that the tessellation might be the rst sign
for myopic eyes to become pathologic.
Progressive Choroidal Thinning From Tessellation to
PDCA, and to MDCA, But Not Thereafter. It was shown
that the mean subfoveal choroidal thickness in eyes with
a normal fundus was 274.5 μm, tessellated fundus was
129.1 μm, PDCA was 84.6 μm, MDCA was 50.2 μm, patchy
atrophy was 48.6 μm, MNV-related macular atrophy was
27.3 μm, and patchy-related macular atrophy was 3.5 μm
(Fig. 20).7The choroidal thickness in all locations decreased
from normal fundus to tessellated fundus, to PDCA, and to
MDCA, as the severity of the myopic maculopathy increased.
But there was no signicant difference in choroidal thick-
ness between eyes with MDCA and patchy atrophy in all
locations except for those at nasally. Because the other
two studies did not differentiate MDCA from PDCA, it is
reasonable that the choroidal thickness in diffuse atrophy,
which might include both PDCA and MDCA, was signi-
cantly thicker than those eyes with patchy atrophy.113,136
The subfoveal choroidal thickness of eyes with macu-
lar atrophy (both MNV related and patchy related or
either of them) was signicantly thinner than that in any
other groups.7The subfoveal choroidal thickness in eyes
with patchy-related macular atrophy was even thinner than
choroidal thickness in MNV-related macular atrophy. It was
noted that there was no difference among MNV-related
macular atrophy, MDCA, and patchy atrophy in choroidal
thickness at temporal, nasal, superior, and inferior locations.
The result from other two studies also indicated that the
choroidal thickness was negatively correlated with sever-
ity of myopic maculopathy.113,136 A high myopia clinic-
based study from Zhongshan Ophthalmic Center113 inves-
tigated the choroidal thickness in a large population. In this
study, the median subfoveal choroidal thickness was 165 μm
in normal fundus (C0), 80 μm in tessellated fundus (C1),
49 μm in diffuse atrophy (C2), 35 in patchy atrophy (C3),
and 6.5 μm in macular atrophy (C4). It also showed that
IMI Pathologic Myopia IOVS | Special Issue | Vol. 62 | No. 5 | Article 5 | 28
the subfoveal choroidal thickness became signicantly thin-
ner with the increasing severity of maculopathy in C0 to
C4 but the eyes with C3 to C4 shared similar parafoveal
choroidal thickness, leading to the conclusion that C4 was
not the result of progression from C3 which was consistent
with long-term follow-up study by Fang et al.77
Cut-Off Value of Choroidal Thickness for Identifying
PDCA and MDCA. Fang et al.7used a receiver operating
characteristic curve and Youden’s index to determine the
optimal cut-off choroidal thickness value of 56.5 μm in nasal
choroidal thickness (3000 μm from fovea) for the diagno-
sis of PDCA. The performance is particularly excellent in
the less than 20 years of age group with a high sensitiv-
ity of 90% and a good specicity of 88%. The area under
curve of choroidal thickness in each location became lower
in the older age group. For the 60 to 79 years group,
only the subfoveal choroidal thickness can be used for
diagnosis.
The nasal choroidal thickness is not able to differenti-
ate eyes with MDCA from those with PDCA. Instead, the
choroidal thickness cut-off value of 62 μm at the subfovea
(sensitivity, 71%; specicity, 72%), 73 μm at the temporal
location (sensitivity, 67%; specicity, 90%), 83 μm at the
superior location (sensitivity, 67%;specicity, 80%), 84.5 μm
at the inferior location (sensitivity, 81%; specicity, 65%)
can be used to dene the eyes with MDCA.7Although the
area under curve of subfoveal choroidal thickness is not the
largest among all the locations, the cut-off value is still based
on the subfoveal choroidal thickness, because the measure-
ment at the fovea is easier to take and more accurate than
the parafoveal points.
Summary of OCT-Based Classication of Myopic Macu-
lopathy. Combining the hallmarks of myopic maculopathy
in pathologic myopia, a new classication based on OCT
ndings has been proposed. In this new system, diffuse
choroidal atrophy, for PDCA and MDCA, is suggested to
be called “peripapillary choroidal thinning” and “macular
choroidal thinning” (Table 3). Based on these results, the
cut-off value of choroidal thickness as a diagnostic tool for
diffuse atrophy has been added to this system. That is, peri-
papillary choroidal thinning is dened as a choroidal thick-
ness of less than 56.5 μm at 3000 μm nasal from the fovea
and macular choroidal thinning is dened as a choroidal
thickness of less than 62 μm at the subfovea. Patchy atrophy
and MNV-related macular atrophy are not simply owing to
atrophy,but to holes in Bruch’s membrane. Patchy atrophy is
seen as a well-dened, grayish white lesion by fundus photo-
graph seldomly involving the central fovea which is appro-
priate called as “extrafoveal Bruch’s membrane defects”
by OCT denition. In contrast, foveal Bruch’s membrane
defects is named for macular atrophy, that is, category 4
in the META-PM classication, for both MNV-related and
patchy-related disease. In addition, myopic traction macu-
lopathy and dome-shaped macula both as potential vision-
threatening macular complications that only can be detected
on OCT are also included in the OCT-based classication of
myopic maculopathy.
Further studies are needed to validate whether the cut-
off values of choroidal thickness from a single high myopia
clinic can work well in clinical practice. More studies should
investigate the role of the choroid in high myopia, not only
by a measurement of the thickness, but also by examin-
ing other parameters, such as choroidal blood ow and the
morphologic and vascular features of the choroid. Longitu-
dinal studies on choroidal change will help us to depict a
real-world picture of the choroidal changes in patients with
high myopia.
FUTURE PERSPECTIVES
Diagnostic methods as well as therapies have been greatly
advancing for pathologic myopia. In particular, anti-VEGF
therapies as well as vitreoretinal surgeries have improved the
anatomical and visual outcomes of myopic MNV and myopic
traction maculopathy. However, therapeutic approaches are
not sufcient for other complications, such as choroidal atro-
phies and optic nerve damage. The diagnosis of glaucoma is
difcult in eyes with pathologic myopia, because of a defor-
mity of the optic disc appearance and the scotoma caused
by myopic macular lesions and a large gamma zone. How to
diagnose glaucoma in its early stage of patients with patho-
logic myopia needs to be established in the future, because
the optic nerve damage is considered an important cause of
blindness in pathologic myopia.
Posterior staphyloma causes a deformity of the area
containing visually important tissues, namely, macula and
the optic nerve. It is in contrast with most of the axial elon-
gation in myopic eyes in general occurs in the equator of
the eye. Thus, a formation of posterior staphyloma mechan-
ically damages these nerve tissues. Before developing irre-
versible blinding complications, approaches to prevent and
treat staphylomas are expected.
Finally, clarifying which genes are responsible for patho-
logic myopia (not high myopia) is important. With this infor-
mation, it will nally become clear whether or not pathologic
myopia is different from myopia in general. In addition,iden-
tifying children who will become pathologically myopic will
be possible.
Based on the consistent denition of pathologic myopia
and the objective detection of its major feature—posterior
staphyloma—future studies regarding the global prevalence
of pathologic myopia and its impact on vision and quality of
life294 should be undertaken.
Acknowledgments
The authors thank Monica Jong for facilitation of the process.
Supported by the International Myopia Institute. The publica-
tion costs of the International Myopia Institute reports were
supported by donations from the Brien Holden Vision Institute,
Carl Zeiss Vision, CooperVision, Essilor, and Alcon.
Disclosure: K. Ohno-Matsui, Santen (C), Nevakar (C); P. - C . W u ,
None; K. Yamashiro,None;K. Vutipongsatorn,None;Y. Fan g ,
None; C.M.G. Cheung, Novartis, Bayer, Roche, Topcon, Zeiss,
Allergan, and Boehringer Ingelheim (F, C); T.Y.Y. L a i ,Bayer
Healthcare (C, F, R), Boehringer Ingelheim (C), Roche (C, F, R),
Novartis (C, F, R); Y. Ikuno, Novartis Pharma (R); S.Y. Cohen,
Allergan (C), Bayer (C), Novartis (C), Thea (C), Roche (C); A.
Gaudric,None;J.B. Jonas, Europäische Patentanmeldung 16
720 043.5 and Patent application US 2019 0085065 A1 „Agents
for use in the therapeutic or prophylactic treatment of myopia
or hyperopia” (P)
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