Progress in Retinal and Eye Research 88 (2022) 101020

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Progress in Retinal and Eye Research

journal homepage: www.elsevier.com/locate/preteyeres

Tilted disc syndrome (TDS): New hypotheses for posterior segment

complications and their implications in other retinal diseases
Salomon Yves Cohen a, b, *, Catherine Vignal-Clermont c, Liem Trinh d, Kyoko Ohno-Matsui e
a
Ophthalmic Center of Imaging and Laser, Paris, France
b
Department of Ophthalmology, Intercity Hospital and University of Paris Est, Creteil, France
c
Department of Ophthalmology, Rothschild Foundation Hospital, Paris, France
d
CHNO des Quinze-Vingts, IHU Foresight, INSERM-DGOS CIC 1423, Paris, France
e
Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University, Tokyo, Japan

A R T I C L E I N F O A B S T R A C T

Keywords: Tilted disc syndrome (TDS) is considered a congenital anomaly due to a delayed closure of the embryonic fissure.
Tilted disc syndrome It is characterized by an oblique orientation of the axis of the optic disc, associated with other posterior pole
Inferior staphyloma anomalies such as inferior crescent, situs inversus and inferior staphyloma. The aim of this review was to sum­
Macular serous retinal detachment
marize the data supporting the current hypotheses for the pathogenesis of TDS, and its anatomical and functional
Wide-field imaging
clinical consequences. Recent imaging techniques, such as magnetic resonance imaging, wide-field fundus im­
aging, and 2- and 3-D optical coherence tomography have provided a new perspective on TDS and its compli­
cations. Different abnormalities have previously been reported, both in the anterior and posterior segments. The
focus was on vision-threatening chorioretinal changes or complications, including choroidal neovascularization
and serous retinal detachments and their therapeutic options. Based on clinical observations, assumptions were
proposed to understand the occurrence of complications such as chorioretinal degenerative changes, choroidal
neovascularization and polypoidal choroidal vasculopathy, macular serous retinal detachment, myopic foveo­
schisis and chorioretinal folds. These hypotheses could be referred to as the curvature “breaking point” hy­
pothesis, the uneven growth “tractional” hypothesis, the “container-content” imbalance hypothesis, and the
“choroidal funnel” hypothesis. Because these complications could also occur in other contexts, understanding the
pathogenesis of TDS complications could help to understand their pathophysiology.

1. Introduction
1.1. Definitions
The definitions of congenital tilted disc syndrome (TDS) include a
pure description of the morphological abnormalities of the optic nerve
head (ONH) (tilting, oblique orientation), and/or of the usually associ­
ated fundus findings, and/or of its visual functional consequences. For
example, congenital TDS has been defined in previous reports as an
abnormality consisting of an inferonasal “tilting” of the optic disc,
usually associated with an inferonasal crescent (conus), a thinning of the
retinal pigment epithelium (RPE) and choroid in the inferonasal fundus,
a posterior staphyloma and the affected inferonasal region of the fundus,
and situs inversus of the retinal vessels (Apple et al., 1982) (Fig. 1). It has
also been described as an optic disc tilt and/or torsion, an astigmatic
refractive error, situs inversus of the retinal vessels, β-peripapillary at­
rophy (PPA), an inferonasal chorioretinal thinning, a posterior staph­
yloma or coloboma, and visual field defects (Vongphanit et al., 2002).
The last definition includes a small ONH with an oblique or horizontal
orientation and an oval shape of the disc, occurring in eyes without high
myopia (You et al., 2008). Thus, there is currently no consensus
definition.
A purely descriptive definition would only include a vertical tilting of
the disc, and an oblique or horizontal orientation of the disc axis. Tilted
disc has first been observed by 2D and color fundus photography, and
then clinically, by binocular indirect ophthalmoscopy or stereo
photography, allowing a 3D perception without objective quantifica­
tion. The use of color and infrared fundus photography in combination
with enhanced depth imaging optical coherence tomography (EDI-OCT)
has allowed specifying and quantifying the changes of a tilted optic disc

* Corresponding author. Ophthalmic Center of Imaging and Laser, Paris, France.

E-mail addresses: sycsyc75@gmail.com, sycsyc75@gmail.com (S.Y. Cohen).

https://doi.org/10.1016/j.preteyeres.2021.101020
Received 16 August 2021; Received in revised form 5 November 2021; Accepted 8 November 2021
Available online 17 November 2021
1350-9462/© 2021 Elsevier Ltd. All rights reserved.
S.Y. Cohen et al.
Fig. 1. Typical congenital tilted disc with inferonasal crescent (black arrows),
situs inversus (yellow arrows) and inferior pallor of the fundus, corresponding to
the inferior staphyloma. The limits between the superior area corresponding to
the normal fundus, and the inferior staphylomatous area of the fundus are well
delimited (black arrowheads).
in each of the 3 planes of the space. The disc rotation around its vertical
axis (“vertical rotation”) leads to a horizontally shortened image of the
ONH as the temporal edge of the disc is located more posteriorly than
the nasal edge; the disc rotation around its sagittal axis (“sagittal rota­
tion”) moves the superior pole towards the temporal direction, and the
disc rotation around its horizontal axis (“horizontal rotation”) tilts the
ONH with a prominent and slightly unsharp disc edge in the superior
disc region associated with an inferior scleral crescent ((Dai et al., 2015;
Hosseini et al., 2013). Thus, the term “tilted” barely reflects the
complexity of the shape of the ONH in TDS.
However, associated fundus changes are part of the clinical spectrum
of the condition, and have frequently been included in the definition of
TDS itself. They include an inferonasal crescent, also called β-PPA, an
abnormal insertion of the retinal vessels with frequent situs inversus, and
an inferior pallor of the fundus usually corresponding to an inferior
staphyloma. Refractive errors, usually mild to moderate myopia and
myopic astigmatism should not be part of the definition. On the other
hand, an inferior staphyloma, classified as Type V staphyloma by Curtin
(1977), may also be found in highly myopic eyes. In these cases, a
myopic crescent is usually present, along with a disc obliquity. Thus, the
precise distinction between TDS and high myopia with inferior staph­
yloma may be difficult to make since their consequences or complica­
tions are similar.
1.2. First description
The first description of TDS was made by Ernst Fuchs in 1882 (Fuchs,
1982). Fuchs has reported that the inferior pole of each disc was rotated
temporally “each points toward its respective macula”, and that the
inferonasal margin of each disc was continuous with an inferior crescent
or coloboma (currently known as Fuchs’ coloboma). He has also
described the abnormal entry point of the retinal vessels and identified
the staphyloma as an area in which the diopters to be focused by direct
ophthalmoscopy were different (Fig. 2).
2. Anatomy, pathology, and pathogenesis of TDS
Tilted discs can be classified into two groups based on their suspected
etiology: congenital TDS (CTDS), which is an anomaly of the eye char­
acterized by an inferior or inferonasal tilting of the optic disc, and
myopic tilted disc (MTD), which is an acquired change related to the
progression of myopia (Apple et al., 1982; Witmer et al., 2010). CTDS is
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Progress in Retinal and Eye Research 88 (2022) 101020
Fig. 2. Original plate by Ernst Fuchs reporting different disc malformations.
Magnification of a typical case of tilted disc syndrome, described by Fuchs as
the 2 discs of case 23. Oval oblique discs with a significant inferior crescent, the
right disc being excavated with slightly crooked vessels at the inferior edge of
the crescent (translated from German).
considered a congenital but non-inherited anomaly, reported in
0.4–3.5% of the population with a wide phenotypic spectrum that ex­
plains this significant difference in range. In clinical studies, the fre­
quency of bilateral tilted discs ranges from 37.5% to 80% and this
difference is also due to various inclusion criteria. These large variations
could also be explained by the fact that there is no recognized limit of
refractive changes that could allow a simple classification and differ­
entiation between CTDS and MTD. Furthermore, there is no longitudinal
study of eyes with TDS allowing documenting the progression of CTDS.
Indeed, most papers have studied adult patients and neither the tilt
index nor the direction of PPA is specified. Thus, some studies have
included patients with non-myopic and myopic tilted discs, inferior or
inferonasal tilting but also inferotemporal myopic tilting. This could
explain the high prevalence of tilted disc reported in some papers (How
et al., 2009). Moreover, optic disc tilt has been described in children
(Kim et al., 2019), but long-term follow-up data that could allow
concluding on the co-existence of the disc anomalies and an inferior
staphyloma at birth, their progression or not during life, and their
relationship with myopia in adulthood are lacking.
2.1. Anatomical findings
In tilted optic disc, two abnormal anatomical findings related to the
ONH and the point where it leaves the sclera have been reported. They
both modify the appearance of the disc, the adjacent retina and vessels.
In clinical practice, the diagnosis of TDS is based on the ophthalmos­
copic appearance of the optic disc.
1 The first finding is the apparent oblique angle at which the optic
nerve leaves the eye. This oblique angle creates a disparity between
the maximum and minimum surface elevations of the disc.
2 The rotation of the optic nerve around the sagittal axis creates a
torsion of the disc, so that the longest disc diameter is ≥ 15◦ outside
the vertical meridian.
Clinically, a tilted disc appears as an exaggerated oval ONH with one
hemi-disc, usually the superotemporal portion, that is more elevated
than the contralateral half (inferonasal). The steeper the slope is, the
greater the tilt is and usually, the greater the elliptical structure of the
disc is. The elevated portion of the disc margin is usually adjacent to the
intact neurosensory retina, RPE and choroid and may appear blurred.
The less elevated portion of the disc is usually contiguous to an atrophic
RPE and thin choroid.
This rotation is often (in 70% of eyes with tilted disc) enhanced by
S.Y. Cohen et al.
the orientation of the retinal vessels emerging nasally from the disc
before turning temporally, and seems to compensate for the position of
the tilted disc (situs inversus). However, many eyes with TDS do not
present any sign of situs inversus. Some retinal findings may be associated
with a tilted optic disc, such as PPA with an inferonasal or annular
crescent (conus) corresponding to the absence of RPE and choroid, and
posterior staphyloma corresponding to a localized ectasia with thinning
of the sclera, choroid and retina. Indeed, the few published pathology
reports of TDS have shown a relative hypoplasia of the retina, a reduced
density of the choroidal vessels, and a thin sclera (Elschnig, 1900; Young
et al., 1976). In the latter study, the authors have reported an asym­
metric disc elevation, but also a thin sclera and fewer large choroidal
vessels in the inferior part of the eyeball compared to the superior part.
2.2. Associated findings
An association between TDS and other ocular or systemic malfor­
mations has occasionally been reported: tilted disc without retinal
ectasia in patients with transsphenoidal encephalocele (Brodsky et al.,
1995), congenital tumors of the anterior visual pathway (Taylor, 1982),
X-linked congenital stationary night blindness (Witmer et al., 2010),
Goldenhar-Gorlin syndrome (Margolis et al., 1984), translocation 46XY,
t (17,18) (q25; q21) (Smith et al., 1979), X-linked recessive congenital
stationary night blindness (Hittner et al., 1981). TDS may also be asso­
ciated with ocular congenital changes, including: dominant inherited
TDS and lacquer cracks (Bottoni et al., 1990), bilateral type 3 Duane
retraction syndrome (Kim et al., 2019), fovea plana (see below, (Cohen
et al., 2013). Other changes in the disc area itself have occasionally been
reported in eyes with TDS, including medullated nerve fibers (Cockburn,
1982) or optic disc drusen (Giuffré, 2005). A case of bilateral tilted optic
discs with facial hemiatrophy and congenital horizontal gaze palsy has
also been reported (Rothkoff and Beidner, 1979).
2.3. Current pathophysiological hypotheses
A classical hypothesis assumes a relationship between TDS and an
abnormal closure of the embryonic fissure. Indeed, many authors agree
on the fact that the ectasia observed in the fundus of patients with TDS
occurs in the inferonasal part of the fundus because this is the last site of
fetal fissure closure (Dorrell, 1978; Giuffré, 1985a; Witmer et al., 2010;
Young et al., 1976)
The optic nerve originates from the embryonic optic stalk. During the
earliest stages of development (third week of gestation), the cavity of the
optic vesicle maintains an open communication with the ventricle
through the optic stalk. The first nerve fibers form as buds from the
retinal ganglion cells at about six weeks of gestation and course
centripetally through the embryonic fissure and optic stalk toward the
brain. Myelination takes place in the opposite direction. The lumen of
the stalk narrows as it is replaced by the nerve parenchyma. The
development of the eye requires a secondary invagination of the anterior
wall of the vesicle forming the optic cup and the embryonic ocular
fissure. This fissure is transient, and its closure leads to the formation of
an intact eyeball. The cause of TDS is unknown but the inferonasal or
inferior location of the excavation suggests a pathogenetic relationship
with a retinochoroidal coloboma and with a malclosure of the embry­
onic optic fissure (Apple et al., 1982). However, this hypothesis does not
explain the origin of all the anomalies found in CTDS, in particular the
crescent appearance of the ONH.
Giuffrè has suggested a hypothesis to explain all the findings
observed in TDS (Giuffré, 1985a). He has also considered the hypothesis
of a delayed closure of the embryonic optic fissure. Because of the
centripetal development of retinal ganglion cells, some fibers could be
misdirected toward the orbit through an abnormal embryonic fissure,
and could thus not reach the optic stalk and might degenerate. A similar
theory has been proposed in aplasia of the optic nerve and disc (Weiter
et al., 1977). After closure of the embryonic fissure, all external layers, i.
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Progress in Retinal and Eye Research 88 (2022) 101020
e., the choroid and sclera, will develop secondarily and their shape will
depend on the shape of the retina. In this inferonasal part of the eye
where there is a relative loss of fibers, the retina will be thinner and,
thus, will be more likely to expand because it could barely resist to the
intraocular pressure (locus minoris resistentiae). The choroid and the
sclera will adapt to the shape of this expanded retina, explaining, ac­
cording to Giuffrè, the inferonasal staphyloma (Fig. 3) (Giuffré, 1985b).
Giuffrè has also suggested that the crescent could originate from the lack
of fibers in the inferior optic disc, and the abnormal appearance of the
ONH and the retinal vessels could result from a shifting of the disc up­
ward due to the imbalance between the ganglion cell fibers coming from
superior and inferior retina.
However, other theories have been proposed. One argument is that
the prevalence of TDS was, in some studies, by far higher than the
prevalence of other congenital disorders related to a malclosure of the
embryonic fissure. The incidence of TDS was 3.5% in the Tanjong Pagar
Study, by far higher than the incidence of coloboma (How et al., 2009).
Histologically, both myopic discs with temporal crescent and PPA and
TDS show no or attenuated RPE and choroid (Kim et al., 2019). Young
et al. have examined an autopsy eye with TDS histologically and re­
ported that the sclera appeared thinner in its bottom part compared to its
top part, suggesting an inferior ectasia (Young et al., 1976). A study
evaluating non-highly myopic (n = 16) and highly myopic (n = 38) eyes
with TDS with swept-source OCT and 3D MRI has shown various ab­
normalities that appeared to be specific to TDS. All eyes showed a pro­
trusion of the lower part of the posterior segment and the optic nerve
was attached at the upper nasal edge of the protrusion. The attachment
site of the nerve was oblique when viewed from the nasal side. Overall,
these studies could suggest that the main features of TDS correspond to a
simple deformity of the inferior eyeball with a thin inferior sclera
beneath the optic nerve and that the spatial relationship between the
fovea and the inferior protrusion could determine the degree of myopia
(Shinohara et al., 2018). In summary, the pathogenesis of TDS is not
fully understood. However, we support the assumption that TDS is a
congenital disorder and that the hypotheses by Giuffrè are probably
exact. The congenital origin is supported by the report of pediatric cases
(Pichi et al., 2014), the location of the abnormalities in the peculiar area
related to the embryonic fissure, i.e., the inferonasal part of the fundus,
the report of cases of TDS in association with chorioretinal colobomas
(Witmer et al., 2010), and the presence of unilateral TDS, associated
with a full optic nerve coloboma in the contralateral eye (Fig. 4).
3. Functional anomalies related to TDS
3.1. Refractive errors
The most common cause of correctable visual impairment in TDS is a
refractive error with an increased prevalence of myopia and astigma­
tism. The severity of myopia and the axial length of the eye have been
correlated with the degree of optic disc tilt (Tay et al., 2005) but the
amount of refractive error in patients with tilted disc compared to
controls varies between studies, probably partially because of the
overlapping morphology of myopic eyes and eyes with tilted discs
(Witmer et al., 2010).
Astigmatism is also very common, found in up to 93% of patients
with tilted discs and the risk of tilted discs increases with the increasing
degree of astigmatism in the general population (Dehghani et al., 2010;
Dorrell, 1978). This astigmatism results from the involvement of the
ocular anterior segment, with corneal and lens changes as described
below.
3.2. Visual field defects
Patients with bilateral tilted discs may present with bitemporal
hemianopia, suggesting a chiasmal syndrome. However, this hemi­
anopia is usually incomplete, limited to the superior quadrants, and does
S.Y. Cohen et al. Progress in Retinal and Eye Research 88 (2022) 101020

Fig. 3. Original drawings by Giuffrè describing his

hypothesis about tilted disc syndrome. Because of
the delayed closure of the embryonic fissure, some
fibers will be lost; the inferonasal part of the fundus
will include less nerve fibers than the temporal part
of the fundus (Giuffré, 1985b). This illustration has
been drawn from the article Giuffrè G: Hypothèse
sur la pathogénie du syndrome de dysversion pap­
illaire [Hypothesis on the pathogenesis of the
papillary dysversion syndrome] J Fuchs, 1982; 8
(8–9):565–72. Copyright © 1985 Editions Masson.
All rights reserved. Reproduction with permission.

Fig. 4. 54-year-old patient presenting with a full coloboma of the optic nerve head in the right eye and tilted disc syndrome in the left eye, suggesting a common
congenital origin.

not respect the vertical meridian on both kinetic and static perimetry. scotoma usually secondary to regional ectasia and myopia located at the
The vertex of this defect is directed towards the blind spot (Vuori and inferonasal retina. On Goldmann perimetry, this superotemporal
Mäntyjärvi, 2007) (Fig. 5). This defect is in fact a partially refractive depression is selectively detected with mid-sized isopters, while the

Fig. 5. Two examples of tilted disc syndrome, top

(A) fundus color photography with corresponding
Goldmann perimetry, bottom (B) fundus red-free
photography with Goldmann perimetry and retinal
nerve fiber layer (RNFL) analysis. Relative super­
otemporal defect selectively detected with mid-
sized isopters, whereas the large and small isopters
give normal results (A). The difference may be
explained by the fact that the ectasia is limited to
the midperipheral fundus. However, in some cases,
the defect also involves large isopters (B). There is a
sectorial thinning of the superior and nasal RNFL
(Courtesy Dr. Lamirel, Paris).

4
S.Y. Cohen et al.
large and small isopters give normal results because the ectasia is limited
to the midperipheral fundus. Since the prevalence of myopia and corneal
astigmatism is increased in TDS patients, performing visual fields with
correction of myopic astigmatism may reduce or eliminate this super­
otemporal defect (Phu et al., 2018). But this defect is partially neuro­
genic (because the density of optic nerve axons is focally reduced) and in
some cases, the retinal sensitivity is decreased in the area of the ectasia,
and the decrease thus persists despite appropriate refractive correction
(Pichi et al., 2014). Brazitikos et al. have shown that a slightly decreased
sensitivity may be found in other quadrants, suggesting that TDS may
include some degree of diffuse retinal hypoplasia (Brazitikos et al.,
1990). An enlargement of the blind spot may also be associated with this
bitemporal defect.
The association between TDS and true bitemporal hemianopia found
in some patients with a congenital suprasellar tumor makes neuro­
imaging mandatory in any patient with TDS whose bitemporal hemi­
anopia either respects the vertical meridian or does not respect it to
preferentially involve the midperipheral isopters on kinetic perimetry
(Jeng-Miller et al., 2017).
3.3. Color vision
Two papers on color vision in patients with tilted optic discs have
been published. Vuori and Mâäntyjärvi (Vuori and Mäntyjärvi, 2007),
using Boström-Kugelberg pseudo-isochromatic plates, the Farn­
sworth–Munsell 100-hue test, and the Farnsworth panel D-15 and Lan­
thony desaturated panel D-15 tests, have assessed 35 eyes of 21 patients
and reported that 49% of eyes with tilted optic discs had a color vision
defect. The severity of the defect differed between eyes in 6 out of the 8
patients with bilateral tilted discs and 2 of these patients had a color
vision defect in only one eye. A red-green defect, a blue defect and a
mixed defect were found in respectively 24%, 6% and 70% of eyes with a
color vision defect. Color vision defects were not related to the visual
acuity or to the severity of the visual field defects. However, another
study by Moschos et al. has reported a normal color vision in the 21 eyes
of 12 patients with tilted disc studied by OCT and multifocal electro­
retinography (mfERG) (Moschos et al., 2009).
3.4. Electrophysiology
Some patients with TDS may also show abnormal electrophysiolog­
ical findings. In 1986, Giuffrè and Anastasi have reported the results of
full-field electroretinography (ERG), electro-oculography (EOG) and
visual evoked potentials (VEPs) of 15 patients with TDS. ERG showed
abnormal amplitudes in about a quarter of the eyes and the EOG values
were pathological in 3 patients. The authors have concluded that the
abnormality of the inferonasal portion of the retina and RPE seen in TDS
could induce the changes seen on ERG and EOG. Pattern VEP latency
was delayed in most patients, probably due to the poor focusing of the
light in the retina (Giuffrè and Anastasi, 1986). mfERG has also been
tested in patients with TDS. Moschos et al. have compared the results of
40 normal eyes of 20 age- and sex-matched control subjects to 21 eyes of
12 patients with TDS (Moschos et al., 2009). They have found that the
mean response amplitude density of the fovea and parafovea was
significantly reduced in eyes with tilted disc compared to normal eyes,
suggesting that in TDS, even in the absence of visual impairment, and
the macula show a dysfunction that is not visible using other techniques.
3.5. Hypotheses about functional anomalies related to TDS
Most of the functional changes are related to the overall shape of the
eyeball, both in the anterior and posterior segments (see below) and/or
to the reduced density of retinal axons in the area of the staphyloma.
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Progress in Retinal and Eye Research 88 (2022) 101020
4. Anterior segment anomalies associated with TDS
TDS is mainly known for its optic disc features but, as noted in the
introduction, the whole syndrome also includes an astigmatic refractive
error in most publications (Vongphanit et al., 2002). TDS involves the
ocular anterior segment, and this astigmatic component is induced by
corneal and lens changes. The anterior segment anomalies reported in
TDS are summarized in this section (Table 1).
4.1. Corneal and lenticular astigmatism
The most common refractive error associated with tilted optic discs is
astigmatism that may be found in up to 93.5% of TDS patients, with a
mean astigmatic error of 2.2D. Myopia may also be associated with tilted
optic discs (Lim et al., 2012) in 66.2% of cases, with a mean myopia of
− 2.4D (Vongphanit et al., 2002). TDS is associated with myopic
refraction related to a longer axial length compared to the normal
population, classifying its astigmatism as myopic astigmatism.
Ocular astigmatism in TDS is mainly corneal in origin. Corneal
astigmatism is significantly higher in eyes with tilted discs than in
controls (Jonas et al., 2004). A study has investigated the corneal
topography and shown corneal astigmatism in 22 out of 23 eyes with
TDS (with a mean cylinder of − 1.95D), with an asymmetric bow tie
pattern (11 eyes) and a symmetric bow tie pattern (10 eyes) (Bozkurt
et al., 2002) (Fig. 6). In 10 out of the 11 eyes with an asymmetric bow tie
pattern, the steepening was superior, and most eyes had with-the-rule
(WTR) astigmatism. The axis of corneal astigmatism correlated with
the orientation of the longest disc diameter in tilted discs (Jonas et al.,
1997). The optic disc was most often horizontal in eyes with a steeper
horizontal corneal meridian, and most often vertical in eyes with a
steeper vertical corneal meridian.
Although corneal astigmatism has been described as the primary
factor contributing to total astigmatism in TDS, lenticular astigmatism is
significantly higher in TDS patients compared to controls (Dehghani
et al., 2010; Gundüz et al., 2002). WTR astigmatism predominates in
corneal and total astigmatism. Oblique astigmatism is significantly
higher in TDS patients (Cankaya et al., 2020), but lenticular astigmatism
is mainly against-the-rule (ATR) (Dehghani et al., 2010). Lenticular
astigmatism in TDS may be due to morphological lenticular changes,
since higher lens thickness and lens-axial length factor have been re­
ported in TDS patients (Dehghani et al., 2010), and could have resulted
in a tilted lens.
Astigmatism may be misdiagnosed in childhood, not corrected with
spectacle, a cause of amblyopia, more common in TDS (Dehghani et al.,
2010), and responsible for a decreased best spectacle-corrected visual
acuity (BSCVA) in TDS (Vongphanit et al., 2002). A significant
Table 1
Anterior segment changes reported in eyes with tilted disc syndrome.
Authors Anterior segment changes
Jonas et al. (2004) Corneal astigmatism
Bozkurt et al. (2002)
Dehghani et al. (2010) Lenticular astigmatism
Gundüz et al., 2002
Ciftci, 2011 Keratoconus
Choi et al. (2015) Granular corneal dystrophy type II
Gunduz et al., 2016 Thin central corneal thickness and
Ozsoy et al. (2016) low corneal volume
Ozsoy et al. (2016) Narrow anterior chamber
Ozsoy et al. (2016) Large pupils
S.Y. Cohen et al.
Fig. 6. Corneal topography with Pentacam® showing a case of with-the-rule
corneal astigmatism with a symmetric bow tie pattern.
association has been reported between amblyopia and an elongated
optic disc shape and high corneal astigmatism (Jonas et al., 1997).
Therefore, in young children with tilted disc, refractometry should be
performed to detect and correct astigmatism to prevent amblyopia.
4.2. Keratoconus and other corneal dystrophies
Astigmatism in TDS seems to be mainly regular (Bozkurt et al.,
2002), and may be congenital as the tilted disc. Keratoconus, charac­
terized by acquired and irregular astigmatism, may not be associated
with TDS. However, a case of unilateral tilted disc with ipsilateral ker­
atoconus in the same eye has been reported, but the keratoconus was
barely visible on topography (Ciftci, 2011).
Other corneal dystrophies may be associated with TDS. A case of type
II granular corneal dystrophy (GCDII) in the anterior stroma and a case
of posterior polymorphous corneal dystrophy (PPCD) concomitant with
TDS have been reported (Choi et al., 2015). These patients carried ge­
netic mutations that correlated with these corneal dystrophies. A genetic
association between corneal dystrophy and TDS is not clear but ac­
cording to the embryogenesis, the corneal stroma, the corneal endo­
thelium, and the optic nerve lamina cribrosa differentiate from neural
crest cells. Therefore, the optic disc should be examined in patients with
corneal dystrophy.
4.3. Other corneal changes
A change in central corneal thickness (CCT) in TDS patients is dis­
cussed. In some studies where the CCT was measured by ultrasound
pachymetry, no difference was found between TDS patients and the
control group (Dehghani et al., 2010; Ornek and Ozdemir, 2008).
Nevertheless, another study has shown a negative correlation between
the CCT and the disc area in TDS patients (Lim et al., 2008). More
recently, two studies based on Scheimpflug imaging with PentacamR,
that is more accurate and reproducible than ultrasound contact pachy­
metry, have found significantly thinner CCT and lower corneal volume
(CV) in TDS patients compared to the control group (Gunduz et al.,
2016; Ozsoy et al., 2016). Moreover, Gunduz et al. have also reported a
stronger elevation on anterior corneal topographic maps in TDS
patients.
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Progress in Retinal and Eye Research 88 (2022) 101020
4.4. Anterior chamber changes
In addition to a thinner CCT and a lower CV, TDS patients may show
other anterior segment changes, such as a narrow anterior chamber
angle. Ozsoy et al. have found a narrower anterior chamber angle in TDS
patients compared to the control group (Ozsoy et al., 2016). They have
recommended to monitor TDS patients to control the risk of primary
angle closure glaucoma.
They have also shown significantly larger pupils in TDS patients
(4.59 mm) compared to the control group (3.39 mm) (Ozsoy et al.,
2016) but they did not hypothesize to explain these anatomical differ­
ences on pupils and angles (myogenic, neurogenic or physiologic
phenomenon).
4.5. Particularities for refractive surgery
TDS patients have specific refractive errors, in particular myopic
astigmatism, and may be potential candidates for refractive surgery.
Their anatomical features require special precautions before planning
refractive surgery.
The lenticular component in total astigmatism must be assessed in
TDS if refractive surgery must be performed, because it may induce a
discrepancy between manifest subjective astigmatism and corneal
astigmatism, called ocular residual astigmatism. Several studies have
shown that astigmatism correction with corneal refractive surgery is less
predictable in cases of lenticular astigmatism (Kugler et al., 2010; Qian
et al., 2011). When refractive surgery is performed in TDS patients with
significant lenticular astigmatism, it is unclear what value between
subjective manifest astigmatism and corneal astigmatism should be
entered in laser programming. If lenticular astigmatism is corrected on
the cornea with excimer laser, an astigmatic overcorrection will appear
when the patient will be operated for cataract with lens extraction and
disappearance of previous lenticular astigmatism. Logically, reshaping
of the cornea with an excimer laser should only target corneal astig­
matism, whereas astigmatism due to internal optic defects should be
managed with intraocular refractive surgery. Careful decomposition of
total astigmatism between corneal and lenticular astigmatism is rec­
ommended in TDS patients during the refractive surgery consultation
(Limaiem et al., 2012), and patients should be warned that astigmatic
correction may be incomplete.
Regarding TDS-related corneal features such as a thinner CCT, a
lower CV in peripheral regions and a stronger elevation on anterior
corneal topography, it has been suggested that these patients should
undergo a specific examination because of the risk of ectasia following
refractive surgery (Gunduz et al., 2016). However, no difference in
corneal biomechanical parameters such as corneal hysteresis or the
corneal resistance factor measured by the Ocular Response Analyzer has
been found between TDS patients and control subjects (Lim et al., 2008).
Since the pupil size is larger in TDS patients, a meticulous exami­
nation of the pupil diameter, especially under scotopic conditions, has to
be performed to limit postoperative optical aberrations such as glare and
halo, and to enlarge the optical treatment zone if needed. A larger pupil
diameter may also cause dysphotopsia with refractive multifocal intra­
ocular lenses (MIOLs) during cataract surgery, because these IOLs are
pupil-size dependent. A specific pupil investigation should be performed
in TDS patients before MIOL implantation, and non-pupil-dependent
MIOLs, such as diffractive MIOLs, might be preferred in large pupils.
Centration of photoablation treatment during refractive surgery is
controversial and there is no consensus between choosing centration on
the corneal vertex, or on the pupil center or on both. In TDS patients,
studies have found contradictory results regarding the shifting of the
corneal vertex relative to the pupil center. While a superotemporal
shifting of the corneal vertex has been noted compared to the pupil
center in eyes with TDS (Kosekahya et al., 2018), others have reported a
corneal vertex horizontally closer to the pupil center in TDS patients,
and no difference vertically and in kappa angle (measured as the
S.Y. Cohen et al.
distance between the corneal vertex and the pupil center) compared to
the control group (Cankaya et al., 2020). Nevertheless, centration of
excimer treatment does not change in TDS patients, but the kappa angle
should be carefully analyzed.
To conclude, TDS has to be detected in all candidates for refractive
surgery with a systematic fundus examination, because TDS is associ­
ated with specific features that should be taken into account before
planning refractive surgery. Indeed, astigmatism may be due to anterior
and posterior changes. Due to TDS, the outcomes of refractive surgery
may also deteriorate over time.
4.6. Hypotheses about anterior segment anomalies related to TDS
TDS is a congenital optic disc anomaly that affects the anterior and
posterior segments of the eye. It seems to originate from the incomplete
closure of the embryonic fissure (Apple, 1984). Eyes with an abnormal
disc shape experience high corneal astigmatism, and Jonas et al. have
suggested that the morphogenetic factors responsible for the formation
of the optic disc could also influence the corneal formation (Jonas et al.,
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Progress in Retinal and Eye Research 88 (2022) 101020
1997). The correlation between the optic disc and the presence of
corneal congenital anomalies is supported by the correlation between
the axis of corneal astigmatism and the orientation of the longest disc
diameter (Jonas et al., 1997). The embryonic development of the whole
eye may be affected homogeneously from the cornea to the optic nerve
by a global elongation process. This phenomenon results in the devel­
opment of tilted disc and PPA (Vongphanit et al., 2002), a longer ocular
axial length, a greater lens thickness (Dehghani et al., 2010), and thin­
ning and protrusion of the cornea (Gunduz et al., 2016) with corneal
steepening resulting in congenital corneal astigmatism (Bozkurt et al.,
2002). This stretching phenomenon of the whole ocular tissue might be
accompanied by a rotation and ovalization process, promoting the
oblique orientation of the oval optic disc, a higher rate of oblique
corneal and total astigmatism compared to control eyes (Dehghani et al.,
2010) and a potentially tilted lens that induces stronger lenticular
astigmatism (Gunduz et al., 2016). During embryogenesis, the optic
nerve originates from the optic stalk, composed of neuroectodermal
cells. The cornea and the optic nerve lamina cribrosa differentiate from
neural crest cells. An anterior segment characteristic of TDS may be an
Fig. 7. Methods for quantifying the optic disc tilt.
A. Diagram of the disc showing the method for the
calculation of the ovality index, corresponding to
the longer diameter/smaller diameter ratio, ac­
cording to the method suggested by Giuffrè (1991).
B. Measurement of vertical and horizontal tilts,
respectively from the vertical and horizontal
cross-sectional images obtained by optical coher­
ence tomography, according to Park et al. (2015).
C. Measurement of the disc tilt based on the course
of the retinal pigment epithelium as expressed on a
sine wave. Cross-sectional images of the peripapil­
lary retina and retinal nerve fiber layer thickness
profile allow calculating the amplitude of the tilt.
This amplitude correlates with the ovality ratio,
according to Yamashita et al. (2015).
S.Y. Cohen et al.
embryologic extension of a complete ocular congenital anomaly.
5. Fundus patterns in uncomplicated TDS
5.1. Fundus imaging
On fundus examination and color fundus photography, TDS is usu­
ally clearly visible, easily recognized at a simple glance. However, a
more objective definition is needed. As noted in many reviews, no strict
definition of a ‘‘tilted’’ ONH has been proposed (Apple et al., 1982;
Witmer et al., 2010). However, attempts to propose a more objective
definition have been reported. Giuffrè has introduced a method con­
sisting in dividing the length of the largest diameter of the optic disc by
the diameter perpendicular to this value (Giuffrè, 1991) (Fig. 7A). This
technique is frequently used in studies conducted in eyes with high
myopia that recognize an ovality ratio of the optic disc, defined as the
longest optic disc diameter/the shortest optic disc diameter ratio. An
ovality ratio greater than 1.3 is considered a marker of tilted disc (Sung
et al., 2016a, 2016b). Others have used an inverted index compared to
that described above, i.e., an ovality index corresponding to the mini­
mum diameter/maximum diameter ratio, and considered it as a sign of
tilted disc if less than 0.8, 0.75, or 0.7 (How et al., 2009; Tay et al., 2005;
You et al., 2008). The disc tilt has also been measured using
cross-sectional images obtained by OCT (Fig. 7B). With OCT, the optic
disc tilt angle could be imaged and defined as the angle between the
reference plane and the ONH plane (Yoon et al., 2019). The authors have
measured a vertical tilt angle on a vertical cross-sectional image, and a
horizontal tilt angle on a horizontal cross-sectional image. A positive tilt
angle indicates an inferior and temporal tilt, and a negative angle in­
dicates a superior and upward and nasal tilt (Park et al., 2015). The
circumpapillary course of the RPE could also be fitted into a sine wave
the amplitude of which correlated with the ovality index (Fig. 7C). In a
study of 126 eyes of healthy volunteers, the mean amplitude signifi­
cantly and inversely correlated with the ovality ratio of the optic disc.
The authors have proposed to use this method as a quantifiable and
repeatable method to determine the optic disc tilt (Yamashita et al.,
2015). Most of these studies that aimed to quantify the tilt have been
conducted to better analyze glaucoma-related morphological changes in
eyes with high myopia. However, the same methods could be used in
eyes with TDS.
5.2. Inferior or inferonasal conus or crescent
Inferior or inferonasal conus or atrophy has been reported in the first
description of TDS. It corresponds to a whitish or greyish juxtapapillary
area (Fig. 1). The accurate anatomy of the parapapillary area has
recently been better defined in different studies by Jonas’ team, that
have recently been summarized (Wang et al., 2020a). The authors have
described that the ONH canal comprises three layers: the innermost
layer is the Bruch’s membrane (BM) opening, the middle layer is the
choroid opening, and the outer layer is the peripapillary scleral flange
opening (Jonas et al., 2003; Wang et al., 2020b; Zhang et al., 2019).
The parapapillary region consists of alpha zones (irregular pigmen­
tation due to RPE irregularities and peripheral location), beta zone
(complete RPE loss while the BM is preserved), gamma zone (absence of
BM), and delta zone (elongated and thinned peripapillary scleral flange)
within the gamma zone and located at the peripapillary ring. The infe­
rior or inferonasal crescent observed in TDS corresponds to beta zone
atrophy or, more accurately, retraction. In the Blue Mountains Eye
study, beta papillary atrophy was observed in 64.9% of the 77 eyes
diagnosed with TDS from a database of 3583 fundus photographs
(Vongphanit et al., 2002).
5.3. Situs inversus and other anomalies of vessel insertion
Situs inversus is defined as retinal vessels that exit the optic disc and
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Progress in Retinal and Eye Research 88 (2022) 101020
course nasally before turning temporally (Fig. 1). It has been observed in
70–89% of eyes with TDS (Prost, 1991; Vongphanit et al., 2002).
Interestingly, anomalies of the small vessels have been recently reported
in other congenital disc malformations. A case of hypoplasia of the optic
nerve associated with a vascular loop and a fovea plana has been
recently published, suggesting the presence of multiple developmental
abnormalities (Sekeryapan Gediz and Şekeroğlu, 2020). Moreover, in
optic disc pits, OCT and OCT-Angiography have shown small, abnormal
vessels both within and around the optic disc pits (Adams et al., 2020).
In TDS, an acquired prepapillary arterial loop secondary to central
retinal artery occlusion (CRAO) has been reported in a patient with TDS
and inferior staphyloma (Cohen, 1998). All these reports suggest a
possible relationship between the morphological anomalies of the disc
and a developmental insertion of retinal vessels or acquired morpho­
logical retinal vascular changes.
5.4. Inferior pallor or staphyloma
Since its first description, TDS has been considered a “forme fruste”
of coloboma, involving the optic nerve but also the inferior chorioretina.
Giuffrè has assumed that a delayed closure of the embryonic fissure
could have resulted both in the morphological changes of the disc and in
a loss of retina nerve fibers, explaining the relative thinning of the
retina, choroid and sclera in the inferior part of the fundus (Giuffrè,
1991). This thinning is responsible for an apparent pallor of the inferior
part of the fundus, similar to the tessellated fundus observed in the first
stage of myopic fundus changes (Ohno-Matsui et al., 2015), defined as
well-defined choroidal vessels that can be observed clearly around the
fovea and around the arcade vessels in myopic eyes. The same definition
could be used to describe the area of inferior pallor observed in TDS. The
staphyloma associated with TDS is inferonasal or inferior. However, a
single case of bilateral TDS associated with superior staphyloma has
been reported (Cohen and Quentel, 2008).
6. Multimodal imaging of uncomplicated TDS
6.1. Color, pseudocolor and wide-field color photography
All features of TDS have been described on fundus examination and,
thus, may be observed on color photography. Wide-field fundus
photography is a relatively recent imaging modality. By allowing visu­
alizing a wide part of the fundus, this technique has revealed many novel
findings. In addition to color/pseudocolor photography, wide-field
fundus autofluorescence (FAF), fluorescein angiography (FA), and
indocyanine green angiography (ICGA) can be obtained.
On wide-field pseudocolor images, the entire extent of the inferior
staphyloma is clearly observed (Fig. 8). The area within the staphyloma
shows a tessellated fundus. Although the upper edge of the inferior
staphyloma passes across the central fovea, the lower edge of the
staphyloma is usually not obvious. It seems that the inferior staphyloma
spreads up to the lower margin of wide-field fundus imaging.
The spatial relationship between the optic disc, the macula, and the
inferior staphyloma is clearly visible on wide-field fundus imaging.
There are some variations in TDS and inferior staphyloma. In typical
cases, the upper staphyloma edge is continuous to the lower border of
the tilted optic disc and passes across the central macula. But in some
cases, the upper edge of the inferior staphyloma passes beneath the
macula, and the optic disc is not involved (Fig. 8). In other cases, the
upper edge of the inferior staphyloma passes over the macula. In eyes
with pathologic myopia, the most common type of staphyloma is wide
macular staphyloma (Curtin, 1977; Ohno-Matsui, 2014). In eyes with
wide macular staphyloma, the upper edge of the staphyloma is usually
more abrupt than the lower edge. In eyes with the upper edge of the
inferior staphyloma passing over the macula, it is sometimes difficult to
differentiate TDS from wide macular staphyloma, especially in highly
myopic eyes. One differentiating feature may be that the lower edge of
S.Y. Cohen et al.
the staphyloma can be detected in most cases with wide macular
staphyloma, while the lower edge of the inferior staphyloma is not
obvious in most cases of TDS.
6.2. Red-free photography
Red-free photography may be useful to better visualize the limits
between the inferior staphyloma and the normal superior part of the
fundus. Indeed, the pallor of the fundus corresponding to the tessellated
fundus may be more obvious than on color photography, because red-
free photography enhances the contrast between both areas (Fig. 9).
6.3. Fundus autofluorescence (FAF) and wide-field fundus
autofluorescence
FAF images are useful to observe pigmentary changes frequently
associated with TDS or hyperfluorescent areas that could be seen in
areas of persistent serous retinal detachments (SRDs) (see below,
Figs. 18 and 19). Furthermore, TDS also occurs in eyes with pathologic
myopia (Fig. 8 C and D). In such cases, it is more difficult to differentiate
TDS in highly myopic eyes and wide macular staphyloma. Wide-field
FAF is useful to detect the upper staphyloma edge as a hypore­
flectance. This methodology is also useful to detect TDS-related macular
lesions such as the chorioretinal folds and T signs reported by Cohen and
Quentel (2006) (Fig. 10).
Fig. 9. Congenital tilted disc syndrome (TDS) complicated by choroidal neovascularization (CNV). Color fundus photography shows typical TDS with an inferior
crescent, associated with a grayish foveal lesion (A). The limits of the inferior staphyloma are more easily observed on red-free photography (B). Fluorescein
angiography shows typical foveal CNV (C).
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Progress in Retinal and Eye Research 88 (2022) 101020
Fig. 8. Wide-field fundus imaging and wide-field
fundus autofluorescence (FAF) of 2 eyes with infe­
rior staphyloma due to tilted disc syndrome (TDS).
A and B. TDS in a non-highly myopic eye. The optic
nerve is tilted and an inferior conus is seen. The
inferior fundus shows a tessellation in the area of
the inferior staphyloma. The upper edge of the
staphyloma shows a depigmentation area. FAF
shows a mix of hyper- and hypo-autofluorescent
lesions originating from the upper edge of the
staphyloma. C and D. TDS in a highly myopic eye.
The optic nerve is tilted with a large inferior conus.
Multiple areas of patchy choroidal atrophy are seen
in the area of the inferior staphyloma. The upper
edge of the staphyloma shows depigmentation. FAF
shows a hypofluorescence in the area of patchy
atrophy.
6.4. Fluorescein angiography (FA), indocyanine green angiography
(ICGA) and wide-field angiography
FA enhances the visualization of retinal vessels. Thus, anomalies of
retinal vessel insertion, such as situs inversus, may be very easily
observed (Figs. 10 and 16). Because of the presence of an inferior
staphyloma, differences in sharpness may be seen between the vessels in
the superior and inferior retina (Fig. 11). Pigmentary changes are also
easily visualized on FA, while they are not so apparent on ICGA (Fig. 12).
Also, on wide-field ICGA, the area of the inferior staphyloma shows a
relative hypofluorescence probably due to a decrease in choriocapillaris
and choroidal vessels (Fig. 12).
Ohno-Matsui has reported that a wide staphyloma may be detected
by the presence of pigmentary alterations along the staphyloma edges on
wide-field fundus angiography (Ohno-Matsui, 2014). Using this tech­
nique, Ishida et al. have reported radial tracts originating from the
staphyloma edges in eyes with pathologic myopia (Ishida et al., 2015)
(Fig. 10). FA and ICGA are also useful to detect macular complications
(Nakanishi et al., 2008).
6.5. B-scan ultrasonography
A- and B-scan ultrasonography findings of 4 patients with TDS have
been reported in 1985, with an increased dural diameter of the optic
nerve on the A-scan and an accentuation and doubling of the optic nerve
S.Y. Cohen et al.
Fig. 11. Typical congenital tilted disc with inferonasal crescent (A, black arrows), anomalies of retinal vessel insertion and inferior pallor of the fundus, corre­
sponding to the inferior staphyloma (A). A single dotted pigmentary change may be observed in the superior part of the inferior staphyloma (B, yellow arrow). Note
that the sharpness of the retinal vessels could be seen in the superior retina but not in the inferior retina because of the inferior staphyloma (B, black arrowheads).
outline on the B-scan. Furthermore, ectasia of the inferonasal part of the
eyeball was clearly shown on the B-scans (Singh, 1985) (Fig. 13).
6.6. Spectral-domain, swept-source and wide-field optical coherence
tomography (OCT)
OCT is an easy technique to capture the shape of the eyeball without
using more complex imaging techniques. Indeed, three-dimensional
(3D) magnetic resonance imaging (MRI) has the advantage of allowing
visualizing the shape of the entire eye, including the anterior ocular
segment. However, 3D MRI cannot be used as a screening technique, and
due to a relatively low spatial resolution, subtle changes in shallow
staphylomas are difficult to detect. Also, 3D MRI cannot differentiate the
retinal, choroidal, and scleral tissues. Thus, OCT is probably the best tool
to analyze the curvature of the sclera in eyes with pathologic myopia
(Imamura et al., 2011; Ohno-Matsui et al., 2012). Due to the limited scan
length and depth of devices previously available, the usefulness of the
OCT technology was limited to visualize posterior staphylomas.
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Progress in Retinal and Eye Research 88 (2022) 101020
Fig. 10. Tilted disc syndrome complicated by cho­
rioretinal folds. Fundus color photography shows a
typical tilted disc with an inferonasal crescent, and
an inferonasal staphyloma. Linear pigmentary
changes and radial chorioretinal folds are barely
visible but may be guessed (A) while they are more
easily observed on fundus autofluorescence (B) and,
are clearly visible on fluorescein angiography (C).
OCT also allows visualizing the folding of the
retinal pigment epithelium (D–F). Note that the
OCT mapping is incomplete because of the steep
changes in eyeball curvature in the staphylomatous
area (E).
Compared to spectral-domain OCT, the recently developed swept-source
OCT technology has improved the detectability of staphylomas but it is
strongly limited by its relatively short scanline length.
A new prototype of a wide-field swept-source OCT system (Xephilio,
Canon, Japan; currently available in Europe and in Japan) uses not only
one but multiple scan lines and generates scan maps allowing the 3D
reconstruction of posterior staphylomas in a region of interest of 16 ×
14 mm and with a depth of 5 mm. Using ultra-wide-field OCT (UWF-
OCT), we have conducted a study to visualize the full 3D extent of
posterior staphylomas in highly myopic eyes (Shinohara et al., 2017,
2018; Takahashi et al., 2019, 2021). On UWF-OCT, the entire extent of
inferior staphyloma was visible (Fig. 14). In inferior staphylomas, the
transition to a staphylomatous area was sudden and the scleral curva­
ture protruded abruptly. Because of the high resolution of the images,
details of other structures such as the chorioretinal folds were clearly
seen. Macular complications associated with inferior staphylomas could
also be seen.
S.Y. Cohen et al.
Fig. 13. Wide-field color fundus photography and fundus autofluorescence of a
patient with typical tilted disc syndrome and inferior staphyloma (A, B). The
limits of the inferior staphyloma may be guessed on pseudocolor fundus
photography because of the differences in pigmentation resulting in an inferior
tessellation (A) or a dark depigmented band on fundus autofluorescence (B).
However, B-scan ultrasonography performed in the vertical plane better shows
the outpouching of the inferior wall of the eye with a radius of curvature that is
less than the surrounding curvature of the eye wall (C). Note also the sharp edge
corresponding to the junction between the 2 areas of the fundus (arrow).
Courtesy Dr. Streho, Paris.
6.7. Optical coherence tomography-angiography (OCT-A)
OCT-A is a novel, non-invasive technique that allows an excellent
visualization of the blood flow at different levels of the retina (Fingler
et al., 2009; Jia et al., 2012). It is used routinely for the diagnosis of
many choroidal and retinal vascular diseases, such as exudative
age-related macular degeneration, diabetic maculopathy and vein oc­
clusions (Couturier et al., 2015; de Carlo et al., 2015; Kashani et al.,
2015). In eyes with high myopia but without pathological changes, a
significant decrease in superficial parafoveal vascular density has been
shown compared to controls (Min et al., 2020). However, to date, there
is no OCT-A report of the retinal or choroidal vasculature in eyes with
TDS. When the upper edge of the inferior staphyloma is located within
the foveal area, OCT-A may be difficult to perform because of segmen­
tation issues that are a well-known limitation of the technique (Spaide
et al., 2014). Because of the abnormal curvature of the posterior pole,
the 6x6-mm scan may pass through the choroid in the upper retina, but
through the sensory retina in the lower staphylomatous area (Fig. 15). In
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Progress in Retinal and Eye Research 88 (2022) 101020
Fig. 12. Wide-field fluorescein angiogram (FA) and
indocyanine green angiogram (ICGA) of an eye with
inferior staphyloma. A. Pseudocolor photography
shows a tessellation in the area of the inferior
staphyloma. The upper edge of the inferior staph­
yloma is depigmented. B. Fundus autofluorescence
(FAF) shows a horizontal band of hypo-
autofluorescence along the upper edge of the
staphyloma. A hyperfluorescent T-sign originating
from the upper edge of the staphyloma is seen. C.
Wide-field FA shows a mix of hyper- and hypo­
fluorescence along the upper edge of the staph­
yloma. D. Early phase of ICGA shows a
hypofluorescence along the upper edge of the
staphyloma. E. Late phase of ICGA shows a consis­
tent hypofluorescence along the upper edge of the
staphyloma. Hyperfluorescent dots are seen around
the hypofluorescence. F. Representative drawing
illustrating the limits of the staphyloma and the
pigmentary changes at its superior edge.
case of choroidal neovascularization (CNV), despite this segmentation
issue, OCT-A usually shows the abnormal vascular network corre­
sponding to the CNV, with the associated abnormal blood flow (Fig. 16).
The disappearance of the lesion and abnormal blood flow may be
observed after anti-VEGF therapy.
6.8. Three-dimensional (3D) magnetic resonance imaging (MRI)
MRI findings have been reported in some case reports (Manfrè et al.,
1999; Tarver-Carr and Miller, 2006) and in a series of 11 patients
compared to controls (Orguc et al., 2007). Eyes with TDS showed an
increased antero-posterior diameter related to ectasia of the inferonasal
area of the posterior wall of the eyeball. There was also a wide temporal
and narrow nasal insertion of the optic disc into the eyeball. However,
the analysis was performed in 2 dimensions. 3D MRI, developed later,
has been shown to have the ability to acquire 3D images of human tis­
sues, and we have reported the characteristics of the shape of eyes with
pathologic myopia obtained by 3D MRI. By modifying the signal in­
tensity, it was also possible to visualize the retrobulbar optic nerve and
the entire eye simultaneously (Fig. 17) (Moriyama et al., 2012; Ohno-­
Matsui, 2014).
As initially reported (Moriyama et al., 2011), in emmetropic eyes
without any ophthalmic abnormalities, 3D MRI has shown an almost
hemispheric ocular posterior segment without protrusions. The curva­
ture of the attachment site of the optic nerve was vertically straight
when the eyeball was viewed from the nasal side. Some eyes with high
myopia also showed a protrusion in the lower part of the posterior
segment. But, regardless of the location of the protrusion area, the
attachment site of the optic nerves was located within the protrusion,
and the optic nerves were attached perpendicularly to the eyeballs. The
lower part of the posterior segment was protruded, and the optic nerves
were attached at the upper nasal edge of the protrusion.
Shinohara et al. have analyzed the shape of 22 eyes with TDS by 3D
MRI (Shinohara et al., 2013). In all the 22 TDS eyes, the attachment site
of the optic nerves was oblique when viewed from the nasal side. The
lower half of the eyeball had a completely different curvature than the
upper half of the eye in TDS eyes. Although the lower edge of the
staphyloma is usually visible on 3D MRI in highly myopic eyes without
TDS, the lower eyeball was so extended in TDS eyes that the lower edge
of the inferior staphyloma could not be seen clearly.
Based on these abnormal findings detected by 3D MRI, it may be
assumed that TDS is mainly characterized by a deformity of the inferior
eyeball beneath the optic nerve, and that the spatial relationship be­
tween the fovea and the inferior protrusion may determine the degree of
myopia (Fig. 17).
S.Y. Cohen et al.
Fig. 14. Color fundus photography (A), fundus autofluorescence (FAF) (B), and
ultra-wide field (UWF)-OCT (C, D) of an eye with tilted disc syndrome and
inferior staphyloma. Differences in pigmentation can be observed between the 2
areas of the fundus (A). FAF better shows the pigmentary changes located at the
upper margin of the inferior staphyloma, and associated radial chorioretinal
folds (B). The large scan of UWF-OCT shows the outpouching corresponding to
the staphyloma (C). The 3D reconstruction of the posterior pole allows better
visualizing all the morphological changes associated with condition (D).
7. Retinal or macular changes and complications: description
Many retinal or macular changes may be observed in TDS eyes
(Table 2).
7.1. Intrapapillary hemorrhages
The association between intrapapillary and peripapillary subretinal
hemorrhages and the preservation of optic nerve function, found in
patients with tilted optic discs has been reported by different authors
and appears to be more common in Asians. The pathophysiology of this
benign condition involving a relationship between the prepapillary
vitreous and the tilted ONH is not yet fully understood. Katz and Hoyt
(1995) have described eight young patients referred for disc hemor­
rhage, all with myopia and small dysplastic tilted discs. The
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Progress in Retinal and Eye Research 88 (2022) 101020
hemorrhages resolved without sequelae or visual impairment. In all
cases, the posterior vitreous body was separated from the retina but
remained attached to the disc. The posterior vitreous detachment
remained incomplete because of persistent vitreopapillary attachments.
The authors have postulated that the vitreopapillary traction trauma­
tized the disc vessels, causing hemorrhage in and around the disc. The
superior hemidisc received the shearing force of the detachment, which
teared the superficial vessels, and the force transmitted through the
retina resulted in subretinal bleeding. However, Kokame et al. (2004)
have described the same clinical features in ten eyes of nine patients.
Eight eyes had mild to severe myopia and eight had a tilted disc.
Hemorrhage within the disc and adjacent subretinal hemorrhage were
located nasally in 6 eyes, superiorly in 2 eyes, and temporally in 2 eyes.
Vitreous hemorrhage was noted in 6 out of the 10 eyes. Posterior vit­
reous evaluation by biomicroscopy (10 eyes), B-scan ultrasonography (4
eyes), and by OCT (2 eyes) revealed no evidence of vitreopapillary
traction, except on follow-up OCT in one eye showing a localized vit­
reoretinal separation with residual attachment to the optic disc 10
months after presentation. These authors have concluded that the
structural architecture of the elevated nasal edge of the myopic tilted
disc and the choroidal blood supply of the prelaminar optic nerve were
involved in this condition and could predispose patients to optic disc
hemorrhages, that may be spontaneous or precipitated by acute disc
edema, the Valsalva maneuver, or a vitreopapillary traction. In another
paper using OCT, the authors have found that patients with intra­
papillary hemorrhage with adjacent peripapillary subretinal hemor­
rhage had smaller optic discs and scleral canals than control subjects,
with a higher level of nerve fiber crowding (Teng et al., 2014). Many
other papers have described these hemorrhages in eyes with tilted optic
disc associated with glaucoma, but in these cases, the causality of the
glaucoma and disc anatomy is difficult to establish. Juxtapapillary
hemorrhages may also be due to associated subretinal neo­
vascularization (Khairallah et al., 1996).
7.2. Retinal vein occlusion
A possible relationship between central and hemispheric retinal vein
occlusion (RVO) is debated. A curious case of bilateral RVO occurring in
a 68-year-old man with bilateral TDS has been reported (Lureau et al.,
1995). However, a large study of 287 consecutive patients with CRVO or
hemiretinal vein occlusion has failed to show any significant relation­
ship, TDS being observed in 4 eyes with CRVO and in 2 eyes with
hemicentral RVO (Giuffrè, 1993).
7.3. Chorioretinal and retinal pigment epithelial (RPE) changes
Chorioretinal degenerative changes may be observed in eyes with
TDS, located at the superior margin of the inferior staphyloma, more
precisely in the junctional area between the normal curvature of the
superior part of the fundus, and the inferior staphyloma (Figs. 10, 11 and
18). Different patterns have initially been described: branched, linear or
dotted pigmentary accumulations; or areas of chorioretinal atrophy, and
areas of depigmentation (Giuffrè, 1991). They have been reported in 18
out of 163 eyes with TDS, are more frequently observed in case of deep
ectasia and high-degree tilt of the optic disc. Some eyes may show large
bands of RPE changes as observed in eyes with chronic central serous
chorioretinopathy (CSCR) (Cohen et al., 1998). Moreover, some eyes
may develop a T-shaped band of RPE changes, the band being perpen­
dicular to the superior margin of the staphyloma (Fig. 18) (Cohen et al.,
2009).
7.4. Choroidal neovascularization (CNV)
7.4.1. Clinical patterns
The occurrence of CNV in eyes with TDS has initially been described
in a case report (Stur, 1988) and in a small case series of 2 eyes (Prost
S.Y. Cohen et al.
and De Laey, 1988). However, a previous small series has described 7
eyes with inferior posterior staphyloma and CNV, in which 2 eyes pre­
sented with discrete TDS (Tsuboi et al., 1984). The authors have noted
that CNV developed at the edge of the inferior staphyloma, also
described as the hypoplastic part of the choroid or inferior chorioretinal
dystrophy (Figs. 9 and 16). In all reported cases, the images showed
classic CNV. Larger series have also reported patients with both condi­
tions showing the same findings (Cohen et al., 2013; Furuta et al., 2013).
Interestingly, one patient presented with 4 different areas of CNV in only
one eye, all located at the edge of an inferior staphyloma associated with
TDS (Quaranta et al., 2000). All these reports suggest that the junctional
or transitional area between the upper and lower parts of the fundus
13
Progress in Retinal and Eye Research 88 (2022) 101020
Fig. 15. Color fundus photography of an eye with
tilted disc syndrome (A) with a disc tilt in an obli­
que axis and inferior crescent, also visible on fundus
autofluorescence (B), and inferonasal staphyloma as
shown on the 9-mm oblique OCT scan (C). OCT-A
with automated scan focused on the chorioca­
pillaris (D, E) gives an incomplete image due to
segmentation issues (yellow arrows). Manually
enlarged scan passing through the choroid is also
incomplete (F, G). Because of the eyeball curvature,
corresponding en face OCT (H) shows the choroidal
vasculature in the upper part of the posterior pole
while the retinal vasculature is seen in the lower
staphylomatous part of the posterior pole (blue ar­
rows), illustrating the segmentation issue.
Fig. 16. Typical tilted disc syndrome with an obli­
que disc and inferior staphyloma (A). Early phase of
fluorescein angiography shows an abnormal
vascular network with a feeding vessel (B, arrow).
Leakage is observed on the late frame, associated
with staining of the atrophic area (C). OCT shows a
thick macular area (D), with a subretinal hyper­
reflective exudation (arrow, E). OCT-angiography
also clearly shows the abnormal vascular network
(arrows, F) with the corresponding blood flow (ar­
rows, G).
with different curvatures could present anatomical characteristics that
promote the occurrence of CNV.
7.4.2. Treatment
The therapeutic options used for treating CNV in TDS depended on
the therapeutic era. Laser photocoagulation has been used in cases of
extra- or juxtafoveal CNV, usually resulting in visual acuity stabilization
or improvement (Furuta et al., 2013; Prost and De Laey, 1988; Quaranta
et al., 2000; Stur, 1988). However, subfoveal CNV evolved towards a
fibrovascular subfoveal scar with a poor visual prognosis. In the
anti-VEGF era, subfoveal CNV could be treated but the initial results
were contrasted. Bevacizumab injections did not improve the visual
S.Y. Cohen et al.
acuity and did not inhibit the neovascular activity in 3 patients (Milani
et al., 2009), while 3 consecutive injections of ranibizumab improved
the visual acuity in one patient (Arias and Monés, 2010). A larger series
has also shown the efficacy of ranibizumab in 11 eyes, with a mean
visual gain of 7.9 early-treatment diabetic retinopathy study (ETDRS)
letters (Cohen et al., 2013). No study has compared the results of
intravitreal anti-VEGF agents in myopic CNV. Thus, CNV complicating
TDS may be treated like myopic CNV, using the current protocol vali­
dated by prospective trials (Ikuno et al., 2015; Wolf et al., 2014) and
there is no rationale to prefer the use of one anti-VEGF agent over
another.
7.5. Polypoidal choroidal vasculopathy (PCV)
PCV may develop at the junctional and transitional area corre­
sponding to the superior margin of the inferior staphyloma. PCV is a
subtype of neovascular age-related macular degeneration (AMD) in
which type 1 neovascularization is associated with an abnormal
branching network of vessels with aneurysmal dilations referred to as
polyps. However, several hallmarks of AMD, including drusen,
pigmentary changes, or atrophy, that are uncommon in PCV, could also
develop in relatively young patients (Cheung et al., 2018). In 6 eyes of 5
patients with TDS and inferior staphyloma, all polypoidal dilations,
diagnosed by ICGA were located at the junction between the staphyloma
and the normal retina (Mauget-Faÿsse et al., 2006). The same location
was observed in a subsequent case report (Peiretti et al., 2008), and in a
Japanese series in which PCV was diagnosed in 7 out of 32 eyes (22%)
(Nakanishi et al., 2008). In the previous reports published in the 2000s,
the polypoidal lesions were treated with thermal laser or photodynamic
therapy (PDT), the standards of care at that time. However, the current
management of PCV is usually based on the use of anti-VEGF agents as
the first-line therapy for active polypoidal lesions, either in mono­
therapy or combined with PDT (Cheung et al., 2018). There is no reason
to treat PCV in TDS differently than other cases of PCV.
7.6. Macular serous retinal detachments (SRDs)
7.6.1. Clinical patterns, course and prognosis
Macular SRDs are the most common macular complication of TDS
with inferior staphyloma (Fig. 19). SRDs without signs of CNV have
14
Progress in Retinal and Eye Research 88 (2022) 101020
Fig. 17. Three representative cases of tilted disc
syndrome (TDS) with different degree of myopia.
(Upper row) Emmetropic TDS. (Middle row)
Moderately myopic TDS. (Bottom row) Highly
myopic TDS. Schematic drawing of the fundus with
delineation of the inferior staphyloma limits (A-E-I,
yellow line). The shape of the eyeballs and the optic
nerve attachment pattern are similar regardless of
the degree of myopia (MRI, C-G-K). The entire
lower half of the eyeball is deformed and protruded
(yellow arrows and red arrowheads), and the optic
nerve is attached at the upper nasal edge of the
protrusion by forming an oblique angle. However,
the protrusion tends to be wider and deeper with an
increase in myopia. This is due to the fact that,
when the protrusion is wide enough to include the
fovea, the eye becomes highly myopic. Also,
regardless of the degree of myopia, the eye defor­
mity is not limited to the posterior fundus, but the
shape of the entire lower eyeball is changed. Inter­
estingly, when the lower eyeball is protruded
deeply, the upper eyeball flattens.
initially been reported in 5 eyes with TDS (Cohen et al., 1998). Patients
were 2 men and 3 women, aged 37 to 60. There was a focal leak in 3
cases but multiple and diffuse areas of leakage were found in 2 cases.
Thus, the pattern mimicked acute or chronic CSCR. Leaking areas and
SRDs have also been reported in myopic eyes with posterior staphylomas
(Leys and Cohen, 2002), but most cases have been reported in eyes with
inferior staphylomas, probably because the SRD, located at the superior
margin of the staphyloma, often involved the fovea in these cases. The
prevalence of macular SRDs in eyes with TDS has been estimated in
larger cohorts at 17.3% (Cohen et al., 2013), 29.1% (Maruko et al.,
2011), 29.5% (Garcia-Ben et al., 2020) and 41% (Nakanishi et al.,
2008). SRDs may also be caused by associated PCV or CNV, thus
multimodal imaging is needed before making the diagnosis. The natural
course of SRDs may be variable, with a spontaneous resolution or
persistence. In eyes followed for more than 12 months, the visual
prognosis was better after a spontaneous resolution (Kubota et al.,
2019).
7.6.2. Therapeutic options
Different therapeutic options have been described in case reports for
the management of SRDs in eyes with TDS.
7.6.2.1. Oral therapy. Oral therapy has been tested in several cases. A
rapid resolution of fluid has been reported in one patient treated with
500 mg of oral acetazolamide every 12 h (Tosti, 1999). Eplerenone did
not improve the SRD in one case (Varenne et al., 2017).
7.6.2.2. Laser, photodynamic therapy (PDT). The efficacy of focal ther­
mal laser with the parameters commonly used to treat focal leaks of
CSCR has been shown in the first report of the condition (Cohen et al.,
1998). However, it could not be used in cases of diffuse leakage. Se­
lective retina therapy (SRT) is a laser-based technique allowing treating
only the RPE without damaging the neural retina and choroid (Roider
et al., 1999) with promising results in the treatment of exudation of
diabetic macular edema in CSCR (Park et al., 2016; Yasui et al., 2017).
Eleven eyes of 10 patients with TDS and SRD have been treated with
SRT, with a significant reduction in central macular thickness, but
without significant improvement in best-corrected visual acuity (BCVA).
The SRD completely resolved after 1–5 sessions (mean: 2.6 sessions)
(Hirayama et al., 2021). Confluent endpoint subthreshold argon laser
S.Y. Cohen et al.
has been used to treat the juxtapapillary area, resulting in SRD resolu­
tion, associated with an atrophic juxtapapillary scar (Abalem et al.,
2017). PDT with verteporfin has been used without benefit in 3 patients,
with full- or low-fluence laser delivery (Donati et al., 2013; Varenne
et al., 2017).
7.6.2.3. Intravitreal anti-VEGF therapy. Intravitreal anti-VEGF therapy
has been proposed by different investigators. Bevacizumab has been
considered ineffective in some cases (Milani et al., 2009; Varenne et al.,
2017), while others have observed a significant reduction in SRD in a
single patient after 4 intravitreal injections (Tsubota et al., 2017).
Another case report has shown the resolution of SRD with intravitreal
aflibercept, injected after 5 monthly injections of ranibizumab consid­
ered as ineffective (Hirano et al., 2015). The largest series, to date,
included 6 cases treated with bevacizumab (4 cases), aflibercept (1 case)
or ranibizumab (1 case). The results showed a full resolution of the SRD
in 3 eyes after 1–15 injections. A moderate visual gain of 0.17 logMAR
was also observed (Lee and Yu, 2019). In a Japanese retrospective study,
PDT has been combined with anti-VEGF (intervention group) and no
difference was observed between eyes treated with one or both methods,
while a modest effect on SRD reduction was observed, without
improving the BCVA (Kubota et al., 2019).
15
Progress in Retinal and Eye Research 88 (2022) 101020
Fig. 18. Congenital tilted disc syndrome associated
with inferior staphyloma (A, B arrows), complicated
by linear pigmentary changes developed in the
junctional area between the superior retina and the
staphylomatous inferior retina. Pigmentary changes
are more visible on fundus autofluorescence (C, D).
Fluorescein angiography shows an uneven fluores­
cence of this area with a faint leakage (E, F). Note
that some pigmentary changes developed radially to
the junctional area with a T-shaped pattern in the
left eye (F, yellow lines).
7.6.2.4. Surgical approach. Scleral shortening was performed in one
patient with inferior posterior staphyloma and macular SRD. There was
a large area of RPE changes at the upper edge of the staphyloma. The
surgical procedure consisted in resecting a 4-mm lamellar scleral cres­
cent in the 5-8-o’clock positions, associated with vitrectomy. The au­
thors have reported a full resolution of the SRD at 3 months associated
with an improvement in BCVA from 0.6 to 0.8 logMAR (Kasai et al.,
2016).
Pars plana vitrectomy and ICG-assisted internal limiting membrane
(ILM) peeling were performed in a patient with TDS and foveal
detachment associated with inferior retinoschisis, a condition different
from a typical SRD observed in TDS. The procedure resulted in the
resolution of the retinal detachment (Miura et al., 2006).
A similar procedure, consisting in posterior vitrectomy, posterior
vitreous detachment, ILM peeling, internal gas tamponade and face-
down positioning, was performed in a patient for whom PDT and
eplerenone were ineffective. A full resolution of the SRD was observed 4
months after the procedure, associated with a significant visual gain,
from 0.1 to 0.5 logMAR (Varenne et al., 2017).
In summary, there is no established treatment of SRD complicating
TDS, since all the evidence were only based on case reports and small
case series. Thus, the real effectiveness of all therapies is uncertain.
S.Y. Cohen et al.
7.7. Chorioretinal folds
Staphylomas may cause chorioretinal folds in the area located
outside the staphyloma (Fig. 10). They have initially been reported in an
82-year-old woman with TDS and inferior staphyloma. The folds were
more obvious on FA than on fundus examination (Cohen and Quentel,
2006). A very similar case of chorioretinal folds oriented radially to the
upper edge of the staphyloma has also been reported in an 86-year-old
woman (Ohno-Matsui et al., 2011).
7.8. Vitreoretinal interface changes and retinoschisis
In a monocentric retrospective study of 92 eyes with TDS, an asso­
ciation between TDS and epiretinal membranes and lamellar macular
holes has been reported in 9.7% and 3.2% of eyes, respectively (Cohen
et al., 2013). The authors have not proposed any explanation for these
findings that could be coincidental. Indeed, the study was conducted in a
tertiary care unit specialized in macular diseases and the association
could correspond to a selection bias. They have also reported a possible
association with myopic foveoschisis in 5.4% of cases. The foveoschisis
was observed in the area of the inferior staphyloma (Fig. 20), a finding
that is not specific to this type of staphyloma. Indeed, there is a clear
relationship between the location of the foveoschisis or retinoschisis and
the area of the staphyloma, regardless of the type of staphyloma (Shi­
nohara et al., 2018). In another study of macular complications in eyes
with inferior staphyloma or dome-shaped macula (DSM), an association
with TDS has also been reported. The authors have considered that both
conditions presented a macular bending that could lead to similar
complications. They have reported retinoschisis in 16.6% of included
eyes, but have not differentiated the incidence according to the type of
staphyloma (Coco et al., 2012). The schisis was always located outside
the area of the macular bending.
16
Progress in Retinal and Eye Research 88 (2022) 101020
Fig. 19. Tilted disc syndrome complicated by
macular serous retinal detachment. Red-free
photography shows an oval disc, an inferonasal
crescent, an inferonasal staphyloma (A). Pigmen­
tary changes are visible on fundus autofluorescence
(B). The optical coherence tomography (OCT)
mapping shows an incomplete image, due to
anomalies of the posterior pole curvature and to a
limitation in the range of the OCT analysis, and an
elevated macular thickness (C). The oblique B-scan
shows a macular serous retinal detachment associ­
ated with a flat irregular pigment epithelial
detachment (D).
7.9. Fovea plana
The term “fovea plana” has been proposed as a reassessment of foveal
hypoplasia, in order to describe eyes without foveal pit (Marmor et al.,
2008). The authors have shown that the eyes did not experience any
visual loss and did not show any sign of hypoplasia on mfERG,
high-resolution OCT, and adaptive optics. Foveal hypoplasia is usually
part of various ophthalmic conditions, including albinism, aniridia,
nanophthalmos, incontinentia pigmenti, and retinopathy of prematu­
rity. Conversely, eyes with isolated fovea plana have an excellent visual
prognosis, with a visual acuity usually greater than 20/40. Astigmatism
has recently been reported in this condition (Villegas et al., 2018). Fovea
plana has recently been diagnosed based on OCT-A in members of a
family with North Carolina Macular Disease (NCMD) (Small et al.,
2019), a condition related to mutations in the MCDR1 locus located on
chromosome 6 (chromosome 6q16) (Small et al., 1997). The mechanism
of NCMD could involve a dysregulation of the retinal transcription factor
PRDM13 at the MCDR1 locus (Small et al., 2016). Grade 1 foveal hy­
poplasia could be due to a failure of the vasculature to properly regress
to form the foveal avascular zone. The authors have proposed that a
cellular or molecular signal directed by PRDM13 could regulate the loss
or remodeling of the foveal cellular organization, in order to correlate
this phenocopy.
Fovea plana (Fig. 21) has been found in 5.4% of eyes with TDS and
inferior staphyloma (Cohen et al., 2013). There was no real explanation
for the occurrence of these 2 congenital anomalies. Affected eyes had a
good visual acuity, ranging between 20/32 and 20/20, and there was no
sign of aniridia, albinism or microphthalmia.
8. Protective effect of TDS on retinal diseases
A protective effect of the inferior staphyloma associated with TDS
has been seldom reported. This staphyloma results in the co-existence of
2 distinct parts in the fundus, one with a normal curvature, and one with
S.Y. Cohen et al.
Table 2
Main reports of posterior findings and complications, and their therapeutic approaches.
Author
Khairallah et al. (1996)
Lureau et al. (1995)
Giuffrè (1993)
Giuffrè (1991)
Cohen et al. (1998)
Cohen et al. (2009)
Tsuboi et al. (1984)
Stur (1988)
Prost and De Laey, 1988
Cohen et al. (2013)
Arias and Monés (2010)
Furuta et al. (2013)
Quaranta et al. (2000)
Milani et al. (2009)
Mauget-Faÿsse et al. (2006)
Peiretti et al., 2008
Nakanishi et al., 2008
Cohen et al. (1998)
Leys and Cohen (2002)
Cohen et al. (2013)
Maruko et al. (2011)
Garcia-Ben et al. (2020)
Kubota et al. (2019)
Tosti, 1999
Varenne et al. (2017)
Hirayama et al. (2021)
Abalem et al. (2017)
Donati et al. (2013)
Milani et al. (2009)
Tsubota et al. (2017)
Hirano et al. (2015)
Lee and Yu (2019)
Kasai et al. (2016)
Miura et al. (2006)
Pardo-López et al., 2011
Cohen and Quentel, 2006
Ohno-Matsui et al. (2011)
Cohen et al. (2013)
Table 3
Hypotheses for the occurrence of retinal and macular complications in TDS.
Retinal or macular complication
Band-shaped pigmentary changes
Choroidal neovascularization
Polypoidal choroidal vasculopathy
Chorioretinal folds
Foveoschisis
Serous retinal detachment
Progress in Retinal and Eye Research 88 (2022) 101020
Number of eyes Country Retinal and macular complications Therapeutic approach
(eyes with TDS)
Intrapapillary hemorrhages
Tunisia Peripapillary subretinal neovascularization NA
2 France Retinal vein occlusion NA
6 (287) Italy Retinal vein occlusion NA
18 (163) Italy Chorioretinal and RPE degenerative changes NA
4 France Comet tail-shaped RPE changes NA
6 France T-shaped RPE changes NA
7 Japan
1 Austria Subretinal/choroidal neovascularization Thermal laser photocoagulation (1 eye)
2 Poland Thermal laser photocoagulation (1 eye)
24 (92) France Ranibizumab (11 eyes)
1 Spain Ranibizumab (11 eyes)
9 Japan Thermal laser photocoagulation (1 eye)
1 France Thermal laser photocoagulation (1 eye)
3 Italy Bevacizumab
5 France Polypoidal choroidal vasculopathy Photodynamic therapy (4 eyes), laser (1 eye)
1 Italy Photodynamic therapy
7 (32) Japan NA
4 France Serous retinal detachments Thermal laser photocoagulation (2 eyes)
15 Belgium Thermal laser photocoagulation (5 eyes)
16 (92) France Acetazolamide, Photodynamic therapy, anti-VEGF
7 (24) Japan NA
13 (44) Spain NA
48 Japan Photodynamic therapy and/or Anti-VEGF
1 Italy Acetazolamide
1 France Eplerenone, Photodynamic therapy
Vitrectomy, ILM peeling, Gas tamponade
11 Japan Laser selective retina therapy
1 Brazil Bevacizumab, Subthreshold argon laser
3 Italy Bevacizumab, Photodynamic therapy
2 Italy Bevacizumab
1 Japan Bevacizumab
1 Japan Ranibizumab, Aflibercept
6 Korea Bevacizumab, Ranibizumab, Aflibercept
1 Japan Surgical scleral shortening
1 Japan Pars plana vitrectomy, ILM peeling, Gas tamponade
2 Spain NA
2 France Chorioretinal folds NA
1 Japan NA
9 (92) France Epiretinal membrane NA
5 (92) Myopic foveoschisis NA
3 (92) Lamellar macular hole NA
5 (92) Fovea plana NA
a greater curvature corresponding to the outward protrusion of the
inferior sclera. This myopic part may provide a relative protection
Suggested hypothesis against some conditions.
A protective effect has been reported in diabetic retinopathy (DR) in
Curvature breaking point a very demonstrative case in 1996, with more microaneurysms and hard
Curvature breaking point exudates in the non-staphylomatous area (Malinowski et al., 1996). A
Curvature breaking point protective effect of myopia has also been shown in DR in larger epide­
miological studies, with less cases of DR in myopic eyes compared to
Uneven growth traction
emmetropic eyes (Jain et al., 1967; Pan et al., 2013; Rand et al., 1985).
Container-content imbalance Each millimeter increase in axial length was associated with a lower
Uneven growth traction prevalence of DR (Pan et al., 2013).
A protective effect of high myopia on drusen or pseudodrusen for­
Choroidal funnel
mation has also been suggested in different studies (Mrejen and Spaide,
2014; Pan et al., 2013; Xu et al., 2007). More precisely, myopic eyes
17
S.Y. Cohen et al.
Fig. 21. Tilted disc syndrome associated with fovea plana. The OCT mapping shows a tilted disc with situs inversus, while foveal pits are absent (A). OCT-angiography
shows the persistence of retinal capillaries in the fovea, typical of fovea plana (B). The horizontal B-scan confirms the persistence of internal retinal layers in the
fovea (C).
(spherical equivalent [SE] <-0.5 diopter [D]) were less likely to develop
AMD (early plus late AMD), and each millimeter increase in axial length
was associated with a lower prevalence of AMD (Pan et al., 2013). The
prevalence of high myopia has been significantly associated with a lower
number of macular drusen, and the highly myopic group had a smaller
18
Progress in Retinal and Eye Research 88 (2022) 101020
Fig. 20. Tilted disc syndrome complicated by
myopic foveoschisis in a 55-year-old patient. 50◦
fundus color photography shows an oval disc, an
inferior crescent and an inferior pallor of the fundus
corresponding to the staphylomatous area (A).
Wide-field color fundus photography (B) better
shows the limits of the inferior staphyloma (ar­
rows). The OCT mapping shows changes in the
retinal thickness in the posterior pole with an
increased thickness in the inferior part of the image
(C). The vertical B-scan shows the difference be­
tween the normal superior retina and the inferior
retina in which a myopic foveoschisis developed
(D).
mean macular drusen size and a smaller area covered by drusen (Xu
et al., 2007). Inferior staphyloma may be a protective factor for the
occurrence of soft drusen (Fig. 22). A case report has clearly shown an
uneven distribution of drusen in one eye with TDS. Soft drusen were
present in the upper part of the fundus, but almost totally spared the
S.Y. Cohen et al.
lower staphylomatous fundus. Interestingly, the fellow eye did not have
TDS and showed drusen equally distributed in the superior and inferior
parts of the fundus (Cohen and Quentel, 2008).
A study has assessed the location and number of chorioretinal lesions
in eyes with multifocal choroiditis, respectively in myopic eyes and in
eyes with TDS and inferior staphyloma. Myopic eyes without TDS had
chorioretinal lesions homogeneously distributed in the posterior pole
while eyes with TDS had a higher mean number of chorioretinal lesions
located outside the staphyloma than within the staphyloma, suggesting
a protective role of the inferior staphyloma in this condition (Astroz
et al., 2017).
9. Retinal or macular changes and complications: hypotheses
(Table 3)
9.1. The curvature “breaking point” hypothesis
Anatomical factors may promote the occurrence of CNV and its
development in the subepithelial or subretinal space. Lacquer cracks
that are commonly found in myopic fundus are a well-known factor
promoting the occurrence of myopic CNV (Avila et al., 1984; Ikuno
et al., 2008; Ohno-Matsui et al., 2003). They may enlarge over time
leading to a closer contact between the outer retina and the chorioca­
pillaris (Ohno-Matsui and Tokoro, 1996). Traumatic ruptures of the BM
and angioïd streaks may also contribute to bring together anatomical
layers that are fully separated in normal eyes, and are classic causes of
CNV, especially in young patients (Cohen et al., 1996; Lupidi et al.,
2021).
In TDS, the fundus may be separated into 2 areas with different
curvatures in the posterior pole. The junctional area between the 2
curvatures consists in a more or less acute angle that may be considered
a “breaking point” (Fig. 23A). Progressive limitations in BM elasticity
may occur because of aging, or degenerative disorders such as peu­
doxanthoma elasticum, while an acute rupture may be observed after
trauma (Booij et al., 2010). Since the first reports of CNV complicating
TDS, it has been suggested that anatomical conditions related to the
junctional area associated with the inferior staphyloma could promote
the neovascular process (Prost and De Laey, 1988; Stur, 1988). Changes
in the curvature related to the inferior staphyloma may indeed be a
possible mechanism for microruptures in the BM and thus, promote CNV
onset and development. This hypothesis could also explain the
Fig. 22. Tilted disc syndrome with uneven distribution of drusen. Color fundus
photography shows a tilted disc and differences in retinal vessel sharpness
between the upper and lower parts of the retina (arrowheads). Note that
numerous soft drusen are seen in the upper and temporal parts of the fundus,
while they are absent in the inferior staphylomatous part.
19
Progress in Retinal and Eye Research 88 (2022) 101020
occurrence of large areas of pigmentary changes always located in the
junctional areas (Giuffrè, 1991). Indeed, BM changes are associated with
RPE changes.
PCV is characterized by the presence of dilated, choroidal vascular
channels of an abnormal branching vascular network ending in orange,
bulging, polyp-like dilations that elevate the RPE. In TDS, PCV is always
located at the border between the hypoplastic and normal choroid at the
temporal crest of the inferonasal posterior staphyloma. Two assump­
tions have previously been made: the hypovascularized choriocapillaris
located in the area of the inferior staphyloma could induce hypoxia
followed by CNV or PCV and/or the difference in curvature in the area of
the staphyloma could induce blood flow disturbances (Mauget-Faÿsse
et al., 2006). The latter could be included in the present “breaking point”
hypothesis because Mauget-Faÿsse et al. have postulated that the change
in eyeball curvature could be associated with choroidal abnormalities at
the edge of staphylomas that could induce blood flow disturbances.
9.2. The uneven growth “tractional” hypothesis
Progression is a well-described finding in staphylomas related to
myopia (Hayashi et al., 2010; Lee and Yu, 2019; Yan et al., 2018). Thus,
in inferior staphylomas, the affected area will grow over time, while the
non-affected area will not. This could enhance the microdefects in the
BM, but could also explain the occurrence of chorioretinal folds. Since
the first description of the association between chorioretinal folds and
TDS, it has been assumed that the increase in inferior staphyloma could
exert a significant traction on the RPE, BM and choriocapillaris complex,
leading to the formation of chorioretinal folds radiating from the upper
edge of the staphyloma. This could be compared to folds occurring in a
tablecloth when traction is exerted on its floating part. The upper edge of
the staphyloma corresponds to a fixed ridge that could promote the
radial orientation of the folds. According to us, the folds are due to the
progressive growth of the inferior staphyloma. This is what we called the
uneven growth “tractional” hypothesis (Fig. 23B).
9.3. The “container-content” imbalance hypothesis
Foveoschisis usually develops in areas of staphylomas while sparing
areas where the retina is relatively elevated, as in DSM or macular
bending (Dormegny et al., 2020; García-Ben et al., 2014). It is thought to
correspond to a separation of the retinal layers due to an inward traction
caused by a progressive ectasia of the sclera and the relative resistance to
a stretch of the inner retinal layers and retinal vessels (Gohil et al., 2015;
Ikuno, 2017; Wu et al., 2009). Indeed, a study has found a difference in
the structure of the inner surface of the ILM with more collagen fibers
and cell debris in eyes with foveoschisis compared to eyes with idio­
pathic macular holes (Bando et al., 2005). This strongly suggests an
internal tractional component. Thus, we assumed that the progressive
growth of the inferior staphyloma could exert a traction on the
BM-RPE-outer retina layers while the inner retina remains adherent to a
strong and fibrous ILM. This anterior traction may also be due to less
stretchable retinal vessels that may act as a partial cause of retinal
dissociation. Regardless of the mechanism, an imbalance could appear
between the container (sclera and adherent layers formed by the
choroid, BM, RPE and outer retina) and the content (vitreous and
adherent layers formed by the ILM and inner retina and retinal vessels).
This is what we called the “container-content” imbalance hypothesis
(Fig. 23C).
9.4. The “choroidal funnel” hypothesis
The pathogenesis of SRD complicating TDS is not yet fully eluci­
dated. In the first reports, leakage points were occasionally observed in
the junctional area in both TDS and posterior staphylomas, thus sug­
gesting a mechanism close to that of the leakages associated with CSCR
(Cohen et al., 1998; Leys and Cohen, 2002). However, the finding was
S.Y. Cohen et al.
abrupt reduction in choroidal thickness may disturb the choroidal blood flow with turbulences (red arrow) with pressure on the retinal pigment epithelial resulting in
external blood-retinal barrier failure with serous retinal detachment.
not constantly observed in larger series of eyes imaged with FA (Cohen
et al., 2013; Nakanishi et al., 2008). In the first descriptions, the authors
have also assumed that the associated choroidal disturbances and RPE
changes found in the junctional area could promote the occurrence of
SRD (Cohen et al., 1998). A leakage from the disc, comparable to a SRD
associated with optic pits, has also been suggested (Tosti, 1999) but the
absence of communications between the disc and the area of SRD in TDS
did not support this hypothesis. It has also been suggested that the
choroidal vascular hyperpermeability found in this particular area could
be a possible mechanism (Nakanishi et al., 2008). Later, it has been
suggested that the scleral protrusion at the posterior staphyloma edge
could induce mechanical RPE alterations, leading to its dysfunction with
a reduced ability to manage the fluid movements from the retina to the
choroid. Indeed, in a series of 34 eyes with TDS analyzed by
high-penetration OCT, it has been shown that the subfoveal sclera was
thicker than in the lower area of the fundus (Maruko et al., 2011). This
study has shown differences in choroidal thickness between the normal
and staphylomatous areas of the fundus with a thinner choroid in the
lower staphylomatous part. The authors have postulated that the
choroidal thinning and RPE alterations were due to a relative scleral
protrusion and that secondary RPE atrophy would cause a breakdown of
the blood-retinal barrier and subsequent SRD. The same hypothesis has
also been accepted in other studies (Hirano et al., 2015; Pardo-López
et al., 2011). In a small series of 5 cases analyzed by EDI-OCT, the au­
thors have compared the choroidal thickness at the fovea and at 0.5 mm
and 1.0 mm above and below the fovea. The study has clearly shown a
constant thinning of the choroid at the upper staphyloma edge, and
concluded that both RPE dysfunction and choroidal circulatory distur­
bances could be involved in the pathogenesis of SRD (Yamagishi et al.,
2012). Indeed, experimental studies conducted in rabbits have previ­
ously demonstrated that RPE damage was not sufficient to induce SRD
and that both the RPE and the choroid must be impaired to induce SRD
(Yao and Marmor, 1992). A larger series of 42 eyes of 32 patients with
inferior staphyloma, published the same year, has confirmed that the
choroid was thinner in the staphylomatous area, with presence of a
belt-shaped area with the thinnest choroid along the upper staphyloma
edge (Ellabban et al., 2012). Furthermore, this thinning seemed to
progress with age. Indeed, studies of pediatric TDS have not reported
any significant choroidal thinning in the staphylomatous area in young
patients, while they have shown peripapillary changes and a thinning of
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Progress in Retinal and Eye Research 88 (2022) 101020
Fig. 23. Hypotheses for retinal complications of
tilted disc syndrome (TDS). A. Breaking point hy­
pothesis. Schematic diagram of a fundus showing
TDS features, and a junctional area of pigmentary
disturbances (blue arrows). This area corresponds
to the change in eyeball curvature (red arrow). B.
The uneven growth “tractional” hypothesis. Sche­
matic diagram of a fundus showing TDS features
and superior chorioretinal folds that developed
radially to the junctional area. The progressive
growth of the staphyloma may (red arrows) exert a
traction on the superior chorio-retina (blue arrow)
and may lead to chorioretinal folding. C. The
“container-content” hypothesis. Schematic diagram
of a fundus showing TDS features. The inferior
retinoschisis cannot be diagnosed on fundus exam­
ination, but is seen on the oblique or vertical OCT B-
scans. This schisis may be due to the progressive
growth of the staphyloma (red arrows) while the
inner retina remains unchanged (blue arrows). D.
The “choroidal funnel” hypothesis. Schematic rep­
resentation of an oblique OCT B-scan in a case of
TDS with macular serous retinal detachment. The
choroidal thickness markedly changed between the
superior area of the fundus and the staphyloma. An
the retinal layers in the staphylomatous area in elderly patients (Pichi
et al., 2014; Xu et al., 2017). It has also been reported that, in eyes of
patients with TDS, the choroid was the thinnest at approximately 1 mm
inferior to the fovea at the upper edge of the posterior staphyloma rather
than at the bottom of the posterior staphyloma (Ueno et al., 2014).
Additional studies in eyes with TDS or DSM have also shown greater
changes in choroidal thickness in eyes with SRD compared to eyes
without SRD (Tan et al., 2017). The authors have assumed that an
abrupt transition in the choroidal thickness could be involved in the
pathogenesis of SRD.
A few years ago, it has been reported that macular buckling with
Ando plombe could increase the choroidal permeability and mimic SRD
seen in TDS (Mateo and Burés-Jelstrup, 2016). The authors have shown
changes in choroidal thickness that reflected changes in choroidal blood
flow leading to SRD. These changes regressed after explantation of the
buckle. It could thus be assumed that progressive as well as acute
changes in choroidal blood flow could result in the breakdown of the
blood-retinal barrier with occurrence of a SRD. However, the authors
have observed a thicker macular choroid after Ando plombe. According
to Pascal and Laplace laws, others have suggested that changes in
choroidal blood flow, promoted by the anatomical changes observed in
TDS and DSM, could lead to a turgid choroid, capable of fluid accu­
mulation or leakage. Drainage of the choroid would be impaired when
passing from an area of relatively normal choroid in the macular area to
a thinner choroid in the staphylomatous area and could result in
back-pressure and a turgid macular choroid similar to that seen in CSCR
(Gaynon et al., 2018).
Based on all these observations, it can be asserted that there is a
reduction in choroidal thickness between the upper and lower parts of
the fundus (Fig. 24) that progresses with aging. Reported images have
shown, in some cases, a progressive and smooth reduction in choroidal
thickness, while other reports consider these changes as abrupt. But, in
all cases, this transition could be compared to a funnel. The choroidal
blood flow could thus be partially obstructed, and this process could
induce both RPE alterations and choroidal hyperpermeability. This is
what we called the “choroidal funnel” hypothesis (Fig. 23D).
S.Y. Cohen et al.
Fig. 24. Color photography and OCT of an eye with tilted disc syndrome and
inferior staphyloma. An inferonasal pallor of the fundus may be observed (A).
The vertical (B) and oblique OCT scans (C) show the changes in choroidal
thickness between the 2 areas of the fundus with a thinner choroid in the
staphylomatous inferior area. This change is indicated by the yellow lines (C).
10. How hypotheses for TDS complications could help to
understand other diseases and differential diagnoses
10.1. Other disc congenital anomalies
Congenital malformations of the optic disc itself or the optic disc area
include megalopapilla, optic disc aplasia, optic disc hypoplasia, optic
disc coloboma, Morning Glory syndrome, optic disc pit, optic disc
dysplasia, hyaloid system remnants, myelinated nerve fibers, and optic
disc drusen (Apple et al., 1982).
10.1.1. Hypoplasia of the optic nerve
Segmental optic nerve hypoplasia due to intrauterine injury to the
optic nerve, to the chiasm (achiasmia or intrauterine compression by
glioma) or to the posterior visual pathway can give the optic disc a tilted
appearance due to the asymmetric loss of axons. Depending on the
location of intrauterine injury, this theory implies a trans-synaptic
degeneration of ganglion cells, which in turn results in the asymmetric
loss of nerve axons. Retinal vascular changes, such as tortuosity, may be
associated. The clinical history and examination orientate the diagnostic
work-up of segmental optic nerve hypoplasia, but MRI is needed to
localize the site of primary injury along the visual pathway and detect
associated anomalies (Denis et al., 2019; Jeng-Miller et al., 2017).
10.1.2. Optic disc coloboma
Optic disc coloboma (ODC), a rare congenital disorder occurring
unilaterally and bilaterally at equal rates, and resulting from the
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Progress in Retinal and Eye Research 88 (2022) 101020
incomplete closure of the embryonic fissure during the 5th to 7th week
of gestational age, results in a sharply delimited, glistening white, bowl-
shaped excavation occupying an enlarged optic disc. This excavation is
decentered inferiorly, reflecting the position of the embryonic fissure.
The inferior neuroretinal rim is thin or absent, while the superior neu­
roretinal rim is relatively spared. Rarely, the entire disc may be exca­
vated; however, the colobomatous nature of the defect is still visible
because the excavation is deeper inferiorly and, in a limited number of
cases, this congenital disorder can lead to misdiagnosis with congenital
tilted optic disc. Colobomas are the most common segmental forms of
optic nerve hypoplasia found in clinical practice. Coronal T1-weighted
MRI is used to confirm that the size of the intracranial portion of the
optic nerve is reduced. ODC can be sporadic or inherited in an autosomal
dominant pattern, with reported associations with PAX2 variants and
can also be accompanied by multiple systemic abnormalities in condi­
tions, including the CHARGE association, Walker-Warburg syndrome,
Aicardi syndrome, and Goldenhar sequence (Jay, 2017). The Morning
Glory syndrome is a specific type of optic nerve coloboma associated
with characteristic retinal vascular anomalies, glial proliferation and
metaplasia, and peripapillary pigmentary changes (Apple et al., 1982).
10.2. Visual field defects related to glaucoma or other conditions
Because of the common inferior or inferonasal ectasia and myopia,
and the inferiorly reduced density of optic nerve axons in congenital
TDS, the most common locations of the visual field defects are super­
otemporal and superior. These defects look fascicular and are related to
the blind spot. As discussed previously, in the cases of bilateral optic disc
tilt, a bilateral superotemporal visual field defect suggests an incomplete
chiasmal syndrome, but in tilted discs, it fails to respect the vertical
meridian. The visual field defects are different in myopic eyes with ac­
quired optic disc tilt and torsion in which the mechanism of morpho­
logical changes in the ONH are secondary to the axial elongation of the
eye. Tilted disc associated with staphyloma and corresponding scotoma
simulates glaucoma-related defects and the difficulties in analyzing the
neuroretinal rim in such optic discs make the diagnosis difficult. Pub­
lications on unilateral glaucomatous visual field defects in myopic Asian
patients with temporal tilting of the ONH have shown that, while there
was no asymmetry in intraocular pressure, the degree of optic disc tor­
sion was higher in eyes with an affected visual field than in the
contralateral normal eyes (Lee et al., 2014). However, a recent
meta-analysis has found that there is no evidence of the effects of the
optic nerve deformation (tilt and torsion) on glaucoma progression in
acquired tilt associated with open angle glaucoma (Ha et al., 2021).
10.3. Disc anomalies and staphylomas related to high myopia
A posterior staphyloma is a hallmark abnormality of the eyeball of
eyes with pathologic myopia, in which a part of the posterior pole
protrudes posteriorly (Curtin, 1977). It has been defined by Spaide in
2014 as “an outpouching of the wall of the eye that has a radius of
curvature that is less than the surrounding curvature of the wall of the
eye” (Spaide et al., 2014). Since a posterior staphyloma rarely occurs
except in pathologic myopia, it is a very characteristic and specific
condition associated with pathologic myopia.
10.3.1. Evolving classifications of staphylomas
The most commonly used classification is the Curtin classification
(Curtin, 1977), based on his observation and charts of the fundus using
an ophthalmoscope. The classification includes 10 types from I to X.
Types I–V are primary staphylomas and Types VI-X are compound
staphylomas. Posterior staphylomas located in the posterior pole are
classified as Type I, in the macula as Type II, in the peripapillary region
as Type III, in the nasal side of the optic disc as Type IV, and in the
inferior side of the optic disc as Type V.
For compound staphylomas, the shape of the posterior pole of the eye
S.Y. Cohen et al.
is based on the complex combination of several primary types. Type VI is
the combination of Types I and II and Type VII is the combination of
Types I and III. Type VIII has tiers or steps across the wall of Type I
staphyloma. Type XI has a vertical septum passing from the upper to the
lower edge of the staphyloma through, or to either side of, the optic
nerve. Type X has thin plicae dividing the staphyloma into several
compartments and typically extends from the optic nerve to the staph­
yloma margin.
Using wide-field fundus photography and 3D MRI, Ohno-Matsui has
proposed the TMDU classification, which simplifies and makes the
Curtin classification easier to use and has renamed very rare cases as
others (Ohno-Matsui, 2014). In this classification, the range of the
posterior staphyloma is assessed by the range of the outermost edge. As a
result, Types VI-X in the Curtin classification have been integrated into
Type I. In addition, Types I–V have been renamed according to the range
of the staphyloma. Type I corresponds to a wide, macular staphyloma,
involving the optic disc and macula. Type II corresponds to a narrow,
macular staphyloma, limited to a narrow area of the posterior pole. Type
III corresponds to a peripapillary staphyloma, protruding in a circle
around the optic disc. Type IV corresponds to a nasal staphyloma,
extending to the nasal side of the optic disc. Type V corresponds to an
inferior staphyloma, protruding in the lower half of the eye. Staph­
ylomas other than Types I–V have been defined as “others” (Fig. 25).
10.3.2. Disc shape aspect according to staphyloma types
In eyes with pathologic myopia with posterior staphyloma, various
aspects of the optic disc are seen. Nagaoka et al. have previously
assessed the prevalence of glaucoma in 336 eyes with high myopia
defined by a myopic refractive error > -8D or an axial length ≥26.5 mm
(Nagaoka et al., 2015). Patients’ mean age was 61.9 ± 12.3 years, the
mean axial length was 30.1 ± 2.3 mm, and the mean optic disc area was
3.18 ± 1.94 mm2. Based on the findings of the Beijing Eye Study, the
optic discs were classified into three types: “small discs” were defined as
discs of less than 1.51 mm2, and “megalodiscs” as discs greater than
3.79 mm2 “Normal sized discs” were the remaining discs. Of the 336
eyes, the proportion of small discs, normal sized discs, and megalodiscs
was 64 eyes (19%), 173 eyes (52%), and 99 eyes (29%), respectively. In
the multivariate analysis, glaucoma prevalence was 3.2 times higher in
eyes with megalodiscs than in eyes with normal sized discs or small discs
after adjusting for an older age. The axial length was not significantly
associated with glaucoma prevalence in this model. Glaucoma preva­
lence increased by a factor of 1.39 for each increase in optic disc area by
one mm2.
The aspect of the optic disc correlates with the type of posterior
staphyloma. In eyes with wide macular staphyloma, the optic disc area is
enlarged and an acquired ‘megalodisc’ is seen. In eyes with narrow
macular staphyloma, the nasal edge of the staphyloma is usually just
temporal to the optic disc. Thus, the optic disc is horizontally tilted and a
vertically long optic disc is seen. In extreme cases, the optic disc itself is
not visible due to an extreme tilting. In eyes with nasal staphyloma, the
optic disc is tilted inferiorly-nasally, and an inferior conus is present,
that needs to be differentiated from TDS.
2D and 3D OCT may be very useful to analyze the different layers of
Fig. 25. Using Optos and 3D MRI, Ohno-Matsui has proposed the TMDU classification, which simplified and made the Curtin classification easier to use and renamed
very rare cases as others (Ohno-Matsui, 2014). Copyright Ophthalmology: Journal of the American Academy of Ophthalmology, with permission.
22
Progress in Retinal and Eye Research 88 (2022) 101020
the disc and the peripapillary area. In myopic eyes with tilted disc, it
could show the protrusion of the BM and choroid toward the optic disc
area along its upper margin (Fig. 26).
10.4. Dome-shaped macula (DSM)
10.4.1. DSM as an atypical staphyloma
A previously undescribed cause of visual loss in myopic patients,
called DSM has been reported in 2008 (Gaucher et al., 2008). The
condition was characterized by an inward bulge of the macula within
the chorioretinal posterior concavity of the eye, mainly visualized by
OCT. Subtypes of DSM have been identified depending on the dome
shape: round or oval with a vertical or horizontal axis (Caillaux et al.,
2013).
10.4.2. DSM with SRD
The main complication of DSM is the occurrence of a SRD. A macular
SRD has been observed in all studies, with an incidence varying from
1.8% to 54% of cases (Liang et al., 2015; Soudier et al., 2020). A SRD is
more commonly observed when the bulge height is greater than 350 μm,
and in eyes with vertical oval DSM (Caillaux et al., 2013; Hocaoglu et al.,
2019). Atypical staphylomas observed in DSM are very similar to the
inferior staphylomas commonly observed in eyes with TDS, because of
an area of protrusion, referred to as macular bending. Indeed, both
conditions include a change in eyeball curvature that may lead to similar
complications such as pigmentary changes, CNV, PCV, and SRD.
10.4.3. Similarities between DSM and TDS and the “choroidal funnel”
hypothesis
Similarities between both conditions have been highlighted in
different studies (Coco et al., 2012; Pardo-López et al., 2011; Tan et al.,
2017). Indeed, both conditions include anomalies of the eyeball curva­
ture frequently associated with SRD. More precisely, it has been shown
that, in DSM, the mean central choroidal thickness was thicker than the
choroid in the surrounding staphyloma, and that the mean central
choroidal thickness-to-mean perimacular choroidal thickness ratio was
greater in DSM eyes compared to other myopic eyes with the same axial
length (Soudier et al., 2020). Thus, DSM seems to be associated with
relatively thicker sclera and choroid at the bulge apex. It has recently
been shown that the submacular choroidal blood flow measured on the
OCTA B-scan was greater in eyes with SRD than in eyes without SRD
(Soudier et al., 2020). Thus, the changes in choroidal thickness at the
transition area between the bulge and the staphyloma observed by
different teams in DSM (Deobhakta et al., 2015; Ellabban et al., 2013)
may correspond to abrupt changes in choroidal blood flow, leading to
outer blood-retina barrier breakdown, resulting in the occurrence of a
SRD. Thus, the “choroidal funnel” hypothesis could also be considered in
DSM with SRD, as we did for TDS with SRD.
10.5. Foveoschisis in myopic fundus
10.5.1. Myopic foveoschisis
The term “myopic foveal retinoschisis” has been introduced in 1999
S.Y. Cohen et al.
beneath the protruded Bruch’s membrane-choroid complex and bent superiorly (arrowheads) beyond the upper margin of the optic disc. E. Fundus photograph of the
right eye with an axial length of 29.8 mm. The optic disc is tilted and an inferior conus is seen. The OCT scan direction for Figure F is shown as a white line with
arrow. F. The vertical OCT scan is shown as a white line in Figure E. The Bruch’s membrane-choroid complex is protruded (red arrow) toward the optic disc area
along the upper margin of the disc. The nerve tissue is herniated beneath the protruded Bruch’s membrane-choroid complex and bent superiorly (arrowheads)
beyond the upper margin of the optic disc. Scale bars = 1 mm.
(Takano and Kishi, 1999). They have described the splitting of the inner
retinal layers at the macula in patients with high myopia and posterior
staphyloma. Later, in a series of 134 eyes of 78 patients with high
myopia imaged by OCT, all seven eyes with myopic retinoschisis were in
the group with staphyloma, and no eyes were in the group without
posterior staphyloma, suggesting a relationship between both findings.
10.5.2. The uneven growth “tractional” and “container-content”
imbalance hypotheses in myopic foveoschisis
Since 2003, it has been postulated that a foveal detachment and a
foveoschisis could occur secondarily to a scleral enlargement and the
inability of the retina to stretch (Baba et al., 2003). In another series of
21 eyes, the authors have shown that, in all eyes, the retinal thickening
was mainly due to an extensive hyporeflective space splitting the neu­
roretina into a thick inner layer and a thin outer layer (Benhamou et al.,
2002), confirming the initial findings showing that the splitting plane
was usually located between the Henle’s fiber layer and the photore­
ceptor layer (Takano and Kishi, 1999). All subsequent studies and re­
views have systematically supported that the progressive growth of the
posterior staphyloma is the main factor that induces retinal layer split­
ting, leading to foveoschisis in patients with high or pathologic myopia
(Ohno-Matsui, 2016; Ruiz-Medrano et al., 2019). That is why this lesion
could also fit in the uneven growth “tractional” hypothesis when reti­
noschisis progressively develops in the area of the inferior staphyloma
because its growth will promote an indirect traction on the outer layers
of the fundus.
However, an internal component is also widely supported. In a series
of 10 eyes, three factors were independently associated with foveo­
schisis and foveal detachment without macular hole: axial length,
macular chorioretinal atrophy, and vitreoretinal interface factors. The
authors have concluded that both intraocular and extraocular wall fac­
tors play important roles in the pathogenesis of the condition (Wu et al.,
2009). Furthermore, myopic foveoschisis is widely considered to be part
of myopic traction maculopathy (Gómez-Resa et al., 2014; Müller and
Joussen, 2011). Thus, the problem may be considered as an imbalance
between the relatively fixed outer and inner layers, leaving the retina
stretched in between. That is why the term “container-content” imbal­
ance may better reflect this hypothesis, with a clear demonstration of the
23
Progress in Retinal and Eye Research 88 (2022) 101020
Fig. 26. Protrusion of the Bruch’s membrane and
choroid toward the optic disc area along its upper
margin. A. Fundus photograph of the right eye with
an axial length of 31.4 mm. The optic disc is tilted
and a conus is seen infero-temporally to the optic
disc. The OCT scan direction for Figure B is shown
as a white line with arrow. B. The oblique OCT scan
is shown as a white line in Figure A. The Bruch’s
membrane-choroid complex is protruded (red
arrow) toward the optic disc area along the upper
margin of the disc. The nerve tissue is herniated
beneath the protruded Bruch’s membrane-choroid
complex and bent superiorly (arrowheads) beyond
the upper margin of the optic disc. C. Fundus
photograph of the right eye with a refractive error
(spherical equivalent) of − 12.5 diopters and an
axial length of 28.7 mm. The optic disc is tilted and
a conus is seen infero-temporally to the optic disc.
The OCT scan direction for Figure D is shown as a
white line with arrow. D. The oblique OCT scan is
shown as a white line in Figure C. The Bruch’s
membrane-choroid complex is protruded (red
arrow) toward the optic disc area along the upper
margin of the disc. The nerve tissue is herniated
differences between affected and non-affected areas of the fundus in
patients with TDS because the myopic retinoschisis is thus limited to the
inferior staphyloma that corresponds to the growing part of the fundus.
10.6. Chorioretinal folds
10.6.1. Pathogenesis of chorioretinal folds
According to Gass, any condition resulting in a reduction in the inner
surface area of the sclera (scleral thickening or shrinkage) will cause the
inner portion of the choroid, including the BM, the overlying RPE and
the outer retinal layers, to be thrown into a series of folds or wrinkles
(Gass, 1997). Chorioretinal folds may thus be observed in many
ophthalmic and orbital conditions, including orbital malformations or
compressive orbital disorders, thyroid-related orbitopathy, posterior
scleritis, hypotonia, hyperopia, exudative macular degeneration, and
optic nerve disorders (Leahey et al., 1993; Olsen et al., 2014). Different
hypotheses could explain their occurrence.
10.6.2. A “container-content” imbalance issue
Many causes of chorioretinal folds fit in what we called the
“container-content” imbalance issue. Compressive etiologies of cho­
rioretinal folds, such as compressive orbital disorders, will cause an
inward protrusion of the sclera, leaving less room for the choroid and the
overlying layers of the fundus. Posterior scleritis also leads to a thick­
ening of the sclera (Benson, 1988). Choroidal tumors, such as malignant
melanomas and metastatic carcinomas, may also exert a compression of
the inner choroid and overlying fundus layers (Shields et al., 1992).
Hypotony may lead to contraction and swelling of the sclera with sub­
sequent reduction in intraocular volume and appearance of chorior­
etinal folds (Völcker and Naumann, 1979). Thus, many causes of
chorioretinal folds fit in this “container-content” imbalance issue.
10.6.3. The “tractional” hypothesis
However, other etiologies may better fit in the “tractional” hypoth­
esis. Gass had initially reported the possible occurrence of chorioretinal
folds in AMD patients with CNV. The radial pattern of chorioretinal folds
surrounding the margins of the macular detachment observed by bio­
microscopy and FA suggested that the contraction of a subpigment
S.Y. Cohen et al.
epithelial choroidal neovascular membrane caused a focal area of
shrinkage of the choroid, leading to radiating chorioretinal folds (Gass,
1981). The same pattern of radiating folds is also found in chorioretinal
folds associated with staphylomas. They have initially been reported in
inferior staphylomas associated with TDS, but have been described later
in typical or even more atypical posterior staphylomas (Giocanti-Aur­
egan et al., 2020; Ishida et al., 2015). The term “staphyloma-related
chorioretinal folds” has been suggested to describe these findings (Gio­
canti-Auregan et al., 2020). In this condition, an uneven growth of the
eyeball, with progressive elongation of its staphylomatous part has been
suggested to explain the development of radial folds, by exerting trac­
tion on fixed parts of the fundus. The “tractional” hypothesis could thus
explain the occurrence of chorioretinal folds in different contexts.
11. Future directions and conclusions
The present review stressed the need to better understand the
pathophysiology of TDS. Studies with a longitudinal follow-up of pa­
tients, especially of younger patients, are needed to improve our
knowledge and could help to solve the discussions about congenital
findings and acquired complications. It also pointed out the confusion
observed in the literature between congenital TDS and myopic TD, and
stressed the need for a better classification of the conditions associated
with an oval-shaped disc. However, our review was mainly focused on
the clinical consequences of TDS and aimed to emphasize that TDS is, by
far, more than a disc malformation. Its wide range of macular compli­
cations frequently leads to misdiagnosis. The fact that usual fundus
imaging, including fundus photography and OCT B-scans, presents a
limited field of investigation and is observed on screens or printed in 2
dimensions could be a possible explanation. More advanced imaging
includes wide-field photography and angiography, but also wide-field
OCT that allows clinicians to easily obtain a 3D representation of the
fundus changes. Most complications are indeed related to a malforma­
tion of the entire eyeball, as also observed on 3D MRI. More precisely,
the co-existence of a normal superior part and a staphylomatous inferior
part of the fundus will impair the junctional area, as described above. In
the present review, the authors proposed different hypotheses to better
understand the occurrence of retinal and macular complications in these
malformed eyes. These hypotheses could also be used to understand the
occurrence of similar complications in non-TDS disorders. The gener­
alization of wide-field imaging will probably help to demonstrate the
role of TDS in these complications. Understanding the pathogenesis
could also help researchers and clinicians to improve the management of
complications, such as macular SRD, for which no satisfactory therapy is
currently available.
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
All authors have seen and approved the final version of the manu­
script being submitted. The article is the authors’ original work, hasn’t
received prior publication and isn’t under consideration for publication
elsewhere.
Funding source
CIL-ASSOC, an association for education and research, without
involvement in the study design, data collection, analysis and inter­
pretation, writing of the report and decision to submit the article for
publication.
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