- Email: [email protected]
Updates of pathologic myopia
Accepted Manuscript Updates of Pathologic Myopia Kyoko Ohno-Matsui, MD., Timothy Y.Y. Lai, Chi-Chun Lai, Chiu Ming Gemmy Cheung PII:
S1350-9462(15)30003-3
DOI:
10.1016/j.preteyeres.2015.12.001
Reference:
JPRR 615
To appear in:
Progress in Retinal and Eye Research
Received Date: 15 November 2015 Revised Date:
28 December 2015
Accepted Date: 30 December 2015
Please cite this article as: Ohno-Matsui, K., Lai, T.Y.Y., Lai, C.-C., Cheung, C.M.G., Updates of Pathologic Myopia, Progress in Retinal and Eye Research (2016), doi: 10.1016/ j.preteyeres.2015.12.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Updates of Pathologic Myopia Kyoko Ohno-Matsui1, Timothy Y. Y. Lai2, Chi-Chun Lai3, Chiu Ming Gemmy Cheung4
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1: Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 1138510, Japan
2: Department of Ophthalmology & Visual Sciences, The Chinese University of
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Hong Kong, Hong Kong Eye Hospital, 147K Argyle Street, Kowloon, HONG KONG
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3:Department of Ophthalmology, Chang Gung Memorial Hospital, Chang Gung University. No.5, Fuxing Street, Guishan Dist., Taoyuan City 33305, Taiwan 4: Singapore National Eye Center, 11 Third Hospital Avenue, Singapore
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Corresponding to; Kyoko Ohno-Matsui, MD.
Department of Ophthalmology
and Visual Science, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku,
Tokyo
1138510,
Japan.
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+81-3-3818-7188, email; [email protected]
Tel;
+81-3-5803-5302,
Fax;
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Abstract Complications from pathologic myopia are a major cause of visual impairment and blindness, especially in east Asia.
The eyes with pathologic myopia may
macula, peripheral retina and the optic nerve.
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develop loss of the best-corrected vision due to various pathologies in the
Despite its importance, the definition of pathologic myopia has been inconsistent.
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The refractive error or axial length alone often does not adequately reflect the ‘pathologic myopia’. Posterior staphyloma, which is a hallmark lesion of
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pathologic myopia, can occur also in non-highly myopic eyes.
Recently a
revised classification system for myopic maculopathy has been proposed to standardize the definition among epidemiological studies. In this META-PM (meta analyses of pathologic myopia) study classification, pathologic myopia
than diffuse atrophy.
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was defined as the eyes having chorioretinal atrophy equal to or more severe
In addition, the advent of new imaging technologies such as optical coherence
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tomography (OCT) and three dimensional magnetic resonance imaging (3D MRI) has enabled the detailed observation of various pathologies specific to New therapeutic approaches including intravitreal
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pathologic myopia.
injections of anti-vascular endothelial growth factor agents and the advance of vitreoretinal surgeries have greatly improved the prognosis of patients with pathologic myopia. The purpose of this review article is to provide an update on topics related to the field of pathologic myopia, and to outline the remaining issues which need to be solved in the future.
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Keywords Pathologic myopia; myopic maculopathy; posterior staphyloma; optic nerve
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changes; choroidal neovascularization
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1.
Introduction
2. 3.
Epidemiology Complications of Pathologic Myopia Posterior staphyloma Definition of staphyloma
3.1. 3.1.1.
New classification using three-dimensional magnetic resonance imaging (3D MRI) and wide-field fundus imaging Incidence of staphyloma and related factors
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3.1.2.
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Table of Contents
3.1.4. 3.1.5. 3.2. 3.2.1. a. b. c.
3.3. 3.3.1. 3.3.2. 3.3.3.
maculopathy Myopic CNV Prevalence, incidence and bilaterality Diagnosis of myopic CNV based on imaging Differential diagnoses
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3.2.2. 3.2.3.
Lacquer cracks (Plus sign) Myopic CNV (Plus sign) Natural Progression of each lesion Pathogenesis and Potential Therapy for myopic
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d. e.
Macular complications of eyes with staphylomas Therapies targeting staphylomas Myopic Maculopathy Classification in META-PM study Details of each lesion Diffuse Chorioretinal atrophy (Category 2) Patchy Chorioretinal atrophy (Category 3)
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3.1.3.
a.
b. c. d. e.
3.3.4. 3.3.5.
Subretinal bleeding due to new lacquer crack formation Punctate inner choroidopathy
Idiopathic CNV Serous detachment in dome-shaped macula Polyps at edge of tilted disc syndrome Natural prognosis and development of CNV-related macular atrophy Anti-VEGF therapy for myopic CNV
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Diagnostic and treatment flow-charts for myopic CNV Other fundus lesions in the posterior fundus Dome-shaped Macula Radial ascending tracts emanating from staphyloma
3.4.3. 3.5.
edge Chorioretinal folds from staphyloma edge Surgical conditions Macular Hole, Macular Hole Retinal Detachment
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3.3.6. 3.4. 3.4.1. 3.4.2.
3.5.1.
Myopic traction maculopathy (MTM) Surgical techniques to treat MTM Surgical outcome of MTM Peripheral retinal degenerative changes
3.5.3.1. 3.5.3.2. 3.6.
Lattice degeneration, retinal holes, Retinal tears Rhegmatogenous retinal detachment Optic Disc Changes and glaucoma in Pathologic Myopia Histological changes of papillary and peripapillary
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3.6.1.
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3.5.2. 3.5.2.1. 3.5.2.2. 3.5.3.
4. 5. 6.
Current challenges and direction of future research Acknowledgements References
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3.6.2.
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3.6.3.
region Structural abnormalities detected by optical coherence tomography (OCT) Visual field (VF) changes in highly myopic eyes
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Introduction Complications from pathologic myopia are a major cause of visual impairment and
blindness, especially in east Asia (Chan et al., 2015; Foster and Jiang, 2014; Morgan et al., 2012; Wong et al., 2014).
The eyes with pathologic myopia may develop visual loss due to
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various pathologies in the macula, peripheral retina and the optic nerve (Morgan et al., 2012). The deformity of the globe including posterior staphyloma may facilitate the development of these pathologies.
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The definition of pathologic myopia has been inconsistent. The term “pathologic myopia” was originally described as myopia accompanied by characteristic degenerative
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changes in the sclera, choroid, and retinal pigment epithelium, with compromised visual function (Morgan et al., 2012; Tokoro, 1988). Excessive elongation of the globe and posterior staphyloma are believed to be important factors in the development of these degenerative changes in pathologic myopia (Moriyama et al., 2011b).
However, the
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refractive error or axial length alone often does not adequately reflect the ‘pathologic myopia’. Posterior staphyloma, which is a hallmark lesion of pathologic myopia, can occur also in non-highly myopic eyes (Curtin, 1977, 1985; Wang et al., 2015a). Recently an international
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panel of researchers in myopia reviewed previous published studies and classifications and proposed a simplified, uniform classification system for pathologic myopia for use in future
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studies (Ohno-Matsui et al., 2015b).
In this META-PM (meta analyses of pathologic
myopia) study classification, pathologic myopia was defined as the eyes having chorioretinal atrophy equal to or more severe than diffuse atrophy. Over the past two decades, advances in imaging technologies such as optical coherence tomography (OCT), wide-field imaging, and three-dimensional magnetic resonance imaging (MRI) have greatly enhanced our understanding in the ocular complications associated with high myopia. OCT enables the high-resolution in vivo assessment of the optic nerve and macula and new disease entities such as myopic traction
ACCEPTED MANUSCRIPT maculopathy (Panozzo and Mercenti, 2004) and dome-shaped macula (Gaudric, 2008) have been described.
New treatment technologies such as anti-angiogenesis therapy and small
gauge vitrectomy have also enhanced the treatment outcomes of some complications associated with high myopia.
However, despite these advancements, considerable
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challenges still exist in the management of irreversible vision loss in high myopia due to macular or optic nerve atrophy. This review will highlight our current understanding of the various ocular complications in high myopia as well as our current limitations in managing
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these conditions. To-date there is no proven method to prevent or retard the development
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or progression of these complications.
Epidemiology
The prevalence of pathologic myopia has been evaluated in several population studies, although some variations in the definition of pathologic myopia exist between
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studies (Asakuma et al., 2012; Gao et al., 2011; Hsu et al., 2004; Hu, 1987; Liang et al., 2008; Liu et al., 2010; Pan et al., 2013; Vongphanit et al., 2002b; Wong et al., 2014). Recently, these publications have been evaluated and summarized in an evidence-based
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systematic review (Wong et al., 2014).
Prevalence of pathologic myopia from 4 studies in
Asian populations ranged from 0.9% to 3.1%, while the Blue Mountains Eye Study (BMES)
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reported 1.2% in an Australian population (Vongphanit et al., 2002b). Furthermore, pathologic myopia has been reported as the primary cause of blindness or low vision in 7% in European populations (Cedrone et al., 2006; Klaver et al., 1998) and in 12-27% in Asian populations (Iwase et al., 2006; Xu et al., 2006; Yamada et al., 2010).
The impact of
pathologic myopia on vision and vision-specific quality of life is further amplified by the high likelihood of bilateral involvement in young individuals (Verkicharla et al., 2015).
Among the
pathologic changes, current treatment is only available for selected lesions, such as
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ACCEPTED MANUSCRIPT choroidal neovascularization and tractional maculopathy.
No effective restorative treatment
is currently available for eyes with progressive deterioration due to development of chorioretinal atrophy or optic neuropathy. In addition to the severity of myopia, increasing age is also an important risk factor
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for the development of pathologic changes in high myopia (Chen et al., 2012c; Shih et al., 2006; Silva, 2012; Verkicharla et al., 2015). The prevalence of myopic maculopathy has been shown to be low in children (Kobayashi et al., 2005; Samarawickrama et al., 2011), but
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increases (Chang et al., 2013) with age. In teenage children with high myopia, myopic maculopathy was rare, and the most common changes noted were tilted disc (37%) and
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β-peripapillary atrophy (39%) (Samarawickrama et al., 2011).
In an adult population aged
40 years and above with high myopia, both the prevalence and severity of maculopathy were much higher (staphyloma 23%, chorioretinal atrophy 19.3%) (Chang et al., 2013). Furthermore, continued elongation of the globe and progression of maculopathy lesions with
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time have been demonstrated in follow-up studies (Hayashi et al., 2010; Saka et al., 2010). Hayashi et al. reported that 40% of the highly myopic eyes had progression of myopic maculopathy during a mean follow-up of 12.7 years (Hayashi et al., 2010).
In the BMES,
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17.5% of eyes had progression of myopic retinopathy over a 5-year follow up period (Vongphanit et al., 2002b). The changes noted included new or expansion of pre-existing
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chorioretinal atrophy, and new or increased numbers of lacquer cracks. Similar progression patterns have also been noted in longitudinal follow up in the Beijing Eye Study (Liu et al., 2010).
In another study with 10 year follow-up, Shih et al. demonstrated that apart from
development of choroidal neovascularization or macular atrophy, fusion of areas with other patchy atrophy caused significant decrease in vision (Shih et al., 2006).
The incidence and
type of progression have also been shown to be influenced by the types of fundus lesions. Detailed evaluation of the longitudinal progression patterns of each lesion subtype suggest
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ACCEPTED MANUSCRIPT that eyes that have advanced past the tessellated fundus stage appear to progress more quickly (Hayashi et al., 2010) (see section on Myopic Maculopathy). The prevalence rates of pathologic myopia mirror the prevalence rates of high myopia (Verkicharla et al., 2015). The prevalence of myopia and high myopia has been
2012; Vitale et al., 2009).
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increasing rapidly, possibly due to changes in environmental and lifestyle factors (Pan et al., Therefore, the prevalence of vision threatening complications
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due to pathologic myopia is likely to increase dramatically over the next few decades.
Pathologic myopia has been reported as one of the most common causes of
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blindness both from population surveys and from blind registry data. Analysis of blind registry data from several countries estimated pathologic myopia as the cause of blindness in 6.0-9.1% of white populations (Avisar et al., 2006; Ghafour et al., 1983; Krumpaszky et al., 1999; Macdonald, 1965) and much higher (26.1%) in Chinese (Wu et al., 2011).
The
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annual incidence of blindness attributable to pathologic myopia in the general population can further be estimated to range from 0.77 per 100,000 for Germany (Krumpaszky et al., 1999) to 2.1-4.3 per 100,000 for Israel (Avisar et al., 2006). The Beijing Eye Study estimated a
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0.05% incidence of pathologic myopia from the 5-year follow-up data (Liu et al., 2010). It is clear that pathologic myopia is a major public health problem worldwide and its
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disease burden likely to increase. condition.
Significant challenges remain in the management of this
First, in order to facilitate further studies and comparison between different
populations, a standardized set of definitions for the classification of myopic maculopathy and, in turn, pathologic myopia is needed.
Recently a revised classification system for
myopic maculopathy based on detailed definitions of individual fundus signs has been proposed in order to address this issue (see Myopic Maculopathy section for details) (Ohno-Matsui et al., 2015b).
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Second, it is now clear that pathologic myopia is not a static
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Yet, the risk factors for progression
remain poorly understood. There is thus an urgent need to better understand the underlying pathologic processes, such as mechanical stress, degeneration and ischemia with aging, and whether these factors may be modifiable.
Finally, despite recent advances
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in the treatment of choroidal neovascularization with anti-vascular endothelial growth factor (Ikuno et al., 2015; Sakaguchi et al., 2007; Wolf et al., 2014; Wong et al., 2015), and the ability to operate on tractional myopic maculopathy with increasingly sophisticated surgery,
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most complications of pathologic myopia, such as macular atrophy, chorioretinal atrophy and optic neuropathy remain untreatable. Studies on the long-term outcome of CNV and
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tractional myopic maculopathy are also limited. Nonetheless, promising novel therapies, including pharmacological (Chia et al., 2012; Chia et al., 2014; Chia et al., 2015) and surgical approaches, aiming to reduce the incidence and severity of myopia are on the horizon.
It remains to be seen whether such measures will translate into a reduction in the
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incidence and severity of pathologic myopia and the associated devastating impact on vision.
Complications of Pathologic Myopia
3.1.
Posterior staphyloma
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A posterior staphyloma is an outpouching of a limited area of the posterior segment of the eye, which is a representative deformity of eyes with pathologic myopia. Posterior staphyloma is a reliable indicator for pathologic myopia. However, there has been some confusion about how staphylomas should be regarded. In some earlier studies, a posterior staphyloma was regarded as one of the lesions of myopic retinopathy or myopic maculopathy (Avila et al., 1984; Chang et al., 2013; Chen et al., 2012b; Gao et al., 2011; Vongphanit et al., 2002a).
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However, a staphyloma can also be considered to be a cause of
ACCEPTED MANUSCRIPT myopic maculopathy and not a lesion of myopic maculopathy itself. The sclera protects the central nervous tissues, e.g., the neural retina and the optic nerve from mechanical insults. Thus, it is reasonable that a deformity of the eye by a staphyloma may result in a mechanical damage of the retina and optic nerve.
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Nevertheless, the best way to detect the presence of a staphyloma has not been determined. Earlier studies used conventional fundus photography (Chang et al., 2013; Chen et al., 2012a; Gao et al., 2011; Samarawickrama et al., 2011; Vongphanit et al., 2002b),
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ophthalmoscopy and fundus drawings (Curtin, 1977), ultrasonography (Hsiang et al., 2008; Steidl and Pruett, 1997), OCT (Ikuno and Tano, 2009; Lim et al., 2014; Miyake et al., 2014), OCT is a useful tool to show the shape of the sclera,
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or a combination of these methods.
and Ohno-Matsui et al. (Ohno-Matsui et al., 2012a) used swept-source OCT to determine the entire thickness of the sclera and the contour of the sclera in many highly myopic eyes. However, the scan length of currently available OCT instruments is not long enough to cover
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the entire extent of a wide staphyloma. Computed tomography (Anderson et al., 1983; Osborne and Foulks, 1984; Smith and Castillo, 1994; Swayne et al., 1984) and MRI (Mafee et al., 2005; Malhotra et al., 2011) have been reported to be able to obtain images of However, these studies also used 2-dimensional images and did not show
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staphylomas.
the entire shape of the staphylomas.
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Recently, new imaging modalities that can obtain images of the entire globe, e.g., 3D MRI (Moriyama et al., 2011a; Moriyama et al., 2012; Ohno-Matsui, 2014a) or ultra-wide fundus imaging (e.g. Optos) have become available.
By using a combination of 3D MRI
and Optos, Ohno-Matsui (Ohno-Matsui, 2014a) examined the prevalence and types of posterior staphylomas. These advances in ocular imaging have made the objective and quantitative evaluations of posterior staphylomas possible.
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ACCEPTED MANUSCRIPT Thus, this section covers many aspects of posterior staphylomas including the historical background to future therapies targeting the slowing or halting of the progression
3.1.1. Definition of staphyloma (Figure 1)
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of staphylomas.
A uniformly accepted definition of a posterior staphyloma has not been made.
It is
still common for clinicians and researchers to refer to abnormal structures in the posterior
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pole of myopic eyes, even those that do not involve an outpouching, as being staphylomas. Spaide (Spaide, 2013) made a clear definition of a staphyloma as “an outpouching of the
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wall of the eye that has a radius of curvature that is less than the surrounding curvature of the wall of the eye” (Figures 1A to 1C) in Pathologic Myopia. In addition, our clinical experience suggests that peripapillary and nasal staphylomas do not have a distinct and abrupt change in the curvature from the surrounding curvature of the wall of the eye in many Instead, the shape of eyes with peripapillary and nasal staphylomas appear to be
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cases.
nasally distorted (Ohno-Matsui et al., 2012a). Thus, the nasally distorted type of globe was added to the definition of staphylomas (Figure 1D).
It is expected that OCT will be useful in
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detecting the posterior scleral curvature in eyes with peripapillary staphylomas, based on an ongoing study in the High Myopia clinic of the Tokyo Medical and Dental University.
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Once a staphyloma is formed, the area of the posterior fundus including the macula and optic nerve is greatly elongated and the AXL could be doubled. Thus, it can be imagined that the mechanical stretching is increased considerably in highly myopic eyes with a staphyloma compared to those without it.
3.1.2. Classification using three-dimensional magnetic resonance imaging (3D MRI) and wide-field fundus imaging
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ACCEPTED MANUSCRIPT Based on ophthalmoscopic observation and fundus drawing, Curtin (Curtin, 1977) first classified posterior staphylomas in eyes with pathologic myopia into 10 different types based on ophthalmoscopy and fundus drawings.
Types I to V were considered primary
staphylomas, and types VI to X were combined staphylomas.
Curtin (Curtin, 1977) also
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described five other varieties of compound posterior staphylomas with each essentially a variation of the primary Type I. These types of staphylomas can consist of a combination of Type I with another type such as Type II or Type III.
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Recently, Moriyama and Ohno-Matsui used 3D MRI to analyze the entire shape of the eye (Moriyama et al., 2011a; Moriyama et al., 2012). The 3D MRI technique was found
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to be well suited for examining the eye shape over a wide area that can encompass even a large posterior staphyloma. This technique also allows a view of a staphyloma from any angle. They used 3D MRI to determine the presence and types of staphylomas, and proposed a simple classification of staphylomas based on the 3D MRI results (Moriyama et
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al., 2011a; Moriyama et al., 2012). To make the classification useful for clinicians, Ohno-Matsui (Ohno-Matsui, 2014a) correlated the 3D MRI findings with the funduscopic features seen by ophthalmoscopy.
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A relatively new imaging technology, the Optos Optomap Panoramic 200A imaging system (Optos, PLC, Dunfermline, Scotland), was used to obtain noncontact, non-mydriatic,
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panoramic images of the fundus.
Ultra-widefield fundus images of 200° of the retina were
recorded. In these images, the peripheral retina is photographed simultaneously without the need for refixation by the patient. Ohno-Matsui (Ohno-Matsui, 2014b) then correlated the shapes of the staphyloma detected by 3D MRI with the abnormal findings seen in the Optos images, and constructed a classification that can be used to analyze the Optos images obtained under conventional clinical conditions.
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Her classification is a slight modification of
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Briefly, the basic principles are as follows:
Only the contour of the outermost border of a posterior staphyloma was analyzed.
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Combined staphylomas in Curtin's classification (Curtin, 1977) are characterized by the presence of irregularities within the staphylomatous area. This resulted in the Curtin types VI to X being placed into the Type I category.
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Type I → wide, macular staphyloma
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The staphyloma type is renamed according to its location and extent (Figure 2).
Type II → narrow, macular staphyloma Type III → peripapillary staphyloma Type IV → nasal staphyloma
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Type V → inferior staphyloma
Others → staphylomas other than types I to V
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3.1.3. Incidence of staphyloma and related factors Moriyama et al. (Moriyama et al., 2011a) examined 198 eyes of 105 patients with
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pathologic myopia (mean age, 64.3 ± 11.5 years and mean AXL, 30.0 ± 2.3 mm) and found that 98 eyes (49.5%) had no evidence of a staphyloma by 3D MRI.
All of these eyes were
barrel-shaped (Figure 3) in both the horizontal and vertical sections in the 3D MRI. The other 100 (50.5%) eyes had a posterior staphyloma in the 3D MRI. The most common type was the wide macular type with 74 of the 100 eyes (74%, Figure 4), followed by the narrow macular type with 14 (14%) eyes, the inferior type with 3 (3%) eyes, the peripapillary type with 5 (5%) eyes, and the nasal type with 2 (2%) eyes.
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ACCEPTED MANUSCRIPT The age and the AXL have been found to be highly correlated with the development and progression of staphylomas (Gozum et al., 1997).
Curtin and Karlin (Curtin and Karlin,
1970) examined the ophthalmoscopic findings and fundus drawings of 500 eyes, and they reported that the prevalence of posterior staphyloma increased from 1.4% in eyes with an Hsiang et al.
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AXL of 26.5 to 27.4 mm to 71.4% in eyes having an AXL of 33.5 to 36.6 mm.
(Hsiang et al., 2008) used ultrasonography and determined that staphylomas were present in 90% of a group of 209 eyes with high myopia (defined by myopic refractive error > 8 D or Gozum et al. (Gozum et al., 1997) reported that the percentage of eyes
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AXL≥ 26.5 mm).
with a posterior staphyloma increased significantly with an increase in AXL and also with
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age. However, Curtin also reported a wide variation of AXLs even among the same type of staphylomas, e.g., the AXL varied from 25.1 to 38.0 mm in the eyes with Type I staphyloma (Curtin, 1977).
Based on this, he suggested that AXL might be an unreliable indicator of
pathologic myopia, and pathologic myopia should be defined by the presence of a
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staphyloma.
It has been reported that children and young individuals do not generally have staphylomas even though they are highly myopic (Kobayashi et al., 2005).
Curtin reported
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that staphylomas were found in 13.2% of younger highly myopic patients with ages ranging between 3 to 19 years, but they were found in 53.5% of older highly myopic patients whose
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ages ranged between 60 to 86 years (Curtin, 1977).
3.1.4. Macular complications of eyes with staphylomas Earlier studies showed the worse vision in highly myopic eyes with staphyloma than those without.
Steidl and Pruett analyzed the macular complications in 116 eyes of 58
patients with high myopia (Steidl and Pruett, 1997).
The staphylomas were graded 0 to 4
based on only the contour changes in B-scan ultrasonographic images.
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A linear
ACCEPTED MANUSCRIPT relationship was observed between the staphyloma grade and lacquer cracks and chorioretinal atrophy.
They reported that the best-corrected visual acuity (BCVA) was
reduced in eyes with all types of staphylomas. By using ultra-wide field fundus imaging, Ohno-Matsui (Ohno-Matsui, 2014a) found that the mean BCVA was significantly better in
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eyes without a staphyloma than in eyes with any type of staphyloma (P = 0.0024, 0.30 ± 0.05 logMAR units vs. 0.54 ± 0.06 logMAR units) and in eyes with the wide macular type of staphyloma (P = 0.0002, 0.30 ± 0.05 logMAR units vs. 0.61 ± 0.07 logMAR units).
They
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also found that eyes with the shallowest staphyloma depth had the largest decrease in the BCVA as well as the greatest incidence of macular CNV.
Based on these findings, they
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suggested that the development of a CNV might require preservation of the choriocapillaris in eyes with less advanced stages of posterior staphyloma formation. Some earlier studies using OCT to detect the staphylomas reported a higher prevalence of myopic traction maculopathy in eyes with staphylomas (Baba et al., 2003;
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Benhamou et al., 2002; Forte et al., 2008; Henaine-Berra et al., 2013; Hirakata and Hida, 2006; Oie et al., 2005; Panozzo and Mercanti, 2004; Rahimy et al., 2013; Takano and Kishi, 1999; Wu et al., 2009), although the change of scleral curvature in axially-elongated eyes
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are sometimes confused as having staphylomas. Oie et al. (Oie et al., 2005) analyzed 28 highly myopic eyes with macular hole retinal detachment (MHRD) and 47 highly myopic
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eyes without MHRD, and reported that staphylomas were significantly more frequent in the eyes with MHRD than highly myopic eyes without MHRD.
The rate of type II staphylomas
(Curtin’s classification) was significantly higher in the eyes with MHRD.
The presence of a
severe degree of staphyloma has been reported to develop vitreoretinal complications by Ripandeli et al. (Ripandelli et al., 2008). Ohno-Matsui (Ohno-Matsui, 2014a) reported that diffuse chorioretinal atrophy was present significantly more frequently in eyes with a wide macular staphyloma than in eyes
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ACCEPTED MANUSCRIPT without a staphyloma (P = 0.016).
Patchy chorioretinal atrophy and CNV (including
macular atrophy) were found significantly more frequently in eyes with any type of staphyloma and eyes with the wide macular staphyloma than in eyes without a staphyloma. Myopic traction maculopathy (MTM) was present significantly less frequently in eyes without
staphyloma, and eyes with a narrow, macular staphyloma. was found in 62 of the 68 eyes with MTM.
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a staphyloma than in eyes with any types of staphyloma, in eyes with a wide, macular Myopic macular retinoschisis
Myopic retinoschisis was found significantly less
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frequently in eyes without a staphyloma than in eyes with any type of staphyloma, eyes with a wide macular staphyloma, and eyes with a narrow macular staphyloma.
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3.1.5. Therapies targeting staphylomas
Earlier studies showed that the presence of staphylomas was significantly correlated with worse vision, more frequent development of myopic macular complications, and optic nerve damage. Thus, therapies targeting the sclera are considered potentially useful to McBrien and Gentle (McBrien
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prevent the development and progression of staphylomas.
and Gentle, 2003) published an extensive review on the role of the sclera in the development and pathological complications of myopia.
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Scleral reinforcement and collagen crosslinking are being considered for the treatment of eyes with pathologic myopia.
Posterior scleral reinforcement surgery for high
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myopia has been mainly performed in Russia and China, and some groups in the United States and Australia have also advocated scleral reinforcement for pathologic myopia. Various types of human tissues such as autologous fascia lata (Nesterov and Libenson, 1970; Nesterov et al., 1976), lyophilized dura (Momose, 1983), strips of tendon (Scott, 1964), and homologous human sclera (Curtin and Whitmore, 1987; Whitmore and Curtin, 1987) have been used.
Curtin (Curtin and Whitmore, 1987) advocated donor-sclera grafting for
posterior ocular reinforcement and Momose (Momose, 1983) introduced Lyodura for scleral
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ACCEPTED MANUSCRIPT reinforcement.
Artificial materials such as artificial pericardium (Castro and Duker, 2010),
all-dermal matrix derived from animal skin (Castro and Duker, 2010), and polytetrafluoroethylene (Jacob-LaBarre et al., 1993) have also been used. best material for reinforcement surgery remains controversial.
However, the
Most investigators in the
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United States have used homologous sclera in the form of a belt or cinch placed vertically over the posterior pole, under the inferior and superior oblique muscles and sutured to the anterior sclera. The shapes of the reinforced sclera can be different; single strip, X-shaped,
SC
and Y-shaped. Later, Snyder and Thompson (Snyder and Thompson, 1972) reported their experiences with a modified scleral reinforcement technique. Thompson (Thompson,
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1978) offered a further simplification of Borley and Snyder’s scleral reinforcement approach. After years of experience with their own variations of scleral reinforcement, Thompson (Thompson, 1985) and Momose (Momose, 1983) expressed satisfaction with the efficacy and safety of their results.
In contrast, Curtin and Whitmore (Curtin and Whitmore,
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1987) had negative conclusions on the outcomes for their reinforcement techniques. However, there have been no clinical studies with appropriate control groups. Gerinec and Slezakova (Gerinec and Slezakova, 2001) performed scleral
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reinforcement using the Thompson method on 251 eyes of 154 children from 2 to 18 years of age with high myopia using Zenoderm (porcine skin) and reported that during the 10 years
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of postsurgical check-up, stabilization of the AXL was achieved in 53.8% of eyes and stabilization of the refractive error was achieved in 52.9% of eyes. The advancement of myopia in the other 47% of patients had decreased from 1.1 D per year before surgery to 0.1 D per year till 10 years after surgery.
More recently, Ward et al. (Ward et al., 2009)
reported the 5-year results of scleral reinforcement using donor sclera in a total of 59 adult eyes, with myopic refractive errors ranging from -9.0 to -22.0 D and AXL from 27.8 to 34.6 mm with a follow-up of 5 years.
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The average increase in AXL was 0.2 mm in sutured eyes
ACCEPTED MANUSCRIPT versus 0.6 mm in non-sutured fellow eyes.
Zhu et al. (Zhu et al., 2009) and Ji et al. (Ji et
al., 2011) also reported a postoperative decrease in myopic refractive error of 0.59 Dand 0.8 D, respectively.
These findings suggest that the effect of scleral reinforcement is limited.
Another study reported a complete lack of an effect (Nesterov et al., 1976).
Curtin and
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Whitmore (Curtin and Whitmore, 1987) investigated 23 patients who were followed up for ≥5 years after scleral reinforcement surgery. Of the 20 eyes that had preoperative axial measurements, 18 (90%) had an increase in the axial diameter of ≥0.3 mm. Progression of
eyes.
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the posterior staphyloma or the onset of myopic fundus degeneration was observed in ten In addition to the lack of long-term effectiveness after surgery, serious complications
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have been reported including retinal detachment (Borley, 1949; Curtin and Whitmore, 1987; Nesterov et al., 1976); ocular motility disorders (Curtin and Whitmore, 1987; Gerinec and Slezakova, 2001); retinal, choroidal, and vitreous hemorrhages; optic nerve damage because of circulatory decompensation; and compression of the optic nerve, vortex veins
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(Whitwell, 1971), or cilioretinal artery (Karabatsas et al., 1997).
Collagen cross-linking was recently introduced for the treatment of progressive keratoconus and post-refractive surgery corneal ectasia (Caporossi et al., 2006; Henriquez
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et al., 2011; Snibson, 2010; Wollensak, 2006; Wollensak et al., 2003). Wollensak et al. (Wollensak et al., 2003) have pioneered the use of riboflavin and ultraviolet light (UVA) to
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cross-link collagen and enhance the mechanical properties of the cornea.
By actively
increasing the degree of the bonding between collagen molecules, therapeutic cross-linking could reasonably be expected to enhance corneal rigidity.
Collagen fibrils cross-link
naturally as a part of their maturation process. In the normal cornea, covalently bonded molecular bridges or cross-links exist between adjacent tropocollagen helices and between microfibrils and fibrils at intervals along their length (Robins, 2007; Snibson, 2010). The collagen cross-linking method shows promise for treating keratoconus, and other
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ACCEPTED MANUSCRIPT cross-linking approaches, e.g., glyceraldehyde and nitro-alcohols, may provide stabilization of scleral shape in eyes with progressive myopia (Paik et al., 2010; Wollensak and Iomdina, 2008, 2009). It has been reported that scleral collagen contained similar cross-linked peptides to those found in the cornea (Crabbe and Harding, 1979; Harding and Crabbe, Different from the corneal collagen cross-linking, the scleral collagen cross-linking
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1979).
is still in the experimental stage and no human clinical trials have been performed.
McBrien
and Norton (McBrien and Norton, 1994) treated tree shrews with agents that block collagen
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crosslinking (β-aminopropionitrile [β-APN], or D-penicillamine [DPA]) and they underwent monocular deprivation of form vision by eyelid closure to induce myopia. The results
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showed that the amount of vitreous chamber elongation and induced myopia approximately doubled in the β-APN-treated monocular deprived eyes compared with that of the saline-treated monocular deprived eyes. There was a significant increase in the degree of scleral thinning at the posterior pole in the deprived eyes of the β-APN-treated animals.
For
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exogenous collagen cross-linking, compounds such as glutaraldehyde, glyceraldehyde (Mattson et al., 2010; Wollensak and Iomdina, 2008), methylglyoxal (naturally occurring Mailard intermediate), and genipin (natural collagen cross-linker obtained from geniposide),
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(Avila and Navia, 2010) and alcohols (Paik et al., 2010) have been used and they have been shown to increase the stiffness of ocular tissue (Wollensak and Spoerl, 2004).
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Wollensak and Iomdina (Wollensak and Iomdina, 2008) performed scleral collagen cross-linking in rabbits with sub-Tenon injections of glyceraldehyde into the superonasal quadrant of the eye and reported that glyceraldehyde cross-linking of scleral collagen increased the scleral biomechanical rigidity efficiently as shown in stress-strain parameters and Young’s modulus without causing side effects on the retina. Wollensak (Wollensak, 2010) also showed that the scleral collagen cross-linking by glyceraldehyde proved very efficient in increasing the scleral thermomechanical stability. Wollensak and Iomdina
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ACCEPTED MANUSCRIPT (Wollensak and Iomdina, 2009) reported that scleral crosslinking by the photosensitizer riboflavin and UVA was effective and constant over a time interval up to 8 months in increasing the scleral biomechanical strength. Wang et al. (Wang et al., 2012a) showed that both the equatorial and posterior human scleral strips were enhanced by collagen
3.2.
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cross-linking with riboflavin/UVA irradiation.
Myopic Maculopathy
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Curtin and Karlin first proposed a definition of myopic maculopathy that included the features of chorioretinal atrophy, central pigment spot, lacquer cracks, posterior staphyloma Later, Tokoro updated the
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and optic disc changes in 1970 (Curtin and Karlin, 1970).
classification of myopic macular lesions into four categories: (1) tessellated fundus, (2) diffuse chorioretinal atrophy, (3) patchy chorioretinal atrophy, and (4) macular hemorrhage. Subsequently, Avila et al. (Avila et al., 1984)developed a classification which included
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myopic retinopathy according to severity, from M0- normal-appearing posterior pole; M1choroidal pallor and tessellation; M2- M1 changes with posterior staphyloma; M3- M2 changes with lacquer cracks; M4- M3 changes with focal areas of deep choroidal atrophy; to
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the most severe grade M5- M4 changes with large geographic areas of deep chorioretinal atrophy and bare sclera.
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Despite the efforts from Curtin and Avila, the definition of myopic maculopathy has not been consistent across studies.
For example, some studies defined pathologic myopia
as eyes exhibiting “typical myopic degeneration” without specific definition (Avisar et al., 2006; Buch et al., 2004; Cedrone et al., 2003; Cotter et al., 2006; Iwase et al., 2006; Klaver et al., 1998). The Beijing Eye Study defined “degenerative myopia” as an eye with myopic refractive error of at least -6 diopters and myopic atrophic changes with stretching of the macula(Liu et al., 2010).
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The Hisayama study defined myopic retinopathy more stringently
ACCEPTED MANUSCRIPT as “the presence of at least one of the following: diffuse chorioretinal atrophy at the posterior pole, patchy chorioretinal atrophy, lacquer cracks, or macular atrophy” (Asakuma et al., 2012).
In the BMES myopic retinopathy was defined to include staphyloma, lacquer cracks,
Fuchs’ spot and myopic chorioretinal thinning or atrophy (Vongphanit et al., 2002b). The
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lack of a common classification makes it impossible to perform direct comparison or pooling of data from different studies to evaluate the prevalence, incidence, and pattern of individual lesion subtypes. There are also limitations in the Avila classification noted from a
For example, the inclusion of
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longitudinal study by Hayashi et al (Hayashi et al., 2010).
posterior staphyloma as a grade of myopic maculopathy (Avila grade M2) was thought to be
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problematic as posterior staphyloma is now believed to be a major cause of the development of myopic maculopathy and thus has been proposed to be included separately (Kim et al., 2011), rather than as a part of myopic maculopathy (Hayashi et al., 2010). Similarly, lacquer cracks often develop relatively early in young individuals.
It is possible
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that with advances in imaging such as indocyanine green angiography (ICGA) and OCT (Liu et al., 2014), lacquer cracks can be diagnosed even earlier than relying on color fundus photographs. Thus the placement of lacquer crack as M3 in the Avila grading has also
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2010).
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raised concerns that it may not represent the progression pattern adequately (Hayashi et al.,
3.2.1. Classification in META-PM study (Table 1) Recently an international panel of researchers in myopia reviewed previous published studies and classifications and proposed a simplified, uniform classification system for pathologic myopia for use in future studies (Ohno-Matsui et al., 2015b).
In this
simplified system (META-PM classification), myopic maculopathy lesions are categorized into 5 categories from “no myopic retinal lesions” (Category 0), “tessellated fundus only”
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ACCEPTED MANUSCRIPT (Category 1; Figure 5A), “diffuse chorioretinal atrophy” (Category 2; Figure 5B), “patchy chorioretinal atrophy” (category 3; Figure 5C), to “macular atrophy” (Category 4; Figure 5D). These categories were defined based on long-term clinical observation that informed on the progression patterns and risk of myopic CNV development for each stage.
Three additional
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features were added to these categories and were included as “plus signs”: (1) lacquer cracks (Figure 5E), (2) myopic CNV, and (3) Fuchs spot (Figure 5F). The reason for separately defining these “plus signs” is that these 3 lesions have been shown to be strongly
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associated with central vision loss, but they do not fit into any particular category and may develop from, or coexist, in eyes with any of the myopic maculopathy categories described Based on this new classification, pathologic myopia is defined as myopic
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above.
maculopathy category 2 or above, or presence of “plus” sign, or the presence of posterior staphyloma (Ohno-Matsui et al., 2015b; Verkicharla et al., 2015).
It is hoped that future
clinical trials and epidemiological studies will adopt this uniform classification to facilitate Further details of individual lesions will be
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communication and comparison of findings. discussed in the following section.
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3.2.2. Details of each lesion
In addition to the basic eye examinations (visual acuity, intraocular pressure,
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refractive error, axial length), more specific examinations (such as SD-OCT, fundus autofluorescence, fluorescein and indocyanine green angiograms, detailed fundus examination with direct or indirect ophthalmoscope) would provide important information for diagnosing and managing the lesions of myopic maculopathy. a. Diffuse Chorioretinal atrophy (Category 2) Few previous studies that evaluated chorioretinal atrophy have discussed diffuse and patchy types separately.
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Diffuse chorioretinal atrophy can be identified by the
ACCEPTED MANUSCRIPT yellowish white appearance of the posterior pole. The extent of the diffuse atrophy may vary from a restricted area around the optic disc and a part of the macula to the entire posterior pole. The area of atrophy generally first appears around the optic disc, often increasing with age and finally covers the entire area within the staphyloma.
Both age and
al., 2010).
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AXL have been described as risk factors for the development of diffuse atrophy (Hayashi et
On fluorescein angiography (FA), diffuse atrophy exhibits mild hyperfluorescence in On ICGA, a marked decrease of the choroidal
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the late phase due to tissue staining.
capillary and medium and large-sized choroidal vessels has been described within the area Marked thinning of the choroidal layer in the area of diffuse atrophy can
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of diffuse atrophy.
be appreciated on OCT, with occasional sporadic large choroidal vessels remaining. b. Patchy Chorioretinal atrophy (Category 3)
Patchy chorioretinal atrophy appears as well-defined, grayish white lesion(s) in the
choroidal lobules.
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macular area or around the optic disc. The size may vary between one and several Patchy chorioretinal atrophy is characterized by a complete loss of
choriocapillaris and can progress to an absence of outer retina and retinal pigment
atrophy.
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epithelium. Large choroidal vessels can be seen to course within the area of patchy In advanced cases, the sclera or even retrobulbar blood vessels may be observed
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through transparent retinal tissue, and the posterior fundus shows a “bare sclera” appearance.
Stereoscopic fundus examination is helpful as one may appreciate the
excavation of the area compared to surrounding diffuse atrophy.
Pigment clumping may be
observed within the area of patchy atrophy, especially along the margin of the atrophy or along the large choroidal vessels.
The lesion appears hypofluorescent on FA and ICGA
due to choroidal filling defect. The overlying RPE is lost, leading to hypoautofluorescence usually with distinct borders.
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On OCT, the area of patchy atrophy is characterized by
ACCEPTED MANUSCRIPT absence of the entire thickness of the choroid and the RPE as well as outer retina. Hyper-transmission through the underlying sclera can be seen. Patchy atrophy may develop from three sources: (1) from lacquer cracks, P(Lc), (2) within the area of advanced diffuse chorioretinal atrophy, P(D), and (3) along the border of
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the posterior staphyloma P(St) (Hayashi et al., 2010). The shape of the patchy
chorioretinal atrophy may help to distinguish these three types, as atrophy which develops from lacquer cracks often have a longitudinally oval shape while patchy atrophy which
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develops from diffuse chorioretinal atrophy is often circular or elliptical.
In a cohort of 806
eyes from the High Myopia Clinic at Tokyo Medical and Dental University, 20.2% of eyes had In the general population aged 40
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patchy atrophy at the initial visit (Hayashi et al., 2010).
years and above, patchy atrophy has been reported to be present in 0.4% in the Hisayama study (Asakuma et al., 2012).
However the frequency increases with longer AXL (3.3% in
eyes with AXL of 27.0 to 27.9mm; >25% in eyes longer than 31mm, and >50% in eyes
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longer than 32mm) (Asakuma et al., 2012).
The frequencies of chorioretinal atrophy progression and the risk of CNV development are significantly higher in eyes with patchy chorioretinal atrophy, compared to
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those with diffuse chorioretinal atrophy at baseline (Ohno-Matsui et al., 2015b). 29.7% showed no progression in atrophy.
Only
In the majority of eyes, patchy atrophy enlarged
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in area (67.6%), some fuse with other areas of patchy atrophy (13.5%) and a minority developed CNV (2.7%).
In another longitudinal study with 10 years follow-up, although the
authors used the Avila grading, it was noted that patchy atrophy and CNV showed poorer visual outcome than lacquer cracks (Shih et al., 2006). The authors of this paper also noted fusion of areas with other patchy atrophy was associated with significant decrease in vision and proposed that RPE dysfunction, particularly in older patients may play a role in the progression of myopic maculopathy (Shih et al., 2006).
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In the BMES, 5.2% of
ACCEPTED MANUSCRIPT participants had new or expanded areas of patchy chorioretinal atrophy over 5 years (Vongphanit et al., 2002b). Macular retinoschisis and retinal detachment secondary to posterior paravascular linear retinal breaks have been reported to occur preferably in areas of patchy atrophy.
It is
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possible that adhesion between the inner retina and sclera in these areas are weakened (Baba et al., 2003; Fang et al., 2009b). c. Lacquer cracks (Plus sign)
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Lacquer cracks appear as yellowish linear lesions in the macula. They can often be seen to crisscross over the underlying choroidal vessels. Lacquer cracks are believed to
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represent mechanical breaks of the Bruch’s membrane (Gao et al., 2011; Hayashi et al., 2010; Neelam et al., 2012; Zheng et al., 2011b).
They may appear as linear horizontal or
vertical cracks or exhibit a crisscrossing (stellate) pattern (Ikuno et al., 2008b). The frequency of lacquer crack in patients with pathologic myopia has been
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estimated to fall between 4.3 and 15.7% in several cohort studies (Curtin and Karlin, 1970; Grossniklaus and Green, 1992; Klein and Curtin, 1975; Ohno-Matsui et al., 2003).
Lacquer
cracks can develop at a relatively early age. Klein and Curtin reported that the mean age of
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patients with lacquer cracks was 32 years (Klein and Curtin, 1975). However, as with other myopic maculopathy lesions, the frequency of lacquer cracks increases with age (Klein and
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Green, 1988).
Detection of lacquer cracks with conventional examination methods is difficult. The appearance varies according to the stage of lacquer crack and the amount of retinal atrophy surrounding it.
ICGA is widely accepted as the best method for detecting lacquer cracks,
which typically appear as linear hypofluorescence in the late phase ICGA (Ikuno et al., 2008b; Ohno-Matsui et al., 1998).
The lacquer cracks may radiate from the disc, at the
papillomacular bundle, through the macula and around the macula (Axer-Siegel et al., 2004).
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ACCEPTED MANUSCRIPT FA, on the other hand, is less useful in demonstrating lacquer cracks, particularly during the early stages of rupture (Axer-Siegel et al., 2004; Liu et al., 2014). The reason is thought to be due to leakage from the surrounding normal choriocapillaris, which may obscure the lacquer crack, and the lack of atrophy of the overlying retinal pigment epithelium during the
months after the onset of rupture.
Atrophy in the RPE usually develops several
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early stages of lacquer crack formation.
At this point, lacquer cracks can be observed as
yellowish linear lesions ophthalmoscopically or as linear hyperfluorescence in FA due to
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window defect (Ohno-Matsui and Tokoro, 1996). With the advent of angiography using the confocal scanning laser ophthalmoscopy system (cSLO), ICGA using cSLO has been shown
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to provide even more details both on lacquer cracks and myopic CNV (Ikuno et al., 2008b; Kim et al., 2011).
Other imaging modalities for visualizing lacquer cracks have been investigated.
Liu
et al. compared multimodal imaging in detecting lacquer cracks in highly myopic eyes (Liu et In addition to reporting lower sensitivity of FA compared to ICGA, the authors of
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al., 2014).
the paper reported that near-infrared reflectance (NIR) had relatively high sensitivity (92.9%) for detecting lacquer cracks, which appear as hyperreflective lines. This NIR appearance
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was frequently associated with continuous retinal pigment epithelium-Bruch’s membrane complex, thinner choroid and acoustic shadow on the corresponding OCT. Thus NIR
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imaging, coupled with SD-OCT is potentially a good non-invasive method to screen for lacquer cracks.
Fundus autofluorescence (FAF) imaging, on the other hand, only detected
12.5% of lacquer cracks, which appear as linear hypo-autofluorescence.
The low rate of
detection was thought to be related to the presence of a continuous RPE-BM line overlying the lacquer crack, as seen on SD-OCT. Lacquer cracks may appear as discontinuities of the RPE and increased hyper-transmission into the deeper tissue beyond the RPE on OCT. However, detection rate is low because the lesions are often very narrow and hardly visible
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ACCEPTED MANUSCRIPT on OCT.
Another feature associated with lacquer cracks which may be observed on OCT is
reduction in macular choroidal thickness (Wang et al., 2013; Wang et al., 2012b; Wang et al., 2015b).
A study reported that a subfoveal choroidal thickness cutoff value of 58.93µm may
be useful for screening eyes for the presence of lacquer cracks (Wang et al., 2013).
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Risk factors for lacquer crack development have been investigated in several studies. Interestingly, there is no obvious correlation between AXL and lacquer cracks, and association with refractive error is weak.
Kim et al. followed 66 patients with myopic CNV,
2011).
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and reported presence of lacquer crack in 37 eyes with CNV and 26 fellow eyes (Kim et al., Although older age, higher refractive error, absence of a dark rim and greater extent
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of peripapillary choroidal atrophy were associated with the presence of lacquer crack, only peripapillary atrophy remained a significant association after multivariate logistic regression analysis (Kim et al., 2011).
Subretinal bleeding is often observed at the onset of lacquer cracks (Klein and Ohno-Matsui et al.
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Green, 1988; Ohno-Matsui et al., 1996; Shapiro and Chandra, 1985).
reported that in 17 (77.3%) of 22 eyes with subretinal bleeding without CNV, lacquer cracks appeared at the corresponding site of the previous bleeding (Ohno-Matsui et al., 1996).
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This subretinal bleeding is usually absorbed spontaneously with good visual recovery and has therefore been called simple hemorrhage (Asai et al., 2014; Goto et al., 2015).
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However in eyes in which the bleeding was thick and penetrated into the inner retina beyond the external limiting membrane, a defect in the ellipsoid zone may persist, leaving permanent vision loss (Asai et al., 2014; Moriyama et al., 2011c). Asai et al. reported the tops of the hemorrhages and intraretinal hyperreflectivity may extend into the internal limiting membrane in over 30% (Asai et al., 2014). It is important to exclude the presence of a myopic CNV in cases of subretinal bleeding. Progression of lacquer cracks has been observed in longitudinal studies in eyes with
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ACCEPTED MANUSCRIPT and without myopic CNV (Kim et al., 2011; Vongphanit et al., 2002b).
In the BMES, 56.1%
of eyes with lacquer cracks at baseline showed progression after an average follow up of 72.8 months (Vongphanit et al., 2002b).
Progression may be in the form of increase in
number or development into other myopic maculopathy such as patchy or diffuse
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chorioretinal atrophy and CNV. Progression of lacquer cracks may be observed with the production of increasing amounts of small crack fragments. This may appear as elongation from the tip of an existing lacquer crack, at the side of an existing lacquer crack in a
bridging pattern.
A mixture of these three patterns often exists in the same eye (Kim et al.,
Presence of lacquer cracks extending to the fovea has also been shown to be a
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2011).
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branching pattern, or remote from an existing lacquer crack and connecting later in a
significant negative prognostic factor for vision (Yoon et al., 2012). Lacquer cracks may also increase in width and progress to patchy atrophy and increase in number.
Hayashi et
al. reported that only 30.7% of eyes with lacquer cracks did not progress over their 12.7 year Progression of lacquer cracks was more frequent in
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follow-up study (Hayashi et al., 2010).
eyes with a posterior staphyloma but was not associated with AXL. Lacquer crack has been suggested to be an important risk factor in the formation of
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myopic CNV. The prevalence of lacquer crack is high in eyes that developed myopic CNV, although the prevalence is likely to be underestimated due to limitation in visualization (Avila
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et al., 1984; Ikuno et al., 2010; Ikuno et al., 2008b; Ohno-Matsui et al., 2003).
In a
longitudinal follow-up study, the incidence of myopic CNV was highest in eyes with lacquer cracks (29.4%), compared to 20% in eyes with patchy atrophy and only 3.7% in eyes with diffuse chorioretinal atrophy (Ohno-Matsui et al., 2003).
In the longitudinal study by
Hayashi et al. 13.3% of eyes with lacquer cracks develop myopic CNV, and 42.7% develop patchy chorioretinal atrophy (Hayashi et al., 2010; Ikuno et al., 2008b; Ohno-Matsui et al., 2003; Wang et al., 2012b).
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In addition, recurrence of CNV, particularly in cases where the
ACCEPTED MANUSCRIPT recurrence is at a different location from the original CNV, progression of lacquer cracks has been observed frequently (Kim et al., 2011). Myopic stretch lines need to be differentiated from lacquer cracks. Myopic stretch lines were first reported by Yannuzzi as linear hyper-autofluorescent lesions that were
cracks but the detail was not described (Yannuzzi, 2010).
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observed in the fundus of eyes with pathologic myopia and were the precursors of lacquer Myopic stretch lines, unlike
lacquer cracks, are observed as hypofluorescent lines throughout all phases of FA
On fundus examination, myopic stretch lines are observed as
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(Shinohara et al., 2014).
pigmented brown lines running along the large choroidal vessels. Although ICGA showed
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similar hypofluorescence as lacquer cracks, FAF demonstrated hyper-autofluorescent lines corresponding to the hypofluorescent lines by FA.
OCT showed that the choroid was
extremely thin with occasional visible large choroidal vessels visible.
Irregularities or
clumps of RPE at the site of the stretch lines on and around the protruded large choroidal
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vessels could also be seen.
d. Myopic CNV (Plus sign)
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Myopic CNV is a major sight threatening complication of pathologic myopia.
It is
the commonest cause of CNV in individuals aged below 50 years, and the second
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commonest cause of CNV overall (Neelam et al., 2012; Ohno-Matsui et al., 2003).
It has
been included as a “plus” sign in the proposed international classification for myopic maculopathy, in view of its major impact on vision (Ohno-Matsui et al., 2015b). details are discussed under the section on Myopic CNV.
Further
Studying the progression pattern
of various myopic maculopathy changes and the risk they confer on CNV development can improve our understanding of the pathogenesis of myopic CNV.
Most myopic CNVs
appear to emanate from lacquer cracks (Ikuno et al., 2010; Ikuno et al., 2008b; Kim et al.,
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ACCEPTED MANUSCRIPT 2011). Vascular endothelial growth factor has also been shown to be elevated in myopic CNV (Chen et al., 2015).
3.2.3. Natural Progression of each lesion
time.
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Few studies have followed up eyes with myopic maculopathy over long periods of A study from the High Myopia Clinic of the Tokyo Medical and Dental University
reviewed 806 eyes of 429 patients with high myopia over a mean follow-up period of 12.7 Overall, progression was seen in 40.6%. However, the rate of
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years (Hayashi et al., 2010).
progression varied according to the baseline lesion, and some eyes showed progression to
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a second and even a third pattern after the first progression. Thus progression of myopic maculopathy is complex and long-term follow up studies are essential to understanding the pathogenesis and risk factors.
The rate of progression ranged from only 13.4% in eyes with tessellated fundus, to
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49.2% in eyes with diffuse chorioretinal atrophy, 69.3% in eyes with lacquer cracks, 70.3% in eyes with patchy chorioretinal atrophy and as high as 90.1% in eyes with CNV at the initial examination (Hayashi et al., 2010).
Below is a summary of the progression pattern of
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individual lesions described by Hayashi et al. (Hayashi et al., 2010). The majority of eyes (86.6%) with tessellated fundus at the initial examination did not
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progress, while 10.1% developed diffuse chorioretinal atrophy, 2.9% developed lacquer cracks and 0.4% developed CNV.
Older age and presence of a posterior staphyloma were
associated with progression, but AXL was not. Seven out of eight eyes that developed lacquer cracks showed further progression, mostly to patchy atrophy, and less frequently to development of CNV. A third pattern of progression was seen in 3 eyes, in the form of CNV development at the edge of the fovea of patchy atrophy in 2 eyes, and in the form of macular atrophy development after CNV. The period from first to second progression ranged from 1
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ACCEPTED MANUSCRIPT to 9 years, while the period from second to third progression ranged from 1.5 to 3 years. Nearly half of the eyes with diffuse chorioretinal atrophy at the initial visit showed progression (49.2%). Most eyes progressed in the form of enlargement of the area of diffuse chorioretinal atrophy (26.9%), while others developed patchy atrophy (19.4%),
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lacquer cracks (2.2%) and CNV (1.6%). The presence of posterior staphyloma and longer AXL, were associated with enlargement of diffuse chorioretinal atrophy and development of patchy atrophy.
In addition, eyes that progressed to patchy chorioretinal atrophy had
progression.
All the eyes that developed a CNV progressed further to develop macular
Less frequently seen patterns of second progression were from diffuse
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atrophy.
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markedly higher frequency of having a type IX staphyloma compared to those without
chorioretinal atrophy to lacquer cracks and subsequently to patchy atrophy associated with lacquer cracks P(Lc); and from diffuse chorioretinal atrophy to patchy chorioretinal atrophy and subsequently to macular atrophy.
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Progression was significantly more common in eyes with lacquer cracks at initial examination (69.3% had progression).
Most eyes with lacquer crack (42.7%) progressed
to develop patchy atrophy around lacquer crack, P(Lc), 13.3% developed a CNV and a
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further 13.3% developed an increase in number of lacquer cracks. Presence of a posterior staphyloma, was significantly more frequent in eyes that progressed to patchy chorioretinal
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atrophy, but age and AXL were not significantly different between those with and without progression from lacquer cracks.
Some eyes may have a second and third progression
pattern after the first progression from lacquer cracks to patchy atrophy.
These eyes may
progress from lacquer crack to patchy atrophy and later develop CNV and eventually macular atrophy (Hayashi et al., 2010). Most eyes with patchy chorioretinal atrophy at the initial visit (70.3%) developed progression, most frequently in the form of enlargement of the patchy area (67.6%), while
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ACCEPTED MANUSCRIPT 13.5% of eyes showed a fusion with diffuse chorioretinal atrophy P(D) and patchy atrophy along the edge of posterior staphyloma P(St), and 2.7% developed a CNV.
Presence of
posterior staphyloma (particularly type IX staphyloma) and longer AXL were associated with progression.
A second and third progression may develop either in the form of CNV from
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the foveal edge of patchy atrophy which subsequently progress to macular atrophy; or in the form of fusion with other P(D) or P(St) to form an enlarged area of patchy atrophy and ultimately progressing to macular scar.
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Overall, these long-term progression data suggest that myopic maculopathy tends to progress more quickly after the myopic maculopathy has advanced past the tessellated Patient age, severity of myopia, AXL and the presence of posterior
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fundus stage.
staphyloma were frequently associated with progression, although small differences exist between their influence on individual lesion. Of the various individual lesions, the development of a CNV and macular atrophy were significantly associated with worse vision.
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In addition, the fusion of patches of atrophy with other areas was also associated with a significant decrease in vision.
CNV may develop from any stage of myopic maculopathy,
but the incidence was highest in eyes with lacquer cracks or patchy atrophy.
Once
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developed, most of the eyes with a CNV showed a progression to macular atrophy.
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3.2.4. Pathogenesis and Potential Therapy for myopic maculopathy In animal models of myopia, the choroidal circulation has been shown to decrease in high myopia (Shih et al., 1993).
Evidence from various modes of choroidal imaging has
also supported the hypothesis that choroidal circulation decreases in high myopia. Narrowing and loss of large choroidal vessels have been observed in eyes with high myopia (Akyol et al., 1996; Moriyama et al., 2007; Quaranta et al., 1996).
Loss of choroidal large
vessels and fibrotic changes within choroidal vessels may lead to obstruction of choroidal
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ACCEPTED MANUSCRIPT blood flow and be replaced eventually with fibrous tissue, ultimately resulting in myopic chorioretinal atrophy (Hirata and Negi, 1998a, b; Sayanagi et al., 2009). The marked thinning of the choroid in diffuse chorioretinal atrophy has led to the hypothesis that obliteration of pre-capillary arterioles or post-capillary venules may be the underlying cause
the choriocapillaris.
This may then be followed by occlusion of
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of the choroidal changes in pathologic myopia.
In the most advanced stage, even the large choroidal vessels are
obliterated. Loss of choroidal melanocytes, possibly secondary to the vascular changes,
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has been suggested to be partly responsible for the pale appearance of the fundus.
However, the reason for the relative preservation of the RPE and outer retina, despite the
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marked thinning of the choroid, is not clear.
The mechanism underlying the development of patchy atrophy is somewhat different from that proposed for diffuse chorioretinal atrophy.
Jonas reported that macular Bruch’s
membrane defects are commonly detected histologically and that these defects might be In particular, the lack of
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related to the development of patchy atrophy (Xu et al., 2007).
tensile strength from Bruch’s membrane, in addition to lack of choroid on the thin sclera, result in the area of patchy atrophy being subjected to the inner pressure load (You et al., Patchy chorioretinal atrophy that develops in conjunction with lacquer cracks may
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2014).
result from multiple factors, including mechanical stretching in the form of lacquer cracks and
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choroidal filling delay. The latter is supported by observation of tiny hypofluorescent areas on FA at the posterior pole during the early stage of patchy atrophy development (Ohno-Matsui and Tokoro, 1996).
Lacquer cracks are believed to represent ruptures in Bruch membrane. Stretching of the tissue because of axial elongation is believed to play an important role in the pathogenesis (Curtin and Karlin, 1970).
In animal models of lacquer crack, Bruch’s
membrane was noted to be totally broken up and rupturing of the collagen fibrillar network
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ACCEPTED MANUSCRIPT was found (Hirata and Negi, 1998a).
Isolated cases of lacquer crack development
following ocular surgery as well as LASIK further suggest that physical stress and changes in intraocular pressure during surgery may play a role (Chen et al., 2014; Ruiz-Moreno et al., 2003; Shaw and Chen, 2015). The observation that lacquer cracks are associated with
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larger extent of peripapillary atrophy also supports the theory that mechanical stretching likely plays an important role in the pathogenesis of both features (Kim et al., 2011; Yasuzumi et al., 2003; You et al., 2014).
However, somewhat contradictory to this
AXL (Curtin and Karlin, 1970).
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hypothesis, risk factor analysis has shown that lacquer cracks are not directly correlated with Querques et al. reported a new SD-OCT based finding that
(Querques et al., 2015).
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retrobulbar vessels were found to perforate the sclera at the site of the lacquer crack They hypothesized that scleral expansion at the location of these
perforating vessels where scleral continuity is interrupted may play a role in the formation of lacquer cracks (Pedinielli et al., 2013; Querques et al., 2015).
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In addition to mechanical stress, a vascular or ischemic component has also been proposed to have an important role in the pathogenesis of lacquer cracks and chorioretinal atrophy.
Recent studies based on choroidal thickness measurements reported an
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association between choroidal thinning and lacquer cracks (Wang et al., 2013). Interestingly, Wang et al. not only reported an association between thinner macular choroid
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and the presence of both lacquer cracks and CNV, but also concluded that thinner choroid was a factor independent of AXL or refractive error (Wang et al., 2015b). There is also evidence from animal studies to suggest a vascular component in addition to mechanical stress in the pathogenesis of lacquer cracks. In chick models of high myopia and lacquer crack, the choroidal capillary network was found to be ruptured with highly atrophied marginal capillaries (Hirata and Negi, 1998a, b).
The retina was continuous, but was
depressed to form a groove in the lesion with the apparently intact inner retina and
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ACCEPTED MANUSCRIPT degenerated photoreceptor cells.
Attenuated fibroblasts encompassed the outer
circumference of the lesion while RPE cells were scattered in the tissue space inside the fibroblastic investment and in the choroidal stroma (Hirata and Negi, 1998a, b). The authors of the study proposed that metabolic insufficiency may thus be considered a
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causative factor in the disruption of Bruch’s membrane and the degenerative changes of the outer retina.
Lacquer cracks are observed at higher rates in eyes with myopic CNV, compared to
(Noble and Carr, 1982; Ohno-Matsui et al., 2003).
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highly myopic eyes without CNV, suggesting a relationship between these two pathologies Ikuno et al. (Ikuno et al., 2008b)
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reported that lacquer cracks were present in 95% of 37 eyes with myopic CNV.
In addition,
myopic CNV originated from lacquer cracks or areas adjacent to lacquer cracks in 94%. Recurrence of myopic CNV has also been found to develop particularly in areas surrounded by new small crack fragments (Kim et al., 2011).
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In summary, a plethora of signs in the macula are associated with pathologic myopia. Correlation with natural progression from long-term studies has improved our understanding of the relative risk profile and impact on vision of each individual stage and lesion. The new
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international myopic maculopathy grading aims to simplify and standardize the classification
3.3.
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of myopic maculopathy and facilitate future collaborative research.
Myopic CNV
3.3.1. Prevalence, incidence and bilaterality Myopic CNV is one of the most sight-threatening complications in high myopia (Avila et al., 1984).
Based on published studies, it has been estimated that the prevalence of
myopic CNV ranges from 5% to 11% among individuals with high myopia (Curtin and Karlin, 1970; Grossniklaus and Green, 1992; Hayashi et al., 2010; Wong et al., 2014).
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Myopic
ACCEPTED MANUSCRIPT CNV is also the most common cause of choroidal neovascularization among patients aged 50 years or below (Cohen et al., 1996). In a study of 32 patients with pathologic myopia who were followed for at least 3 years, the incidence of myopic CNV was 10.2% of eyes over a mean follow-up of 10.8 years (Ohno-Matsui et al., 2003).
Highly myopic individuals who
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already had myopic CNV in one eye were found to have an even higher risk of myopic CNV development in the fellow eye, as myopic CNV developed in 34.8% of patients with myopic CNV already in one eye, compared with 6.1% of patients without a history of pre-existing
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CNV (Ohno-Matsui et al., 2003).
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3.3.2. Diagnosis of myopic CNV based on imaging (Figure 6)
On clinical examination, myopic CNV typically appears as a flat, small, greyish subretinal lesion beneath or in close proximity to the fovea with or without hemorrhage. There are usually minimal subretinal fluid or exudative changes associated with the myopic
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CNV. The diagnosis of myopic CNV can be confirmed by FA and SD-OCT.
FA findings in
myopic CNV usually demonstrate well-defined hyperfluorescence in the early phase with leakage in the late phase in a classic CNV pattern of leakage.
SD-OCT has the advantage
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of being non-invasive and fast to perform. Therefore, SD-OCT is routinely utilized to differentiate myopic CNV from other macular conditions in high myopia such as myopic
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foveoschisis and myopic macular hole, and for monitoring of the myopic CNV treatment response.
In order to maximize the detection and diagnosis rates of myopic CNV, it is
generally recommended to perform both FA and SD-OCT as there might be poor agreement between FA and SD-OCT findings in eyes with myopic CNV (Goto et al., 2015). The concordance between FA and SD-OCT findings usually increases with follow-up after anti-angiogenesis therapy and it was therefore recommended to use FA to diagnose myopic CNV and to use SD-OCT to assist the monitoring of CNV treatment (Iacono et al., 2014).
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ACCEPTED MANUSCRIPT Active myopic CNV in SD-OCT appears as a dome-shaped hyper-reflective elevation above the RPE as most myopic CNV are type 2 CNV. Subretinal hyperreflective exudation on SD-OCT has also been suggested to be a feature of active myopic CNV(Bruyere et al., 2015).
Other SD-OCT features of myopic CNV include absence of Bruch’s membrane and
thickening (Milani et al., 2014).
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photoreceptor ellipsoid zone, absence of external limiting membrane (ELM) and retinal A recent study evaluated the correspondence of FA and
SD-OCT findings in myopic CNV eyes receiving intravitreal bevacizumab treatment and
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found that absence of ELM was a more reliable parameter for assessing myopic CNV than intra- or sub-retinal fluid (Battaglia Parodi et al., 2015). With the use of enhanced-depth
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imaging OCT, patients with myopic CNV have been found to have thinner choroidal thickness compared with normal control eyes (Wang et al., 2015b). Swept-source OCT has also demonstrated that in eyes with dome-shaped macula, CNV is significantly associated with longer AXL and thinner choroidal thickness (Ohsugi et al., 2014).
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Other imaging techniques which might provide adjunctive information in the assessment of myopic CNV include ICGA and FAF (Kim et al., 2011; Parodi et al., 2009; Parodi et al., 2015; Sawa et al., 2008).
ICGA is particularly useful in the assessment of
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lacquer crack formation associated with myopic CNV (Kim et al., 2011).
FAF findings in
myopic CNV may include hyperautofluorescent or patchy FAF pattern, and eyes with
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hyperautofluorescent pattern have been found to have greater extent of visual acuity improvement and fewer atrophic changes after intravitreal ranibizumab treatment for myopic CNV (Parodi et al., 2015).
3.3.3. Differential diagnoses a. Subretinal bleeding due to new lacquer crack formation Although myopic CNV is one of the main causes of macular hemorrhage in patients
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ACCEPTED MANUSCRIPT with high myopia, macular hemorrhage in highly myopic patient can also be associated with lacquer crack without CNV (Klein and Green, 1988; Ohno-Matsui et al., 1996). This is also known as simple hemorrhage and the hemorrhages in these cases are due to mechanical stretching and rupture of the Bruch’s membrane resulting in new lacquer crack formation The visual prognosis of simple
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(Moriyama et al., 2011c; Ohno-Matsui et al., 1996).
hemorrhage is generally more favorable compared with myopic CNV as the simple
hemorrhage will resolve spontaneously without requiring treatment with anti-angiogenesis FA and ICGA are useful to differentiate hemorrhage due to
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therapy (Goto et al., 2015).
myopic CNV from simple hemorrhage due to lacquer crack as the former will show
b. Punctate inner choroidopathy
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hyperfluorescence associated with the macular hemorrhage.
Punctate inner choroidopathy (PIC) is an inflammatory disorder of unknown etiology characterized by small creamy yellow-white lesions located at the RPE and inner choroid
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without concomitant intraocular inflammation (Leung et al., 2014; Watzke et al., 1984). CNV can also develop as a complication of PIC resulting in acute visual loss (Amer and Lois, 2011; Leung et al., 2014).
Since PIC patients commonly have moderate or even high
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myopia, PIC should be differentiated from myopic CNV by the fundus appearance of the characteristic small multiple fundus lesions.
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c. Idiopathic CNV
Idiopathic CNV is one of the most common causes of CNV in young patients and was found to account for 17% of CNV in patients under the age of 50 years (Cohen et al., 1996).
It can also occur in patients with high myopia.
By definition, an idiopathic CNV
occurring in an eye with myopia of −6D or more is considered to be a myopic CNV rather than an idiopathic CNV. d. Serous detachment in dome-shaped macula
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ACCEPTED MANUSCRIPT Due to RPE atrophy or abnormal choroidal vasculature, a central serous chorioretinopathy-like serous macular detachment can develop in eyes with dome-shaped macula (Caillaux et al., 2013). This can mimic myopic CNV and FA is very useful to distinguish the two as management of the two conditions is rather different. The
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dome-shaped macula will be described in details later. e. Polyps at edge of tilted disc syndrome
It has been reported that highly myopic eyes with tilted disc syndrome may
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sometimes develop polypoidal neovascular lesions in the inner choroid at the border of the posterior staphyloma similar to those seen in polypoidal choroidal vasculopathy (PCV)
identify polyps at these locations.
ICGA is the investigation of choice to
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(Mauget-Faysse et al., 2006; Nakanishi et al., 2008).
Nonetheless, it has been shown that PCV is rarely found
in patients with myopic CNV as ICGA of a consecutive series of 297 eyes with myopic CNV did not identify any case of PCV (Kang and Koh, 2014). This might be related to the
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thinning of the choroidal layer in high myopia patients with myopic CNV and thus a reduced likelihood of PCV development in these eyes with high myopia. 3.3.4. Natural prognosis and development of CNV-related macular atrophy (Figure 7)
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Several studies have evaluated the natural history of pathologic myopia including myopic CNV. The natural history of myopic CNV is generally poor without treatment.
In
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one of the retrospective studies with the longest follow-up conducted by Yoshida et al. (Yoshida et al., 2003) 27 eyes of 25 consecutive patients with myopic CNV were followed for 10 years after the onset of myopic CNV. better than 20/200.
At baseline, 70.4% of eyes had a visual acuity of
However, at 5 and 10 years after the onset of myopic CNV, visual
acuity dropped significantly to 20/200 or worse in 88.9% and 96.3% of eyes, respectively. In a study by Kojima et al. (Kojima et al., 2006) 54 eyes of 54 patients with myopic CNV without treatment were followed for at least 5 years.
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Analysis showed that factors
ACCEPTED MANUSCRIPT significantly related to good prognosis with final visual acuity better than 20/40 included younger age, smaller CNV, juxtafoveal CNV and better initial visual acuity.
Development of
chorioretinal atrophy around the regressed CNV is the main reason for the poor visual prognosis in eyes with myopic CNV (Ohno-Matsui and Yoshida, 2004).
Recent study using
(Ohno-Matsui et al., 2015a).
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swept-source OCT showed that CNV-related macular atrophy was Bruch’s membrane hole Another reason for the poor visual outcome in myopic CNV
eyes might be due to formation of myopic macula hole.
Eyes at the atrophic stage of
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myopic CNV with chorioretinal atrophy of greater than 1 disc area are particular at risk of macular hole formation, as macular hole was found in 14% of these eyes, compared with
no CNV (Shimada et al., 2008a).
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none in myopic CNV eyes with less than 1 disc area of chorioretinal atrophy and eyes with Based on these findings of the poor natural history
outcome of myopic CNV, eyes with myopic CNV should therefore be offered active effective
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treatment to improve the visual prognosis.
3.3.5. Anti-VEGF therapy for myopic CNV (Figure 8) Several treatment options including thermal laser photocoagulation, macular surgery
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and verteporfin photodynamic therapy (vPDT) have previously been used for the treatment of myopic CNV but the outcomes of these treatment modalities are generally poor with no
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significant visual improvement and high risk of myopic CNV recurrence.
Since the
introduction of anti-VEGF agents in ophthalmology around 10 years ago, anti-angiogenesis treatment with intravitreal anti-VEGF therapy has become the standard-of-care first-line treatment for myopic CNV (Lai, 2012). Similar to CNV in other macular diseases, increased level of VEGF has been found to be associated with myopic CNV and therefore anti-VEGF therapy is useful in myopic CNV (Chan et al., 2008; Tong et al., 2006).
A large
number of retrospective and prospective studies have demonstrated the beneficial effects of
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ACCEPTED MANUSCRIPT anti-VEGF therapy for the treatment of myopic CNV (Chan et al., 2009; Gharbiya et al., 2010b; Iacono et al., 2012; Ikuno et al., 2009; Lai et al., 2009; Ruiz-Moreno et al., 2009; Tufail et al., 2013). Systematic reviews have also demonstrated beneficial visual outcomes in the use of intravitreal anti-VEGF therapy for myopic CNV (Neelam et al., 2012; Wang and In addition, two large multi-centered, double-masked, randomized, controlled
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Chen, 2013).
clinical trials have been performed to evaluate the use of anti-VEGF therapy for myopic CNV (Ikuno et al., 2015; Wolf et al., 2014). The RADIANCE (The Ranibizumab and PDT
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[verteporfin] evaluation in myopic choroidal neovascularization) study was a 12-month, randomized clinical trial which randomized 275 patients to two regimens of intravitreal 0.5mg
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ranibizumab (guided by visual acuity stabilization or by disease activity) versus vPDT for the treatment of myopic CNV (Wolf et al., 2014). The primary endpoint was mean BCVA change measured at 3 months.
Results showed that at 3 months, both ranibizumab
treatment groups had significantly better visual acuity improvement compared with vPDT
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group, with BCVA gains of 10.5 letters for the ranibizumab guided by visual acuity stabilization, 10.6 letters for the ranibizumab guided by disease activity and 2.2 letters for the vPDT group.
At 6 months, it was shown that the ranibizumab guided by diseases activity
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group was non-inferior in terms of visual again compared with the ranibizumab guided by visual acuity stabilization group. The improvement in BCVA after intravitreal ranibizumab
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treatment was maintained at 12 months, with BCVA gains of 13.8 and 14.4 letters in the two ranibizumab treatment groups, respectively.
The number of injections was low in the study
at 12 months with a mean of 4.0 injections in the group guided by visual acuity stabilization and 3.5 injections for the group guided by disease activity.
In the MYRROR study, the use
of intravitreal 2mg aflibercept was compared with a sham control group for the treatment of myopic CNV (Ikuno et al., 2015). The primary outcome measure was assessed at 6 months and it was shown that intravitreal aflibercept resulted in significantly better BCVA
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ACCEPTED MANUSCRIPT improvement compared with sham control group, with a gain of 12.1 letters in the aflibercept group and a loss of 2 letters in the sham group.
Similar to the RADIANCE study, the mean
number of injections was low in the MYRROR study, with a mean of 4.2 injections over 12 months for the aflibercept group.
In both the RADIANCE and MYRROR studies, adverse
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events were infrequent and there were no abnormal safety issues related to ranibizumab and aflibercept injections.
Several studies have evaluated the long-term outcomes of anti-VEGF therapy for
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myopic CNV for two years or more. Gharbiya et al. evaluated the second year results of 20 eyes with myopic CNV which have already been treated with intravitreal bevacizumab The long-term results showed that at 24 months, the mean visual
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(Gharbiya et al., 2010a).
acuity improved significantly from 20/80 at baseline to 20/33 at 24 months. of eyes had improvement of 10 letters or more at 24 months.
Moreover, 85%
In a retrospective study by
Lai et al. (Lai et al., 2012) 37 treatment naïve eyes of 37 patients with subfoveal myopic CNV
years.
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were treated with intravitreal bevacizumab or ranibizumab and were followed for at least 2 It was found that the mean logMAR visual acuity improved significantly from 0.86 to
0.48. The mean visual improvement at 2 years was 2.8 lines for the bevacizumab group and
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5.1 lines for the ranibizumab group but the difference was not statistically significant. The number of intravitreal anti-VEGF injections over 24 months was low, with a mean of 3.8
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injections for both the bevacizumab and ranibizumab groups.
In terms of ocular adverse
events, it was uncommon and complications observed included three cases of cataract requiring surgery, two cases of increase in myopic foveoschisis, and one case each of cellophane maculopathy, myopic macular hole, retinal detachment, and peripheral retinal degeneration requiring barrier laser treatment.
Yang et al. retrospectively evaluated the
use of intravitreal bevacizumab in 103 myopic CNV eyes of 89 patients who had follow-up of at least 2 years (Yang et al., 2013).
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After a mean follow-up of 44 months, the mean
ACCEPTED MANUSCRIPT logMAR visual acuity improved from 0.57 to 0.41.
Recurrence was observed in 23.3% of
eyes and the number of bevacizumab injections was considerably higher for eyes with recurrence, with a mean of 6.9 injections for eyes with recurrence and 2.7 injections for eyes without recurrence. Multivariate analysis showed that larger size of myopic CNV was the In another retrospective study,
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only significant factor associated with CNV recurrence.
Franqueira et al. evaluated the efficacy and safety of intravitreal ranibizumab in the
treatment of myopic CNV after 3 years (Franqueira et al., 2012). The mean visual acuity
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improved significantly from 55.4 letters at baseline to 63.4 letters at 36 months. The mean number of ranibizumab injections was 4.1, 2.4 and 1.1 in the first, second and third year, Peiretti et al. assessed the long-term results of intravitreal bevacizumab in 21
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respectively.
eyes of 20 patients who were followed for up to 52 months (Peiretti et al., 2012). found that 85.7% of eyes had stable or improved vision at the last follow-up.
It was
The results
demonstrated that anti-VEGF therapy is beneficial compared with the natural history of Oishi et al. further evaluated the use of intravitreal
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myopic CNV in the long-term.
bevacizumab in 22 eyes with myopic CNV and patients were followed for at least 4 years (Oishi et al., 2013).
It was shown that following intravitreal bevacizumab treatment for
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myopic NV, significant visual improvements were observed at 1, 2 and 3 years.
The
improvement in visual acuity became marginally non-significant at 4 years after treatment.
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The main reason for the slight decline in visual improvement at 4 years might be related to chorioretinal atrophy, as 73% of eyes were found to have new development or enlargement of chorioretinal atrophy at the last visit. Ruiz-Moreno et al. also reported the 4-year outcome in the use of anti-VEGF therapy for myopic CNV (Ruiz-Moreno et al., 2013). The study found that the mean visual acuity improved significantly from 46.1 letters at baseline to 53.1 letters at 48 months. The mean number of injections was low at 4.9 over 4 years and both bevacizumab and ranibizumab groups showed similar effects in myopic CNV (Peiretti et al.,
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ACCEPTED MANUSCRIPT 2012).
However, a more recent study by the authors which evaluated the 6 years outcome
of anti-VEGF therapy in 97 patients with myopic CNV showed that the visual acuity improvement after bevacizumab or ranibizumab treatment was no longer significant after 4, 5 and 6 years (Ruiz-Moreno et al., 2015).
Based on the previously described long-term
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studies in the use of intravitreal anti-VEGF therapy, it can be concluded that anti-VEGF therapy is an effective and safe treatment option for myopic CNV in the long-term and can
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provide visual improvement up to 4 years and visual stabilization up to 6 years.
The optimal current management of patients with myopic CNV is to diagnose the
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myopic CNV accurately and timely so that the eye with myopic CNV can be treated with intravitreal anti-VEGF therapy as soon as possible.
The standard investigations for
diagnosing myopic CNV include both FA and SD-OCT assessments of the macula.
FA is
important to confirm the presence of fluorescein leakage from the myopic CNV in order to
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prevent unnecessary treatment with anti-VEGF agents for simple hemorrhage not associated with myopic CNV.
SD-OCT can be used to monitor the change in myopic CNV
activity before and after anti-VEGF therapy, and to detect any other pathology like myopic
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traction maculopathy or dome-shaped macula with are not uncommon findings in patients with pathologic myopia.
The main limitation of the current treatment of myopic CNV is the
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development of chorioretinal atrophy around the myopic CNV, thereby limiting the visual improvement potential of the patients.
Low vision rehabilitation is useful for the patients
with advanced vision loss due to CNV-related macular atrophy or scaring in both eyes.
3.3.6. Diagnostic and treatment flow-charts for myopic CNV (Figure 9)
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3.4.
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Other fundus lesions in the posterior fundus
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3.4.1. Dome-shaped Macula (Figure 10)
Dome-shaped macula was first described by Gaucher et al. in eyes with myopic posterior staphyloma (Gaucher et al., 2008).
A characteristic inward bulge inside the
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chorioretinal posterior concavity of the eye in the macular area was noted in 15 eyes of 10 patients out of a series of 140 highly myopic eyes.
This bulge was hardly detectable on
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fundus biomicroscopy but OCT has greatly enhanced in the diagnosis, typically exhibiting a convex, curved, elevated profile within the concavity of the staphyloma. Subsequent imaging studies demonstrated that the bulge is associated with a local thickening of subfoveal sclera (Imamura Y, 2010).
After Gaucher et al. first reported DSM in 10.7% of a series of 140 highly myopic eyes, a subsequent series in European patients reported a similar prevalence of 12.0% in a series of 200 highly myopic eyes (Chebil et al., 2014).
Coco et al. reported macular
bending in 13.63% in 330 highly myopic eyes, of which most eyes had DSM, while a small
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ACCEPTED MANUSCRIPT proportion was associated with tilted disc syndrome (Coco et al., 2012). The prevalence of DSM in other ethnic groups is less well studied.
Ohsugi et al. reported DSM was observed
in 9.3% of 528 highly myopic eyes in a Japanese cohort (Ohsugi et al., 2014).
Liang et al.
(Liang et al., 2015) reported the prevalence of DSM was 20.1% in a cohort of 1118 eyes in Recently, the prevalence of DSM was evaluated in
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Japanese patients with high myopia.
the RADIANCE study which recruited 277 eyes with myopic CNV and DSM was present in 18% of patients (Ceklic et al., 2014).
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Clinical Features
In the earliest series by Gaucher et al. (Gaucher et al., 2008), the mean refractive
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error of the affected eyes was -8.25D and the mean visual acuity was 20/50.
A type I or
type II staphyloma, according to the Curtin classification (Curtin, 1977), was present in all eyes. Most series reported DSM in patients with mean age of 50 years or above and bilateral DSM was reported in 50% to 78% of patients (Coco et al., 2012; Errera et al., 2014; Gaucher DSM was first thought to be a complex type of
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et al., 2008; Imamura et al., 2011b).
staphyloma (Byeon and Chu, 2011; Gaucher et al., 2008).
However, the understanding of
the extended clinical phenotypes of DSM has advanced with subsequent reports.
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Advances in imaging have led to the ability to study scleral shape and thickness in detail with EDI-OCT. These later studies reported that some eyes with DSM did not exhibit the feature
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of a staphyloma as described by Curtin (Curtin, 1977), as local protrusion of thin sclera and uveal tissue was not present.
Therefore, DSM may in fact represent a novel feature rather
than a variation of staphyloma. This hypothesis was further supported by the three-dimensional magnetic resonance imaging analyses of the globe, which showed that more than half of eyes with DSM did not have a staphyloma, and the eyes were simply elongated into a barrel-shaped globe (Ohno-Matsui, 2014b). Gaucher et al. reported that visual impairment and metamorphopsia was common in
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ACCEPTED MANUSCRIPT their series of eyes with DSM (Gaucher et al., 2008).
Several complications resulting in
visual loss in DSM have been described, including atrophic changes in the RPE, foveal serous retinal detachment (sRD) and CNV. Coco et al. reported further on the wide range of complications, and noted as high as 60.29% of eyes with DSM had at least one
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complication, including CNV, subretinal fluid without CNV, atrophy and macular hole.
Other
series have reported DSM complicated by retinal schisis which may be extrafoveal or fovea-involving (Ellabban et al., 2013; Errera et al., 2007; Viola et al., 2015).
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One of the most common complications of DSM is foveal sRD.
In the initial
description by Gaucher et al, foveal sRD was present in 66.7% (10 out of 15 eyes) of eyes However subsequent series have reported highly
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with DSM (Gaucher et al., 2008).
variable figures, most likely due to differences in inclusion criteria and patient population. However, most series from European populations have reported higher prevalence of foveal retinal detachment (52.1% (Caillaux et al., 2013) and 44% (Viola et al., 2015)) compared to
(Ohsugi et al., 2014)).
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Japanese population (5.9%(Ellabban et al., 2013), 9%(Imamura et al., 2011b) and 9.3%
The prevalence of choroidal neovascularization (CNV) in eyes with DSM was also
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variable, and ranged from 12.2% (Ohsugi et al., 2014) to 47.8%(Imamura et al., 2011b). Atrophy of the RPE was reported in a high proportion of eyes with DSM.
Gaucher et al
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reported presence of RPE atrophy in all eyes in their series, while a lower prevalence was noted in other series (11.76% by Coco et al. (Coco et al., 2012), 37.2% by Ellabban et al. (Ellabban et al., 2014)) Imaging Most authors have noted that the dome-shaped elevation was hardly observable on fundus biomicroscopy. However, horizontal ridges connecting the optic disc and the fovea may be observed on fundus examination and these may act as an important clue to suspect
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ACCEPTED MANUSCRIPT the presence of DSM (Ohno-Matsui, 2014b). B-scan ultrasonography and OCT can effectively detect the bulge confined within the surrounding staphyloma.
Vertical OCT
scans in particular were found to detect the convex curvature of the bulge (Gaucher et al., 2008).
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With the advent of EDI-OCT, Imamura et al. reported that the subfoveal scleral thickness was markedly thicker in eyes with DSM compared with highly myopic eyes without DSM (570µm vs 281µm, p<0.001), whereas the subfoveal choroidal thickness was only
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slightly thicker (58.1µm vs 35.7µm, p=0.48) (Imamura, et al. 2011b).
Subsequent work by Ellabban et al. reconstructed 3-dimensional images of the
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posterior eye shape using swept-source OCT (Ellabban et al., 2013). They demonstrated that the sclera in the posterior pole showed an uneven thickness, being relatively thick in the fovea (518µm) compared with parafoveal areas in all four quadrants (277.2 to 360.3µm). These findings led the authors to propose that DSM may result from a relative localized
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thickness variation of the sclera under the macula in highly myopic eyes. Different subtypes of DSM were also demonstrated by Caillaux et al. (Caillaux et al., 2013).
Three patterns were described: (i) dome-shaped pattern, (20.8%); (ii) roughly
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horizontally orientated oval-shaped dome, (62.5%); and (iii) vertically orientated oval-shaped dome, (16.7%). Importantly, the finding that most DSM did not display a round dome
fovea.
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highlights that the diagnosis of DSM could be missed on a single OCT scan through the Recently, Liang et al. also reported that 77% of DSM was detectable along only the
vertical section, whereas only 2% of DSM was detected in only the horizontal section and 20% of DSM was detected in both vertical and horizontal OCT sections (Liang et al., 2015). Pathogenesis The underlying mechanism for the development of DSM remains unclear.
Both
posterior staphyloma and DSM are associated more frequently with a higher severity of
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ACCEPTED MANUSCRIPT myopia or increased AXL.
However, DSM may also be observed in eyes with low spherical
equivalent refractions and short AXL (Errera et al., 2014; Gaucher et al., 2008; Liang et al., 2015), as well as in eyes with retinal dystrophies (Errera et al., 2014). There has been much research into the relative role played by the choroid and
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sclera in the pathogenesis of DSM, and in the development of subfoveal sRD in DSM. Gaucher et al. observed that the choroid beneath the bulge appeared to be thickened in some eyes, and postulated that the convex curvature of the macular profile may result from
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thickening of the underlying choroid or from a change in the scleral wall shape or thickness, possibly a protective mechanism resulting from resistance of the sclera to the Some authors proposed that the
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staphylomatous deformation (Gaucher et al., 2008).
development of DSM in myopic eyes could represent an adaptive phenomenon in a proportion of myopic patients to reduce defocus in the macula (Keane et al., 2012). The demonstration using three dimensional reconstruction of uneven thinning of the
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sclera on either side of the area of convexity led to the postulation that asymmetric expansion of the eyeball could lead to the formation of DSM.
Importantly, no change in the
external scleral curvature of the macula was observed (Caillaux et al., 2013; Ellabban et al., It is possible that regional differences in biochemical structure of scleral lamellae or
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2013).
organization of the collagen bundles may be responsible for this observation (Ellabban et al., This theory is further supported by the longitudinal findings of progressive
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2013).
asymmetric scleral thinning, which was more pronounced in the parafoveal area than at the foveal center, resulting in an increase of the macular bulge height (Ellabban et al., 2014). The mechanism for the development of foveal sRD in eyes with DSM is unclear. Foveal sRD was significantly more common when the macular bulge height was greater than 350um (Caillaux et al., 2013). The findings of thickened sclera and, to a lesser extent, choroid led Imamura et al. to propose obstruction of choriocapillaris outflow secondary to
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ACCEPTED MANUSCRIPT localized relative scleral thickening as a mechanism for the development of subretinal fluid accumulation and foveal sRD in DSM (Imamura et al., 2011b).
Gaucher et al. studied eyes
with DSM with FA and observed focal leakage points in 7 eyes(Gaucher et al., 2008). The fluorescein dynamics of the focal leaking points was thought to be a complication of the
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abnormal curvature of the macula. There were also some similarities between the
fluorescein dynamics in DSM and in chronic central serous chorioretinopathy (CSC) and tilted disc syndrome, particularly the association with atrophic changes in the RPE.
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However, in DSM, these leakage points tended to be localized at the top of the dome where atrophic RPE is noted. Errera et al. reported that choroidal thickening was particularly
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marked in eyes with DSM with a CSC-like phenotype (defined as presence of subretinal fluid and/or focal hyperfluorescent areas on FA) (Errera et al., 2014). Outcome and complications
Currently, treatment is not recommended for DSM without complications. The
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optimal treatment for subretinal fluid and foveal sRD in DSM is unclear.
This is further
complicated by the variable natural history, as spontaneous resolution has been described (Gaucher et al., 2008; Tamura et al., 2014; Viola et al., 2015).
Several treatment options
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have been attempted with variable success. Laser photocoagulation (Gaucher et al., 2008; Pardo-Lopez et al., 2011), verteporfin photodynamic therapy (Arapi et al., 2015; Chinskey
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and Johnson, 2013), intravitreal anti-vascular endothelial growth factor (Chinskey and Johnson, 2013) and medical therapy with spironolactone (Dirani et al., 2014).
However, all
of these studies lack control groups. In the RADIANCE study which recruited eyes with myopic CNV, no substantial differences in visual outcome or number of ranibizumab injections were needed for patients with or without DSM, despite worse baseline visual acuity scores in patients with DSM (Ceklic et al., 2014).
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ACCEPTED MANUSCRIPT Interestingly, extrafoveal retinal schisis was more common than foveal schisis in eyes with DSM (Ellabban et al., 2013; Viola et al., 2015).
Ellabban et al. proposed that the
bulge in eyes with DSM may act as a macular buckle-like mechanism, indenting the fovea and thus may alleviate tractional forces over the fovea (Ellabban et al., 2013). Similarly,
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Ellabban et al. reported that the bulge height of a DSM without CNV is significantly higher than that with CNV, and speculated that the dome may also be playing a protective role in
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reducing the mechanical damage (Ellabban et al., 2013).
3.4.2. Radial ascending tracts emanating from staphyloma edge
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Ultra-widefield fundus images show radial ascending tracts as linear or leaf-like lesions with an abnormal FAF pattern which radiate from the staphyloma edge toward the peripheral fundus in 7.7% of highly myopic eyes with a posterior staphyloma (Ishida et al., 2014).
The linear tracts are observed as an increase in pigmentation or de-pigmentation OCT images of the
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ophthalmoscopically, however they are more obvious in the AF images.
staphyloma edge show serous retinal detachments in some cases. Three-dimensional magnetic resonance imaging (3D MRI) of the eyes show a clear outpouching in the eyes
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with linear tracts, and the upper edge of a wide macular staphyloma was more abrupt than the lower edge. The fundus features of the radial tracts are similar to those of the
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descending tracts in chronic CSC (Imamura et al., 2011a; Spaide and Klancnik), even though there are no staphylomas in eyes with CSC. is different in these two conditions.
In addition, the orientation of the tracts
Our results suggest that a sRD first developed at the
staphyloma edge where the RPE is damaged and then spread towards the periphery against gravity.
The RPE damage at the abrupt edge of a staphyloma and the directional spread of
subretinal fluid might be related to the development of the radial tracts.
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ACCEPTED MANUSCRIPT 3.4.3. Chorioretinal folds from staphyloma edge Chorioretinal folds have been reported to be present in various ocular and systemic conditions including hyperopia, CNV, and eyes with an orbital mass (Olsen et al., 2014). Chorioretinal folds are also known to develop in eyes with the tilted disc syndrome (Cohen In eyes with an inferior staphyloma due to
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and Quentel, 2006; Ohno-Matsui et al., 2011b).
the tilted disc syndrome, the upper edge of the staphyloma is located in the foveal region,
(Cohen and Quentel, 2006; Ohno-Matsui et al., 2011b).
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and the chorioretinal folds run radially from the upper edge of the inferior staphylomas
Ishida et al. (Ishida et al., 2015) examined the ultra-widefield fundus images and
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FAF images and showed that the chorioretinal folds emanated from the staphyloma edge in highly myopic eyes even though the edge was away from the macula.
In some cases,
choroidal folds were observed to run in parallel with radially ascending tracts.
In addition,
choroidal folds were present outside the staphyloma with relatively preserved choroid, and
they have staphylomas.
Surgical conditions
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3.5.
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they might also be present even in less myopic eyes of patients with unilateral high myopia if
3.5.1. Macular Hole, MHRD (Figure 11)
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The presence of a macular hole (MH), is not an uncommon complication that can be observed in highly myopic eyes.
The prevalence of MH has been reported to be 8.4% in
214 eyes with pathologic myopia (AL>30 mm and posterior staphyloma) using OCT (Ripandelli et al., 2012).
Coppe et al. examined 383 asymptomatic highly myopic patients
(between -14 and -32 D) with OCT and reported full thickness macula hole (FTMH) in 24 eyes (6.26%) (Coppe et al., 2005).
Retinal detachment associated with MH (MHRD)
accounts for less than 1% of all cases (Margheria and Schepens, 1972), although some
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ACCEPTED MANUSCRIPT studies from Asian population reported 9% and 21% (Minoda, 1979; Zhang and Hu, 1982). Spectral domain optical coherence tomography (SD-OCT), which allows in vivo examination of macular morphology, is invaluable in differentiating between a full-thickness MH, lamellar hole, MHRD, and macular retinoschisis.
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Gass emphasized the role of vitreous and hypothesized that tangential traction was an important factor in the pathogenesis of macular hole (Gass, 1988).
The pathogenesis of
MH and MHRD in high myopia is considered distinct from idiopathic MH, which includes
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anteroposterior vitreous traction on the posterior pole due to axial elongation or posterior staphyloma (Morita et al., 1991), tangential traction on the macula from the contraction of the
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cortical vitreous and epiretinal membrane (Oshima et al., 1998; Seike et al., 1997; Stirpe and Michels, 1990); and reduced chorioretinal adhesion due to RPE atrophy (Morita et al., 1991). Vitrectomy has become standard procedure to treat idiopathic MH as well as MH in high myopia.
Because ILM peeling can remove premacular tractional elements, such as
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vitreous cortex, epiretinal membrane; remove scaffold for cellular proliferation, and increase flexibility of the retina to facilitate closure of MH (Almony et al., 2012; Funata et al., 1992; Madreperla et al., 1994), studies of MH in high myopia with ILM peeling showed higher
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successful closure rate (ranging from 87 to 100%) (Alkabes et al., 2013; Chuang et al., 2014; Garcia-Arumi et al., 2001; Kwok and Lai, 2003; Qu et al., 2012) than studies without ILM
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peeling (ranging from 60 to 77%) (Patel et al., 2001; Sulkes et al., 2000).
Inverted ILM flap
technique has been reported with initial closure rate of 83.3% for treating MH in high myopia (Kuriyama et al., 2013).
Surgical outcomes of MHRD are disappointing.
Vitrectomy in combination with ILM
peeling and a short- or long-acting gas tamponade is commonly used to treat MHRD.
The
retinal reattachment rate following vitrectomy for MHRD has been reported to vary widely from approximately 40% to 93% (Chen et al., 2006; Ichibe et al., 2003; Ikuno et al., 2003;
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ACCEPTED MANUSCRIPT Kadonosono et al., 2001), however, MH closure rate following vitrectomy for MHRD, ranging from 10% to 91% using OCT examination (Ichibe et al., 2003; Ikuno et al., 2003; Kadonosono et al., 2001), are usually not as high as MH closure rate for MH alone in high myopia.
In addition, post-operative MH enlargement has been reported due to the Inverted
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imbalance between the retina and choroid-sclera complex (Ichibe et al., 2003).
ILM with or without autologous blood have been reported to increase the MH closure rate in MHRD (Kuriyama et al., 2013; Lai et al., 2015).
Several studies using vitrectomy with
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scleral shortening or imbrication for treating primary or refractory MHRD reported MH closure rate of 82.4% and 75%, respectively (Fujikawa et al., 2014; Kono et al., 2006).
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Although macula buckle is not a new technique, it has been applied to treat MHRD with posterior staphyloma. Ando et al. reported a 93% retinal reattachment rate and MH closure in 10 of 12 eyes (83%) (Ando et al., 2007).
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3.5.2. Myopic traction maculopathy (Figure 12)
Phillips first described a retinal detachment, without hole, localized to the area of a posterior staphyloma in a highly myopic eye (-20D) in 1958 (Phillips, 1958).
He used
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fundus slit lamp to demonstrate the retinal detachment, and assumed a posterior staphyloma played an important part in cases with retinal detachment with or without macula
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hole (Phillips, 1958). Forty years later, Takano and Kishi first demonstrated foveal retinal detachment and retinoschisis in severely myopic eyes with posterior staphyloma using optical coherence tomography (Takano and Kishi, 1999).
Panozzo and Mercanti proposed
the term “myopic traction maculopathy (MTM)” to encompass various findings with traction in common by optical coherence tomography in highly myopic eyes (Panozzo and Mercanti, 2004).
Myopic traction maculopathy, also called foveal retinoschisis (Takano and Kishi,
1999), macular retinoschisis (Benhamou et al., 2002), or myopic foveoschisis (Ikuno et al.,
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ACCEPTED MANUSCRIPT 2004), includes schisis-like inner retinal fluid, schisis-like outer retina fluid, foveal detachment, lamellar or full-thickness macular hole and/or macular detachment (Johnson, 2012). The features of myopic traction maculopathy were not characterized before optical
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coherence tomography (OCT), and the pathogenesis is not completely understood.
Based
on the finding from optical coherence tomography and surgical reports, several mechanisms have been proposed, including vitreomacular traction from partial posterior vitreous
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detachment (Panozzo and Mercanti, 2004; Takano and Kishi, 1999), remnant cortical vitreous layer after posterior vitreous detachment (Spaide and Fisher, 2005), epiretinal
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membrane, intrinsic internal limiting membrane noncompliance (Ikuno et al., 2004; Kanda et al., 2003; Kobayashi and Kishi, 2003; Kuhn, 2003), and retinal arteriolar stiffness (Ikuno et al., 2005; Johnson, 2012; Sayanagi et al., 2005). Therefore, MTM can be regarded as a split between the flexible outer retina and the inflexible inner retina (Ikuno, 2014).
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OCT is an indispensable tool to diagnose MTM, which allows in vivo examination of macular morphology, such as schisis-like inner retinal fluid, schisis-like outer retina fluid, foveal detachment, lamellar or full-thickness macular hole and/or macular detachment.
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Examinations other than OCT were used and might help diagnosis of MTM. Sayanagi et al. reported a subtle mottled pattern of hyper fundus autofluorescence, and found a different
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pattern between MTM and full-thickness macula hole with retinal detachment (Sayanagi et al., 2007).
Recently, retro-mode imaging (RMI) has been used noninvasively to visualize
chorioretinal disorder based on the infrared laser in the confocal scanning laser ophthalmoscope (SLO), which can produce a pseudo-three-dimensional image showing the details of deep retinal structures.
A characteristic fingerprint and firework pattern at the
corresponding area of macular retinoschisis have been reported in macula retinoschisis using RMI (Su et al., 2014; Tanaka et al., 2010).
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Although RMI provides more information
ACCEPTED MANUSCRIPT regarding the extent of the macular retinoschisis than fundus autofluorescence, both examinations have limitations in showing the height of MTM and structure between vitreoretinal interfaces. Shimada et al. have classified myopic traction maculopathy according to its location
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and extent from S0 through S4: S0: no retinoschisis; S1: extrafoveal; S2: foveal; S3: both foveal and extrafoveal but not the entire macula; and S4: entire macula (Shimada et al., 2013).
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Tanaka et al. found 23 (95.8%) of 24 eyes with lamellar macula hole did not show any changes in the OCT images during a mean follow-up of 19.2 months (Tanaka et al.,
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2011). They reported that a lamellar macula hole might be a relative stable condition in highly myopic eyes (Tanaka et al., 2011).
Although some eyes with MTM showed
spontaneously resolution(Polito et al., 2003; Shimada et al., 2013), several studies reported progression during its natural course from MTM to more serious complications such as
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foveal detachment, ranging from 3.4% to 37.5% (Fujimoto et al., 2010; Shimada et al., 2006a; Shimada et al., 2013) or full-thickness MH, ranging from 0.9% to 33% (Benhamou et
2013).
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al., 2002; Fujimoto et al., 2010; Gaucher et al., 2007; Shimada et al., 2006a; Shimada et al.,
Shimada et al. further defined the progression as (1) an increase of the extent or
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height of retinoschisis (more than 100 µm) or the development of an inner lamellar macula hole, foveal detachment, or full-thickness macula hole (Shimada et al., 2013). They reported progression during the mean follow-up of 36.2 months in 24 (11.6%) of 207 eyes, which includes 0.9% who progressed to full-thickness macula hole and 3.4% who progressed to foveal detachment. The eyes with extensive macular retinoschisis (S4) showed progression significantly more commonly (42.9%) than the eyes having less extensive macular retinoschisis areas (6.7%).
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Six (21.4%) of 28 eyes with S4 MTM
ACCEPTED MANUSCRIPT progressed to foveal detachment. However, some eyes (3.9%) showed a decreased or complete resolution of macular retinoschisis (Shimada et al., 2013). 3.5.2.1. Surgical techniques to treat MTM Shimada et al. investigated five eyes of MTM and showed that the progression from
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MTM to foveal detachment passed through four stages based on the OCT images. In stage 1, focal irregularity of the thickness of the external retina; stage 2, an outer lamellar hole and a small retinal detachment developed; stage 3, column-like structures overlying the
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holes separated horizontally and enlarged vertically; stage 4, the upper edge of the external retina was further elevated and attached to the upper part of the retinoschisis layer by further
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enlargement of the detachment (Shimada et al., 2008b). They recommended considering surgical treatment between stage 3 and 4. Surgery is also recommended if visual acuity decreases or additional pathology develops (Chang et al., 2014). Due to the possible mechanisms involved in the pathogenesis of MTM, vitrectomy is
and epiretinal membrane.
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the most common treatment to release all retinal tractions, which include cortical vitreous Use of coating materials such as triamcinolone or blood clot
allows visualization of any remaining vitreous cortex (Lai et al., 2011; Yamamoto et al., 2004)
membrane scraper.
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and facilitates its separation from the retina with intravitreal forceps or Tano diamond-dusted Then epiretinal membrane and cellular constituents must be confirmed
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and removed with or without dye staining.
Internal limiting membrane peeling remains
controversial in MTM. Although it is thought that ILM peeling is a definitive method of removing all overlying residual vitreous cortex, epiretinal membrane and cellular constituents, several studies reported full-thickness macular hole formation after vitrectomy for MTM (Gao et al., 2013a; Gaucher et al., 2007; Hirakata and Hida, 2006; Ho et al., 2014; Panozzo and Mercanti, 2007). Ikuno and Tano reported surgical outcome in 8 eyes with macula hole with myopic
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ACCEPTED MANUSCRIPT retinoschisis.
All the eyes underwent ILM peeling at the first surgery, and the ILM was
peeled extensively (5 to 6 disc diameters) in all the second surgeries.
Temporal scleral
shortening was performed during re-operation in one case. Although all the retinoschisis resolved, the macula holes closed in only two (25%) eyes (Ikuno and Tano, 2006). Gao et
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al. investigated the risk factors for development of full-thickness macular holes after
vitrectomy for MTM, and found that pre-operative ellipsoid zone (inner segment/outer segment) defect can be a risk factor for the development of macular hole (Gao et al., 2013a).
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Foveolar ILM sparing technique was used in an attempt to reduce the development of post-vitrectomy macula hole, which was a severe complication and resulted in poor visual Several studies showed good visual and anatomic outcomes with this technique
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recovery.
(Ho et al., 2012; Ho et al., 2014; Shimada et al., 2012).
Ho et al. compared foveal ILM
non-peeling and total ILM peeling in patients with MTM, and found that macular hole developed in only 2 (28.6%) of the 7 eyes with total ILM peeling after the mean follow-up of
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55.6 months.
Other surgical techniques other than vitrectomy have been used, such as intravitreal injection of gas (Gili et al., 2010; Wu et al., 2013), scleral buckling or reinforcement on the
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macular area alone (Baba et al., 2006; Zhu et al., 2009), combined scleral reinforcement with vitrectomy (Bures-Jelstrup et al., 2014; Mateo et al., 2012; Mateo et al., 2013), or
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combined supra choroidal buckling with vitrectomy (El Rayes, 2014). 3.5.2.2. Surgical outcome of MTM The anatomic and functional outcome using different surgical procedures for MTM is summarized in Table 2 (Baba et al., 2006; Bures-Jelstrup et al., 2014; Chang et al., 2014; El Rayes, 2014; Fang et al., 2009a; Gaucher et al., 2007; Hirakata and Hida, 2006; Ho et al., 2012; Ho et al., 2014; Hwang et al., 2013; Ikuno et al., 2003; Ikuno et al., 2008a; Ikuno and Tano, 2006; Kanda et al., 2003; Kim et al., 2012; Kobayashi and Kishi, 2003; Kumagai et al.,
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ACCEPTED MANUSCRIPT 2010; Kwok et al., 2005; Lim et al., 2012; Mateo et al., 2012; Mateo et al., 2013; Panozzo and Mercanti, 2007; Scott et al., 2006; Shin and Yu, 2012; Spaide and Fisher, 2005; Taniuchi et al., 2013; Wang et al., 2012c; Wu et al., 2013; Yeh et al., 2008; Zheng et al., 2011a; Zhu et al., 2009).
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In general, full-thickness macular hole or MHRD are the most common
post-vitrectomy complications, which may result in unsatisfactory visual outcomes.
Additional procedures such as fluid gas exchange (Rao et al., 2013), episcleral macula
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buckling (Bures-Jelstrup et al., 2014), inverted ILM with or without autologous blood (Kuriyama et al., 2013; Lai et al., 2015), scleral shortening or imbrication (Fujikawa et al.,
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2014; Kono et al., 2006) provide other options to restore the anatomic structure.
Although
several reports using scleral reinforcement on the macula area alone or combined with vitrectomy showed good anatomic success, choroidal detachment, retinal pigment epithelium disturbance or atrophy around the buckle and buckle protrusion may develop
al., 2013; Zhu et al., 2009).
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after the surgery (Baba et al., 2006; Bures-Jelstrup et al., 2014; Mateo et al., 2012; Mateo et Post-vitrectomy gas tamponade showed more rapid anatomical
resolution and greater improvement than without gas tamponade (Kim et al., 2012; Zheng et
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al., 2011a). The prognosis is generally better in cases involving only macular hole without foveoschisis than in cases with macula holes and associated foveoschisis.
Persistent MHs
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are more frequent in eyes with concomitant retinoschisis, and this seems to represent a possible risk factor for late retinal detachment in the case of unsuccessful vitreous surgery (Alkabes et al., 2014).
There were some different characteristics in highly myopic eyes compared with emmetropic eyes, which include longer axial length (AL); presence of staphyloma; presence of premacular tractional elements, such as vitreous cortex, epi-retinal membrane, and increased rigidity of internal limiting membrane (ILM); thinner sclera, choroid and retina; and
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ACCEPTED MANUSCRIPT presence of diffuse or patchy chorioretinal atrophy. These characteristics lead to more technically challenging surgery and are associated with lower anatomical successful rate and functional visual outcome.
Using regular instruments (without long-shaft forceps (Gao
et al., 2013b)), surgeons may have difficulty in inducing posterior vitreous detachment,
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reaching the surface of the retina, removing premacular tractional elements, and doing membrane peeling, especially in eye with higher axial length (> 30mm) and the presence of posterior staphyloma. Complications may occur easily, such as iatrogenic retinal damage
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while attempting to elevate or re-grasp the ILM with unmatched intraocular forceps. The thinner and fragile sclera may result in unstable intraocular pressure during the surgery
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which may easily cause choroidal detachment or even suprachoroidal hemorrhage. Presence of diffuse or patchy chorioretinal atrophy is associated with thinner and vulnerable choroid and retina, which usually need dye to enhance contrast of the membrane and facilitate membrane peeling during the surgery.
Although new technology enables
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visualization of microstructure and provides more information to understand the pathogenesis of myopic macular traction, the surgical and visual outcomes are still not very satisfactory.
Photoreceptor layer defects and chorioretinal degeneration persist despite
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surgery and may be the underlying mechanism of the association of unsatisfactory
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post-operative visual recovery and outcome.
3.5.3. Peripheral retinal degenerative changes and complications 3.5.3.1. Lattice degeneration, Retinal holes, Retinal tears Highly myopic eyes with increased axial lengths have been reported with higher incidence of peripheral chorioretinal changes, such as lattice degeneration, retinal tears and holes, and retinal detachment (Celorio and Pruett, 1991; Gozum et al., 1997; Karlin and Curtin, 1976; Lam et al., 2005; Pierro et al., 1992; Yura, 1998).
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Karlin and Curtin studied
ACCEPTED MANUSCRIPT 1437 myopic eyes and found statistically significant association of increasing axial length of the eye with four principle varieties of peripheral chorioretinal changes, namely white without pressure, pigmentary degeneration, paving stone degeneration, and lattice degeneration(Karlin and Curtin, 1976).
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Risk factors for rhegmatogenous retinal detachment include axial myopia, cataract surgery, ocular trauma and a history of retinal detachment and certain peripheral retinal degeneration including lattice degeneration. Although lattice degeneration is the most
treatment remains controversial.
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significant predisposing factor for retinal breaks or detachments, prophylactic laser
Byer studied 423 eyes with lattice degeneration in 276 Subclinical RD was seen in 10
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patients over an average of 10.8 months (Byer, 1989).
(6.7%) of 150 eyes with atrophic holes in lattice, involving 9 (7.5%) of 120 patients.
Clinical
retinal detachments (RDs) occurred in 3 (1.08%) of 276 patients and 0.7% of eyes.
These
data indicated that patients with lattice degeneration with or without round holes are at very
eye (Byer, 1989).
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low risk for progression to clinical retinal detachment without a previous RRD in the fellow Ray suggested treating only after careful examination in eyes with
residual vitreous traction on the lattice, and the symptomatic eyes had a detachment related
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to lattice with a horseshoe tear (Ray, 2000). Even though treatment is only warranted in cases of expanding retinal detachments or vitreous traction, patients with lattice
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degeneration should be informed about the symptoms of acute posterior vitreous detachment and retinal detachment, and be instructed to follow-up for ophthalmic evaluation whenever such symptoms occurs. Asymptomatic breaks include operculated and atrophic round holes. Because there is no vitreous traction at the edge of these breaks, retinal detachments are unlikely to occur.
Current recommendations are close follow-up without prophylactic treatment. Symptomatic U-tears, characterized by the perception of increased flashes or
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ACCEPTED MANUSCRIPT floaters, are usually associated with persistent vitreous traction at their edge. These symptomatic U-tears result in retinal detachments 50% of the time and therefore should be treated with laser photocoagulation immediately, which reduces the risk of retinal detachment to less than 5%.
In addition, there is a strong evidence base to recommended
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treating symptomatic U-tears to prevent retinal detachment (Celorio and Pruett, 1991; Pollak and Oliver, 1981; Robertson and Norton, 1973; Shea et al., 1974; Verdaguer and Vaisman, 1979; Wilkinson, 2000).
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The goal of laser photocoagulation is to create chorioretinal adhesion completely surrounding the retinal break which can counter vitreoretinal traction and prevent liquefied Generally speaking, at least 3 near
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vitreous from passing into the subretinal space.
confluent rows of laser should be applied to closely and completely surround the retinal breaks.
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3.5.3.2. Rhegmatogenous retinal detachment
Rhegmatogenous retinal detachment from peripheral retinal breaks in highly myopic eyes can be treated with scleral buckling alone, or vitrectomy with gas or silicon oil
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tamponade or combination of scleral buckling and vitrectomy, as for non-myopic eyes. Surgeons can decide which procedure for treating retinal detachment based on the location
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and types of retinal breaks, lens status, ocular media clarity, as well as their experiences. In general, scleral buckling is the first choice although there are some limitations such as being a more painful procedure which may need general anesthesia, it can’t be used in retinal detachments caused by large of posterior retinal tears, and it may not be sufficient when there is advanced proliferative vitreoretinopathy.
Risks and side effects of scleral
buckling procedures include scleral perforation and strabismus.
However, patients who
undergo scleral buckling usually don’t need to keep a prone position for weeks as do
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ACCEPTED MANUSCRIPT patients who undergo vitrectomy.
Unlike in patients undergoing vitrectomy, occurrence of
post-operative cataract is lower in patients undergoing scleral buckling.
In addition,
refractive errors change may occur in cases with encircling scleral buckles with subsequent axial length elongation.
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Treating retinal detachment with vitrectomy has some advantages, such as: removal of vitreous traction along the tears or peripheral retinal degeneration, release of proliferative vitreoretinal membrane, better visualization of retinal tears with vitreous opacity and removal
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of sub-retinal fibrotic bands in longstanding retinal detachment from an internal approach. It has less limitation compared to scleral buckling and the procedure can be performed However, the patient may need to keep
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under local anesthesia with a small-gauge system. a prone position for weeks.
In the patient who cannot maintain a prone position or needs to
travel by flight after surgery, an alternative is to use silicon oil tamponade.
Another
disadvantage of vitrectomy is the development and progression of cataract (de Bustros et al., Cataract surgery in a previously
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1988; Hsuan et al., 2001; Melberg and Thomas, 1995).
vitrectomized eye is more technically challenging due to lack of vitreous support, weakened zonules (Pinter and Sugar, 1999; Smiddy et al., 1988), which cause the lens-iris diaphragm
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to move excessively, and fluctuation of anterior chamber depth which causes pupil constriction (Braunstein and Airiani, 2003). All of these disadvantages may increase the
3.6.
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risk of complications, especially in highly myopic eyes with long axial length.
Optic Disc Changes and glaucoma in Pathologic Myopia The papillary and peripapillary regions of highly myopic eyes are distorted by the
mechanical stretching of the globe.
The stretching results in the formation of various kinds
of deformities of the optic discs including tilted optic discs (You et al., 2008), acquired megalodiscs (Jonas, 2005; Jonas et al., 1988; Wang et al., 2006), and small discs.
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Hyung
ACCEPTED MANUSCRIPT et al. (Hyung et al., 1992) stated that as the degree of myopia increases, the ratio of the vertical to horizontal disc diameters increases, thus tilting the optic disc.
Jonas et al.
(Jonas, 2005; Jonas et al., 1988) reported that the optic discs were significantly larger and more oval than normal optic discs in eyes with myopic refractive errors <-8.0 D. Highly
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myopic optic discs can be regarded as secondary acquired macrodiscs, and they should be differentiated from the secondary acquired macrodiscs in eyes with congenital glaucoma and also from primary macrodiscs.
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The results of earlier studies indicated that the high prevalence of glaucoma in highly myopic eyes was a great concern because the diagnosis of glaucoma was difficult in highly Chen et al. (Chen et al., 1997) reported
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myopic eyes and thus it tended to be overlooked.
that glaucoma was a more pronounced issue in eyes with long AXL than eyes with short AXLs.
Chihara et al. (Chihara et al., 1997) showed that severe myopia (<-4.0D) but not
mild myopia was a significant risk factor for visual field loss in patients with primary
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open-angle glaucoma.
Nagaoka et al. (Nagaoka et al., in press) determined the prevalence of glaucoma in 172 patients (336 eyes) with high myopia (defined as myopic refractive error of <-8D or Highly myopic eyes with megalodiscs had a 3.2 times higher risk of having
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AXL>26.5 mm).
glaucomatous optic neuropathy than highly myopic eyes with normal sized or smaller optic The increased prevalence of glaucoma in eyes with axial high myopia was primarily
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discs.
associated with axial myopia-associated optic disc enlargement and not with just axial elongation.
3.6.1. Histological changes of papillary and peripapillary region of highly myopic eyes Jonas et al. (Jonas et al., 2011) examined the parapapillary region in highly myopic eyes histomorphometrically and showed that the length of the scleral flange, the sclera
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ACCEPTED MANUSCRIPT between the optic nerve edge and optic nerve dura mater, increased as the AXL increased. In highly myopic eyes, the parapapillary region consisted of an elongated parapapillary scleral flange, and the parapapillary retina was composed of only the retinal nerve fiber layer or its remnants without any other retinal layers.
The underlying Bruch’s membrane and
non-highly myopic eyes.
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choroid were also absent. These histologic features were not detected in any of the Up to a 10-fold elongation and thinning of the peripapillary scleral
susceptibility of highly myopic eyes to glaucoma.
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flange was found (Jonas and Xu, 2014). These findings may partially explain the increased
Jonas et al. (Jonas et al., 2013) also reported that the distance between the
eyes.
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Zinn-Haller arterial ring and the optic disc border was markedly increased in highly myopic Because the Zinn-Haller arterial ring is the main arterial source for the lamina
cribrosa, this finding may be related to the pathogenesis of the higher incidence of glaucoma in highly myopic eyes.
The increased distance of the Zinn-Haller ring from the optic nerve
(Ohno-Matsui et al., 2013).
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has also been confirmed by enhanced depth imaging OCT (EDI-OCT) in highly myopic eyes
Peripapillary atrophy had been considered to be composed of an alpha zone and a However, Jonas et al. (Jonas et al., 2012) recently found that there was a large
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beta zone.
area of defective Bruch’s membrane in the peripapillary atrophy of highly myopic eyes.
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This area lacking Bruch’s membrane was termed the ‘gamma zone’, i.e., the peripapillary sclera without overlying choroid, Bruch's membrane, and absence of the deeper retinal layers.
They showed that the gamma zone was associated with axial globe elongation and
was independent of glaucoma. These findings suggested that an expansion of a hole in Bruch’s membrane around the optic nerve might be the main cause of an enlargement of the myopic conus in highly myopic eyes.
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ACCEPTED MANUSCRIPT 3.6.2. Structural abnormalities on and around the optic nerve in pathologic myopia detected by OCT The subarachnoid space containing the cerebrospinal fluid is not generally observed in normal eyes in situ, however in highly myopic eyes with a large conus, the SAS is visible
2011a).
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in EDI-OCT scans (Park et al., 2012) or in the swept-source OCT scans (Ohno-Matsui et al., In the B-scan images of highly myopic eyes, the SAS is triangular with the base
towards the eye that surrounds the optic nerve in the region of the scleral flange.
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Ohno-Matsui et al. (Ohno-Matsui et al., 2011a) reported that the optic SAS was present in 93% of highly myopic eyes, and the SAS appears to be dilated in the highly myopic eyes.
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The dilated area exposed to the cerebrospinal fluid pressure along with thinning of the posterior eye wall may influence the formation of staphylomas and the way in which certain diseases, such as glaucoma, are manifested.
By using swept-source OCT, Ohno-Matsui et al. (Ohno-Matsui et al., 2012b) found
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pit-like clefts at the outer border of the optic disc or within the adjacent scleral crescent in 32 (16.2%) of 198 highly myopic eyes but none in emmetropic eyes.
The pits were located
either in the optic disc area, optic disc pits, or in the conus area and conus pits, outside the
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optic disc. The optic disc pits were associated with discontinuities of the lamina cribrosa, whereas the conus pits appeared to develop from a scleral stretch-associated schisis or
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emissary openings for the short posterior ciliary arteries in the sclera.
The nerve fiber
tissue overlying the pits was discontinuous at the site of the pits, and this might explain the cause of VF defects in highly myopic eyes in some cases. The locations of the conus pits might partly explain why the papillomacular bundles tend to be damaged in highly myopic eyes.
Kimura et al. (Kimura et al., 2014) reported a high prevalence of defects of the
lamina in highly myopic eyes with glaucoma. Peripapillary intrachoroidal cavitation (ICC) was observed as yellowish-orange
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ACCEPTED MANUSCRIPT lesions located most typically inferior to the optic disc in highly myopic eyes (Freund et al., 2003; Toranzo et al., 2005). They are not uncommon and can be found in 4.9% of highly myopic eyes (Shimada et al., 2006b).
You et al. (You et al., 2013) reported that
peripapillary ICC was found in 16.9 ± 4.0% of highly myopic eyes in an adult Chinese Spaide et al. (Spaide et al., 2012) found that the sclera
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population in the Beijing Eye Study.
in the area of ICCs was displaced posteriorly without affecting the overall curvature of the retina, retinal pigment epithelium (RPE), and the Bruch’s membrane complex.
The
and the posterior surface of Bruch’s membrane.
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cavitation was created by the expansion of the distance between the inner wall of the sclera
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Shimada et al. (Shimada et al., 2006b) reported that visual field (VF) defects were found in as many as 70% of highly myopic eyes with a peripapillary ICC.
Spaide et al.
(Spaide et al., 2012) and Shimada et al. (Shimada et al., 2007) reported that a full thickness defect in the retina along the margin of the ICC was the cause of the VF defects. Although
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ICCs were first reported in highly myopic eyes, recent studies have shown that peripapillary ICCs were also present in emmetropic eyes and even hyperopic eyes (Yeh et al., 2013). Dai et al. suggested that rotation of the optic disc along the vertical axis may cause the
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development of ICCs (Dai et al., 2015).
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3.6.3. Glaucoma and visual field (VF) changes in eyes with high myopia Chihara et al. (Chihara et al., 1997) examined 122 eyes with primary open-angle glaucoma with fair to good control of the intraocular pressure and evidence of optic nerve damage. When the refractive error was used to stratify the eyes into severely myopic (≤ -4 D), mildly myopic (-0.25 to -4 D), and emmetropic or hyperopic (≥ 0 D) eyes, only eyes with severe myopia was a significant risk factor for progressive VF loss.
Chihara et al. (Chihara
and Sawada, 1990) also investigated the parameters that were associated with multiple
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ACCEPTED MANUSCRIPT defects in the retinal nerve fiber layer (RNFL) in eyes with glaucoma.
Multivariate analysis
showed that refractive error was a high-ranking risk factor for multiple RNFL defects.
Eyes
with multiple defects tended to have moderate myopia, focal nerve fiber layer defects, and small optic discs and were less likely to have a diffuse defect in the nerve fiber layer, The multiple defects in the RNFL in
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emmetropia or hyperopia, and a normal discs.
glaucomatous eyes were frequently focal and correlated with the degree of myopia and a small optic disc.
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The VF findings are difficult to interpret in eyes with pathologic myopia.
Highly
myopic eyes usually have a large conus together with various extents of myopic
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maculopathy, which make the analyses and interpretations of automated VF examinations difficult. Thus, most of the studies examining the prevalence of glaucoma have excluded highly myopic eyes.
To overcome the disadvantage of Humphrey 30-2 automated VF test,
Ohno-Matsui et al. (Ohno-Matsui et al., 2011c) used Goldmann kinetic perimetry and
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reported that the incidence of significant VF defects in myopic eyes was significantly higher in eyes with an oval optic disc than that in eyes with a round optic disc.
During a mean
follow-up of 10.2 ± 3.4 years, 73.8% of eyes had significant progression of the VF defects.
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Because the VF defects were progressive, they suggested that high myopia is a high risk factor for VF defects, and that these eyes should be examined at least annually.
The
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combination of stretching and distortion of the optic nerve fibers result in abrupt changes of the scleral curvature which may be the factors that lead to the damage of the optic nerve fibers in highly myopic eyes. There are many issues that have not been satisfactorily explained.
For example, it
is not clear whether the measured intraocular pressure (IOP) is accurate in eyes with very thin sclera.
In eyes with pathologic myopia and myopic maculopathy, the Goldmann kinetic
perimetry can be a powerful tool to detect the existence of VF defects.
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However, how we
ACCEPTED MANUSCRIPT determine the VF defects were attributable to glaucoma or myopic optic neuropathy needs further consideration.
4.
Current challenges and direction of future research For example, how and
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There are many unsolved mysteries in pathologic myopia.
why the posterior staphyloma (a hallmark lesion of pathologic myopia) develops in the patients is still unclear.
McBrien and Gentle (McBrien and Gentle, 2003) proposed that the
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relatively annular organization of the bundles of collagen, around the optic nerve insertion and macular area, result in a local area which is particularly susceptible to the expansive
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force of the normal intra-ocular pressure. This proposal is based on histological observations of patterns of scleral collagen bundles and the biomechanics of sclera. However, this hypothesis has not been proven in the patients with pathologic myopia. The entire thickness of the sclera is visible in eyes with pathologic myopia by using swept-source In addition, the recent polarization-sensitive OCT
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OCT or enhanced depth imaging OCT.
enables the observation of collagen fiber bundles in cornea and sclera (Yamanari, et al., 2008).
Thus, the advance in fundus imaging may make clear whether McBrien and
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Gentle’s proposal is true in the patients with pathologic myopia in the near future. Immense efforts have been devoted to the study of genetic risk factors for ‘high However, the genes responsible for ‘pathologic myopia’ accompanying with
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myopia’.
pathologic complications have not been determined.
Genetic studies reporting
associations with pathologic myopia, have in fact used the terms ‘pathologic myopia’ and ‘high myopia’ interchangeably and based their definition on refractive error and /or axial length alone (Lam et al., 2008; Li et al., 2011; Li et al., 2009; Lu et al., 2011; Nakanishi et al., 2009; Verhoeven et al., 2013). With the standardization of pathologic myopia definition based on the META-PM classification, there are international collaborative effort to search
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ACCEPTED MANUSCRIPT for genes that may be responsible for the development of pathologic myopia per se. If the genes responsible for ‘pathologic myopia’ are identified, it would be clarified whether ‘pathologic myopia’ is genetically different condition than ‘high myopia’, or these 2 conditions are regulated by the same genes.
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The recent epidemiological study showed that in populations where the prevalence of myopia is high, the prevalence of high myopia starts to increase after the age of 10-13 (Li, et al., 2004, Xiang, et al., 2013).
However, it is still uncertain whether ‘high myopia’
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eventually progress to pathologic myopia (characterized by posterior staphyloma or severe myopic maculopathy), or pathologic myopia is a different disease spectrum from ‘high Posterior staphyloma, which is a hallmark of pathologic
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degree of myopic refractive error.
myopia occurs even in non-highly myopic eyes.
Since pathologic myopia is a major cause
of the loss of the best-corrected vision due to its pathological complications especially in East Asia, it is important to clarify whether high degree of myopia can progress to pathologic
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myopia or not. It is also unclear what is the first sign to show myopia is ‘pathologic’? Although imaging studies can be used to show the thinning of the retina, choroid, and sclera, it is still uncertain which one of these changes occurs first and how these changes progress.
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The lack of good animal models mimicking features of human patients with pathologic myopia is another issue.
Most of the animal models reproduce an axial
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elongation, however, they did not reproduce important features of pathologic myopia (posterior staphyloma, severe chorioretinal atrophy).
However recently, Cases et al.
(Cases, et al., 2015) reported that in the adult Lrp2-deficient mouse developed chorioretinal atrophy and posterior staphyloma, and suggested the possibility that this mouse can be a unique tool to further study human pathologic myopia.
In order to evaluate various
pharmaceutical approaches for preventing or treating pathologic myopia, establishing good animal models for pathologic myopia should be developed.
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ACCEPTED MANUSCRIPT Finally, to reduce the blindness due to pathologic myopia, global action should be
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facilitated.
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ophthalmology 157, 451-457 e451. Chia, A., Lu, Q.S., Tan, D., 2015. Five-Year Clinical Trial on Atropine for the Treatment of Myopia 2: Myopia Control with Atropine 0.01% Eyedrops. Ophthalmology. Chihara, E., Liu, X., Dong, J., Takashima, Y., Akimoto, M., Hangai, M., Kuriyama, S., Tanihara, H., Hosoda, M., Tsukahara, S., 1997. Severe myopia as a risk factor for progressive visual field loss in primary open-angle glaucoma. Ophthalmologica 211, 66-71. Chihara, E., Sawada, A., 1990. Atypical nerve fiber layer defects in high myopes with
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ACCEPTED MANUSCRIPT Figure legends Figure 1.
Definition of a posterior staphyloma (cited from reference number 25).
Normal eye shape.
A.
B. Axial length elongation occurring in the equatorial region that
does not induce any alteration in the curvature of the posterior part of the eye. This C.
A second curvature develops
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eye would have axial myopia but no staphyloma.
in the posterior portion of the eye, and this second curvature has a shorter radius (r2)
staphyloma.
This secondary curve is due to a
D. Nasally-distorted type of the eye.
Figure 2.
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definition of staphylomas in this study.
This shape is added to the
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of curvature than the surrounding eye wall (r1).
New classification and re-naming of staphylomas according to their
location (Ohno-Matsui 2014).
Highly myopic eyes without a staphyloma (Ohno-Matsui 2014).
A and B.
Right fundus of a 50-year-old woman with refractive error of -12.5 D and
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Figure 3.
axial length of 29.2 mm. The fundus images taken by Optos shows diffuse
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chorioretinal atrophy is seen around the optic disc.
There is no obvious pigmentary
change suggesting the border of a staphyloma in the pseudocolor image (A), and no
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abnormal-autofluorescence (B).
C. and D. 3D MRI images of the globe.
No
obvious outpouching of the posterior segment is seen viewed nasally (C) and inferiorly (D).
Figure 4.
Eyes with a wide, macular staphyloma (Ohno-Matsui 2014).
A and B. Right fundus of an 83-year-old woman with an axial length of 30.0 mm (pseudophakic eye).
Right fundus photographs taken by Optos (A) shows that the
upper edge of the staphyloma is pigmented in the pseudocolor image (arrows in A),
ACCEPTED MANUSCRIPT and shows granular hypo-autofluorescence (arrows in B).
C and D.
3D MRI
images of this patient show a wide area of posterior outpouching due to a staphyloma. In the image viewed nasally (C), the maximally protruded point exists at the central A slight depression is found along the upper and lower border of the
outpouching (arrows in C).
In the image viewed inferiorly (D), the change of
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point vertically.
curvature is more evident along the temporal margin of the staphyloma than the nasal Thus, the temporal border is observed as a notch (arrow).
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margin.
Figure 5. Myopic Maculopathy Classification according to META-PM study Category 1 maculopathy is characterized by
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based on color fundus photographs.
tessellated fundus, in which outline of choroidal vessels are easily visible throughout the posterior pole (A). Category 2 maculopathy is characterized by diffuse chorioretinal atrophy, in which the posterior pole appears yellowish white in
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appearance (B). Category 3 maculopathy is characterized by patchy chorioretinal atrophy (black arrowheads), which appears as well-defined, grayish-white lesions (C). Category 4 is characterized macular atrophy, which appears as a well-defined, round
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grayish white chorioretinal atrophic lesion around a regressed fibrovascular membrane (D). Lacquer crack (white arrow) is one of the plus lesions, and appears
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as yellowish thick linear pattern (E). Fuchs spot (black arrow) is a pigmented spot representing the scarring phase of myopic choroidal neovascularization (F).
Figure 6. Imaging of myopic CNV.
Fundus photo of the right eye of a 64-year-old
female with -14D myopia presenting the fibrovascular membrane surrounded by macular hemorrhage (A).
Macular choroidal neovascularization (CNV) shows a
clear hyper-fluorescence (B). coherence tomography (OCT).
CNV is observed as subretinal elevation by optical Serous retinal detachment is also seen.
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Figure 7. Development of macular atrophy related to myopic choroidal neovascularization (CNV-related macular atrophy). At the onset, the CNV surrounded by macular hemorrhage is seen (A).
? years later,
Figure 8. Anti-VEGF therapy for myopic CNV.
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the well-defined macular atrophy (B) develops around the scarred CNV.
Fundus photo of the right eye of a
Late phase fluorescein angiography (FA) showing active
leakage from a myopic CNV (B).
Horizontal spectral domain optical coherence
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shallow subretinal fluid (A).
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52-year-old female with -12D myopia presenting with macular hemorrhage and
tomography (SD-OCT) showing hyper-reflective material in the subretinal space due to macular hemorrhage with adjacent subretinal fluid due to active CNV (C).
At 12
months after commencement of intravitreal ranibizumab injections, there was Post-treatment
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complete resolution of macular hemorrhage and subretinal fluid (D).
FA showed staining of scar due to fibrosis of CNV and no leakage was seen (E). Horizontal scan of SD-OCT showed resolution of subretinal hyperreflective material
Diagnostic and treatment flowchart for the management of suspected
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Figure 9.
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with complete absence of subretinal fluid after anti-VEGF therapy (F).
myopic CNV.
Figure 10. Dome-shaped macula. Dome shaped macula are difficult to observe on fundus photograph or biomicroscopy. On optical coherence tomography (OCT), an invward bulge within the concavity of the posterior pole over the macula is clearly visible in the vertical section but less obvious in the horizontal section (indicated by black lines on fundus image). The subfoveal sclera (black double-headed arrow) is
ACCEPTED MANUSCRIPT markedly thickened compared to parafoveal regions.
Figure 11. Macular Hole with Retinal Detachment A 44 year old man with type 1 macular hole retinal detachment underwent vitrectomy
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with internal limiting membrane repositioning and autologous blood showed re-attachment of the retina in the macula area. Spectral domain optical coherence tomography images before, 2months, and ten months after surgery showed gradual
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the internal limiting membrane reposition.
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resolution of the retinoschisis and sub-retinal fluid (arrowheads). Asterisk indicated
Figure 12. Myopic Traction Maculopathy (MTM)
Myopic traction maculopathy (MTM) can be classified using spectral domain optical coherence tomography as macular retinoschisis (MRS), MRS with foveal detachment,
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MRS with lamellar hole, MRS with full thickness macular hoe and macular hole with retinal detachment. Shimada et al. have classified myopic traction maculopathy according to its location and extent from S0 through S4: S0: no retinoschisis; S1:
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extrafoveal; S2: foveal; S3: both foveal and extrafoveal but not the entire macula; and S4: entire macula (Shimada, Tanaka et al. 2013). S1 upper image shows progression
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from S0 image. S4 images showed horizontal (upper) and vertical (lower) scans from the same eye.
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Table 1. Summary of the Classification of Myopic Maculopathy according to META-PM study.
Category 2
Diffuse chorioretinal atrophy
Category 3
Patchy chorioretinal atrophy
Category 4
Macular atrophy
+ Lc + CNV
Lacquer cracks Choroidal neovascularization
+ Fs
Fuchs spot
-
Posterior staphyloma
Well-defined choroidal vessels can be observed clearly around the fovea and arcade vessels The posterior pole appears yellowish white, extent of which is variable Well-defined, grayish white lesions, size variable between 1 and several choroidal lobules Well-defined, round chorioretinal atrophic lesion that is grayish white or whitish around a regressed fibrovascular membrane that enlarges with time. Generally macular atrophy is centered on the central fovea and has a round shape. Yellowish thick linear pattern Active CNV should be accompanied by exudative activity or hemorrhage. Serous retinal detachments can be present Pigmented spot representing the dry fibrovascular scar of myopic CNV Local bulging of the sclera at the posterior pole that has a radius of less than the surrounding curvature of the wall of the eye
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Fundus Appearance
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Myopic Retinal Changes No myopic retinal changes Tessellated fundus
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META-PM Classification Category 0 Category 1
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OCT findings Mean BCVA, mean (range) Age (years), Axial length
Mean
Gas Surgical
Year
Author(s)
eyes
mean (range)
(range)
After surgery
ILM
(mm), mean follow-up
decimal or Snellen or logMAR tamponad
Procedures (patient)
Before surgery
Complete/Partia
Complications
peeling
(months)
e
MRS/FD/FTMH/LMH/MHRD l resolution of
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No. of
Before surgery
After surgery
RD and MRS
63.8
28.47
24
33 (5-46)
NA
2012 Mateo et al.
16
60.3 (42-79)
NA
2013 Mateo et al.
39(36)
59 (35-79)
2009
2014
2014
2012
2014
2003
Zhu et al.
Burés-Jelstr up et al.
Ei Rayes EN et al.
Ho et al.
(26.3-34.5)
16
52.2 (36-63) (28.34-31.48
NA
logMAR 0.81
logMAR 0.99
25.7
MB
-
NA
6/3/0/0/0
2/6
0.3
0.57
MB
-
NA
24/NA
20/4
NA
NA
14.7
MB and VT
-
+
16/13/0/8/0
16/0
20/125
20/50
16
MB and VT
NA
NA
39/28/0/9/0
NA
logMAR 0.76
logMAR 0.43
25.3
MB and VT
33 (29-38)
12
choroidal MB
8
58 (38-70)
NA
5.4
Vitrectomy
12
58.2
NA
52.4
Vitrectomy
7
54.4
NA
55.6
Vitrectomy
20.4
Vitrectomy
8 and 12
2(2)
52 and 84
2004 Ikuno et al.
6(9)
59.5 (51-63)
6(5)
61
er
7/1
and VT
2003 Kanda et al.
Spaida&Fish
10/10/0/0/0
supra 23
54.7 (36-74)
al.
+
)
Ho et al.
Kobayashi et
-
30.19
9(7)
2005
30.8
IVI gas
27.5 (26.5-28.5) NA 29.2 (27.9-29.9) NA
+
-
foveola
nonpeeling foveola
NA
+
NA NA
nonpeeling total
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6(5)
11.65
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58.80 ± 8.28 30.43 ± 2.42
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2006 Baba et al.
10
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Wu et al.
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2013
SRH in 2, CNV 1, CRA in 1 eye MRS recurred in 3, MH in one eye CD in 3, RPE atrophy in 5 RPE atrophy in 6, buckle removal in 3, RD in 2 eyes
16/0/16/0/0
NA
20/125
20/50
11/0/0/0/12
23/0
NA
NA
logMAR 1.75
logMAR 1.17
(1.70-3.0)
(0.70-2.0)
extrusion of exoplant in 1 eye choroidal hemorrhage and macula hole
8/NA
11/NA
7/1/ NA
logMAR 1.7±0.4
logMAR 0.89±0.56
-
MH in 2 eyes
logMAR
logMAR
1.67±0.23
1.39±0.33
8/1
0.17 (0.02-0.4)
0.48 (0.4-0.6)
FTMH in 1 eye
2/1/0/0/0
1/1
NA
NA
-
+
6/6/0/0/0
5/1
0.1
0.43
-
+
4?/4?/0/1/0
6/0
20/100
20/60
-
NA
7/NA
NA
+
+
9/9/0/0/0
Vitrectomy
+
1/2 eyes
14
Vitrectomy
+
19.1
Vitrectomy
-
peeling
2 unchnaged
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2006 Ikuno&Tano
8(8)
63.1
2006 Scott et al.
3(3)
53, 31, 69
24
58 (32-79)
11
55 (43-70)
3(3)
58.3 (52-62)
2008 Ikuno et al.
44(42)
63.3 (43-79)
2009 Fang et al.
6(6)
53.1
39(39)
66.3 (44-80)
2011 Zheng et al.
18(17)
51.3 (25-78)
2012 Wang et al.
11
2007
2007
2008
2010
al.
Pannozzo & Mercanti Gaucher et al. Yeh et al.
Kumagai et al.
Vitrectomy
25.6
Vitrectomy
NA
Vitrectomy
+
8,7,1
Vitrectomy
2/3 eyes
NA
29.6
Vitrectomy 24/24 eyes
NA
26.9
Vitrectomy
12
Vitrectomy
-
12
Vitrectomy
+
9.8
Vitrectomy
-
41
Vitrectomy
+
17.5
Vitrectomy
6
Vitrectomy
11.8
Vitrectomy
28.0 (24.9-30.2) 29 32.6mm in 1 case
30.0 (28.8-31.1) 29.1 (24.4-34.6) 29 28.6 (24.4-34.7) 29.7 (26.8-34.1)
51.3 (39-60) 29.32±1.81
2012
Lim et al.
15(13)
60.3 ± 12.5
30.8±2.6
2012
Kim et al.
17(17)
61.9 (44-78) (27.80-32.95 13 or 15.3 ) 29.16
2012
Shin & Yu
38(36)
63.5 (32-84) (26.61-36.17 )
2013
2013
Taniuchi et al. Hwang JU et al.
71(64)
33(29)
65.5 ± 8.6
63.2 ± 9.3
29.01
6
9/9/0/0/0
7/2
20/80
20/50
-
16/11/2/0/0
16/0
NA
NA
FTMH in 5 eyes
8/8 eyes
8/0/8/0/0
8/0
20/300
20/130
3/3 eyes
3/2/0/0/0
3/0
NA
NA
NA
+
24/5/0/0/0
23/0
logMAR 0.6
logMAR 0.43
FTMH in 5 eyes, 1
(1.1-0.2)
(1.1 to -0.1)
unchanged FTMH in 3 eyes
1/11 eyes 6/11 eyes
Vitrectomy
Vitrectomy
+
6/16 eyes 12/16 eyes
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29.75
-
hole size in 1 eye
4/4
logMAR 0.97
logMAR 0.63
3/3/0/0/0
1/2
CF-0.04
0.27 (0.2-0.3)
+
16/17/11/0/0
44/0
NA
NA
FTMH in 2 eyes
+
6/6/0/0/0
4/2
20/400
20/160
-
34/39 eyes
39/27/0/0/0
39/0
logMAR
logMAR
0.79±0.60
0.54±0.60
logMAR 0.94
logMAR 0.49
(2-0.15)
(1.3-0.15)
0.1
0.18
+
+
11/18 eyes
18/12/0/0/0
18/0
+
+
11/6/0/0/0
11/0
+
-
15/NA
15/0
+
9/17 eyes
10/7/0/0/0
12/2
+
+
38/7/2/0/0
34/3
26/30/15/0/0
NA
+
FTMH in 6, enlarged
11/5/0/0/0
27.7 ± 25.9 Vitrectomy 61/71 eyes 35/71 eyes
29.73 ± 2.08 19.3 ± 12.8 Vitrectomy
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64.9 (53-77)
Hirakata et
17.2
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16(14)
2006
29.0 (26.3-32.1)
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9(8)
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2005 Kwok et al.
air, gas or silicon oil
33/7/5/4/3
33/0
logMAR
logMAR
0.78±0.53
0.61±0.75
logMAR 0.81-0.83
logMAR 0.56
RD in 1 and retinal breaks in 1 eye
-
FTMH in 2 eyes
FTMH in 2 eyes, 3 unchanged
logMAR
logMAR
0.84±0.53
0.53±0.54
logMAR
logMAR
0.64±0.41
0.43±0.38
logMAR
logMAR
MH in 1 eyes,
1.01±0.47
0.76±0.64
persistent MRS in 1
FTMH in 1 eye
MHRD in 7, MH in 4, TMD in 2, RRD in 3 eyes
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2014 Chang et al.
10(9)
41
60.4 (45-74) 30.76 ± 2.40
61 (36-86)
NA
17
6.4
Vitrectomy
+
-
Vitrectomy 35/41 eyes 34/41 eyes
10/6/0/0/0
41/16/11/0/0
5/3
NA
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2014 Uchida et al.
(20/200)
(20/120)
0.61
0.47
20/130
20/70
eye MHRD in 2 eyes, RD in 1 eye re-operation in 11 eyes
IVI: intravitreal injection; MB: macular buckling or reinforcement; VT: vitrectomy; ILM: internal limiting membrane; NA: not available; MRS: macular retinoschisis; FD: foveal detachment; FTMH: full thickness macular hole, LMH: lamellar macula hole; MHRD: macular hole with retinal detachment; BCVA: best corrected visual acuity; BCVA was expressed as decimal data, Snellen, or logMAR (minimum angle or resolution) based on
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original data; SRH: subretinal hemorrhage; CRA: chorioretinal atrophy; RD, retinal detachment; RPE: retinal pigment epithelium.
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S1350-9462(15)30003-3
DOI:
10.1016/j.preteyeres.2015.12.001
Reference:
JPRR 615
To appear in:
Progress in Retinal and Eye Research
Received Date: 15 November 2015 Revised Date:
28 December 2015
Accepted Date: 30 December 2015
Please cite this article as: Ohno-Matsui, K., Lai, T.Y.Y., Lai, C.-C., Cheung, C.M.G., Updates of Pathologic Myopia, Progress in Retinal and Eye Research (2016), doi: 10.1016/ j.preteyeres.2015.12.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Updates of Pathologic Myopia Kyoko Ohno-Matsui1, Timothy Y. Y. Lai2, Chi-Chun Lai3, Chiu Ming Gemmy Cheung4
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1: Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 1138510, Japan
2: Department of Ophthalmology & Visual Sciences, The Chinese University of
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Hong Kong, Hong Kong Eye Hospital, 147K Argyle Street, Kowloon, HONG KONG
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3:Department of Ophthalmology, Chang Gung Memorial Hospital, Chang Gung University. No.5, Fuxing Street, Guishan Dist., Taoyuan City 33305, Taiwan 4: Singapore National Eye Center, 11 Third Hospital Avenue, Singapore
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Corresponding to; Kyoko Ohno-Matsui, MD.
Department of Ophthalmology
and Visual Science, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku,
Tokyo
1138510,
Japan.
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+81-3-3818-7188, email; [email protected]
Tel;
+81-3-5803-5302,
Fax;
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Abstract Complications from pathologic myopia are a major cause of visual impairment and blindness, especially in east Asia.
The eyes with pathologic myopia may
macula, peripheral retina and the optic nerve.
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develop loss of the best-corrected vision due to various pathologies in the
Despite its importance, the definition of pathologic myopia has been inconsistent.
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The refractive error or axial length alone often does not adequately reflect the ‘pathologic myopia’. Posterior staphyloma, which is a hallmark lesion of
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pathologic myopia, can occur also in non-highly myopic eyes.
Recently a
revised classification system for myopic maculopathy has been proposed to standardize the definition among epidemiological studies. In this META-PM (meta analyses of pathologic myopia) study classification, pathologic myopia
than diffuse atrophy.
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was defined as the eyes having chorioretinal atrophy equal to or more severe
In addition, the advent of new imaging technologies such as optical coherence
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tomography (OCT) and three dimensional magnetic resonance imaging (3D MRI) has enabled the detailed observation of various pathologies specific to New therapeutic approaches including intravitreal
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pathologic myopia.
injections of anti-vascular endothelial growth factor agents and the advance of vitreoretinal surgeries have greatly improved the prognosis of patients with pathologic myopia. The purpose of this review article is to provide an update on topics related to the field of pathologic myopia, and to outline the remaining issues which need to be solved in the future.
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Keywords Pathologic myopia; myopic maculopathy; posterior staphyloma; optic nerve
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changes; choroidal neovascularization
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1.
Introduction
2. 3.
Epidemiology Complications of Pathologic Myopia Posterior staphyloma Definition of staphyloma
3.1. 3.1.1.
New classification using three-dimensional magnetic resonance imaging (3D MRI) and wide-field fundus imaging Incidence of staphyloma and related factors
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3.1.2.
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Table of Contents
3.1.4. 3.1.5. 3.2. 3.2.1. a. b. c.
3.3. 3.3.1. 3.3.2. 3.3.3.
maculopathy Myopic CNV Prevalence, incidence and bilaterality Diagnosis of myopic CNV based on imaging Differential diagnoses
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3.2.2. 3.2.3.
Lacquer cracks (Plus sign) Myopic CNV (Plus sign) Natural Progression of each lesion Pathogenesis and Potential Therapy for myopic
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d. e.
Macular complications of eyes with staphylomas Therapies targeting staphylomas Myopic Maculopathy Classification in META-PM study Details of each lesion Diffuse Chorioretinal atrophy (Category 2) Patchy Chorioretinal atrophy (Category 3)
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3.1.3.
a.
b. c. d. e.
3.3.4. 3.3.5.
Subretinal bleeding due to new lacquer crack formation Punctate inner choroidopathy
Idiopathic CNV Serous detachment in dome-shaped macula Polyps at edge of tilted disc syndrome Natural prognosis and development of CNV-related macular atrophy Anti-VEGF therapy for myopic CNV
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Diagnostic and treatment flow-charts for myopic CNV Other fundus lesions in the posterior fundus Dome-shaped Macula Radial ascending tracts emanating from staphyloma
3.4.3. 3.5.
edge Chorioretinal folds from staphyloma edge Surgical conditions Macular Hole, Macular Hole Retinal Detachment
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3.3.6. 3.4. 3.4.1. 3.4.2.
3.5.1.
Myopic traction maculopathy (MTM) Surgical techniques to treat MTM Surgical outcome of MTM Peripheral retinal degenerative changes
3.5.3.1. 3.5.3.2. 3.6.
Lattice degeneration, retinal holes, Retinal tears Rhegmatogenous retinal detachment Optic Disc Changes and glaucoma in Pathologic Myopia Histological changes of papillary and peripapillary
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3.6.1.
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3.5.2. 3.5.2.1. 3.5.2.2. 3.5.3.
4. 5. 6.
Current challenges and direction of future research Acknowledgements References
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3.6.2.
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3.6.3.
region Structural abnormalities detected by optical coherence tomography (OCT) Visual field (VF) changes in highly myopic eyes
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Introduction Complications from pathologic myopia are a major cause of visual impairment and
blindness, especially in east Asia (Chan et al., 2015; Foster and Jiang, 2014; Morgan et al., 2012; Wong et al., 2014).
The eyes with pathologic myopia may develop visual loss due to
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various pathologies in the macula, peripheral retina and the optic nerve (Morgan et al., 2012). The deformity of the globe including posterior staphyloma may facilitate the development of these pathologies.
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The definition of pathologic myopia has been inconsistent. The term “pathologic myopia” was originally described as myopia accompanied by characteristic degenerative
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changes in the sclera, choroid, and retinal pigment epithelium, with compromised visual function (Morgan et al., 2012; Tokoro, 1988). Excessive elongation of the globe and posterior staphyloma are believed to be important factors in the development of these degenerative changes in pathologic myopia (Moriyama et al., 2011b).
However, the
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refractive error or axial length alone often does not adequately reflect the ‘pathologic myopia’. Posterior staphyloma, which is a hallmark lesion of pathologic myopia, can occur also in non-highly myopic eyes (Curtin, 1977, 1985; Wang et al., 2015a). Recently an international
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panel of researchers in myopia reviewed previous published studies and classifications and proposed a simplified, uniform classification system for pathologic myopia for use in future
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studies (Ohno-Matsui et al., 2015b).
In this META-PM (meta analyses of pathologic
myopia) study classification, pathologic myopia was defined as the eyes having chorioretinal atrophy equal to or more severe than diffuse atrophy. Over the past two decades, advances in imaging technologies such as optical coherence tomography (OCT), wide-field imaging, and three-dimensional magnetic resonance imaging (MRI) have greatly enhanced our understanding in the ocular complications associated with high myopia. OCT enables the high-resolution in vivo assessment of the optic nerve and macula and new disease entities such as myopic traction
ACCEPTED MANUSCRIPT maculopathy (Panozzo and Mercenti, 2004) and dome-shaped macula (Gaudric, 2008) have been described.
New treatment technologies such as anti-angiogenesis therapy and small
gauge vitrectomy have also enhanced the treatment outcomes of some complications associated with high myopia.
However, despite these advancements, considerable
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challenges still exist in the management of irreversible vision loss in high myopia due to macular or optic nerve atrophy. This review will highlight our current understanding of the various ocular complications in high myopia as well as our current limitations in managing
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these conditions. To-date there is no proven method to prevent or retard the development
2.
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or progression of these complications.
Epidemiology
The prevalence of pathologic myopia has been evaluated in several population studies, although some variations in the definition of pathologic myopia exist between
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studies (Asakuma et al., 2012; Gao et al., 2011; Hsu et al., 2004; Hu, 1987; Liang et al., 2008; Liu et al., 2010; Pan et al., 2013; Vongphanit et al., 2002b; Wong et al., 2014). Recently, these publications have been evaluated and summarized in an evidence-based
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systematic review (Wong et al., 2014).
Prevalence of pathologic myopia from 4 studies in
Asian populations ranged from 0.9% to 3.1%, while the Blue Mountains Eye Study (BMES)
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reported 1.2% in an Australian population (Vongphanit et al., 2002b). Furthermore, pathologic myopia has been reported as the primary cause of blindness or low vision in 7% in European populations (Cedrone et al., 2006; Klaver et al., 1998) and in 12-27% in Asian populations (Iwase et al., 2006; Xu et al., 2006; Yamada et al., 2010).
The impact of
pathologic myopia on vision and vision-specific quality of life is further amplified by the high likelihood of bilateral involvement in young individuals (Verkicharla et al., 2015).
Among the
pathologic changes, current treatment is only available for selected lesions, such as
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No effective restorative treatment
is currently available for eyes with progressive deterioration due to development of chorioretinal atrophy or optic neuropathy. In addition to the severity of myopia, increasing age is also an important risk factor
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for the development of pathologic changes in high myopia (Chen et al., 2012c; Shih et al., 2006; Silva, 2012; Verkicharla et al., 2015). The prevalence of myopic maculopathy has been shown to be low in children (Kobayashi et al., 2005; Samarawickrama et al., 2011), but
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increases (Chang et al., 2013) with age. In teenage children with high myopia, myopic maculopathy was rare, and the most common changes noted were tilted disc (37%) and
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β-peripapillary atrophy (39%) (Samarawickrama et al., 2011).
In an adult population aged
40 years and above with high myopia, both the prevalence and severity of maculopathy were much higher (staphyloma 23%, chorioretinal atrophy 19.3%) (Chang et al., 2013). Furthermore, continued elongation of the globe and progression of maculopathy lesions with
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time have been demonstrated in follow-up studies (Hayashi et al., 2010; Saka et al., 2010). Hayashi et al. reported that 40% of the highly myopic eyes had progression of myopic maculopathy during a mean follow-up of 12.7 years (Hayashi et al., 2010).
In the BMES,
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17.5% of eyes had progression of myopic retinopathy over a 5-year follow up period (Vongphanit et al., 2002b). The changes noted included new or expansion of pre-existing
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chorioretinal atrophy, and new or increased numbers of lacquer cracks. Similar progression patterns have also been noted in longitudinal follow up in the Beijing Eye Study (Liu et al., 2010).
In another study with 10 year follow-up, Shih et al. demonstrated that apart from
development of choroidal neovascularization or macular atrophy, fusion of areas with other patchy atrophy caused significant decrease in vision (Shih et al., 2006).
The incidence and
type of progression have also been shown to be influenced by the types of fundus lesions. Detailed evaluation of the longitudinal progression patterns of each lesion subtype suggest
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2012; Vitale et al., 2009).
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increasing rapidly, possibly due to changes in environmental and lifestyle factors (Pan et al., Therefore, the prevalence of vision threatening complications
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due to pathologic myopia is likely to increase dramatically over the next few decades.
Pathologic myopia has been reported as one of the most common causes of
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blindness both from population surveys and from blind registry data. Analysis of blind registry data from several countries estimated pathologic myopia as the cause of blindness in 6.0-9.1% of white populations (Avisar et al., 2006; Ghafour et al., 1983; Krumpaszky et al., 1999; Macdonald, 1965) and much higher (26.1%) in Chinese (Wu et al., 2011).
The
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annual incidence of blindness attributable to pathologic myopia in the general population can further be estimated to range from 0.77 per 100,000 for Germany (Krumpaszky et al., 1999) to 2.1-4.3 per 100,000 for Israel (Avisar et al., 2006). The Beijing Eye Study estimated a
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0.05% incidence of pathologic myopia from the 5-year follow-up data (Liu et al., 2010). It is clear that pathologic myopia is a major public health problem worldwide and its
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disease burden likely to increase. condition.
Significant challenges remain in the management of this
First, in order to facilitate further studies and comparison between different
populations, a standardized set of definitions for the classification of myopic maculopathy and, in turn, pathologic myopia is needed.
Recently a revised classification system for
myopic maculopathy based on detailed definitions of individual fundus signs has been proposed in order to address this issue (see Myopic Maculopathy section for details) (Ohno-Matsui et al., 2015b).
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Second, it is now clear that pathologic myopia is not a static
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Yet, the risk factors for progression
remain poorly understood. There is thus an urgent need to better understand the underlying pathologic processes, such as mechanical stress, degeneration and ischemia with aging, and whether these factors may be modifiable.
Finally, despite recent advances
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in the treatment of choroidal neovascularization with anti-vascular endothelial growth factor (Ikuno et al., 2015; Sakaguchi et al., 2007; Wolf et al., 2014; Wong et al., 2015), and the ability to operate on tractional myopic maculopathy with increasingly sophisticated surgery,
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most complications of pathologic myopia, such as macular atrophy, chorioretinal atrophy and optic neuropathy remain untreatable. Studies on the long-term outcome of CNV and
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tractional myopic maculopathy are also limited. Nonetheless, promising novel therapies, including pharmacological (Chia et al., 2012; Chia et al., 2014; Chia et al., 2015) and surgical approaches, aiming to reduce the incidence and severity of myopia are on the horizon.
It remains to be seen whether such measures will translate into a reduction in the
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incidence and severity of pathologic myopia and the associated devastating impact on vision.
Complications of Pathologic Myopia
3.1.
Posterior staphyloma
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A posterior staphyloma is an outpouching of a limited area of the posterior segment of the eye, which is a representative deformity of eyes with pathologic myopia. Posterior staphyloma is a reliable indicator for pathologic myopia. However, there has been some confusion about how staphylomas should be regarded. In some earlier studies, a posterior staphyloma was regarded as one of the lesions of myopic retinopathy or myopic maculopathy (Avila et al., 1984; Chang et al., 2013; Chen et al., 2012b; Gao et al., 2011; Vongphanit et al., 2002a).
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However, a staphyloma can also be considered to be a cause of
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Nevertheless, the best way to detect the presence of a staphyloma has not been determined. Earlier studies used conventional fundus photography (Chang et al., 2013; Chen et al., 2012a; Gao et al., 2011; Samarawickrama et al., 2011; Vongphanit et al., 2002b),
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ophthalmoscopy and fundus drawings (Curtin, 1977), ultrasonography (Hsiang et al., 2008; Steidl and Pruett, 1997), OCT (Ikuno and Tano, 2009; Lim et al., 2014; Miyake et al., 2014), OCT is a useful tool to show the shape of the sclera,
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or a combination of these methods.
and Ohno-Matsui et al. (Ohno-Matsui et al., 2012a) used swept-source OCT to determine the entire thickness of the sclera and the contour of the sclera in many highly myopic eyes. However, the scan length of currently available OCT instruments is not long enough to cover
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the entire extent of a wide staphyloma. Computed tomography (Anderson et al., 1983; Osborne and Foulks, 1984; Smith and Castillo, 1994; Swayne et al., 1984) and MRI (Mafee et al., 2005; Malhotra et al., 2011) have been reported to be able to obtain images of However, these studies also used 2-dimensional images and did not show
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staphylomas.
the entire shape of the staphylomas.
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Recently, new imaging modalities that can obtain images of the entire globe, e.g., 3D MRI (Moriyama et al., 2011a; Moriyama et al., 2012; Ohno-Matsui, 2014a) or ultra-wide fundus imaging (e.g. Optos) have become available.
By using a combination of 3D MRI
and Optos, Ohno-Matsui (Ohno-Matsui, 2014a) examined the prevalence and types of posterior staphylomas. These advances in ocular imaging have made the objective and quantitative evaluations of posterior staphylomas possible.
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3.1.1. Definition of staphyloma (Figure 1)
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of staphylomas.
A uniformly accepted definition of a posterior staphyloma has not been made.
It is
still common for clinicians and researchers to refer to abnormal structures in the posterior
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pole of myopic eyes, even those that do not involve an outpouching, as being staphylomas. Spaide (Spaide, 2013) made a clear definition of a staphyloma as “an outpouching of the
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wall of the eye that has a radius of curvature that is less than the surrounding curvature of the wall of the eye” (Figures 1A to 1C) in Pathologic Myopia. In addition, our clinical experience suggests that peripapillary and nasal staphylomas do not have a distinct and abrupt change in the curvature from the surrounding curvature of the wall of the eye in many Instead, the shape of eyes with peripapillary and nasal staphylomas appear to be
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cases.
nasally distorted (Ohno-Matsui et al., 2012a). Thus, the nasally distorted type of globe was added to the definition of staphylomas (Figure 1D).
It is expected that OCT will be useful in
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detecting the posterior scleral curvature in eyes with peripapillary staphylomas, based on an ongoing study in the High Myopia clinic of the Tokyo Medical and Dental University.
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Once a staphyloma is formed, the area of the posterior fundus including the macula and optic nerve is greatly elongated and the AXL could be doubled. Thus, it can be imagined that the mechanical stretching is increased considerably in highly myopic eyes with a staphyloma compared to those without it.
3.1.2. Classification using three-dimensional magnetic resonance imaging (3D MRI) and wide-field fundus imaging
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ACCEPTED MANUSCRIPT Based on ophthalmoscopic observation and fundus drawing, Curtin (Curtin, 1977) first classified posterior staphylomas in eyes with pathologic myopia into 10 different types based on ophthalmoscopy and fundus drawings.
Types I to V were considered primary
staphylomas, and types VI to X were combined staphylomas.
Curtin (Curtin, 1977) also
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described five other varieties of compound posterior staphylomas with each essentially a variation of the primary Type I. These types of staphylomas can consist of a combination of Type I with another type such as Type II or Type III.
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Recently, Moriyama and Ohno-Matsui used 3D MRI to analyze the entire shape of the eye (Moriyama et al., 2011a; Moriyama et al., 2012). The 3D MRI technique was found
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to be well suited for examining the eye shape over a wide area that can encompass even a large posterior staphyloma. This technique also allows a view of a staphyloma from any angle. They used 3D MRI to determine the presence and types of staphylomas, and proposed a simple classification of staphylomas based on the 3D MRI results (Moriyama et
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al., 2011a; Moriyama et al., 2012). To make the classification useful for clinicians, Ohno-Matsui (Ohno-Matsui, 2014a) correlated the 3D MRI findings with the funduscopic features seen by ophthalmoscopy.
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A relatively new imaging technology, the Optos Optomap Panoramic 200A imaging system (Optos, PLC, Dunfermline, Scotland), was used to obtain noncontact, non-mydriatic,
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panoramic images of the fundus.
Ultra-widefield fundus images of 200° of the retina were
recorded. In these images, the peripheral retina is photographed simultaneously without the need for refixation by the patient. Ohno-Matsui (Ohno-Matsui, 2014b) then correlated the shapes of the staphyloma detected by 3D MRI with the abnormal findings seen in the Optos images, and constructed a classification that can be used to analyze the Optos images obtained under conventional clinical conditions.
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Her classification is a slight modification of
ACCEPTED MANUSCRIPT that described in Pathologic Myopia (Ohno-Matsui, 2014a; Ohno-Matsui and Moriyama, 2013).
Briefly, the basic principles are as follows:
Only the contour of the outermost border of a posterior staphyloma was analyzed.
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Combined staphylomas in Curtin's classification (Curtin, 1977) are characterized by the presence of irregularities within the staphylomatous area. This resulted in the Curtin types VI to X being placed into the Type I category.
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Type I → wide, macular staphyloma
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The staphyloma type is renamed according to its location and extent (Figure 2).
Type II → narrow, macular staphyloma Type III → peripapillary staphyloma Type IV → nasal staphyloma
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Type V → inferior staphyloma
Others → staphylomas other than types I to V
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3.1.3. Incidence of staphyloma and related factors Moriyama et al. (Moriyama et al., 2011a) examined 198 eyes of 105 patients with
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pathologic myopia (mean age, 64.3 ± 11.5 years and mean AXL, 30.0 ± 2.3 mm) and found that 98 eyes (49.5%) had no evidence of a staphyloma by 3D MRI.
All of these eyes were
barrel-shaped (Figure 3) in both the horizontal and vertical sections in the 3D MRI. The other 100 (50.5%) eyes had a posterior staphyloma in the 3D MRI. The most common type was the wide macular type with 74 of the 100 eyes (74%, Figure 4), followed by the narrow macular type with 14 (14%) eyes, the inferior type with 3 (3%) eyes, the peripapillary type with 5 (5%) eyes, and the nasal type with 2 (2%) eyes.
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ACCEPTED MANUSCRIPT The age and the AXL have been found to be highly correlated with the development and progression of staphylomas (Gozum et al., 1997).
Curtin and Karlin (Curtin and Karlin,
1970) examined the ophthalmoscopic findings and fundus drawings of 500 eyes, and they reported that the prevalence of posterior staphyloma increased from 1.4% in eyes with an Hsiang et al.
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AXL of 26.5 to 27.4 mm to 71.4% in eyes having an AXL of 33.5 to 36.6 mm.
(Hsiang et al., 2008) used ultrasonography and determined that staphylomas were present in 90% of a group of 209 eyes with high myopia (defined by myopic refractive error > 8 D or Gozum et al. (Gozum et al., 1997) reported that the percentage of eyes
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AXL≥ 26.5 mm).
with a posterior staphyloma increased significantly with an increase in AXL and also with
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age. However, Curtin also reported a wide variation of AXLs even among the same type of staphylomas, e.g., the AXL varied from 25.1 to 38.0 mm in the eyes with Type I staphyloma (Curtin, 1977).
Based on this, he suggested that AXL might be an unreliable indicator of
pathologic myopia, and pathologic myopia should be defined by the presence of a
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staphyloma.
It has been reported that children and young individuals do not generally have staphylomas even though they are highly myopic (Kobayashi et al., 2005).
Curtin reported
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that staphylomas were found in 13.2% of younger highly myopic patients with ages ranging between 3 to 19 years, but they were found in 53.5% of older highly myopic patients whose
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ages ranged between 60 to 86 years (Curtin, 1977).
3.1.4. Macular complications of eyes with staphylomas Earlier studies showed the worse vision in highly myopic eyes with staphyloma than those without.
Steidl and Pruett analyzed the macular complications in 116 eyes of 58
patients with high myopia (Steidl and Pruett, 1997).
The staphylomas were graded 0 to 4
based on only the contour changes in B-scan ultrasonographic images.
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A linear
ACCEPTED MANUSCRIPT relationship was observed between the staphyloma grade and lacquer cracks and chorioretinal atrophy.
They reported that the best-corrected visual acuity (BCVA) was
reduced in eyes with all types of staphylomas. By using ultra-wide field fundus imaging, Ohno-Matsui (Ohno-Matsui, 2014a) found that the mean BCVA was significantly better in
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eyes without a staphyloma than in eyes with any type of staphyloma (P = 0.0024, 0.30 ± 0.05 logMAR units vs. 0.54 ± 0.06 logMAR units) and in eyes with the wide macular type of staphyloma (P = 0.0002, 0.30 ± 0.05 logMAR units vs. 0.61 ± 0.07 logMAR units).
They
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also found that eyes with the shallowest staphyloma depth had the largest decrease in the BCVA as well as the greatest incidence of macular CNV.
Based on these findings, they
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suggested that the development of a CNV might require preservation of the choriocapillaris in eyes with less advanced stages of posterior staphyloma formation. Some earlier studies using OCT to detect the staphylomas reported a higher prevalence of myopic traction maculopathy in eyes with staphylomas (Baba et al., 2003;
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Benhamou et al., 2002; Forte et al., 2008; Henaine-Berra et al., 2013; Hirakata and Hida, 2006; Oie et al., 2005; Panozzo and Mercanti, 2004; Rahimy et al., 2013; Takano and Kishi, 1999; Wu et al., 2009), although the change of scleral curvature in axially-elongated eyes
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are sometimes confused as having staphylomas. Oie et al. (Oie et al., 2005) analyzed 28 highly myopic eyes with macular hole retinal detachment (MHRD) and 47 highly myopic
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eyes without MHRD, and reported that staphylomas were significantly more frequent in the eyes with MHRD than highly myopic eyes without MHRD.
The rate of type II staphylomas
(Curtin’s classification) was significantly higher in the eyes with MHRD.
The presence of a
severe degree of staphyloma has been reported to develop vitreoretinal complications by Ripandeli et al. (Ripandelli et al., 2008). Ohno-Matsui (Ohno-Matsui, 2014a) reported that diffuse chorioretinal atrophy was present significantly more frequently in eyes with a wide macular staphyloma than in eyes
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ACCEPTED MANUSCRIPT without a staphyloma (P = 0.016).
Patchy chorioretinal atrophy and CNV (including
macular atrophy) were found significantly more frequently in eyes with any type of staphyloma and eyes with the wide macular staphyloma than in eyes without a staphyloma. Myopic traction maculopathy (MTM) was present significantly less frequently in eyes without
staphyloma, and eyes with a narrow, macular staphyloma. was found in 62 of the 68 eyes with MTM.
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a staphyloma than in eyes with any types of staphyloma, in eyes with a wide, macular Myopic macular retinoschisis
Myopic retinoschisis was found significantly less
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frequently in eyes without a staphyloma than in eyes with any type of staphyloma, eyes with a wide macular staphyloma, and eyes with a narrow macular staphyloma.
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3.1.5. Therapies targeting staphylomas
Earlier studies showed that the presence of staphylomas was significantly correlated with worse vision, more frequent development of myopic macular complications, and optic nerve damage. Thus, therapies targeting the sclera are considered potentially useful to McBrien and Gentle (McBrien
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prevent the development and progression of staphylomas.
and Gentle, 2003) published an extensive review on the role of the sclera in the development and pathological complications of myopia.
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Scleral reinforcement and collagen crosslinking are being considered for the treatment of eyes with pathologic myopia.
Posterior scleral reinforcement surgery for high
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myopia has been mainly performed in Russia and China, and some groups in the United States and Australia have also advocated scleral reinforcement for pathologic myopia. Various types of human tissues such as autologous fascia lata (Nesterov and Libenson, 1970; Nesterov et al., 1976), lyophilized dura (Momose, 1983), strips of tendon (Scott, 1964), and homologous human sclera (Curtin and Whitmore, 1987; Whitmore and Curtin, 1987) have been used.
Curtin (Curtin and Whitmore, 1987) advocated donor-sclera grafting for
posterior ocular reinforcement and Momose (Momose, 1983) introduced Lyodura for scleral
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ACCEPTED MANUSCRIPT reinforcement.
Artificial materials such as artificial pericardium (Castro and Duker, 2010),
all-dermal matrix derived from animal skin (Castro and Duker, 2010), and polytetrafluoroethylene (Jacob-LaBarre et al., 1993) have also been used. best material for reinforcement surgery remains controversial.
However, the
Most investigators in the
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United States have used homologous sclera in the form of a belt or cinch placed vertically over the posterior pole, under the inferior and superior oblique muscles and sutured to the anterior sclera. The shapes of the reinforced sclera can be different; single strip, X-shaped,
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and Y-shaped. Later, Snyder and Thompson (Snyder and Thompson, 1972) reported their experiences with a modified scleral reinforcement technique. Thompson (Thompson,
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1978) offered a further simplification of Borley and Snyder’s scleral reinforcement approach. After years of experience with their own variations of scleral reinforcement, Thompson (Thompson, 1985) and Momose (Momose, 1983) expressed satisfaction with the efficacy and safety of their results.
In contrast, Curtin and Whitmore (Curtin and Whitmore,
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1987) had negative conclusions on the outcomes for their reinforcement techniques. However, there have been no clinical studies with appropriate control groups. Gerinec and Slezakova (Gerinec and Slezakova, 2001) performed scleral
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reinforcement using the Thompson method on 251 eyes of 154 children from 2 to 18 years of age with high myopia using Zenoderm (porcine skin) and reported that during the 10 years
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of postsurgical check-up, stabilization of the AXL was achieved in 53.8% of eyes and stabilization of the refractive error was achieved in 52.9% of eyes. The advancement of myopia in the other 47% of patients had decreased from 1.1 D per year before surgery to 0.1 D per year till 10 years after surgery.
More recently, Ward et al. (Ward et al., 2009)
reported the 5-year results of scleral reinforcement using donor sclera in a total of 59 adult eyes, with myopic refractive errors ranging from -9.0 to -22.0 D and AXL from 27.8 to 34.6 mm with a follow-up of 5 years.
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The average increase in AXL was 0.2 mm in sutured eyes
ACCEPTED MANUSCRIPT versus 0.6 mm in non-sutured fellow eyes.
Zhu et al. (Zhu et al., 2009) and Ji et al. (Ji et
al., 2011) also reported a postoperative decrease in myopic refractive error of 0.59 Dand 0.8 D, respectively.
These findings suggest that the effect of scleral reinforcement is limited.
Another study reported a complete lack of an effect (Nesterov et al., 1976).
Curtin and
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Whitmore (Curtin and Whitmore, 1987) investigated 23 patients who were followed up for ≥5 years after scleral reinforcement surgery. Of the 20 eyes that had preoperative axial measurements, 18 (90%) had an increase in the axial diameter of ≥0.3 mm. Progression of
eyes.
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the posterior staphyloma or the onset of myopic fundus degeneration was observed in ten In addition to the lack of long-term effectiveness after surgery, serious complications
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have been reported including retinal detachment (Borley, 1949; Curtin and Whitmore, 1987; Nesterov et al., 1976); ocular motility disorders (Curtin and Whitmore, 1987; Gerinec and Slezakova, 2001); retinal, choroidal, and vitreous hemorrhages; optic nerve damage because of circulatory decompensation; and compression of the optic nerve, vortex veins
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(Whitwell, 1971), or cilioretinal artery (Karabatsas et al., 1997).
Collagen cross-linking was recently introduced for the treatment of progressive keratoconus and post-refractive surgery corneal ectasia (Caporossi et al., 2006; Henriquez
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et al., 2011; Snibson, 2010; Wollensak, 2006; Wollensak et al., 2003). Wollensak et al. (Wollensak et al., 2003) have pioneered the use of riboflavin and ultraviolet light (UVA) to
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cross-link collagen and enhance the mechanical properties of the cornea.
By actively
increasing the degree of the bonding between collagen molecules, therapeutic cross-linking could reasonably be expected to enhance corneal rigidity.
Collagen fibrils cross-link
naturally as a part of their maturation process. In the normal cornea, covalently bonded molecular bridges or cross-links exist between adjacent tropocollagen helices and between microfibrils and fibrils at intervals along their length (Robins, 2007; Snibson, 2010). The collagen cross-linking method shows promise for treating keratoconus, and other
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ACCEPTED MANUSCRIPT cross-linking approaches, e.g., glyceraldehyde and nitro-alcohols, may provide stabilization of scleral shape in eyes with progressive myopia (Paik et al., 2010; Wollensak and Iomdina, 2008, 2009). It has been reported that scleral collagen contained similar cross-linked peptides to those found in the cornea (Crabbe and Harding, 1979; Harding and Crabbe, Different from the corneal collagen cross-linking, the scleral collagen cross-linking
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1979).
is still in the experimental stage and no human clinical trials have been performed.
McBrien
and Norton (McBrien and Norton, 1994) treated tree shrews with agents that block collagen
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crosslinking (β-aminopropionitrile [β-APN], or D-penicillamine [DPA]) and they underwent monocular deprivation of form vision by eyelid closure to induce myopia. The results
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showed that the amount of vitreous chamber elongation and induced myopia approximately doubled in the β-APN-treated monocular deprived eyes compared with that of the saline-treated monocular deprived eyes. There was a significant increase in the degree of scleral thinning at the posterior pole in the deprived eyes of the β-APN-treated animals.
For
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exogenous collagen cross-linking, compounds such as glutaraldehyde, glyceraldehyde (Mattson et al., 2010; Wollensak and Iomdina, 2008), methylglyoxal (naturally occurring Mailard intermediate), and genipin (natural collagen cross-linker obtained from geniposide),
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(Avila and Navia, 2010) and alcohols (Paik et al., 2010) have been used and they have been shown to increase the stiffness of ocular tissue (Wollensak and Spoerl, 2004).
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Wollensak and Iomdina (Wollensak and Iomdina, 2008) performed scleral collagen cross-linking in rabbits with sub-Tenon injections of glyceraldehyde into the superonasal quadrant of the eye and reported that glyceraldehyde cross-linking of scleral collagen increased the scleral biomechanical rigidity efficiently as shown in stress-strain parameters and Young’s modulus without causing side effects on the retina. Wollensak (Wollensak, 2010) also showed that the scleral collagen cross-linking by glyceraldehyde proved very efficient in increasing the scleral thermomechanical stability. Wollensak and Iomdina
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ACCEPTED MANUSCRIPT (Wollensak and Iomdina, 2009) reported that scleral crosslinking by the photosensitizer riboflavin and UVA was effective and constant over a time interval up to 8 months in increasing the scleral biomechanical strength. Wang et al. (Wang et al., 2012a) showed that both the equatorial and posterior human scleral strips were enhanced by collagen
3.2.
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cross-linking with riboflavin/UVA irradiation.
Myopic Maculopathy
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Curtin and Karlin first proposed a definition of myopic maculopathy that included the features of chorioretinal atrophy, central pigment spot, lacquer cracks, posterior staphyloma Later, Tokoro updated the
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and optic disc changes in 1970 (Curtin and Karlin, 1970).
classification of myopic macular lesions into four categories: (1) tessellated fundus, (2) diffuse chorioretinal atrophy, (3) patchy chorioretinal atrophy, and (4) macular hemorrhage. Subsequently, Avila et al. (Avila et al., 1984)developed a classification which included
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myopic retinopathy according to severity, from M0- normal-appearing posterior pole; M1choroidal pallor and tessellation; M2- M1 changes with posterior staphyloma; M3- M2 changes with lacquer cracks; M4- M3 changes with focal areas of deep choroidal atrophy; to
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the most severe grade M5- M4 changes with large geographic areas of deep chorioretinal atrophy and bare sclera.
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Despite the efforts from Curtin and Avila, the definition of myopic maculopathy has not been consistent across studies.
For example, some studies defined pathologic myopia
as eyes exhibiting “typical myopic degeneration” without specific definition (Avisar et al., 2006; Buch et al., 2004; Cedrone et al., 2003; Cotter et al., 2006; Iwase et al., 2006; Klaver et al., 1998). The Beijing Eye Study defined “degenerative myopia” as an eye with myopic refractive error of at least -6 diopters and myopic atrophic changes with stretching of the macula(Liu et al., 2010).
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The Hisayama study defined myopic retinopathy more stringently
ACCEPTED MANUSCRIPT as “the presence of at least one of the following: diffuse chorioretinal atrophy at the posterior pole, patchy chorioretinal atrophy, lacquer cracks, or macular atrophy” (Asakuma et al., 2012).
In the BMES myopic retinopathy was defined to include staphyloma, lacquer cracks,
Fuchs’ spot and myopic chorioretinal thinning or atrophy (Vongphanit et al., 2002b). The
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lack of a common classification makes it impossible to perform direct comparison or pooling of data from different studies to evaluate the prevalence, incidence, and pattern of individual lesion subtypes. There are also limitations in the Avila classification noted from a
For example, the inclusion of
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longitudinal study by Hayashi et al (Hayashi et al., 2010).
posterior staphyloma as a grade of myopic maculopathy (Avila grade M2) was thought to be
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problematic as posterior staphyloma is now believed to be a major cause of the development of myopic maculopathy and thus has been proposed to be included separately (Kim et al., 2011), rather than as a part of myopic maculopathy (Hayashi et al., 2010). Similarly, lacquer cracks often develop relatively early in young individuals.
It is possible
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that with advances in imaging such as indocyanine green angiography (ICGA) and OCT (Liu et al., 2014), lacquer cracks can be diagnosed even earlier than relying on color fundus photographs. Thus the placement of lacquer crack as M3 in the Avila grading has also
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2010).
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raised concerns that it may not represent the progression pattern adequately (Hayashi et al.,
3.2.1. Classification in META-PM study (Table 1) Recently an international panel of researchers in myopia reviewed previous published studies and classifications and proposed a simplified, uniform classification system for pathologic myopia for use in future studies (Ohno-Matsui et al., 2015b).
In this
simplified system (META-PM classification), myopic maculopathy lesions are categorized into 5 categories from “no myopic retinal lesions” (Category 0), “tessellated fundus only”
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ACCEPTED MANUSCRIPT (Category 1; Figure 5A), “diffuse chorioretinal atrophy” (Category 2; Figure 5B), “patchy chorioretinal atrophy” (category 3; Figure 5C), to “macular atrophy” (Category 4; Figure 5D). These categories were defined based on long-term clinical observation that informed on the progression patterns and risk of myopic CNV development for each stage.
Three additional
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features were added to these categories and were included as “plus signs”: (1) lacquer cracks (Figure 5E), (2) myopic CNV, and (3) Fuchs spot (Figure 5F). The reason for separately defining these “plus signs” is that these 3 lesions have been shown to be strongly
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associated with central vision loss, but they do not fit into any particular category and may develop from, or coexist, in eyes with any of the myopic maculopathy categories described Based on this new classification, pathologic myopia is defined as myopic
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above.
maculopathy category 2 or above, or presence of “plus” sign, or the presence of posterior staphyloma (Ohno-Matsui et al., 2015b; Verkicharla et al., 2015).
It is hoped that future
clinical trials and epidemiological studies will adopt this uniform classification to facilitate Further details of individual lesions will be
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communication and comparison of findings. discussed in the following section.
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3.2.2. Details of each lesion
In addition to the basic eye examinations (visual acuity, intraocular pressure,
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refractive error, axial length), more specific examinations (such as SD-OCT, fundus autofluorescence, fluorescein and indocyanine green angiograms, detailed fundus examination with direct or indirect ophthalmoscope) would provide important information for diagnosing and managing the lesions of myopic maculopathy. a. Diffuse Chorioretinal atrophy (Category 2) Few previous studies that evaluated chorioretinal atrophy have discussed diffuse and patchy types separately.
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Diffuse chorioretinal atrophy can be identified by the
ACCEPTED MANUSCRIPT yellowish white appearance of the posterior pole. The extent of the diffuse atrophy may vary from a restricted area around the optic disc and a part of the macula to the entire posterior pole. The area of atrophy generally first appears around the optic disc, often increasing with age and finally covers the entire area within the staphyloma.
Both age and
al., 2010).
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AXL have been described as risk factors for the development of diffuse atrophy (Hayashi et
On fluorescein angiography (FA), diffuse atrophy exhibits mild hyperfluorescence in On ICGA, a marked decrease of the choroidal
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the late phase due to tissue staining.
capillary and medium and large-sized choroidal vessels has been described within the area Marked thinning of the choroidal layer in the area of diffuse atrophy can
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of diffuse atrophy.
be appreciated on OCT, with occasional sporadic large choroidal vessels remaining. b. Patchy Chorioretinal atrophy (Category 3)
Patchy chorioretinal atrophy appears as well-defined, grayish white lesion(s) in the
choroidal lobules.
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macular area or around the optic disc. The size may vary between one and several Patchy chorioretinal atrophy is characterized by a complete loss of
choriocapillaris and can progress to an absence of outer retina and retinal pigment
atrophy.
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epithelium. Large choroidal vessels can be seen to course within the area of patchy In advanced cases, the sclera or even retrobulbar blood vessels may be observed
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through transparent retinal tissue, and the posterior fundus shows a “bare sclera” appearance.
Stereoscopic fundus examination is helpful as one may appreciate the
excavation of the area compared to surrounding diffuse atrophy.
Pigment clumping may be
observed within the area of patchy atrophy, especially along the margin of the atrophy or along the large choroidal vessels.
The lesion appears hypofluorescent on FA and ICGA
due to choroidal filling defect. The overlying RPE is lost, leading to hypoautofluorescence usually with distinct borders.
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On OCT, the area of patchy atrophy is characterized by
ACCEPTED MANUSCRIPT absence of the entire thickness of the choroid and the RPE as well as outer retina. Hyper-transmission through the underlying sclera can be seen. Patchy atrophy may develop from three sources: (1) from lacquer cracks, P(Lc), (2) within the area of advanced diffuse chorioretinal atrophy, P(D), and (3) along the border of
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the posterior staphyloma P(St) (Hayashi et al., 2010). The shape of the patchy
chorioretinal atrophy may help to distinguish these three types, as atrophy which develops from lacquer cracks often have a longitudinally oval shape while patchy atrophy which
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develops from diffuse chorioretinal atrophy is often circular or elliptical.
In a cohort of 806
eyes from the High Myopia Clinic at Tokyo Medical and Dental University, 20.2% of eyes had In the general population aged 40
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patchy atrophy at the initial visit (Hayashi et al., 2010).
years and above, patchy atrophy has been reported to be present in 0.4% in the Hisayama study (Asakuma et al., 2012).
However the frequency increases with longer AXL (3.3% in
eyes with AXL of 27.0 to 27.9mm; >25% in eyes longer than 31mm, and >50% in eyes
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longer than 32mm) (Asakuma et al., 2012).
The frequencies of chorioretinal atrophy progression and the risk of CNV development are significantly higher in eyes with patchy chorioretinal atrophy, compared to
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those with diffuse chorioretinal atrophy at baseline (Ohno-Matsui et al., 2015b). 29.7% showed no progression in atrophy.
Only
In the majority of eyes, patchy atrophy enlarged
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in area (67.6%), some fuse with other areas of patchy atrophy (13.5%) and a minority developed CNV (2.7%).
In another longitudinal study with 10 years follow-up, although the
authors used the Avila grading, it was noted that patchy atrophy and CNV showed poorer visual outcome than lacquer cracks (Shih et al., 2006). The authors of this paper also noted fusion of areas with other patchy atrophy was associated with significant decrease in vision and proposed that RPE dysfunction, particularly in older patients may play a role in the progression of myopic maculopathy (Shih et al., 2006).
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In the BMES, 5.2% of
ACCEPTED MANUSCRIPT participants had new or expanded areas of patchy chorioretinal atrophy over 5 years (Vongphanit et al., 2002b). Macular retinoschisis and retinal detachment secondary to posterior paravascular linear retinal breaks have been reported to occur preferably in areas of patchy atrophy.
It is
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possible that adhesion between the inner retina and sclera in these areas are weakened (Baba et al., 2003; Fang et al., 2009b). c. Lacquer cracks (Plus sign)
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Lacquer cracks appear as yellowish linear lesions in the macula. They can often be seen to crisscross over the underlying choroidal vessels. Lacquer cracks are believed to
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represent mechanical breaks of the Bruch’s membrane (Gao et al., 2011; Hayashi et al., 2010; Neelam et al., 2012; Zheng et al., 2011b).
They may appear as linear horizontal or
vertical cracks or exhibit a crisscrossing (stellate) pattern (Ikuno et al., 2008b). The frequency of lacquer crack in patients with pathologic myopia has been
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estimated to fall between 4.3 and 15.7% in several cohort studies (Curtin and Karlin, 1970; Grossniklaus and Green, 1992; Klein and Curtin, 1975; Ohno-Matsui et al., 2003).
Lacquer
cracks can develop at a relatively early age. Klein and Curtin reported that the mean age of
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patients with lacquer cracks was 32 years (Klein and Curtin, 1975). However, as with other myopic maculopathy lesions, the frequency of lacquer cracks increases with age (Klein and
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Green, 1988).
Detection of lacquer cracks with conventional examination methods is difficult. The appearance varies according to the stage of lacquer crack and the amount of retinal atrophy surrounding it.
ICGA is widely accepted as the best method for detecting lacquer cracks,
which typically appear as linear hypofluorescence in the late phase ICGA (Ikuno et al., 2008b; Ohno-Matsui et al., 1998).
The lacquer cracks may radiate from the disc, at the
papillomacular bundle, through the macula and around the macula (Axer-Siegel et al., 2004).
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ACCEPTED MANUSCRIPT FA, on the other hand, is less useful in demonstrating lacquer cracks, particularly during the early stages of rupture (Axer-Siegel et al., 2004; Liu et al., 2014). The reason is thought to be due to leakage from the surrounding normal choriocapillaris, which may obscure the lacquer crack, and the lack of atrophy of the overlying retinal pigment epithelium during the
months after the onset of rupture.
Atrophy in the RPE usually develops several
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early stages of lacquer crack formation.
At this point, lacquer cracks can be observed as
yellowish linear lesions ophthalmoscopically or as linear hyperfluorescence in FA due to
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window defect (Ohno-Matsui and Tokoro, 1996). With the advent of angiography using the confocal scanning laser ophthalmoscopy system (cSLO), ICGA using cSLO has been shown
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to provide even more details both on lacquer cracks and myopic CNV (Ikuno et al., 2008b; Kim et al., 2011).
Other imaging modalities for visualizing lacquer cracks have been investigated.
Liu
et al. compared multimodal imaging in detecting lacquer cracks in highly myopic eyes (Liu et In addition to reporting lower sensitivity of FA compared to ICGA, the authors of
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al., 2014).
the paper reported that near-infrared reflectance (NIR) had relatively high sensitivity (92.9%) for detecting lacquer cracks, which appear as hyperreflective lines. This NIR appearance
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was frequently associated with continuous retinal pigment epithelium-Bruch’s membrane complex, thinner choroid and acoustic shadow on the corresponding OCT. Thus NIR
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imaging, coupled with SD-OCT is potentially a good non-invasive method to screen for lacquer cracks.
Fundus autofluorescence (FAF) imaging, on the other hand, only detected
12.5% of lacquer cracks, which appear as linear hypo-autofluorescence.
The low rate of
detection was thought to be related to the presence of a continuous RPE-BM line overlying the lacquer crack, as seen on SD-OCT. Lacquer cracks may appear as discontinuities of the RPE and increased hyper-transmission into the deeper tissue beyond the RPE on OCT. However, detection rate is low because the lesions are often very narrow and hardly visible
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ACCEPTED MANUSCRIPT on OCT.
Another feature associated with lacquer cracks which may be observed on OCT is
reduction in macular choroidal thickness (Wang et al., 2013; Wang et al., 2012b; Wang et al., 2015b).
A study reported that a subfoveal choroidal thickness cutoff value of 58.93µm may
be useful for screening eyes for the presence of lacquer cracks (Wang et al., 2013).
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Risk factors for lacquer crack development have been investigated in several studies. Interestingly, there is no obvious correlation between AXL and lacquer cracks, and association with refractive error is weak.
Kim et al. followed 66 patients with myopic CNV,
2011).
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and reported presence of lacquer crack in 37 eyes with CNV and 26 fellow eyes (Kim et al., Although older age, higher refractive error, absence of a dark rim and greater extent
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of peripapillary choroidal atrophy were associated with the presence of lacquer crack, only peripapillary atrophy remained a significant association after multivariate logistic regression analysis (Kim et al., 2011).
Subretinal bleeding is often observed at the onset of lacquer cracks (Klein and Ohno-Matsui et al.
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Green, 1988; Ohno-Matsui et al., 1996; Shapiro and Chandra, 1985).
reported that in 17 (77.3%) of 22 eyes with subretinal bleeding without CNV, lacquer cracks appeared at the corresponding site of the previous bleeding (Ohno-Matsui et al., 1996).
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This subretinal bleeding is usually absorbed spontaneously with good visual recovery and has therefore been called simple hemorrhage (Asai et al., 2014; Goto et al., 2015).
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However in eyes in which the bleeding was thick and penetrated into the inner retina beyond the external limiting membrane, a defect in the ellipsoid zone may persist, leaving permanent vision loss (Asai et al., 2014; Moriyama et al., 2011c). Asai et al. reported the tops of the hemorrhages and intraretinal hyperreflectivity may extend into the internal limiting membrane in over 30% (Asai et al., 2014). It is important to exclude the presence of a myopic CNV in cases of subretinal bleeding. Progression of lacquer cracks has been observed in longitudinal studies in eyes with
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ACCEPTED MANUSCRIPT and without myopic CNV (Kim et al., 2011; Vongphanit et al., 2002b).
In the BMES, 56.1%
of eyes with lacquer cracks at baseline showed progression after an average follow up of 72.8 months (Vongphanit et al., 2002b).
Progression may be in the form of increase in
number or development into other myopic maculopathy such as patchy or diffuse
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chorioretinal atrophy and CNV. Progression of lacquer cracks may be observed with the production of increasing amounts of small crack fragments. This may appear as elongation from the tip of an existing lacquer crack, at the side of an existing lacquer crack in a
bridging pattern.
A mixture of these three patterns often exists in the same eye (Kim et al.,
Presence of lacquer cracks extending to the fovea has also been shown to be a
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2011).
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branching pattern, or remote from an existing lacquer crack and connecting later in a
significant negative prognostic factor for vision (Yoon et al., 2012). Lacquer cracks may also increase in width and progress to patchy atrophy and increase in number.
Hayashi et
al. reported that only 30.7% of eyes with lacquer cracks did not progress over their 12.7 year Progression of lacquer cracks was more frequent in
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follow-up study (Hayashi et al., 2010).
eyes with a posterior staphyloma but was not associated with AXL. Lacquer crack has been suggested to be an important risk factor in the formation of
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myopic CNV. The prevalence of lacquer crack is high in eyes that developed myopic CNV, although the prevalence is likely to be underestimated due to limitation in visualization (Avila
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et al., 1984; Ikuno et al., 2010; Ikuno et al., 2008b; Ohno-Matsui et al., 2003).
In a
longitudinal follow-up study, the incidence of myopic CNV was highest in eyes with lacquer cracks (29.4%), compared to 20% in eyes with patchy atrophy and only 3.7% in eyes with diffuse chorioretinal atrophy (Ohno-Matsui et al., 2003).
In the longitudinal study by
Hayashi et al. 13.3% of eyes with lacquer cracks develop myopic CNV, and 42.7% develop patchy chorioretinal atrophy (Hayashi et al., 2010; Ikuno et al., 2008b; Ohno-Matsui et al., 2003; Wang et al., 2012b).
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In addition, recurrence of CNV, particularly in cases where the
ACCEPTED MANUSCRIPT recurrence is at a different location from the original CNV, progression of lacquer cracks has been observed frequently (Kim et al., 2011). Myopic stretch lines need to be differentiated from lacquer cracks. Myopic stretch lines were first reported by Yannuzzi as linear hyper-autofluorescent lesions that were
cracks but the detail was not described (Yannuzzi, 2010).
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observed in the fundus of eyes with pathologic myopia and were the precursors of lacquer Myopic stretch lines, unlike
lacquer cracks, are observed as hypofluorescent lines throughout all phases of FA
On fundus examination, myopic stretch lines are observed as
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(Shinohara et al., 2014).
pigmented brown lines running along the large choroidal vessels. Although ICGA showed
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similar hypofluorescence as lacquer cracks, FAF demonstrated hyper-autofluorescent lines corresponding to the hypofluorescent lines by FA.
OCT showed that the choroid was
extremely thin with occasional visible large choroidal vessels visible.
Irregularities or
clumps of RPE at the site of the stretch lines on and around the protruded large choroidal
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vessels could also be seen.
d. Myopic CNV (Plus sign)
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Myopic CNV is a major sight threatening complication of pathologic myopia.
It is
the commonest cause of CNV in individuals aged below 50 years, and the second
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commonest cause of CNV overall (Neelam et al., 2012; Ohno-Matsui et al., 2003).
It has
been included as a “plus” sign in the proposed international classification for myopic maculopathy, in view of its major impact on vision (Ohno-Matsui et al., 2015b). details are discussed under the section on Myopic CNV.
Further
Studying the progression pattern
of various myopic maculopathy changes and the risk they confer on CNV development can improve our understanding of the pathogenesis of myopic CNV.
Most myopic CNVs
appear to emanate from lacquer cracks (Ikuno et al., 2010; Ikuno et al., 2008b; Kim et al.,
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ACCEPTED MANUSCRIPT 2011). Vascular endothelial growth factor has also been shown to be elevated in myopic CNV (Chen et al., 2015).
3.2.3. Natural Progression of each lesion
time.
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Few studies have followed up eyes with myopic maculopathy over long periods of A study from the High Myopia Clinic of the Tokyo Medical and Dental University
reviewed 806 eyes of 429 patients with high myopia over a mean follow-up period of 12.7 Overall, progression was seen in 40.6%. However, the rate of
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years (Hayashi et al., 2010).
progression varied according to the baseline lesion, and some eyes showed progression to
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a second and even a third pattern after the first progression. Thus progression of myopic maculopathy is complex and long-term follow up studies are essential to understanding the pathogenesis and risk factors.
The rate of progression ranged from only 13.4% in eyes with tessellated fundus, to
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49.2% in eyes with diffuse chorioretinal atrophy, 69.3% in eyes with lacquer cracks, 70.3% in eyes with patchy chorioretinal atrophy and as high as 90.1% in eyes with CNV at the initial examination (Hayashi et al., 2010).
Below is a summary of the progression pattern of
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individual lesions described by Hayashi et al. (Hayashi et al., 2010). The majority of eyes (86.6%) with tessellated fundus at the initial examination did not
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progress, while 10.1% developed diffuse chorioretinal atrophy, 2.9% developed lacquer cracks and 0.4% developed CNV.
Older age and presence of a posterior staphyloma were
associated with progression, but AXL was not. Seven out of eight eyes that developed lacquer cracks showed further progression, mostly to patchy atrophy, and less frequently to development of CNV. A third pattern of progression was seen in 3 eyes, in the form of CNV development at the edge of the fovea of patchy atrophy in 2 eyes, and in the form of macular atrophy development after CNV. The period from first to second progression ranged from 1
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ACCEPTED MANUSCRIPT to 9 years, while the period from second to third progression ranged from 1.5 to 3 years. Nearly half of the eyes with diffuse chorioretinal atrophy at the initial visit showed progression (49.2%). Most eyes progressed in the form of enlargement of the area of diffuse chorioretinal atrophy (26.9%), while others developed patchy atrophy (19.4%),
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lacquer cracks (2.2%) and CNV (1.6%). The presence of posterior staphyloma and longer AXL, were associated with enlargement of diffuse chorioretinal atrophy and development of patchy atrophy.
In addition, eyes that progressed to patchy chorioretinal atrophy had
progression.
All the eyes that developed a CNV progressed further to develop macular
Less frequently seen patterns of second progression were from diffuse
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atrophy.
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markedly higher frequency of having a type IX staphyloma compared to those without
chorioretinal atrophy to lacquer cracks and subsequently to patchy atrophy associated with lacquer cracks P(Lc); and from diffuse chorioretinal atrophy to patchy chorioretinal atrophy and subsequently to macular atrophy.
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Progression was significantly more common in eyes with lacquer cracks at initial examination (69.3% had progression).
Most eyes with lacquer crack (42.7%) progressed
to develop patchy atrophy around lacquer crack, P(Lc), 13.3% developed a CNV and a
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further 13.3% developed an increase in number of lacquer cracks. Presence of a posterior staphyloma, was significantly more frequent in eyes that progressed to patchy chorioretinal
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atrophy, but age and AXL were not significantly different between those with and without progression from lacquer cracks.
Some eyes may have a second and third progression
pattern after the first progression from lacquer cracks to patchy atrophy.
These eyes may
progress from lacquer crack to patchy atrophy and later develop CNV and eventually macular atrophy (Hayashi et al., 2010). Most eyes with patchy chorioretinal atrophy at the initial visit (70.3%) developed progression, most frequently in the form of enlargement of the patchy area (67.6%), while
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ACCEPTED MANUSCRIPT 13.5% of eyes showed a fusion with diffuse chorioretinal atrophy P(D) and patchy atrophy along the edge of posterior staphyloma P(St), and 2.7% developed a CNV.
Presence of
posterior staphyloma (particularly type IX staphyloma) and longer AXL were associated with progression.
A second and third progression may develop either in the form of CNV from
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the foveal edge of patchy atrophy which subsequently progress to macular atrophy; or in the form of fusion with other P(D) or P(St) to form an enlarged area of patchy atrophy and ultimately progressing to macular scar.
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Overall, these long-term progression data suggest that myopic maculopathy tends to progress more quickly after the myopic maculopathy has advanced past the tessellated Patient age, severity of myopia, AXL and the presence of posterior
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fundus stage.
staphyloma were frequently associated with progression, although small differences exist between their influence on individual lesion. Of the various individual lesions, the development of a CNV and macular atrophy were significantly associated with worse vision.
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In addition, the fusion of patches of atrophy with other areas was also associated with a significant decrease in vision.
CNV may develop from any stage of myopic maculopathy,
but the incidence was highest in eyes with lacquer cracks or patchy atrophy.
Once
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developed, most of the eyes with a CNV showed a progression to macular atrophy.
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3.2.4. Pathogenesis and Potential Therapy for myopic maculopathy In animal models of myopia, the choroidal circulation has been shown to decrease in high myopia (Shih et al., 1993).
Evidence from various modes of choroidal imaging has
also supported the hypothesis that choroidal circulation decreases in high myopia. Narrowing and loss of large choroidal vessels have been observed in eyes with high myopia (Akyol et al., 1996; Moriyama et al., 2007; Quaranta et al., 1996).
Loss of choroidal large
vessels and fibrotic changes within choroidal vessels may lead to obstruction of choroidal
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ACCEPTED MANUSCRIPT blood flow and be replaced eventually with fibrous tissue, ultimately resulting in myopic chorioretinal atrophy (Hirata and Negi, 1998a, b; Sayanagi et al., 2009). The marked thinning of the choroid in diffuse chorioretinal atrophy has led to the hypothesis that obliteration of pre-capillary arterioles or post-capillary venules may be the underlying cause
the choriocapillaris.
This may then be followed by occlusion of
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of the choroidal changes in pathologic myopia.
In the most advanced stage, even the large choroidal vessels are
obliterated. Loss of choroidal melanocytes, possibly secondary to the vascular changes,
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has been suggested to be partly responsible for the pale appearance of the fundus.
However, the reason for the relative preservation of the RPE and outer retina, despite the
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marked thinning of the choroid, is not clear.
The mechanism underlying the development of patchy atrophy is somewhat different from that proposed for diffuse chorioretinal atrophy.
Jonas reported that macular Bruch’s
membrane defects are commonly detected histologically and that these defects might be In particular, the lack of
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related to the development of patchy atrophy (Xu et al., 2007).
tensile strength from Bruch’s membrane, in addition to lack of choroid on the thin sclera, result in the area of patchy atrophy being subjected to the inner pressure load (You et al., Patchy chorioretinal atrophy that develops in conjunction with lacquer cracks may
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2014).
result from multiple factors, including mechanical stretching in the form of lacquer cracks and
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choroidal filling delay. The latter is supported by observation of tiny hypofluorescent areas on FA at the posterior pole during the early stage of patchy atrophy development (Ohno-Matsui and Tokoro, 1996).
Lacquer cracks are believed to represent ruptures in Bruch membrane. Stretching of the tissue because of axial elongation is believed to play an important role in the pathogenesis (Curtin and Karlin, 1970).
In animal models of lacquer crack, Bruch’s
membrane was noted to be totally broken up and rupturing of the collagen fibrillar network
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ACCEPTED MANUSCRIPT was found (Hirata and Negi, 1998a).
Isolated cases of lacquer crack development
following ocular surgery as well as LASIK further suggest that physical stress and changes in intraocular pressure during surgery may play a role (Chen et al., 2014; Ruiz-Moreno et al., 2003; Shaw and Chen, 2015). The observation that lacquer cracks are associated with
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larger extent of peripapillary atrophy also supports the theory that mechanical stretching likely plays an important role in the pathogenesis of both features (Kim et al., 2011; Yasuzumi et al., 2003; You et al., 2014).
However, somewhat contradictory to this
AXL (Curtin and Karlin, 1970).
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hypothesis, risk factor analysis has shown that lacquer cracks are not directly correlated with Querques et al. reported a new SD-OCT based finding that
(Querques et al., 2015).
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retrobulbar vessels were found to perforate the sclera at the site of the lacquer crack They hypothesized that scleral expansion at the location of these
perforating vessels where scleral continuity is interrupted may play a role in the formation of lacquer cracks (Pedinielli et al., 2013; Querques et al., 2015).
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In addition to mechanical stress, a vascular or ischemic component has also been proposed to have an important role in the pathogenesis of lacquer cracks and chorioretinal atrophy.
Recent studies based on choroidal thickness measurements reported an
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association between choroidal thinning and lacquer cracks (Wang et al., 2013). Interestingly, Wang et al. not only reported an association between thinner macular choroid
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and the presence of both lacquer cracks and CNV, but also concluded that thinner choroid was a factor independent of AXL or refractive error (Wang et al., 2015b). There is also evidence from animal studies to suggest a vascular component in addition to mechanical stress in the pathogenesis of lacquer cracks. In chick models of high myopia and lacquer crack, the choroidal capillary network was found to be ruptured with highly atrophied marginal capillaries (Hirata and Negi, 1998a, b).
The retina was continuous, but was
depressed to form a groove in the lesion with the apparently intact inner retina and
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ACCEPTED MANUSCRIPT degenerated photoreceptor cells.
Attenuated fibroblasts encompassed the outer
circumference of the lesion while RPE cells were scattered in the tissue space inside the fibroblastic investment and in the choroidal stroma (Hirata and Negi, 1998a, b). The authors of the study proposed that metabolic insufficiency may thus be considered a
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causative factor in the disruption of Bruch’s membrane and the degenerative changes of the outer retina.
Lacquer cracks are observed at higher rates in eyes with myopic CNV, compared to
(Noble and Carr, 1982; Ohno-Matsui et al., 2003).
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highly myopic eyes without CNV, suggesting a relationship between these two pathologies Ikuno et al. (Ikuno et al., 2008b)
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reported that lacquer cracks were present in 95% of 37 eyes with myopic CNV.
In addition,
myopic CNV originated from lacquer cracks or areas adjacent to lacquer cracks in 94%. Recurrence of myopic CNV has also been found to develop particularly in areas surrounded by new small crack fragments (Kim et al., 2011).
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In summary, a plethora of signs in the macula are associated with pathologic myopia. Correlation with natural progression from long-term studies has improved our understanding of the relative risk profile and impact on vision of each individual stage and lesion. The new
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international myopic maculopathy grading aims to simplify and standardize the classification
3.3.
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of myopic maculopathy and facilitate future collaborative research.
Myopic CNV
3.3.1. Prevalence, incidence and bilaterality Myopic CNV is one of the most sight-threatening complications in high myopia (Avila et al., 1984).
Based on published studies, it has been estimated that the prevalence of
myopic CNV ranges from 5% to 11% among individuals with high myopia (Curtin and Karlin, 1970; Grossniklaus and Green, 1992; Hayashi et al., 2010; Wong et al., 2014).
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Myopic
ACCEPTED MANUSCRIPT CNV is also the most common cause of choroidal neovascularization among patients aged 50 years or below (Cohen et al., 1996). In a study of 32 patients with pathologic myopia who were followed for at least 3 years, the incidence of myopic CNV was 10.2% of eyes over a mean follow-up of 10.8 years (Ohno-Matsui et al., 2003).
Highly myopic individuals who
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already had myopic CNV in one eye were found to have an even higher risk of myopic CNV development in the fellow eye, as myopic CNV developed in 34.8% of patients with myopic CNV already in one eye, compared with 6.1% of patients without a history of pre-existing
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CNV (Ohno-Matsui et al., 2003).
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3.3.2. Diagnosis of myopic CNV based on imaging (Figure 6)
On clinical examination, myopic CNV typically appears as a flat, small, greyish subretinal lesion beneath or in close proximity to the fovea with or without hemorrhage. There are usually minimal subretinal fluid or exudative changes associated with the myopic
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CNV. The diagnosis of myopic CNV can be confirmed by FA and SD-OCT.
FA findings in
myopic CNV usually demonstrate well-defined hyperfluorescence in the early phase with leakage in the late phase in a classic CNV pattern of leakage.
SD-OCT has the advantage
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of being non-invasive and fast to perform. Therefore, SD-OCT is routinely utilized to differentiate myopic CNV from other macular conditions in high myopia such as myopic
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foveoschisis and myopic macular hole, and for monitoring of the myopic CNV treatment response.
In order to maximize the detection and diagnosis rates of myopic CNV, it is
generally recommended to perform both FA and SD-OCT as there might be poor agreement between FA and SD-OCT findings in eyes with myopic CNV (Goto et al., 2015). The concordance between FA and SD-OCT findings usually increases with follow-up after anti-angiogenesis therapy and it was therefore recommended to use FA to diagnose myopic CNV and to use SD-OCT to assist the monitoring of CNV treatment (Iacono et al., 2014).
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ACCEPTED MANUSCRIPT Active myopic CNV in SD-OCT appears as a dome-shaped hyper-reflective elevation above the RPE as most myopic CNV are type 2 CNV. Subretinal hyperreflective exudation on SD-OCT has also been suggested to be a feature of active myopic CNV(Bruyere et al., 2015).
Other SD-OCT features of myopic CNV include absence of Bruch’s membrane and
thickening (Milani et al., 2014).
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photoreceptor ellipsoid zone, absence of external limiting membrane (ELM) and retinal A recent study evaluated the correspondence of FA and
SD-OCT findings in myopic CNV eyes receiving intravitreal bevacizumab treatment and
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found that absence of ELM was a more reliable parameter for assessing myopic CNV than intra- or sub-retinal fluid (Battaglia Parodi et al., 2015). With the use of enhanced-depth
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imaging OCT, patients with myopic CNV have been found to have thinner choroidal thickness compared with normal control eyes (Wang et al., 2015b). Swept-source OCT has also demonstrated that in eyes with dome-shaped macula, CNV is significantly associated with longer AXL and thinner choroidal thickness (Ohsugi et al., 2014).
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Other imaging techniques which might provide adjunctive information in the assessment of myopic CNV include ICGA and FAF (Kim et al., 2011; Parodi et al., 2009; Parodi et al., 2015; Sawa et al., 2008).
ICGA is particularly useful in the assessment of
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lacquer crack formation associated with myopic CNV (Kim et al., 2011).
FAF findings in
myopic CNV may include hyperautofluorescent or patchy FAF pattern, and eyes with
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hyperautofluorescent pattern have been found to have greater extent of visual acuity improvement and fewer atrophic changes after intravitreal ranibizumab treatment for myopic CNV (Parodi et al., 2015).
3.3.3. Differential diagnoses a. Subretinal bleeding due to new lacquer crack formation Although myopic CNV is one of the main causes of macular hemorrhage in patients
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ACCEPTED MANUSCRIPT with high myopia, macular hemorrhage in highly myopic patient can also be associated with lacquer crack without CNV (Klein and Green, 1988; Ohno-Matsui et al., 1996). This is also known as simple hemorrhage and the hemorrhages in these cases are due to mechanical stretching and rupture of the Bruch’s membrane resulting in new lacquer crack formation The visual prognosis of simple
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(Moriyama et al., 2011c; Ohno-Matsui et al., 1996).
hemorrhage is generally more favorable compared with myopic CNV as the simple
hemorrhage will resolve spontaneously without requiring treatment with anti-angiogenesis FA and ICGA are useful to differentiate hemorrhage due to
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therapy (Goto et al., 2015).
myopic CNV from simple hemorrhage due to lacquer crack as the former will show
b. Punctate inner choroidopathy
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hyperfluorescence associated with the macular hemorrhage.
Punctate inner choroidopathy (PIC) is an inflammatory disorder of unknown etiology characterized by small creamy yellow-white lesions located at the RPE and inner choroid
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without concomitant intraocular inflammation (Leung et al., 2014; Watzke et al., 1984). CNV can also develop as a complication of PIC resulting in acute visual loss (Amer and Lois, 2011; Leung et al., 2014).
Since PIC patients commonly have moderate or even high
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myopia, PIC should be differentiated from myopic CNV by the fundus appearance of the characteristic small multiple fundus lesions.
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c. Idiopathic CNV
Idiopathic CNV is one of the most common causes of CNV in young patients and was found to account for 17% of CNV in patients under the age of 50 years (Cohen et al., 1996).
It can also occur in patients with high myopia.
By definition, an idiopathic CNV
occurring in an eye with myopia of −6D or more is considered to be a myopic CNV rather than an idiopathic CNV. d. Serous detachment in dome-shaped macula
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ACCEPTED MANUSCRIPT Due to RPE atrophy or abnormal choroidal vasculature, a central serous chorioretinopathy-like serous macular detachment can develop in eyes with dome-shaped macula (Caillaux et al., 2013). This can mimic myopic CNV and FA is very useful to distinguish the two as management of the two conditions is rather different. The
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dome-shaped macula will be described in details later. e. Polyps at edge of tilted disc syndrome
It has been reported that highly myopic eyes with tilted disc syndrome may
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sometimes develop polypoidal neovascular lesions in the inner choroid at the border of the posterior staphyloma similar to those seen in polypoidal choroidal vasculopathy (PCV)
identify polyps at these locations.
ICGA is the investigation of choice to
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(Mauget-Faysse et al., 2006; Nakanishi et al., 2008).
Nonetheless, it has been shown that PCV is rarely found
in patients with myopic CNV as ICGA of a consecutive series of 297 eyes with myopic CNV did not identify any case of PCV (Kang and Koh, 2014). This might be related to the
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thinning of the choroidal layer in high myopia patients with myopic CNV and thus a reduced likelihood of PCV development in these eyes with high myopia. 3.3.4. Natural prognosis and development of CNV-related macular atrophy (Figure 7)
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Several studies have evaluated the natural history of pathologic myopia including myopic CNV. The natural history of myopic CNV is generally poor without treatment.
In
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one of the retrospective studies with the longest follow-up conducted by Yoshida et al. (Yoshida et al., 2003) 27 eyes of 25 consecutive patients with myopic CNV were followed for 10 years after the onset of myopic CNV. better than 20/200.
At baseline, 70.4% of eyes had a visual acuity of
However, at 5 and 10 years after the onset of myopic CNV, visual
acuity dropped significantly to 20/200 or worse in 88.9% and 96.3% of eyes, respectively. In a study by Kojima et al. (Kojima et al., 2006) 54 eyes of 54 patients with myopic CNV without treatment were followed for at least 5 years.
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Analysis showed that factors
ACCEPTED MANUSCRIPT significantly related to good prognosis with final visual acuity better than 20/40 included younger age, smaller CNV, juxtafoveal CNV and better initial visual acuity.
Development of
chorioretinal atrophy around the regressed CNV is the main reason for the poor visual prognosis in eyes with myopic CNV (Ohno-Matsui and Yoshida, 2004).
Recent study using
(Ohno-Matsui et al., 2015a).
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swept-source OCT showed that CNV-related macular atrophy was Bruch’s membrane hole Another reason for the poor visual outcome in myopic CNV
eyes might be due to formation of myopic macula hole.
Eyes at the atrophic stage of
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myopic CNV with chorioretinal atrophy of greater than 1 disc area are particular at risk of macular hole formation, as macular hole was found in 14% of these eyes, compared with
no CNV (Shimada et al., 2008a).
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none in myopic CNV eyes with less than 1 disc area of chorioretinal atrophy and eyes with Based on these findings of the poor natural history
outcome of myopic CNV, eyes with myopic CNV should therefore be offered active effective
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treatment to improve the visual prognosis.
3.3.5. Anti-VEGF therapy for myopic CNV (Figure 8) Several treatment options including thermal laser photocoagulation, macular surgery
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and verteporfin photodynamic therapy (vPDT) have previously been used for the treatment of myopic CNV but the outcomes of these treatment modalities are generally poor with no
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significant visual improvement and high risk of myopic CNV recurrence.
Since the
introduction of anti-VEGF agents in ophthalmology around 10 years ago, anti-angiogenesis treatment with intravitreal anti-VEGF therapy has become the standard-of-care first-line treatment for myopic CNV (Lai, 2012). Similar to CNV in other macular diseases, increased level of VEGF has been found to be associated with myopic CNV and therefore anti-VEGF therapy is useful in myopic CNV (Chan et al., 2008; Tong et al., 2006).
A large
number of retrospective and prospective studies have demonstrated the beneficial effects of
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ACCEPTED MANUSCRIPT anti-VEGF therapy for the treatment of myopic CNV (Chan et al., 2009; Gharbiya et al., 2010b; Iacono et al., 2012; Ikuno et al., 2009; Lai et al., 2009; Ruiz-Moreno et al., 2009; Tufail et al., 2013). Systematic reviews have also demonstrated beneficial visual outcomes in the use of intravitreal anti-VEGF therapy for myopic CNV (Neelam et al., 2012; Wang and In addition, two large multi-centered, double-masked, randomized, controlled
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Chen, 2013).
clinical trials have been performed to evaluate the use of anti-VEGF therapy for myopic CNV (Ikuno et al., 2015; Wolf et al., 2014). The RADIANCE (The Ranibizumab and PDT
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[verteporfin] evaluation in myopic choroidal neovascularization) study was a 12-month, randomized clinical trial which randomized 275 patients to two regimens of intravitreal 0.5mg
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ranibizumab (guided by visual acuity stabilization or by disease activity) versus vPDT for the treatment of myopic CNV (Wolf et al., 2014). The primary endpoint was mean BCVA change measured at 3 months.
Results showed that at 3 months, both ranibizumab
treatment groups had significantly better visual acuity improvement compared with vPDT
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group, with BCVA gains of 10.5 letters for the ranibizumab guided by visual acuity stabilization, 10.6 letters for the ranibizumab guided by disease activity and 2.2 letters for the vPDT group.
At 6 months, it was shown that the ranibizumab guided by diseases activity
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group was non-inferior in terms of visual again compared with the ranibizumab guided by visual acuity stabilization group. The improvement in BCVA after intravitreal ranibizumab
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treatment was maintained at 12 months, with BCVA gains of 13.8 and 14.4 letters in the two ranibizumab treatment groups, respectively.
The number of injections was low in the study
at 12 months with a mean of 4.0 injections in the group guided by visual acuity stabilization and 3.5 injections for the group guided by disease activity.
In the MYRROR study, the use
of intravitreal 2mg aflibercept was compared with a sham control group for the treatment of myopic CNV (Ikuno et al., 2015). The primary outcome measure was assessed at 6 months and it was shown that intravitreal aflibercept resulted in significantly better BCVA
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ACCEPTED MANUSCRIPT improvement compared with sham control group, with a gain of 12.1 letters in the aflibercept group and a loss of 2 letters in the sham group.
Similar to the RADIANCE study, the mean
number of injections was low in the MYRROR study, with a mean of 4.2 injections over 12 months for the aflibercept group.
In both the RADIANCE and MYRROR studies, adverse
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events were infrequent and there were no abnormal safety issues related to ranibizumab and aflibercept injections.
Several studies have evaluated the long-term outcomes of anti-VEGF therapy for
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myopic CNV for two years or more. Gharbiya et al. evaluated the second year results of 20 eyes with myopic CNV which have already been treated with intravitreal bevacizumab The long-term results showed that at 24 months, the mean visual
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(Gharbiya et al., 2010a).
acuity improved significantly from 20/80 at baseline to 20/33 at 24 months. of eyes had improvement of 10 letters or more at 24 months.
Moreover, 85%
In a retrospective study by
Lai et al. (Lai et al., 2012) 37 treatment naïve eyes of 37 patients with subfoveal myopic CNV
years.
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were treated with intravitreal bevacizumab or ranibizumab and were followed for at least 2 It was found that the mean logMAR visual acuity improved significantly from 0.86 to
0.48. The mean visual improvement at 2 years was 2.8 lines for the bevacizumab group and
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5.1 lines for the ranibizumab group but the difference was not statistically significant. The number of intravitreal anti-VEGF injections over 24 months was low, with a mean of 3.8
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injections for both the bevacizumab and ranibizumab groups.
In terms of ocular adverse
events, it was uncommon and complications observed included three cases of cataract requiring surgery, two cases of increase in myopic foveoschisis, and one case each of cellophane maculopathy, myopic macular hole, retinal detachment, and peripheral retinal degeneration requiring barrier laser treatment.
Yang et al. retrospectively evaluated the
use of intravitreal bevacizumab in 103 myopic CNV eyes of 89 patients who had follow-up of at least 2 years (Yang et al., 2013).
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After a mean follow-up of 44 months, the mean
ACCEPTED MANUSCRIPT logMAR visual acuity improved from 0.57 to 0.41.
Recurrence was observed in 23.3% of
eyes and the number of bevacizumab injections was considerably higher for eyes with recurrence, with a mean of 6.9 injections for eyes with recurrence and 2.7 injections for eyes without recurrence. Multivariate analysis showed that larger size of myopic CNV was the In another retrospective study,
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only significant factor associated with CNV recurrence.
Franqueira et al. evaluated the efficacy and safety of intravitreal ranibizumab in the
treatment of myopic CNV after 3 years (Franqueira et al., 2012). The mean visual acuity
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improved significantly from 55.4 letters at baseline to 63.4 letters at 36 months. The mean number of ranibizumab injections was 4.1, 2.4 and 1.1 in the first, second and third year, Peiretti et al. assessed the long-term results of intravitreal bevacizumab in 21
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respectively.
eyes of 20 patients who were followed for up to 52 months (Peiretti et al., 2012). found that 85.7% of eyes had stable or improved vision at the last follow-up.
It was
The results
demonstrated that anti-VEGF therapy is beneficial compared with the natural history of Oishi et al. further evaluated the use of intravitreal
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myopic CNV in the long-term.
bevacizumab in 22 eyes with myopic CNV and patients were followed for at least 4 years (Oishi et al., 2013).
It was shown that following intravitreal bevacizumab treatment for
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myopic NV, significant visual improvements were observed at 1, 2 and 3 years.
The
improvement in visual acuity became marginally non-significant at 4 years after treatment.
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The main reason for the slight decline in visual improvement at 4 years might be related to chorioretinal atrophy, as 73% of eyes were found to have new development or enlargement of chorioretinal atrophy at the last visit. Ruiz-Moreno et al. also reported the 4-year outcome in the use of anti-VEGF therapy for myopic CNV (Ruiz-Moreno et al., 2013). The study found that the mean visual acuity improved significantly from 46.1 letters at baseline to 53.1 letters at 48 months. The mean number of injections was low at 4.9 over 4 years and both bevacizumab and ranibizumab groups showed similar effects in myopic CNV (Peiretti et al.,
p. 38
ACCEPTED MANUSCRIPT 2012).
However, a more recent study by the authors which evaluated the 6 years outcome
of anti-VEGF therapy in 97 patients with myopic CNV showed that the visual acuity improvement after bevacizumab or ranibizumab treatment was no longer significant after 4, 5 and 6 years (Ruiz-Moreno et al., 2015).
Based on the previously described long-term
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studies in the use of intravitreal anti-VEGF therapy, it can be concluded that anti-VEGF therapy is an effective and safe treatment option for myopic CNV in the long-term and can
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provide visual improvement up to 4 years and visual stabilization up to 6 years.
The optimal current management of patients with myopic CNV is to diagnose the
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myopic CNV accurately and timely so that the eye with myopic CNV can be treated with intravitreal anti-VEGF therapy as soon as possible.
The standard investigations for
diagnosing myopic CNV include both FA and SD-OCT assessments of the macula.
FA is
important to confirm the presence of fluorescein leakage from the myopic CNV in order to
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prevent unnecessary treatment with anti-VEGF agents for simple hemorrhage not associated with myopic CNV.
SD-OCT can be used to monitor the change in myopic CNV
activity before and after anti-VEGF therapy, and to detect any other pathology like myopic
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traction maculopathy or dome-shaped macula with are not uncommon findings in patients with pathologic myopia.
The main limitation of the current treatment of myopic CNV is the
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development of chorioretinal atrophy around the myopic CNV, thereby limiting the visual improvement potential of the patients.
Low vision rehabilitation is useful for the patients
with advanced vision loss due to CNV-related macular atrophy or scaring in both eyes.
3.3.6. Diagnostic and treatment flow-charts for myopic CNV (Figure 9)
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3.4.
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Other fundus lesions in the posterior fundus
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3.4.1. Dome-shaped Macula (Figure 10)
Dome-shaped macula was first described by Gaucher et al. in eyes with myopic posterior staphyloma (Gaucher et al., 2008).
A characteristic inward bulge inside the
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chorioretinal posterior concavity of the eye in the macular area was noted in 15 eyes of 10 patients out of a series of 140 highly myopic eyes.
This bulge was hardly detectable on
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fundus biomicroscopy but OCT has greatly enhanced in the diagnosis, typically exhibiting a convex, curved, elevated profile within the concavity of the staphyloma. Subsequent imaging studies demonstrated that the bulge is associated with a local thickening of subfoveal sclera (Imamura Y, 2010).
After Gaucher et al. first reported DSM in 10.7% of a series of 140 highly myopic eyes, a subsequent series in European patients reported a similar prevalence of 12.0% in a series of 200 highly myopic eyes (Chebil et al., 2014).
Coco et al. reported macular
bending in 13.63% in 330 highly myopic eyes, of which most eyes had DSM, while a small
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ACCEPTED MANUSCRIPT proportion was associated with tilted disc syndrome (Coco et al., 2012). The prevalence of DSM in other ethnic groups is less well studied.
Ohsugi et al. reported DSM was observed
in 9.3% of 528 highly myopic eyes in a Japanese cohort (Ohsugi et al., 2014).
Liang et al.
(Liang et al., 2015) reported the prevalence of DSM was 20.1% in a cohort of 1118 eyes in Recently, the prevalence of DSM was evaluated in
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Japanese patients with high myopia.
the RADIANCE study which recruited 277 eyes with myopic CNV and DSM was present in 18% of patients (Ceklic et al., 2014).
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Clinical Features
In the earliest series by Gaucher et al. (Gaucher et al., 2008), the mean refractive
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error of the affected eyes was -8.25D and the mean visual acuity was 20/50.
A type I or
type II staphyloma, according to the Curtin classification (Curtin, 1977), was present in all eyes. Most series reported DSM in patients with mean age of 50 years or above and bilateral DSM was reported in 50% to 78% of patients (Coco et al., 2012; Errera et al., 2014; Gaucher DSM was first thought to be a complex type of
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et al., 2008; Imamura et al., 2011b).
staphyloma (Byeon and Chu, 2011; Gaucher et al., 2008).
However, the understanding of
the extended clinical phenotypes of DSM has advanced with subsequent reports.
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Advances in imaging have led to the ability to study scleral shape and thickness in detail with EDI-OCT. These later studies reported that some eyes with DSM did not exhibit the feature
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of a staphyloma as described by Curtin (Curtin, 1977), as local protrusion of thin sclera and uveal tissue was not present.
Therefore, DSM may in fact represent a novel feature rather
than a variation of staphyloma. This hypothesis was further supported by the three-dimensional magnetic resonance imaging analyses of the globe, which showed that more than half of eyes with DSM did not have a staphyloma, and the eyes were simply elongated into a barrel-shaped globe (Ohno-Matsui, 2014b). Gaucher et al. reported that visual impairment and metamorphopsia was common in
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ACCEPTED MANUSCRIPT their series of eyes with DSM (Gaucher et al., 2008).
Several complications resulting in
visual loss in DSM have been described, including atrophic changes in the RPE, foveal serous retinal detachment (sRD) and CNV. Coco et al. reported further on the wide range of complications, and noted as high as 60.29% of eyes with DSM had at least one
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complication, including CNV, subretinal fluid without CNV, atrophy and macular hole.
Other
series have reported DSM complicated by retinal schisis which may be extrafoveal or fovea-involving (Ellabban et al., 2013; Errera et al., 2007; Viola et al., 2015).
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One of the most common complications of DSM is foveal sRD.
In the initial
description by Gaucher et al, foveal sRD was present in 66.7% (10 out of 15 eyes) of eyes However subsequent series have reported highly
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with DSM (Gaucher et al., 2008).
variable figures, most likely due to differences in inclusion criteria and patient population. However, most series from European populations have reported higher prevalence of foveal retinal detachment (52.1% (Caillaux et al., 2013) and 44% (Viola et al., 2015)) compared to
(Ohsugi et al., 2014)).
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Japanese population (5.9%(Ellabban et al., 2013), 9%(Imamura et al., 2011b) and 9.3%
The prevalence of choroidal neovascularization (CNV) in eyes with DSM was also
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variable, and ranged from 12.2% (Ohsugi et al., 2014) to 47.8%(Imamura et al., 2011b). Atrophy of the RPE was reported in a high proportion of eyes with DSM.
Gaucher et al
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reported presence of RPE atrophy in all eyes in their series, while a lower prevalence was noted in other series (11.76% by Coco et al. (Coco et al., 2012), 37.2% by Ellabban et al. (Ellabban et al., 2014)) Imaging Most authors have noted that the dome-shaped elevation was hardly observable on fundus biomicroscopy. However, horizontal ridges connecting the optic disc and the fovea may be observed on fundus examination and these may act as an important clue to suspect
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ACCEPTED MANUSCRIPT the presence of DSM (Ohno-Matsui, 2014b). B-scan ultrasonography and OCT can effectively detect the bulge confined within the surrounding staphyloma.
Vertical OCT
scans in particular were found to detect the convex curvature of the bulge (Gaucher et al., 2008).
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With the advent of EDI-OCT, Imamura et al. reported that the subfoveal scleral thickness was markedly thicker in eyes with DSM compared with highly myopic eyes without DSM (570µm vs 281µm, p<0.001), whereas the subfoveal choroidal thickness was only
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slightly thicker (58.1µm vs 35.7µm, p=0.48) (Imamura, et al. 2011b).
Subsequent work by Ellabban et al. reconstructed 3-dimensional images of the
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posterior eye shape using swept-source OCT (Ellabban et al., 2013). They demonstrated that the sclera in the posterior pole showed an uneven thickness, being relatively thick in the fovea (518µm) compared with parafoveal areas in all four quadrants (277.2 to 360.3µm). These findings led the authors to propose that DSM may result from a relative localized
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thickness variation of the sclera under the macula in highly myopic eyes. Different subtypes of DSM were also demonstrated by Caillaux et al. (Caillaux et al., 2013).
Three patterns were described: (i) dome-shaped pattern, (20.8%); (ii) roughly
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horizontally orientated oval-shaped dome, (62.5%); and (iii) vertically orientated oval-shaped dome, (16.7%). Importantly, the finding that most DSM did not display a round dome
fovea.
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highlights that the diagnosis of DSM could be missed on a single OCT scan through the Recently, Liang et al. also reported that 77% of DSM was detectable along only the
vertical section, whereas only 2% of DSM was detected in only the horizontal section and 20% of DSM was detected in both vertical and horizontal OCT sections (Liang et al., 2015). Pathogenesis The underlying mechanism for the development of DSM remains unclear.
Both
posterior staphyloma and DSM are associated more frequently with a higher severity of
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ACCEPTED MANUSCRIPT myopia or increased AXL.
However, DSM may also be observed in eyes with low spherical
equivalent refractions and short AXL (Errera et al., 2014; Gaucher et al., 2008; Liang et al., 2015), as well as in eyes with retinal dystrophies (Errera et al., 2014). There has been much research into the relative role played by the choroid and
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sclera in the pathogenesis of DSM, and in the development of subfoveal sRD in DSM. Gaucher et al. observed that the choroid beneath the bulge appeared to be thickened in some eyes, and postulated that the convex curvature of the macular profile may result from
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thickening of the underlying choroid or from a change in the scleral wall shape or thickness, possibly a protective mechanism resulting from resistance of the sclera to the Some authors proposed that the
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staphylomatous deformation (Gaucher et al., 2008).
development of DSM in myopic eyes could represent an adaptive phenomenon in a proportion of myopic patients to reduce defocus in the macula (Keane et al., 2012). The demonstration using three dimensional reconstruction of uneven thinning of the
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sclera on either side of the area of convexity led to the postulation that asymmetric expansion of the eyeball could lead to the formation of DSM.
Importantly, no change in the
external scleral curvature of the macula was observed (Caillaux et al., 2013; Ellabban et al., It is possible that regional differences in biochemical structure of scleral lamellae or
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2013).
organization of the collagen bundles may be responsible for this observation (Ellabban et al., This theory is further supported by the longitudinal findings of progressive
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2013).
asymmetric scleral thinning, which was more pronounced in the parafoveal area than at the foveal center, resulting in an increase of the macular bulge height (Ellabban et al., 2014). The mechanism for the development of foveal sRD in eyes with DSM is unclear. Foveal sRD was significantly more common when the macular bulge height was greater than 350um (Caillaux et al., 2013). The findings of thickened sclera and, to a lesser extent, choroid led Imamura et al. to propose obstruction of choriocapillaris outflow secondary to
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ACCEPTED MANUSCRIPT localized relative scleral thickening as a mechanism for the development of subretinal fluid accumulation and foveal sRD in DSM (Imamura et al., 2011b).
Gaucher et al. studied eyes
with DSM with FA and observed focal leakage points in 7 eyes(Gaucher et al., 2008). The fluorescein dynamics of the focal leaking points was thought to be a complication of the
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abnormal curvature of the macula. There were also some similarities between the
fluorescein dynamics in DSM and in chronic central serous chorioretinopathy (CSC) and tilted disc syndrome, particularly the association with atrophic changes in the RPE.
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However, in DSM, these leakage points tended to be localized at the top of the dome where atrophic RPE is noted. Errera et al. reported that choroidal thickening was particularly
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marked in eyes with DSM with a CSC-like phenotype (defined as presence of subretinal fluid and/or focal hyperfluorescent areas on FA) (Errera et al., 2014). Outcome and complications
Currently, treatment is not recommended for DSM without complications. The
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optimal treatment for subretinal fluid and foveal sRD in DSM is unclear.
This is further
complicated by the variable natural history, as spontaneous resolution has been described (Gaucher et al., 2008; Tamura et al., 2014; Viola et al., 2015).
Several treatment options
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have been attempted with variable success. Laser photocoagulation (Gaucher et al., 2008; Pardo-Lopez et al., 2011), verteporfin photodynamic therapy (Arapi et al., 2015; Chinskey
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and Johnson, 2013), intravitreal anti-vascular endothelial growth factor (Chinskey and Johnson, 2013) and medical therapy with spironolactone (Dirani et al., 2014).
However, all
of these studies lack control groups. In the RADIANCE study which recruited eyes with myopic CNV, no substantial differences in visual outcome or number of ranibizumab injections were needed for patients with or without DSM, despite worse baseline visual acuity scores in patients with DSM (Ceklic et al., 2014).
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ACCEPTED MANUSCRIPT Interestingly, extrafoveal retinal schisis was more common than foveal schisis in eyes with DSM (Ellabban et al., 2013; Viola et al., 2015).
Ellabban et al. proposed that the
bulge in eyes with DSM may act as a macular buckle-like mechanism, indenting the fovea and thus may alleviate tractional forces over the fovea (Ellabban et al., 2013). Similarly,
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Ellabban et al. reported that the bulge height of a DSM without CNV is significantly higher than that with CNV, and speculated that the dome may also be playing a protective role in
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reducing the mechanical damage (Ellabban et al., 2013).
3.4.2. Radial ascending tracts emanating from staphyloma edge
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Ultra-widefield fundus images show radial ascending tracts as linear or leaf-like lesions with an abnormal FAF pattern which radiate from the staphyloma edge toward the peripheral fundus in 7.7% of highly myopic eyes with a posterior staphyloma (Ishida et al., 2014).
The linear tracts are observed as an increase in pigmentation or de-pigmentation OCT images of the
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ophthalmoscopically, however they are more obvious in the AF images.
staphyloma edge show serous retinal detachments in some cases. Three-dimensional magnetic resonance imaging (3D MRI) of the eyes show a clear outpouching in the eyes
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with linear tracts, and the upper edge of a wide macular staphyloma was more abrupt than the lower edge. The fundus features of the radial tracts are similar to those of the
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descending tracts in chronic CSC (Imamura et al., 2011a; Spaide and Klancnik), even though there are no staphylomas in eyes with CSC. is different in these two conditions.
In addition, the orientation of the tracts
Our results suggest that a sRD first developed at the
staphyloma edge where the RPE is damaged and then spread towards the periphery against gravity.
The RPE damage at the abrupt edge of a staphyloma and the directional spread of
subretinal fluid might be related to the development of the radial tracts.
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ACCEPTED MANUSCRIPT 3.4.3. Chorioretinal folds from staphyloma edge Chorioretinal folds have been reported to be present in various ocular and systemic conditions including hyperopia, CNV, and eyes with an orbital mass (Olsen et al., 2014). Chorioretinal folds are also known to develop in eyes with the tilted disc syndrome (Cohen In eyes with an inferior staphyloma due to
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and Quentel, 2006; Ohno-Matsui et al., 2011b).
the tilted disc syndrome, the upper edge of the staphyloma is located in the foveal region,
(Cohen and Quentel, 2006; Ohno-Matsui et al., 2011b).
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and the chorioretinal folds run radially from the upper edge of the inferior staphylomas
Ishida et al. (Ishida et al., 2015) examined the ultra-widefield fundus images and
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FAF images and showed that the chorioretinal folds emanated from the staphyloma edge in highly myopic eyes even though the edge was away from the macula.
In some cases,
choroidal folds were observed to run in parallel with radially ascending tracts.
In addition,
choroidal folds were present outside the staphyloma with relatively preserved choroid, and
they have staphylomas.
Surgical conditions
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3.5.
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they might also be present even in less myopic eyes of patients with unilateral high myopia if
3.5.1. Macular Hole, MHRD (Figure 11)
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The presence of a macular hole (MH), is not an uncommon complication that can be observed in highly myopic eyes.
The prevalence of MH has been reported to be 8.4% in
214 eyes with pathologic myopia (AL>30 mm and posterior staphyloma) using OCT (Ripandelli et al., 2012).
Coppe et al. examined 383 asymptomatic highly myopic patients
(between -14 and -32 D) with OCT and reported full thickness macula hole (FTMH) in 24 eyes (6.26%) (Coppe et al., 2005).
Retinal detachment associated with MH (MHRD)
accounts for less than 1% of all cases (Margheria and Schepens, 1972), although some
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ACCEPTED MANUSCRIPT studies from Asian population reported 9% and 21% (Minoda, 1979; Zhang and Hu, 1982). Spectral domain optical coherence tomography (SD-OCT), which allows in vivo examination of macular morphology, is invaluable in differentiating between a full-thickness MH, lamellar hole, MHRD, and macular retinoschisis.
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Gass emphasized the role of vitreous and hypothesized that tangential traction was an important factor in the pathogenesis of macular hole (Gass, 1988).
The pathogenesis of
MH and MHRD in high myopia is considered distinct from idiopathic MH, which includes
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anteroposterior vitreous traction on the posterior pole due to axial elongation or posterior staphyloma (Morita et al., 1991), tangential traction on the macula from the contraction of the
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cortical vitreous and epiretinal membrane (Oshima et al., 1998; Seike et al., 1997; Stirpe and Michels, 1990); and reduced chorioretinal adhesion due to RPE atrophy (Morita et al., 1991). Vitrectomy has become standard procedure to treat idiopathic MH as well as MH in high myopia.
Because ILM peeling can remove premacular tractional elements, such as
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vitreous cortex, epiretinal membrane; remove scaffold for cellular proliferation, and increase flexibility of the retina to facilitate closure of MH (Almony et al., 2012; Funata et al., 1992; Madreperla et al., 1994), studies of MH in high myopia with ILM peeling showed higher
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successful closure rate (ranging from 87 to 100%) (Alkabes et al., 2013; Chuang et al., 2014; Garcia-Arumi et al., 2001; Kwok and Lai, 2003; Qu et al., 2012) than studies without ILM
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peeling (ranging from 60 to 77%) (Patel et al., 2001; Sulkes et al., 2000).
Inverted ILM flap
technique has been reported with initial closure rate of 83.3% for treating MH in high myopia (Kuriyama et al., 2013).
Surgical outcomes of MHRD are disappointing.
Vitrectomy in combination with ILM
peeling and a short- or long-acting gas tamponade is commonly used to treat MHRD.
The
retinal reattachment rate following vitrectomy for MHRD has been reported to vary widely from approximately 40% to 93% (Chen et al., 2006; Ichibe et al., 2003; Ikuno et al., 2003;
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ACCEPTED MANUSCRIPT Kadonosono et al., 2001), however, MH closure rate following vitrectomy for MHRD, ranging from 10% to 91% using OCT examination (Ichibe et al., 2003; Ikuno et al., 2003; Kadonosono et al., 2001), are usually not as high as MH closure rate for MH alone in high myopia.
In addition, post-operative MH enlargement has been reported due to the Inverted
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imbalance between the retina and choroid-sclera complex (Ichibe et al., 2003).
ILM with or without autologous blood have been reported to increase the MH closure rate in MHRD (Kuriyama et al., 2013; Lai et al., 2015).
Several studies using vitrectomy with
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scleral shortening or imbrication for treating primary or refractory MHRD reported MH closure rate of 82.4% and 75%, respectively (Fujikawa et al., 2014; Kono et al., 2006).
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Although macula buckle is not a new technique, it has been applied to treat MHRD with posterior staphyloma. Ando et al. reported a 93% retinal reattachment rate and MH closure in 10 of 12 eyes (83%) (Ando et al., 2007).
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3.5.2. Myopic traction maculopathy (Figure 12)
Phillips first described a retinal detachment, without hole, localized to the area of a posterior staphyloma in a highly myopic eye (-20D) in 1958 (Phillips, 1958).
He used
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fundus slit lamp to demonstrate the retinal detachment, and assumed a posterior staphyloma played an important part in cases with retinal detachment with or without macula
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hole (Phillips, 1958). Forty years later, Takano and Kishi first demonstrated foveal retinal detachment and retinoschisis in severely myopic eyes with posterior staphyloma using optical coherence tomography (Takano and Kishi, 1999).
Panozzo and Mercanti proposed
the term “myopic traction maculopathy (MTM)” to encompass various findings with traction in common by optical coherence tomography in highly myopic eyes (Panozzo and Mercanti, 2004).
Myopic traction maculopathy, also called foveal retinoschisis (Takano and Kishi,
1999), macular retinoschisis (Benhamou et al., 2002), or myopic foveoschisis (Ikuno et al.,
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ACCEPTED MANUSCRIPT 2004), includes schisis-like inner retinal fluid, schisis-like outer retina fluid, foveal detachment, lamellar or full-thickness macular hole and/or macular detachment (Johnson, 2012). The features of myopic traction maculopathy were not characterized before optical
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coherence tomography (OCT), and the pathogenesis is not completely understood.
Based
on the finding from optical coherence tomography and surgical reports, several mechanisms have been proposed, including vitreomacular traction from partial posterior vitreous
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detachment (Panozzo and Mercanti, 2004; Takano and Kishi, 1999), remnant cortical vitreous layer after posterior vitreous detachment (Spaide and Fisher, 2005), epiretinal
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membrane, intrinsic internal limiting membrane noncompliance (Ikuno et al., 2004; Kanda et al., 2003; Kobayashi and Kishi, 2003; Kuhn, 2003), and retinal arteriolar stiffness (Ikuno et al., 2005; Johnson, 2012; Sayanagi et al., 2005). Therefore, MTM can be regarded as a split between the flexible outer retina and the inflexible inner retina (Ikuno, 2014).
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OCT is an indispensable tool to diagnose MTM, which allows in vivo examination of macular morphology, such as schisis-like inner retinal fluid, schisis-like outer retina fluid, foveal detachment, lamellar or full-thickness macular hole and/or macular detachment.
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Examinations other than OCT were used and might help diagnosis of MTM. Sayanagi et al. reported a subtle mottled pattern of hyper fundus autofluorescence, and found a different
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pattern between MTM and full-thickness macula hole with retinal detachment (Sayanagi et al., 2007).
Recently, retro-mode imaging (RMI) has been used noninvasively to visualize
chorioretinal disorder based on the infrared laser in the confocal scanning laser ophthalmoscope (SLO), which can produce a pseudo-three-dimensional image showing the details of deep retinal structures.
A characteristic fingerprint and firework pattern at the
corresponding area of macular retinoschisis have been reported in macula retinoschisis using RMI (Su et al., 2014; Tanaka et al., 2010).
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Although RMI provides more information
ACCEPTED MANUSCRIPT regarding the extent of the macular retinoschisis than fundus autofluorescence, both examinations have limitations in showing the height of MTM and structure between vitreoretinal interfaces. Shimada et al. have classified myopic traction maculopathy according to its location
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and extent from S0 through S4: S0: no retinoschisis; S1: extrafoveal; S2: foveal; S3: both foveal and extrafoveal but not the entire macula; and S4: entire macula (Shimada et al., 2013).
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Tanaka et al. found 23 (95.8%) of 24 eyes with lamellar macula hole did not show any changes in the OCT images during a mean follow-up of 19.2 months (Tanaka et al.,
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2011). They reported that a lamellar macula hole might be a relative stable condition in highly myopic eyes (Tanaka et al., 2011).
Although some eyes with MTM showed
spontaneously resolution(Polito et al., 2003; Shimada et al., 2013), several studies reported progression during its natural course from MTM to more serious complications such as
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foveal detachment, ranging from 3.4% to 37.5% (Fujimoto et al., 2010; Shimada et al., 2006a; Shimada et al., 2013) or full-thickness MH, ranging from 0.9% to 33% (Benhamou et
2013).
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al., 2002; Fujimoto et al., 2010; Gaucher et al., 2007; Shimada et al., 2006a; Shimada et al.,
Shimada et al. further defined the progression as (1) an increase of the extent or
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height of retinoschisis (more than 100 µm) or the development of an inner lamellar macula hole, foveal detachment, or full-thickness macula hole (Shimada et al., 2013). They reported progression during the mean follow-up of 36.2 months in 24 (11.6%) of 207 eyes, which includes 0.9% who progressed to full-thickness macula hole and 3.4% who progressed to foveal detachment. The eyes with extensive macular retinoschisis (S4) showed progression significantly more commonly (42.9%) than the eyes having less extensive macular retinoschisis areas (6.7%).
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Six (21.4%) of 28 eyes with S4 MTM
ACCEPTED MANUSCRIPT progressed to foveal detachment. However, some eyes (3.9%) showed a decreased or complete resolution of macular retinoschisis (Shimada et al., 2013). 3.5.2.1. Surgical techniques to treat MTM Shimada et al. investigated five eyes of MTM and showed that the progression from
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MTM to foveal detachment passed through four stages based on the OCT images. In stage 1, focal irregularity of the thickness of the external retina; stage 2, an outer lamellar hole and a small retinal detachment developed; stage 3, column-like structures overlying the
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holes separated horizontally and enlarged vertically; stage 4, the upper edge of the external retina was further elevated and attached to the upper part of the retinoschisis layer by further
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enlargement of the detachment (Shimada et al., 2008b). They recommended considering surgical treatment between stage 3 and 4. Surgery is also recommended if visual acuity decreases or additional pathology develops (Chang et al., 2014). Due to the possible mechanisms involved in the pathogenesis of MTM, vitrectomy is
and epiretinal membrane.
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the most common treatment to release all retinal tractions, which include cortical vitreous Use of coating materials such as triamcinolone or blood clot
allows visualization of any remaining vitreous cortex (Lai et al., 2011; Yamamoto et al., 2004)
membrane scraper.
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and facilitates its separation from the retina with intravitreal forceps or Tano diamond-dusted Then epiretinal membrane and cellular constituents must be confirmed
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and removed with or without dye staining.
Internal limiting membrane peeling remains
controversial in MTM. Although it is thought that ILM peeling is a definitive method of removing all overlying residual vitreous cortex, epiretinal membrane and cellular constituents, several studies reported full-thickness macular hole formation after vitrectomy for MTM (Gao et al., 2013a; Gaucher et al., 2007; Hirakata and Hida, 2006; Ho et al., 2014; Panozzo and Mercanti, 2007). Ikuno and Tano reported surgical outcome in 8 eyes with macula hole with myopic
p. 52
ACCEPTED MANUSCRIPT retinoschisis.
All the eyes underwent ILM peeling at the first surgery, and the ILM was
peeled extensively (5 to 6 disc diameters) in all the second surgeries.
Temporal scleral
shortening was performed during re-operation in one case. Although all the retinoschisis resolved, the macula holes closed in only two (25%) eyes (Ikuno and Tano, 2006). Gao et
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al. investigated the risk factors for development of full-thickness macular holes after
vitrectomy for MTM, and found that pre-operative ellipsoid zone (inner segment/outer segment) defect can be a risk factor for the development of macular hole (Gao et al., 2013a).
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Foveolar ILM sparing technique was used in an attempt to reduce the development of post-vitrectomy macula hole, which was a severe complication and resulted in poor visual Several studies showed good visual and anatomic outcomes with this technique
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recovery.
(Ho et al., 2012; Ho et al., 2014; Shimada et al., 2012).
Ho et al. compared foveal ILM
non-peeling and total ILM peeling in patients with MTM, and found that macular hole developed in only 2 (28.6%) of the 7 eyes with total ILM peeling after the mean follow-up of
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55.6 months.
Other surgical techniques other than vitrectomy have been used, such as intravitreal injection of gas (Gili et al., 2010; Wu et al., 2013), scleral buckling or reinforcement on the
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macular area alone (Baba et al., 2006; Zhu et al., 2009), combined scleral reinforcement with vitrectomy (Bures-Jelstrup et al., 2014; Mateo et al., 2012; Mateo et al., 2013), or
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combined supra choroidal buckling with vitrectomy (El Rayes, 2014). 3.5.2.2. Surgical outcome of MTM The anatomic and functional outcome using different surgical procedures for MTM is summarized in Table 2 (Baba et al., 2006; Bures-Jelstrup et al., 2014; Chang et al., 2014; El Rayes, 2014; Fang et al., 2009a; Gaucher et al., 2007; Hirakata and Hida, 2006; Ho et al., 2012; Ho et al., 2014; Hwang et al., 2013; Ikuno et al., 2003; Ikuno et al., 2008a; Ikuno and Tano, 2006; Kanda et al., 2003; Kim et al., 2012; Kobayashi and Kishi, 2003; Kumagai et al.,
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ACCEPTED MANUSCRIPT 2010; Kwok et al., 2005; Lim et al., 2012; Mateo et al., 2012; Mateo et al., 2013; Panozzo and Mercanti, 2007; Scott et al., 2006; Shin and Yu, 2012; Spaide and Fisher, 2005; Taniuchi et al., 2013; Wang et al., 2012c; Wu et al., 2013; Yeh et al., 2008; Zheng et al., 2011a; Zhu et al., 2009).
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In general, full-thickness macular hole or MHRD are the most common
post-vitrectomy complications, which may result in unsatisfactory visual outcomes.
Additional procedures such as fluid gas exchange (Rao et al., 2013), episcleral macula
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buckling (Bures-Jelstrup et al., 2014), inverted ILM with or without autologous blood (Kuriyama et al., 2013; Lai et al., 2015), scleral shortening or imbrication (Fujikawa et al.,
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2014; Kono et al., 2006) provide other options to restore the anatomic structure.
Although
several reports using scleral reinforcement on the macula area alone or combined with vitrectomy showed good anatomic success, choroidal detachment, retinal pigment epithelium disturbance or atrophy around the buckle and buckle protrusion may develop
al., 2013; Zhu et al., 2009).
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after the surgery (Baba et al., 2006; Bures-Jelstrup et al., 2014; Mateo et al., 2012; Mateo et Post-vitrectomy gas tamponade showed more rapid anatomical
resolution and greater improvement than without gas tamponade (Kim et al., 2012; Zheng et
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al., 2011a). The prognosis is generally better in cases involving only macular hole without foveoschisis than in cases with macula holes and associated foveoschisis.
Persistent MHs
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are more frequent in eyes with concomitant retinoschisis, and this seems to represent a possible risk factor for late retinal detachment in the case of unsuccessful vitreous surgery (Alkabes et al., 2014).
There were some different characteristics in highly myopic eyes compared with emmetropic eyes, which include longer axial length (AL); presence of staphyloma; presence of premacular tractional elements, such as vitreous cortex, epi-retinal membrane, and increased rigidity of internal limiting membrane (ILM); thinner sclera, choroid and retina; and
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ACCEPTED MANUSCRIPT presence of diffuse or patchy chorioretinal atrophy. These characteristics lead to more technically challenging surgery and are associated with lower anatomical successful rate and functional visual outcome.
Using regular instruments (without long-shaft forceps (Gao
et al., 2013b)), surgeons may have difficulty in inducing posterior vitreous detachment,
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reaching the surface of the retina, removing premacular tractional elements, and doing membrane peeling, especially in eye with higher axial length (> 30mm) and the presence of posterior staphyloma. Complications may occur easily, such as iatrogenic retinal damage
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while attempting to elevate or re-grasp the ILM with unmatched intraocular forceps. The thinner and fragile sclera may result in unstable intraocular pressure during the surgery
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which may easily cause choroidal detachment or even suprachoroidal hemorrhage. Presence of diffuse or patchy chorioretinal atrophy is associated with thinner and vulnerable choroid and retina, which usually need dye to enhance contrast of the membrane and facilitate membrane peeling during the surgery.
Although new technology enables
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visualization of microstructure and provides more information to understand the pathogenesis of myopic macular traction, the surgical and visual outcomes are still not very satisfactory.
Photoreceptor layer defects and chorioretinal degeneration persist despite
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surgery and may be the underlying mechanism of the association of unsatisfactory
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post-operative visual recovery and outcome.
3.5.3. Peripheral retinal degenerative changes and complications 3.5.3.1. Lattice degeneration, Retinal holes, Retinal tears Highly myopic eyes with increased axial lengths have been reported with higher incidence of peripheral chorioretinal changes, such as lattice degeneration, retinal tears and holes, and retinal detachment (Celorio and Pruett, 1991; Gozum et al., 1997; Karlin and Curtin, 1976; Lam et al., 2005; Pierro et al., 1992; Yura, 1998).
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Karlin and Curtin studied
ACCEPTED MANUSCRIPT 1437 myopic eyes and found statistically significant association of increasing axial length of the eye with four principle varieties of peripheral chorioretinal changes, namely white without pressure, pigmentary degeneration, paving stone degeneration, and lattice degeneration(Karlin and Curtin, 1976).
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Risk factors for rhegmatogenous retinal detachment include axial myopia, cataract surgery, ocular trauma and a history of retinal detachment and certain peripheral retinal degeneration including lattice degeneration. Although lattice degeneration is the most
treatment remains controversial.
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significant predisposing factor for retinal breaks or detachments, prophylactic laser
Byer studied 423 eyes with lattice degeneration in 276 Subclinical RD was seen in 10
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patients over an average of 10.8 months (Byer, 1989).
(6.7%) of 150 eyes with atrophic holes in lattice, involving 9 (7.5%) of 120 patients.
Clinical
retinal detachments (RDs) occurred in 3 (1.08%) of 276 patients and 0.7% of eyes.
These
data indicated that patients with lattice degeneration with or without round holes are at very
eye (Byer, 1989).
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low risk for progression to clinical retinal detachment without a previous RRD in the fellow Ray suggested treating only after careful examination in eyes with
residual vitreous traction on the lattice, and the symptomatic eyes had a detachment related
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to lattice with a horseshoe tear (Ray, 2000). Even though treatment is only warranted in cases of expanding retinal detachments or vitreous traction, patients with lattice
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degeneration should be informed about the symptoms of acute posterior vitreous detachment and retinal detachment, and be instructed to follow-up for ophthalmic evaluation whenever such symptoms occurs. Asymptomatic breaks include operculated and atrophic round holes. Because there is no vitreous traction at the edge of these breaks, retinal detachments are unlikely to occur.
Current recommendations are close follow-up without prophylactic treatment. Symptomatic U-tears, characterized by the perception of increased flashes or
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ACCEPTED MANUSCRIPT floaters, are usually associated with persistent vitreous traction at their edge. These symptomatic U-tears result in retinal detachments 50% of the time and therefore should be treated with laser photocoagulation immediately, which reduces the risk of retinal detachment to less than 5%.
In addition, there is a strong evidence base to recommended
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treating symptomatic U-tears to prevent retinal detachment (Celorio and Pruett, 1991; Pollak and Oliver, 1981; Robertson and Norton, 1973; Shea et al., 1974; Verdaguer and Vaisman, 1979; Wilkinson, 2000).
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The goal of laser photocoagulation is to create chorioretinal adhesion completely surrounding the retinal break which can counter vitreoretinal traction and prevent liquefied Generally speaking, at least 3 near
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vitreous from passing into the subretinal space.
confluent rows of laser should be applied to closely and completely surround the retinal breaks.
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3.5.3.2. Rhegmatogenous retinal detachment
Rhegmatogenous retinal detachment from peripheral retinal breaks in highly myopic eyes can be treated with scleral buckling alone, or vitrectomy with gas or silicon oil
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tamponade or combination of scleral buckling and vitrectomy, as for non-myopic eyes. Surgeons can decide which procedure for treating retinal detachment based on the location
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and types of retinal breaks, lens status, ocular media clarity, as well as their experiences. In general, scleral buckling is the first choice although there are some limitations such as being a more painful procedure which may need general anesthesia, it can’t be used in retinal detachments caused by large of posterior retinal tears, and it may not be sufficient when there is advanced proliferative vitreoretinopathy.
Risks and side effects of scleral
buckling procedures include scleral perforation and strabismus.
However, patients who
undergo scleral buckling usually don’t need to keep a prone position for weeks as do
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ACCEPTED MANUSCRIPT patients who undergo vitrectomy.
Unlike in patients undergoing vitrectomy, occurrence of
post-operative cataract is lower in patients undergoing scleral buckling.
In addition,
refractive errors change may occur in cases with encircling scleral buckles with subsequent axial length elongation.
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Treating retinal detachment with vitrectomy has some advantages, such as: removal of vitreous traction along the tears or peripheral retinal degeneration, release of proliferative vitreoretinal membrane, better visualization of retinal tears with vitreous opacity and removal
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of sub-retinal fibrotic bands in longstanding retinal detachment from an internal approach. It has less limitation compared to scleral buckling and the procedure can be performed However, the patient may need to keep
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under local anesthesia with a small-gauge system. a prone position for weeks.
In the patient who cannot maintain a prone position or needs to
travel by flight after surgery, an alternative is to use silicon oil tamponade.
Another
disadvantage of vitrectomy is the development and progression of cataract (de Bustros et al., Cataract surgery in a previously
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1988; Hsuan et al., 2001; Melberg and Thomas, 1995).
vitrectomized eye is more technically challenging due to lack of vitreous support, weakened zonules (Pinter and Sugar, 1999; Smiddy et al., 1988), which cause the lens-iris diaphragm
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to move excessively, and fluctuation of anterior chamber depth which causes pupil constriction (Braunstein and Airiani, 2003). All of these disadvantages may increase the
3.6.
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risk of complications, especially in highly myopic eyes with long axial length.
Optic Disc Changes and glaucoma in Pathologic Myopia The papillary and peripapillary regions of highly myopic eyes are distorted by the
mechanical stretching of the globe.
The stretching results in the formation of various kinds
of deformities of the optic discs including tilted optic discs (You et al., 2008), acquired megalodiscs (Jonas, 2005; Jonas et al., 1988; Wang et al., 2006), and small discs.
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Hyung
ACCEPTED MANUSCRIPT et al. (Hyung et al., 1992) stated that as the degree of myopia increases, the ratio of the vertical to horizontal disc diameters increases, thus tilting the optic disc.
Jonas et al.
(Jonas, 2005; Jonas et al., 1988) reported that the optic discs were significantly larger and more oval than normal optic discs in eyes with myopic refractive errors <-8.0 D. Highly
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myopic optic discs can be regarded as secondary acquired macrodiscs, and they should be differentiated from the secondary acquired macrodiscs in eyes with congenital glaucoma and also from primary macrodiscs.
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The results of earlier studies indicated that the high prevalence of glaucoma in highly myopic eyes was a great concern because the diagnosis of glaucoma was difficult in highly Chen et al. (Chen et al., 1997) reported
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myopic eyes and thus it tended to be overlooked.
that glaucoma was a more pronounced issue in eyes with long AXL than eyes with short AXLs.
Chihara et al. (Chihara et al., 1997) showed that severe myopia (<-4.0D) but not
mild myopia was a significant risk factor for visual field loss in patients with primary
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open-angle glaucoma.
Nagaoka et al. (Nagaoka et al., in press) determined the prevalence of glaucoma in 172 patients (336 eyes) with high myopia (defined as myopic refractive error of <-8D or Highly myopic eyes with megalodiscs had a 3.2 times higher risk of having
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AXL>26.5 mm).
glaucomatous optic neuropathy than highly myopic eyes with normal sized or smaller optic The increased prevalence of glaucoma in eyes with axial high myopia was primarily
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discs.
associated with axial myopia-associated optic disc enlargement and not with just axial elongation.
3.6.1. Histological changes of papillary and peripapillary region of highly myopic eyes Jonas et al. (Jonas et al., 2011) examined the parapapillary region in highly myopic eyes histomorphometrically and showed that the length of the scleral flange, the sclera
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ACCEPTED MANUSCRIPT between the optic nerve edge and optic nerve dura mater, increased as the AXL increased. In highly myopic eyes, the parapapillary region consisted of an elongated parapapillary scleral flange, and the parapapillary retina was composed of only the retinal nerve fiber layer or its remnants without any other retinal layers.
The underlying Bruch’s membrane and
non-highly myopic eyes.
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choroid were also absent. These histologic features were not detected in any of the Up to a 10-fold elongation and thinning of the peripapillary scleral
susceptibility of highly myopic eyes to glaucoma.
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flange was found (Jonas and Xu, 2014). These findings may partially explain the increased
Jonas et al. (Jonas et al., 2013) also reported that the distance between the
eyes.
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Zinn-Haller arterial ring and the optic disc border was markedly increased in highly myopic Because the Zinn-Haller arterial ring is the main arterial source for the lamina
cribrosa, this finding may be related to the pathogenesis of the higher incidence of glaucoma in highly myopic eyes.
The increased distance of the Zinn-Haller ring from the optic nerve
(Ohno-Matsui et al., 2013).
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has also been confirmed by enhanced depth imaging OCT (EDI-OCT) in highly myopic eyes
Peripapillary atrophy had been considered to be composed of an alpha zone and a However, Jonas et al. (Jonas et al., 2012) recently found that there was a large
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beta zone.
area of defective Bruch’s membrane in the peripapillary atrophy of highly myopic eyes.
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This area lacking Bruch’s membrane was termed the ‘gamma zone’, i.e., the peripapillary sclera without overlying choroid, Bruch's membrane, and absence of the deeper retinal layers.
They showed that the gamma zone was associated with axial globe elongation and
was independent of glaucoma. These findings suggested that an expansion of a hole in Bruch’s membrane around the optic nerve might be the main cause of an enlargement of the myopic conus in highly myopic eyes.
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ACCEPTED MANUSCRIPT 3.6.2. Structural abnormalities on and around the optic nerve in pathologic myopia detected by OCT The subarachnoid space containing the cerebrospinal fluid is not generally observed in normal eyes in situ, however in highly myopic eyes with a large conus, the SAS is visible
2011a).
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in EDI-OCT scans (Park et al., 2012) or in the swept-source OCT scans (Ohno-Matsui et al., In the B-scan images of highly myopic eyes, the SAS is triangular with the base
towards the eye that surrounds the optic nerve in the region of the scleral flange.
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Ohno-Matsui et al. (Ohno-Matsui et al., 2011a) reported that the optic SAS was present in 93% of highly myopic eyes, and the SAS appears to be dilated in the highly myopic eyes.
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The dilated area exposed to the cerebrospinal fluid pressure along with thinning of the posterior eye wall may influence the formation of staphylomas and the way in which certain diseases, such as glaucoma, are manifested.
By using swept-source OCT, Ohno-Matsui et al. (Ohno-Matsui et al., 2012b) found
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pit-like clefts at the outer border of the optic disc or within the adjacent scleral crescent in 32 (16.2%) of 198 highly myopic eyes but none in emmetropic eyes.
The pits were located
either in the optic disc area, optic disc pits, or in the conus area and conus pits, outside the
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optic disc. The optic disc pits were associated with discontinuities of the lamina cribrosa, whereas the conus pits appeared to develop from a scleral stretch-associated schisis or
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emissary openings for the short posterior ciliary arteries in the sclera.
The nerve fiber
tissue overlying the pits was discontinuous at the site of the pits, and this might explain the cause of VF defects in highly myopic eyes in some cases. The locations of the conus pits might partly explain why the papillomacular bundles tend to be damaged in highly myopic eyes.
Kimura et al. (Kimura et al., 2014) reported a high prevalence of defects of the
lamina in highly myopic eyes with glaucoma. Peripapillary intrachoroidal cavitation (ICC) was observed as yellowish-orange
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ACCEPTED MANUSCRIPT lesions located most typically inferior to the optic disc in highly myopic eyes (Freund et al., 2003; Toranzo et al., 2005). They are not uncommon and can be found in 4.9% of highly myopic eyes (Shimada et al., 2006b).
You et al. (You et al., 2013) reported that
peripapillary ICC was found in 16.9 ± 4.0% of highly myopic eyes in an adult Chinese Spaide et al. (Spaide et al., 2012) found that the sclera
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population in the Beijing Eye Study.
in the area of ICCs was displaced posteriorly without affecting the overall curvature of the retina, retinal pigment epithelium (RPE), and the Bruch’s membrane complex.
The
and the posterior surface of Bruch’s membrane.
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cavitation was created by the expansion of the distance between the inner wall of the sclera
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Shimada et al. (Shimada et al., 2006b) reported that visual field (VF) defects were found in as many as 70% of highly myopic eyes with a peripapillary ICC.
Spaide et al.
(Spaide et al., 2012) and Shimada et al. (Shimada et al., 2007) reported that a full thickness defect in the retina along the margin of the ICC was the cause of the VF defects. Although
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ICCs were first reported in highly myopic eyes, recent studies have shown that peripapillary ICCs were also present in emmetropic eyes and even hyperopic eyes (Yeh et al., 2013). Dai et al. suggested that rotation of the optic disc along the vertical axis may cause the
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development of ICCs (Dai et al., 2015).
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3.6.3. Glaucoma and visual field (VF) changes in eyes with high myopia Chihara et al. (Chihara et al., 1997) examined 122 eyes with primary open-angle glaucoma with fair to good control of the intraocular pressure and evidence of optic nerve damage. When the refractive error was used to stratify the eyes into severely myopic (≤ -4 D), mildly myopic (-0.25 to -4 D), and emmetropic or hyperopic (≥ 0 D) eyes, only eyes with severe myopia was a significant risk factor for progressive VF loss.
Chihara et al. (Chihara
and Sawada, 1990) also investigated the parameters that were associated with multiple
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ACCEPTED MANUSCRIPT defects in the retinal nerve fiber layer (RNFL) in eyes with glaucoma.
Multivariate analysis
showed that refractive error was a high-ranking risk factor for multiple RNFL defects.
Eyes
with multiple defects tended to have moderate myopia, focal nerve fiber layer defects, and small optic discs and were less likely to have a diffuse defect in the nerve fiber layer, The multiple defects in the RNFL in
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emmetropia or hyperopia, and a normal discs.
glaucomatous eyes were frequently focal and correlated with the degree of myopia and a small optic disc.
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The VF findings are difficult to interpret in eyes with pathologic myopia.
Highly
myopic eyes usually have a large conus together with various extents of myopic
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maculopathy, which make the analyses and interpretations of automated VF examinations difficult. Thus, most of the studies examining the prevalence of glaucoma have excluded highly myopic eyes.
To overcome the disadvantage of Humphrey 30-2 automated VF test,
Ohno-Matsui et al. (Ohno-Matsui et al., 2011c) used Goldmann kinetic perimetry and
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reported that the incidence of significant VF defects in myopic eyes was significantly higher in eyes with an oval optic disc than that in eyes with a round optic disc.
During a mean
follow-up of 10.2 ± 3.4 years, 73.8% of eyes had significant progression of the VF defects.
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Because the VF defects were progressive, they suggested that high myopia is a high risk factor for VF defects, and that these eyes should be examined at least annually.
The
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combination of stretching and distortion of the optic nerve fibers result in abrupt changes of the scleral curvature which may be the factors that lead to the damage of the optic nerve fibers in highly myopic eyes. There are many issues that have not been satisfactorily explained.
For example, it
is not clear whether the measured intraocular pressure (IOP) is accurate in eyes with very thin sclera.
In eyes with pathologic myopia and myopic maculopathy, the Goldmann kinetic
perimetry can be a powerful tool to detect the existence of VF defects.
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However, how we
ACCEPTED MANUSCRIPT determine the VF defects were attributable to glaucoma or myopic optic neuropathy needs further consideration.
4.
Current challenges and direction of future research For example, how and
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There are many unsolved mysteries in pathologic myopia.
why the posterior staphyloma (a hallmark lesion of pathologic myopia) develops in the patients is still unclear.
McBrien and Gentle (McBrien and Gentle, 2003) proposed that the
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relatively annular organization of the bundles of collagen, around the optic nerve insertion and macular area, result in a local area which is particularly susceptible to the expansive
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force of the normal intra-ocular pressure. This proposal is based on histological observations of patterns of scleral collagen bundles and the biomechanics of sclera. However, this hypothesis has not been proven in the patients with pathologic myopia. The entire thickness of the sclera is visible in eyes with pathologic myopia by using swept-source In addition, the recent polarization-sensitive OCT
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OCT or enhanced depth imaging OCT.
enables the observation of collagen fiber bundles in cornea and sclera (Yamanari, et al., 2008).
Thus, the advance in fundus imaging may make clear whether McBrien and
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Gentle’s proposal is true in the patients with pathologic myopia in the near future. Immense efforts have been devoted to the study of genetic risk factors for ‘high However, the genes responsible for ‘pathologic myopia’ accompanying with
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myopia’.
pathologic complications have not been determined.
Genetic studies reporting
associations with pathologic myopia, have in fact used the terms ‘pathologic myopia’ and ‘high myopia’ interchangeably and based their definition on refractive error and /or axial length alone (Lam et al., 2008; Li et al., 2011; Li et al., 2009; Lu et al., 2011; Nakanishi et al., 2009; Verhoeven et al., 2013). With the standardization of pathologic myopia definition based on the META-PM classification, there are international collaborative effort to search
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ACCEPTED MANUSCRIPT for genes that may be responsible for the development of pathologic myopia per se. If the genes responsible for ‘pathologic myopia’ are identified, it would be clarified whether ‘pathologic myopia’ is genetically different condition than ‘high myopia’, or these 2 conditions are regulated by the same genes.
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The recent epidemiological study showed that in populations where the prevalence of myopia is high, the prevalence of high myopia starts to increase after the age of 10-13 (Li, et al., 2004, Xiang, et al., 2013).
However, it is still uncertain whether ‘high myopia’
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eventually progress to pathologic myopia (characterized by posterior staphyloma or severe myopic maculopathy), or pathologic myopia is a different disease spectrum from ‘high Posterior staphyloma, which is a hallmark of pathologic
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degree of myopic refractive error.
myopia occurs even in non-highly myopic eyes.
Since pathologic myopia is a major cause
of the loss of the best-corrected vision due to its pathological complications especially in East Asia, it is important to clarify whether high degree of myopia can progress to pathologic
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myopia or not. It is also unclear what is the first sign to show myopia is ‘pathologic’? Although imaging studies can be used to show the thinning of the retina, choroid, and sclera, it is still uncertain which one of these changes occurs first and how these changes progress.
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The lack of good animal models mimicking features of human patients with pathologic myopia is another issue.
Most of the animal models reproduce an axial
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elongation, however, they did not reproduce important features of pathologic myopia (posterior staphyloma, severe chorioretinal atrophy).
However recently, Cases et al.
(Cases, et al., 2015) reported that in the adult Lrp2-deficient mouse developed chorioretinal atrophy and posterior staphyloma, and suggested the possibility that this mouse can be a unique tool to further study human pathologic myopia.
In order to evaluate various
pharmaceutical approaches for preventing or treating pathologic myopia, establishing good animal models for pathologic myopia should be developed.
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ACCEPTED MANUSCRIPT Finally, to reduce the blindness due to pathologic myopia, global action should be
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facilitated.
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ACCEPTED MANUSCRIPT References Akyol, N., Kukner, A.S., Ozdemir, T., Esmerligil, S., 1996. Choroidal and retinal blood flow
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changes in degenerative myopia. Can. J. Ophthalmol. 31, 113-119. Alkabes, M., Padilla, L., Salinas, C., Nucci, P., Vitale, L., Pichi, F., Bures-Jelstrup, A., Mateo, C., 2013. Assessment of OCT measurements as prognostic factors in myopic macular hole surgery without foveoschisis. Graefes Arch. Clin. Exp. Ophthalmol. 251, 2521-2527. Alkabes, M., Pichi, F., Nucci, P., Massaro, D., Dutra Medeiros, M., Corcostegui, B., Mateo, C., 2014. Anatomical and visual outcomes in high myopic macular hole (HM-MH) without retinal detachment: a review. Graefes Arch. Clin. Exp. Ophthalmol. 252, 191-199.
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Almony, A., Nudleman, E., Shah, G.K., Blinder, K.J., Eliott, D.B., Mittra, R.A., Tewari, A., 2012. Techniques, rationale, and outcomes of internal limiting membrane peeling. Retina 32, 877-891. Amer, R., Lois, N., 2011. Punctate inner choroidopathy. Surv. Ophthalmol. 56, 36-53.
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Anderson, R.L., Epstein, G.A., Dauer, E.A., 1983. Computed tomographic diagnosis of posterior ocular staphyloma. AJNR Am. J. Neuroradiol. 4, 90-91. Ando, F., Ohba, N., Touura, K., Hirose, H., 2007. Anatomical and visual outcomes after episcleral macular buckling compared with those after pars plana vitrectomy for retinal detachment caused by macular hole in highly myopic eyes. Retina 27, 37-44. Arapi, I., Neri, P., Mariotti, C., Gesuita, R., Pirani, V., Freddo, F., Lutaj, P., Giovannini, A., 2015. Considering photodynamic therapy as a therapeutic modality in selected cases of dome-shaped
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macula complicated by foveal serous retinal detachment. Ophthalmic Surg Lasers Imaging Retina 46, 217-223. Asai, T., Ikuno, Y., Nishida, K., 2014. Macular microstructures and prognostic factors in myopic subretinal hemorrhages. Invest. Ophthalmol. Vis. Sci. 55, 226-232.
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Chinese population. Am. J. Ophthalmol. 94, 817-819. Zheng, B., Chen, Y., Chen, Y., Zhao, Z., Zhang, Z., Zheng, J., You, Y., Wang, Q., Shen, L., 2011a. Vitrectomy and internal limiting membrane peeling with perfluoropropane tamponade or balanced saline solution for myopic foveoschisis. Retina 31, 692-701. Zheng, Y., Lavanya, R., Wu, R., Wong, W.L., Wang, J.J., Mitchell, P., Cheung, N., Cajucom-Uy, H., Lamoureux, E., Aung, T., Saw, S.M., Wong, T.Y., 2011b. Prevalence and causes of visual impairment and blindness in an urban Indian population: the Singapore Indian Eye Study. Ophthalmology 118, 1798-1804. Zhu, Z., Ji, X., Zhang, J., Ke, G., 2009. Posterior scleral reinforcement in the treatment of macular retinoschisis in highly myopic patients. Clin. Experiment. Ophthalmol. 37, 660-663.
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ACCEPTED MANUSCRIPT Figure legends Figure 1.
Definition of a posterior staphyloma (cited from reference number 25).
Normal eye shape.
A.
B. Axial length elongation occurring in the equatorial region that
does not induce any alteration in the curvature of the posterior part of the eye. This C.
A second curvature develops
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eye would have axial myopia but no staphyloma.
in the posterior portion of the eye, and this second curvature has a shorter radius (r2)
staphyloma.
This secondary curve is due to a
D. Nasally-distorted type of the eye.
Figure 2.
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definition of staphylomas in this study.
This shape is added to the
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of curvature than the surrounding eye wall (r1).
New classification and re-naming of staphylomas according to their
location (Ohno-Matsui 2014).
Highly myopic eyes without a staphyloma (Ohno-Matsui 2014).
A and B.
Right fundus of a 50-year-old woman with refractive error of -12.5 D and
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Figure 3.
axial length of 29.2 mm. The fundus images taken by Optos shows diffuse
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chorioretinal atrophy is seen around the optic disc.
There is no obvious pigmentary
change suggesting the border of a staphyloma in the pseudocolor image (A), and no
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abnormal-autofluorescence (B).
C. and D. 3D MRI images of the globe.
No
obvious outpouching of the posterior segment is seen viewed nasally (C) and inferiorly (D).
Figure 4.
Eyes with a wide, macular staphyloma (Ohno-Matsui 2014).
A and B. Right fundus of an 83-year-old woman with an axial length of 30.0 mm (pseudophakic eye).
Right fundus photographs taken by Optos (A) shows that the
upper edge of the staphyloma is pigmented in the pseudocolor image (arrows in A),
ACCEPTED MANUSCRIPT and shows granular hypo-autofluorescence (arrows in B).
C and D.
3D MRI
images of this patient show a wide area of posterior outpouching due to a staphyloma. In the image viewed nasally (C), the maximally protruded point exists at the central A slight depression is found along the upper and lower border of the
outpouching (arrows in C).
In the image viewed inferiorly (D), the change of
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point vertically.
curvature is more evident along the temporal margin of the staphyloma than the nasal Thus, the temporal border is observed as a notch (arrow).
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margin.
Figure 5. Myopic Maculopathy Classification according to META-PM study Category 1 maculopathy is characterized by
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based on color fundus photographs.
tessellated fundus, in which outline of choroidal vessels are easily visible throughout the posterior pole (A). Category 2 maculopathy is characterized by diffuse chorioretinal atrophy, in which the posterior pole appears yellowish white in
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appearance (B). Category 3 maculopathy is characterized by patchy chorioretinal atrophy (black arrowheads), which appears as well-defined, grayish-white lesions (C). Category 4 is characterized macular atrophy, which appears as a well-defined, round
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grayish white chorioretinal atrophic lesion around a regressed fibrovascular membrane (D). Lacquer crack (white arrow) is one of the plus lesions, and appears
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as yellowish thick linear pattern (E). Fuchs spot (black arrow) is a pigmented spot representing the scarring phase of myopic choroidal neovascularization (F).
Figure 6. Imaging of myopic CNV.
Fundus photo of the right eye of a 64-year-old
female with -14D myopia presenting the fibrovascular membrane surrounded by macular hemorrhage (A).
Macular choroidal neovascularization (CNV) shows a
clear hyper-fluorescence (B). coherence tomography (OCT).
CNV is observed as subretinal elevation by optical Serous retinal detachment is also seen.
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Figure 7. Development of macular atrophy related to myopic choroidal neovascularization (CNV-related macular atrophy). At the onset, the CNV surrounded by macular hemorrhage is seen (A).
? years later,
Figure 8. Anti-VEGF therapy for myopic CNV.
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the well-defined macular atrophy (B) develops around the scarred CNV.
Fundus photo of the right eye of a
Late phase fluorescein angiography (FA) showing active
leakage from a myopic CNV (B).
Horizontal spectral domain optical coherence
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shallow subretinal fluid (A).
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52-year-old female with -12D myopia presenting with macular hemorrhage and
tomography (SD-OCT) showing hyper-reflective material in the subretinal space due to macular hemorrhage with adjacent subretinal fluid due to active CNV (C).
At 12
months after commencement of intravitreal ranibizumab injections, there was Post-treatment
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complete resolution of macular hemorrhage and subretinal fluid (D).
FA showed staining of scar due to fibrosis of CNV and no leakage was seen (E). Horizontal scan of SD-OCT showed resolution of subretinal hyperreflective material
Diagnostic and treatment flowchart for the management of suspected
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Figure 9.
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with complete absence of subretinal fluid after anti-VEGF therapy (F).
myopic CNV.
Figure 10. Dome-shaped macula. Dome shaped macula are difficult to observe on fundus photograph or biomicroscopy. On optical coherence tomography (OCT), an invward bulge within the concavity of the posterior pole over the macula is clearly visible in the vertical section but less obvious in the horizontal section (indicated by black lines on fundus image). The subfoveal sclera (black double-headed arrow) is
ACCEPTED MANUSCRIPT markedly thickened compared to parafoveal regions.
Figure 11. Macular Hole with Retinal Detachment A 44 year old man with type 1 macular hole retinal detachment underwent vitrectomy
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with internal limiting membrane repositioning and autologous blood showed re-attachment of the retina in the macula area. Spectral domain optical coherence tomography images before, 2months, and ten months after surgery showed gradual
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the internal limiting membrane reposition.
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resolution of the retinoschisis and sub-retinal fluid (arrowheads). Asterisk indicated
Figure 12. Myopic Traction Maculopathy (MTM)
Myopic traction maculopathy (MTM) can be classified using spectral domain optical coherence tomography as macular retinoschisis (MRS), MRS with foveal detachment,
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MRS with lamellar hole, MRS with full thickness macular hoe and macular hole with retinal detachment. Shimada et al. have classified myopic traction maculopathy according to its location and extent from S0 through S4: S0: no retinoschisis; S1:
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extrafoveal; S2: foveal; S3: both foveal and extrafoveal but not the entire macula; and S4: entire macula (Shimada, Tanaka et al. 2013). S1 upper image shows progression
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from S0 image. S4 images showed horizontal (upper) and vertical (lower) scans from the same eye.
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Table 1. Summary of the Classification of Myopic Maculopathy according to META-PM study.
Category 2
Diffuse chorioretinal atrophy
Category 3
Patchy chorioretinal atrophy
Category 4
Macular atrophy
+ Lc + CNV
Lacquer cracks Choroidal neovascularization
+ Fs
Fuchs spot
-
Posterior staphyloma
Well-defined choroidal vessels can be observed clearly around the fovea and arcade vessels The posterior pole appears yellowish white, extent of which is variable Well-defined, grayish white lesions, size variable between 1 and several choroidal lobules Well-defined, round chorioretinal atrophic lesion that is grayish white or whitish around a regressed fibrovascular membrane that enlarges with time. Generally macular atrophy is centered on the central fovea and has a round shape. Yellowish thick linear pattern Active CNV should be accompanied by exudative activity or hemorrhage. Serous retinal detachments can be present Pigmented spot representing the dry fibrovascular scar of myopic CNV Local bulging of the sclera at the posterior pole that has a radius of less than the surrounding curvature of the wall of the eye
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EP AC C
Fundus Appearance
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Myopic Retinal Changes No myopic retinal changes Tessellated fundus
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META-PM Classification Category 0 Category 1
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OCT findings Mean BCVA, mean (range) Age (years), Axial length
Mean
Gas Surgical
Year
Author(s)
eyes
mean (range)
(range)
After surgery
ILM
(mm), mean follow-up
decimal or Snellen or logMAR tamponad
Procedures (patient)
Before surgery
Complete/Partia
Complications
peeling
(months)
e
MRS/FD/FTMH/LMH/MHRD l resolution of
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No. of
Before surgery
After surgery
RD and MRS
63.8
28.47
24
33 (5-46)
NA
2012 Mateo et al.
16
60.3 (42-79)
NA
2013 Mateo et al.
39(36)
59 (35-79)
2009
2014
2014
2012
2014
2003
Zhu et al.
Burés-Jelstr up et al.
Ei Rayes EN et al.
Ho et al.
(26.3-34.5)
16
52.2 (36-63) (28.34-31.48
NA
logMAR 0.81
logMAR 0.99
25.7
MB
-
NA
6/3/0/0/0
2/6
0.3
0.57
MB
-
NA
24/NA
20/4
NA
NA
14.7
MB and VT
-
+
16/13/0/8/0
16/0
20/125
20/50
16
MB and VT
NA
NA
39/28/0/9/0
NA
logMAR 0.76
logMAR 0.43
25.3
MB and VT
33 (29-38)
12
choroidal MB
8
58 (38-70)
NA
5.4
Vitrectomy
12
58.2
NA
52.4
Vitrectomy
7
54.4
NA
55.6
Vitrectomy
20.4
Vitrectomy
8 and 12
2(2)
52 and 84
2004 Ikuno et al.
6(9)
59.5 (51-63)
6(5)
61
er
7/1
and VT
2003 Kanda et al.
Spaida&Fish
10/10/0/0/0
supra 23
54.7 (36-74)
al.
+
)
Ho et al.
Kobayashi et
-
30.19
9(7)
2005
30.8
IVI gas
27.5 (26.5-28.5) NA 29.2 (27.9-29.9) NA
+
-
foveola
nonpeeling foveola
NA
+
NA NA
nonpeeling total
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6(5)
11.65
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58.80 ± 8.28 30.43 ± 2.42
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2006 Baba et al.
10
EP
Wu et al.
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2013
SRH in 2, CNV 1, CRA in 1 eye MRS recurred in 3, MH in one eye CD in 3, RPE atrophy in 5 RPE atrophy in 6, buckle removal in 3, RD in 2 eyes
16/0/16/0/0
NA
20/125
20/50
11/0/0/0/12
23/0
NA
NA
logMAR 1.75
logMAR 1.17
(1.70-3.0)
(0.70-2.0)
extrusion of exoplant in 1 eye choroidal hemorrhage and macula hole
8/NA
11/NA
7/1/ NA
logMAR 1.7±0.4
logMAR 0.89±0.56
-
MH in 2 eyes
logMAR
logMAR
1.67±0.23
1.39±0.33
8/1
0.17 (0.02-0.4)
0.48 (0.4-0.6)
FTMH in 1 eye
2/1/0/0/0
1/1
NA
NA
-
+
6/6/0/0/0
5/1
0.1
0.43
-
+
4?/4?/0/1/0
6/0
20/100
20/60
-
NA
7/NA
NA
+
+
9/9/0/0/0
Vitrectomy
+
1/2 eyes
14
Vitrectomy
+
19.1
Vitrectomy
-
peeling
2 unchnaged
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2006 Ikuno&Tano
8(8)
63.1
2006 Scott et al.
3(3)
53, 31, 69
24
58 (32-79)
11
55 (43-70)
3(3)
58.3 (52-62)
2008 Ikuno et al.
44(42)
63.3 (43-79)
2009 Fang et al.
6(6)
53.1
39(39)
66.3 (44-80)
2011 Zheng et al.
18(17)
51.3 (25-78)
2012 Wang et al.
11
2007
2007
2008
2010
al.
Pannozzo & Mercanti Gaucher et al. Yeh et al.
Kumagai et al.
Vitrectomy
25.6
Vitrectomy
NA
Vitrectomy
+
8,7,1
Vitrectomy
2/3 eyes
NA
29.6
Vitrectomy 24/24 eyes
NA
26.9
Vitrectomy
12
Vitrectomy
-
12
Vitrectomy
+
9.8
Vitrectomy
-
41
Vitrectomy
+
17.5
Vitrectomy
6
Vitrectomy
11.8
Vitrectomy
28.0 (24.9-30.2) 29 32.6mm in 1 case
30.0 (28.8-31.1) 29.1 (24.4-34.6) 29 28.6 (24.4-34.7) 29.7 (26.8-34.1)
51.3 (39-60) 29.32±1.81
2012
Lim et al.
15(13)
60.3 ± 12.5
30.8±2.6
2012
Kim et al.
17(17)
61.9 (44-78) (27.80-32.95 13 or 15.3 ) 29.16
2012
Shin & Yu
38(36)
63.5 (32-84) (26.61-36.17 )
2013
2013
Taniuchi et al. Hwang JU et al.
71(64)
33(29)
65.5 ± 8.6
63.2 ± 9.3
29.01
6
9/9/0/0/0
7/2
20/80
20/50
-
16/11/2/0/0
16/0
NA
NA
FTMH in 5 eyes
8/8 eyes
8/0/8/0/0
8/0
20/300
20/130
3/3 eyes
3/2/0/0/0
3/0
NA
NA
NA
+
24/5/0/0/0
23/0
logMAR 0.6
logMAR 0.43
FTMH in 5 eyes, 1
(1.1-0.2)
(1.1 to -0.1)
unchanged FTMH in 3 eyes
1/11 eyes 6/11 eyes
Vitrectomy
Vitrectomy
+
6/16 eyes 12/16 eyes
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29.75
-
hole size in 1 eye
4/4
logMAR 0.97
logMAR 0.63
3/3/0/0/0
1/2
CF-0.04
0.27 (0.2-0.3)
+
16/17/11/0/0
44/0
NA
NA
FTMH in 2 eyes
+
6/6/0/0/0
4/2
20/400
20/160
-
34/39 eyes
39/27/0/0/0
39/0
logMAR
logMAR
0.79±0.60
0.54±0.60
logMAR 0.94
logMAR 0.49
(2-0.15)
(1.3-0.15)
0.1
0.18
+
+
11/18 eyes
18/12/0/0/0
18/0
+
+
11/6/0/0/0
11/0
+
-
15/NA
15/0
+
9/17 eyes
10/7/0/0/0
12/2
+
+
38/7/2/0/0
34/3
26/30/15/0/0
NA
+
FTMH in 6, enlarged
11/5/0/0/0
27.7 ± 25.9 Vitrectomy 61/71 eyes 35/71 eyes
29.73 ± 2.08 19.3 ± 12.8 Vitrectomy
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64.9 (53-77)
Hirakata et
17.2
SC
16(14)
2006
29.0 (26.3-32.1)
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52.7 (40-65)
TE D
9(8)
EP
2005 Kwok et al.
air, gas or silicon oil
33/7/5/4/3
33/0
logMAR
logMAR
0.78±0.53
0.61±0.75
logMAR 0.81-0.83
logMAR 0.56
RD in 1 and retinal breaks in 1 eye
-
FTMH in 2 eyes
FTMH in 2 eyes, 3 unchanged
logMAR
logMAR
0.84±0.53
0.53±0.54
logMAR
logMAR
0.64±0.41
0.43±0.38
logMAR
logMAR
MH in 1 eyes,
1.01±0.47
0.76±0.64
persistent MRS in 1
FTMH in 1 eye
MHRD in 7, MH in 4, TMD in 2, RRD in 3 eyes
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2014 Chang et al.
10(9)
41
60.4 (45-74) 30.76 ± 2.40
61 (36-86)
NA
17
6.4
Vitrectomy
+
-
Vitrectomy 35/41 eyes 34/41 eyes
10/6/0/0/0
41/16/11/0/0
5/3
NA
RI PT
2014 Uchida et al.
(20/200)
(20/120)
0.61
0.47
20/130
20/70
eye MHRD in 2 eyes, RD in 1 eye re-operation in 11 eyes
IVI: intravitreal injection; MB: macular buckling or reinforcement; VT: vitrectomy; ILM: internal limiting membrane; NA: not available; MRS: macular retinoschisis; FD: foveal detachment; FTMH: full thickness macular hole, LMH: lamellar macula hole; MHRD: macular hole with retinal detachment; BCVA: best corrected visual acuity; BCVA was expressed as decimal data, Snellen, or logMAR (minimum angle or resolution) based on
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original data; SRH: subretinal hemorrhage; CRA: chorioretinal atrophy; RD, retinal detachment; RPE: retinal pigment epithelium.
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