Progress in Retinal and Eye Research xxx (xxxx) xxx

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Progress in Retinal and Eye Research

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

Optic nerve head anatomy in myopia and glaucoma, including

parapapillary zones alpha, beta, gamma and delta: Histology and
clinical features
Ya Xing Wang a, *, Songhomitra Panda-Jonas b, 1, Jost B. Jonas b, c, 1
a
Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology and Visual Sciences Key Laboratory, Beijing, China
b
Institute for Clinical and Scientific Ophthalmology and Acupuncture Jonas & Panda, Heidelberg, Germany
c
Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht-Karis-University, Mannheim, Germany

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

Keywords: The optic nerve head can morphologically be differentiated into the optic disc with the lamina cribrosa as its
High myopia basis, and the parapapillary region with zones alpha (irregular pigmentation due to irregularities of the retinal
Myopia pigment epithelium (RPE) and peripheral location), beta zone (complete RPE loss while Bruch’s membrane (BM)
Glaucoma
is present), gamma zone (absence of BM), and delta zone (elongated and thinned peripapillary scleral flange)
Glaucomatous optic neuropathy
Optic nerve head
within gamma zone and located at the peripapillary ring. Alpha zone is present in almost all eyes. Beta zone is
Optic disc associated with glaucoma and may develop due to a IOP rise-dependent parapapillary up-piling of RPE. Gamma
Parapapillary gamma zone zone may develop due to a shift of the non-enlarged BM opening (BMO) in moderate myopia, while in highly
Parapapillary delta zone myopic eyes, the BMO enlarges and a circular gamma zone and delta zone develop. The ophthalmoscopic shape
Lamina cribrosa and size of the optic disc is markedly influenced by a myopic shift of BMO, usually into the temporal direction,
leading to a BM overhanging into the intrapapillary compartment at the nasal disc border, a secondary lack of
BM in the temporal parapapillary region (leading to gamma zone in non-highly myopic eyes), and an ocular optic
nerve canal running obliquely from centrally posteriorly to nasally anteriorly. In highly myopic eyes (cut-off for
high myopia at approximately − 8 diopters or an axial length of 26.5 mm), the optic disc area enlarges, the
lamina cribrosa thus enlarges in area and decreases in thickness, and the BMO increases, leading to a circular
gamma zone and delta zone in highly myopic eyes.

1. Introduction
The optic nerve head (ONH) is the structure in the posterior ocular
fundus that allows the exit of the retinal ganglion cell axons and the
entry and exit of the retinal blood vessels. It is located at a distance of
about 4–5 mm (mean: 4.76 ± 0.34 mm) from the fovea (in emmetropic
eyes) in nasal slightly superior direction (mean disc-fovea angle: 7.76 ±
3.63◦ ) (Jonas et al., 2015a,b). From an anatomical point of view, the
ONH canal can be regarded to consist of three layers, with the opening in
Bruch’s membrane (BM) as its inner layer, the opening in the choroid as
its middle layer, and the opening in the peripapillary scleral flange as its
outer layer (Jonas et al., 2003, 2004; Wang et al., 2020b; Zhang et al.,
2019) (Fig. 1). The latter is covered by the lamina cribrosa allowing the
entry and exit of the retinal ganglion cell axons and retinal blood vessels
and simultaneously mostly preventing the exchange of fluid between the
vitreous cavity on its inner side and the optic nerve and the retrobulbar
cerebrospinal fluid (CSF) space on its outer side. The lamina cribrosa
also serves as pressure barrier between the intravitreal compartment
with the pulsating intraocular pressure (IOP) (better termed “trans
corneal pressure difference”) and the retrobulbar compartment with the
pulsating CSF pressure (Burgoyne et al., 2005; Jonas et al., 2003, 2004;
Morgan et al., 1995, 1998). With all visual afference passing through the
ONH in a highly concentrated manner and with the ONH having the load
of a pulse phase shift-related fluctuating pressure difference between the
high-pressure compartment on its inner side and a low-pressure
compartment on its outer side, the ONH forms a locus minoris resis­
tenciae for the visual system. The ONH can be divided into the optic disc
which may be defined as all the region with the lamina cribrosa as its

* Corresponding author. Beijing Institute of Ophthalmology, 17 Hougou Lane, Chong Wen Men, 100005, Beijing, China.
E-mail address: yaxingw@gmail.com (Y.X. Wang).
1
JBJ and SPJ equally contributed to the study and share the last authorship.

https://doi.org/10.1016/j.preteyeres.2020.100933
Received 16 August 2020; Received in revised form 22 November 2020; Accepted 27 November 2020
Available online 9 December 2020
1350-9462/© 2020 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).

Please cite this article as: Ya Xing Wang, Progress in Retinal and Eye Research, https://doi.org/10.1016/j.preteyeres.2020.100933
Y.X. Wang et al.
bottom, and the peripapillary area with the parapapillary zones alpha,
beta, gamma and delta.
The purpose of this review is to summarize the anatomical features of
the ONH and to discuss their meaning for the physiology and patho­
physiology of the ONH including its biomechanics, in normal eyes and
glaucomatous eyes with special reference to eyes with myopia and high
myopia.
2. Optic disc size
The optic disc that may be defined as the whole area with the lamina
cribrosa as its bottom, can morphologically be described by its size and
shape. The optic disc size shows a marked inter-individual variability of
about 1:7 within Caucasian populations (Bengtsson, 1976; Betz et al.,
1981; Britton et al., 1987; Franceschetti and Bock, 1950; Jonas et al.,
1988a,b,c, 1989a; Omodaka et al., 2017; Ramrattan et al., 1999; San­
filippo et al., 2009; Tomita et al., 1989; Varma et al., 1994) (Fig. 2). In
addition, the disc size depends on the ethnic background, being largest
in populations from Sub-Sahara Africa, followed by South Asians, Chi­
nese and eventually European-descent individuals (Chi et al., 1989; Tsai
et al., 1995; Varma et al., 1994). Within a group of Caucasian in­
dividuals, the disc size was not correlated with iris color (Budde et al.,
1998). Based on the Gaussian-like distribution curve of the optic disc
area, one may define minidiscs by a disc area of the mean minus twofold
standard deviation, and one may define macrodiscs by disc area of the
mean plus twofold standard deviation (Jonas et al., 1988a, 1989a,
1990a) (Figs. 2 and 3). The macrodiscs may further be subdivided into
primary macrodiscs and secondary macrodiscs. The primary macrodiscs
remain constant in size after the age of about 20 years and their size is
not correlated with axial length or refractive error. They can be sub­
classified into “asymptomatic primary macrodiscs” without any
morphologic or functional defects, and into “symptomatic primary
macrodiscs” with morphologic and functional defects such as congenital
pits of the optic disc (Jonas and Naumann, 1987) and the “Morning-­
Glory-Syndrome” (Jonas et al., 1989b). Eyes with primary macrodiscs
tend to have a large and flat cornea (Jonas and Königsreuther, 1994).
Secondary macrodiscs occur in highly myopic eyes (defined by an axial
Fig. 1. Optic disc histograph and optical coherence tomographic (OCT) image showing the three layers of the optic nerve head canal, including Bruch’s membrane
opening (yellow line), the choroidal opening (red line), and the opening of the peripapillary scleral flange (black line), covered by the lamina cribrosa (green tri­
angle), shown in non-myopic eyes (above) and moderate myopic eyes (below).
In the myopic eyes (below), with Bruch’s membrane opening layer shifting, an oblique canal orientation and an oval optic disc shape are present. An overhanging of
Bruch’s membrane on the left side and lack of Bruch’s membrane (parapapillary gamma zone) on the right side are shown in both histo-photograph and OCT image.
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Progress in Retinal and Eye Research xxx (xxxx) xxx
length of larger than approximately 26.5 mm), and their size increases
with longer axial length (Jonas et al., 1988c; Xu et al., 2010) (Fig. 2).
Secondary macrodiscs can further be subdivided into secondary mac­
rodiscs in eyes with primary high myopia, and into secondary macro­
discs in eyes with secondary high myopia due to congenital glaucoma. In
both subtypes of secondary macrodiscs, a larger optic disc area is
correlated with longer axial length (Jonas and Dichtl, 1997; Jonas et al.,
1988c). Since the axial elongation continues in highly myopic eyes
beyond the age of 20 years, the size of secondary macrodiscs in highly
myopic eyes is indirectly associated with older age (Fang et al., 2018).
The inter-individual variation in disc size may be considered, if the optic
disc diameter is taken as a size unit to compare intraocular lesions such
as malignant melanomas.
When discussing the disc size and shape, one may take into account
that the studies and findings mentioned above refer to the oph­
thalmoscopically visible part of the optic disc as it appears on fundus
photographs (or upon ophthalmoscopy). That part of the optic disc
covered by an overhanging BM has usually not been included into the
measured optic disc so that the disc size and shape data relate only to the
ophthalmoscopically assessable part.
In non-highly myopic eyes, the optic disc area is mostly independent
of age beyond an age of about 20 years (Bengtsson, 1976; Betz et al.,
1981; Jonas et al., 1988a; Ramrattan et al., 1999; Varma et al., 1994). In
eyes with a refractive error − 5 to +2 diopters, the disc size is mostly
independent of the refractive error or axial length or shows a slight in­
crease with increasing myopic refractive error (Britton et al., 1987;
Jonas et al., 1988a; Ramrattan et al., 1999; Varma et al., 1994). In hy­
peropic eyes with a refractive error of more than +2 diopters, the optic
disc is significantly smaller, and in highly myopic eyes, the disc is
significantly larger than in the remaining eyes.
According to histomorphometric studies, the interindividual vari­
ability in optic disc size is morphogenetically important, since a larger
disc size is correlated with a larger neuroretinal rim (Jonas et al.,
1988a), a higher count of optic nerve fibers (Jonas et al., 1992a), less
nerve fiber crowding per mm2 disc area (Jonas et al., 1992a), a higher
count and a larger total area of lamina cribrosa pores (Jonas et al.,
1991a), a higher ratio of inter-pore connective tissue area to total lamina
Y.X. Wang et al.
Fig. 2. Figure showing the primary macrodisc and secondary macrodisc.
The group of primary macrodiscs include the asymptomatic primary macrodisc (with the physiologic shape of the neuroretinal rim) and symptomatic primary
macrodiscs (congenital pit of the optic nerve head and the “Morning Glory Syndrome”) (above). The group of secondary macrodiscs include the secondary macrodisc
in eyes with primary high myopia and those in eyes with secondary high myopia due to congenital glaucoma (below).
cribrosa area (Jonas et al., 1991a), a higher count of cilioretinal arteries
(Jonas et al., 1988d), and a higher count of retinal photoreceptors
(Panda-Jonas et al., 1994) and retinal pigment epithelium (RPE) cells
(Panda-Jonas et al., 1996) in combination with a larger retinal surface
area and longer horizontal and vertical diameters of the globe (Papas­
tathopoulos et al., 1995). As shown in a series of studies on twin pop­
ulations, the optic disc morphology shows a marked hereditary
association, with about 70–80% of the variance in the optic disc
morphology determined by genetics. In contrast, the optic disc vessels
showed a less marked heredity association (Healey et al., 2008; He et al.,
2008; Hewitt et al., 2007) (Fig. 4).
In the population-based Beijing Eye Study, the disc size correlated
with the cognitive function in a multivariable analysis adjusting for
parameters such as age, gender, level of education and region of habi­
tation (Jonas et al., 2013a). The disc size is of clinical importance, since
some optic nerve abnormalities and diseases preferentially occur in
small discs, such as optic disc drusen (Spencer, 1978; Jonas et al., 1987),
pseudo-papilledema (Jonas et al., 1988e) and non-arteritic anterior
ischemic optic neuropathy (Beck et al., 1984; Jonas et al., 1988f; Jonas
and Xu, 1993a), while others are preferentially found in large discs, such
as congenital ONH pits (Jonas and Naumann, 1987) and the Morning
Glory syndrome (Jonas et al., 1989b) (Figs. 2 and 3). Interestingly, the
prevalence of central retinal artery occlusions and central retinal vein
occlusions was independent of the optic disc size, probably since the size
of the central lamina cribrosa pore for the passage of the retinal artery
and vein was independent of the disc size (Gusek et al., 1990; Jonas
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Progress in Retinal and Eye Research xxx (xxxx) xxx
et al., 1991a; Strahlman et al., 1989) (Fig. 5). In a similar manner, the
prevalence of an arteritic ischemic optic neuropathy due to a giant cell
arteritis and the prevalence of glaucoma was not related to the disc size
(Jonas et al., 1988f,g,h, 1991b).
The pathogenetic reasons for these associations with the disc size
have remained unclear yet. In the case of optic disc drusen, one may
assume that a relative blockade of the orthograde axoplasmic flow due
to the small optic disc damaged the optic nerve fibers, leading to
calcification of their mitochondria with eventual loss of optic nerve fiber
and appearance of ophthalmoscopically detectable calcified drusen
(Minckler et al., 1976; Tso 1981). In the case of non-arteritic anterior
ischemic optic neuropathy, a small vascular insufficiency in the ONH,
occurring predominantly during sleeping, may lead to a localized tissue
swelling (Hayreh, 1974a, 1995). Due to the lack of space, caused by the
smallness of the optic disc, a vicious circle may start so that the ischemic
swelling-induced lack of space leads to a secondary occlusion of the
neighboring blood vessels which swell and then again need more space.
In the case of papilledema, it may just be a crowding of the retinal nerve
fibers in the small opening of the optic disc (Jonas et al., 1991c). In
contrast to a true papilledema, the central retinal vein in eyes with
pseudopapilledema is not engorged and may show a spontaneous pul­
sation, suggesting a normal brain pressure (Jonas 2004). From a clinical
diagnostic point of view, the associations of ONH anomalies and disor­
ders with the disc size are helpful for the ophthalmoscopical differen­
tiation between the non-arteritic form and the arteritic form of anterior
ischemic optic neuropathy, and for the differentiation between
Y.X. Wang et al.
Fig. 3. The asymptomatic microdisc without any abnormality (upper left image), the asymptomatic microdisc with pseudo-papilledema (upper right image), the
microdisc with disc drusen (lower left image), and the microdisc with an acute non-arteritic ischemic optic neuropathy (NAION) in the inferior disc half and a non-
glaucomatous optic nerve damage in the superior disc half after a NAION (lower right image).
pseudopapilledema and true papilledema (Jonas and Budde, 2000a).
The reasons for the marked inter-individual, and inter-ethnic, dif­
ference in optic size have remained unclear. One may discuss that the
size of the disc is governed by the number of embryologically formed
primitive retinal ganglion cell axons (Chalupa et al., 1984; Crespo et al.,
1985; Provis et al., 1985; Sefton and Lam, 1984). As a corollary, the
variability in the size of the optic cup may be connected with the number
of regressed retinal ganglion cell axons, which were formed but then
vanished (Chalupa et al., 1984; Crespo et al., 1985; Provis et al., 1985;
Sefton and Lam, 1984). The reason for the regression of theses fibers
may be that they arrive late at the optic disc (and are therefore located in
the center of the primitive ONH), and arrive late in the lateral geniculate
ganglion where all available synapses may already have been occupied
(Jonas and Naumann, 1992).
2.1. Optic disc size in myopia
In highly myopic eyes, the optic disc enlarges with longer axial
length or more myopic refractive error, starting at a cut-off value of
about − 8 diopters or an axial length of about 26.5 mm (Xu et al., 2007a,
2010; Zhang et al., 2019). The relationship between disc size and axial
length in highly myopic eyes may not be linear due to various reasons.
Studies have shown that in moderately myopic eyes, the BM is often
overhanging into the intrapapillary compartment on the nasal side, so
that a part the nasal part of the lamina cribrosa cannot be seen upon
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Progress in Retinal and Eye Research xxx (xxxx) xxx
ophthalmoscopy (Reis et al., 2012a; Zhang et al., 2019) (Fig. 1). It leads
to a decrease in the ophthalmoscopically visible part of the lamina cri­
brosa and thus to a decrease in the disc size (and ovalization of the optic
disc shape) as assessed by ophthalmoscopy. Beyond an axial length of
approximately 26.5 mm, the BMO enlarges so that the part of BM
overhanging into the intrapapillary compartment recedes and a circular
gamma parapapillary gamma zone develops (Zhang et al., 2019). By the
uncovering of the nasal part of the lamina cribrosa which then becomes
assessable for the ophthalmoscopy examination, the ophthalmoscopic
optic disc image gets larger. Simultaneously, the lamina cribrosa and
thus the optic disc itself enlarges (and gets stretched) (Jonas et al., 2003,
2004), so that two mechanisms lead to an enlargement of the optic disc
image: The ophthalmoscopic uncovering and the real enlargement of the
lamina cribrosa. While the ophthalmoscopic enlargement of the disc
image by the receding of the overhanging BM may not have an influence
on the lamina cribrosa architecture, the further enlargement of lamina
cribrosa and thus true enlargement of the optic disc is associated with an
increase in the prevalence of a glaucomatous optic neuropathy (GON) or
glaucoma-like optic neuropathy (Jonas et al., 2017a). The axial
elongation-associated enlargement of the optic disc and lamina cribrosa
is associated with a thinning of the lamina cribrosa and changes in the
inner-lamina cribrosa morphology, potentially leading to an increased
susceptibility of the optic nerve fibers when passing through the lamina
cribrosa (Dichtl et al., 1998; Jonas et al., 2003, 2004) (Fig. 6).
Y.X. Wang et al.
Fig. 4. Optic disc images of primary macrodiscs from monozygotic twins (2–1 above and 2-2 below). The optic nerve head parameters were highly consistent, while
the vascular features showed more variability between the twins.
Fig. 5. Photograph of the lamina cribrosa after trypsinization of the optic nerve
fibers; green arrows: peripapillary ring; yellow arrows: central retinal artery
and vein pores.
2.2. Optic disc size in glaucoma
For the diagnosis of GON, it is important to estimate the optic disc
size, since the latter is positively correlated with the size of the optic cup
and the area of the neuroretinal rim (Bengtsson, 1976; Betz et al., 1981;
Britton et al., 1987; Caprioli and Miller, 1987; Jonas et al., 1988a;
Varma et al., 1994). It indicates that the occurrence of a small cup in a
small disc can indicate GON, while the presence of a large cup (“primary
macrocup) in a large disc “primary macrocup) can be normal (Jonas
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Progress in Retinal and Eye Research xxx (xxxx) xxx
et al., 1990a).
In non-highly myopic eyes, the presence of glaucoma is likely not
dependent on the disc size, and the disc size does not differ markedly
between the various types of primary and secondary open-angle glau­
comas (Caprioli, 1993; Jonas et al., 1988d,e; Jonas and Gründler, 1996a;
Jonas and Gründler, 1996b; Jonas and Papastathopoulos, 1997; Jonas
et al., 1998; Nagaoka et al., 2015; Tuulonen and Airaksinen, 1992). In
highly myopic eyes, the presence and size of a secondary macrodisc is
associated with a higher prevalence of GON (Chihara et al., 1997; Jonas
et al., 2002, 2017a; Kuzin et al., 2010; Leske et al., 1995; Mitchell et al.,
1999; Wong et al., 2003; Xu et al., 2007b).
It has been discussed whether the disc size in non-highly myopic eyes
is related to the glaucoma susceptibility (Jonas et al., 2002). Reasons in
favor of a correlation between a large disc and an increased glaucoma
susceptibility were the larger optic disc size in patients with
normal-pressure glaucoma as compared to patients with high-pressure
glaucoma as found in hospital-based studies on Caucasians (Burk
et al., 1992; Tuulonen and Airaksinen, 1992), and that Afro-Americans
as compared to Caucasians have a larger optic disc and a presumably
higher glaucoma susceptibility (Chi et al., 1989; Martin et al., 1985; Tsai
et al., 1995; Varma et al., 1994). In addition, the trans-lamina cribrosa
pressure gradient is, due to mechanical reasons, supposed to cause a
greater lamina cribrosa displacement in large than in small discs (Bur­
goyne et al., 2005; Chi et al., 1989), and the glaucoma-related optic
nerve fiber loss within the optic disc is greater in areas with a longer
distance to the central retinal vessel trunk (Jonas and Fernández, 1994.
Furthermore, a modeling study at the microscale has reported that a
reduction in hemodynamics and in oxygen concentrations in the lamina
cribrosa was related with a larger diameter of lamina cribrosa, and a
larger optic disc (Chuangsuwanich et al., 2016), so that the risk for
glaucomatous damage may be higher in large discs. On the other side,
disorders which potentially might share some aspects in their
Y.X. Wang et al. Progress in Retinal and Eye Research xxx (xxxx) xxx

Fig. 6. Illustrations of the landmarks of the optic nerve head (ONH), including the peripapillary scleral flange, lamina cribrosa, the peripapillary border tissue of the
choroid and the peripapillary border tissue of the peripapillary scleral flange. A. Histological illustration of a normal ONH; B. The magnification of the blue-bordered
area of A. C. Optical coherence tomography illustration (OCT) of an ONH with a normal optic nerve; D. Histological illustration of a highly myopic ONH with
glaucomatous optic nerve damage, presenting with a markedly thinned lamina cribrosa (asterisk: orbital cerebrospinal fluid space); E. Optical coherence tomography
illustration of a highly myopic ONH, presenting with an elongated peripapillary border tissue of the choroid.

pathogenesis with GON, such as non-arteritic anterior ischemic optic
neuropathy with a capillary malperfusion and optic disc drusen with an
impediment of the orthograde axoplasmic flow occur more often in
small discs (Beck et al., 1984; Spencer, 1978; Minckler et al., 1976).
Also, eyes with smaller discs may have a lower number of optic nerve
fibers (Jonas et al., 1992a; Quigley et al., 1991), parallel to a lower
number of retinal photoreceptors (Panda-Jonas et al., 1994) and RPE
cells (Panda-Jonas et al., 1996) in combination with a smaller retinal
surface area (Panda-Jonas et al., 1994) and shorter horizontal and ver­
tical diameters of the globe (Papastathopoulos et al., 1995). Another
reason for a potentially increased glaucoma susceptibility in small discs
could be that the disc regions with the preferential glaucomatous loss of
optic nerve fibers, i.e. the temporal superior area and the temporal
inferior area (Pederson and Anderson, 1980; Radius 1981; Radius et al.,
1978) are characterized by a higher ratio of pore area to inter-pore
connective tissue area (Dandona et al., 1990; Jonas et al., 1991a), and
this ratio is higher in smaller optic discs (Jonas et al., 1991a). At the
bottom line, the disc size was not related to the amount of glaucomatous
optic nerve damage in an inter-eye comparison, in patients with primary
open-angle glaucoma with normal or elevated IOP (Jonas et al., 1991b,
1995). It suggests that the factors having an influence on the glaucoma
susceptibility may compensate each other so that the disc size is not
related to the susceptibility of GON in non-highly myopic eyes. The
finding of a larger disc size in patients with normal-pressure glaucoma is
a selection-artefact in these hospital-based investigations (Jonas, 1992;
Jonas et al., 1995; Burk et al., 1992; Tuulonen and Airaksinen, 1992).
3. Optic disc shape
Upon ophthalmoscopy, the optic disc shape, as the disc appears on
fundus photographs and upon ophthalmoscopy, usually is slightly
vertically oval and shows a marked inter-individual variability (Jonas
et al., 1988a, i). Often the vertical disc diameter is the longest one, and
the horizontal disc diameter the shortest one. The ratio of the
minimal-to-maximal disc diameter has been used to describe the disc
shape and it ranged between 0.64 and 0.98 (Jonas and Papastatho­
poulos, 1996) while the ratio between the horizontal to vertical disc
diameter differed between 0.70 and 1.37. The ratio of the minimal to
maximal disc diameter has also been termed the disc ovality index
(Kimura et al., 2014.; Shin et al., 2015; Tay et al., 2005). In addition, the
disc shape, as it appears on optical coherence tomography (OCT) im­
ages, has been determined by the shape of the neural canal opening
using the parameter of the ratio of ellipse minor axis to ellipse major axis
(Strouthidis et al., 2009; Wang et al., 2020b).
In general, the disc shape can be described by the rotation around the
three geometrical axes. The rotation around the vertical axis leads to a
vertically oval appearance of a circular structure with a perspective
shortening of the horizontal diameter, while the vertical diameter is
unchanged. The rotation around the horizontal axis is associated with a
perspective shortening of the vertical diameter while the horizontal
diameter remains unchanged. Rotation around the sagittal axis does not
change any disc diameter and occurs usually with a rotation of the su­
perior disc pole into temporal direction (Dai et al., 2015a; Zhang et al.,
2019).
In particular in moderately myopic eyes, the position of the optic disc
moves nasally in relationship to the fovea at the posterior pole. Reason is
the increased disc-fovea distance elongated by the developing gamma
zone on the temporal disc side (Jonas, R.A., et al., 2015b). The relative
nasal position of the disc leads to an oblique view onto the optic disc and
thus to an (only) seemingly vertical rotation of the disc with a
perspective shortening of the horizontal disc diameter (Dai et al.,
2015a). In highly myopic eyes with marked axial elongation, a true

6
Y.X. Wang et al.
vertical rotation of the disc may develop, due to a (hypothetical) back­
ward pull of the optic nerve dura mater on the peripapillary scleral
flange at the temporal and inferior disc border (Demer, 2016; Fan et al.,
2017; Wang, X., et al., 2016a, b, 2017). This force may be caused by an
optic nerve being too short to allow a full adduction of a markedly
axially elongated eye.
Formerly called “tilted discs” are characterized by a relatively small
discs with a horizontally oval shape, a disc border prominence at the
superior disc margin and an inferior “crescent” at the inferior disc
border. These “tilted discs” may better be described as discs with a BMO
shifted inferiorly, so that there is a BM overhanging at the superior disc
border, a parapapillary gamma zone inferiorly, an oblique nerve fiber
exit from inferior to superior, and a crowing of optic nerve fibers at the
superior disc border (leading to the prominent disc border superiorly).
In eyes with these “tilted discs”, the foveola is located relatively
inferiorly.
In a previous hospital-based study, an abnormal optic disc shape, like
vertically or horizontally oval disc or “tilted disc”, was associated with a
larger corneal astigmatism and amblyopia in non-highly myopic eyes
(Jonas et al., 1997). It has remained unclear whether this finding can be
generalized. A reason against an association between the disc shape and
corneal astigmatism may be that the corneal dimensions including the
corneal astigmatism are usually relatively constant beyond an age of
about 10 years, while the disc shape often changes during the time of
myopization in adolescence (Guo et al., 2015; Kim, T.W., et al., 2012;
Lim et al., 2008; Samarawickrama et al., 2011).
In eyes with a disc rotation around the horizontal axis (“tilted discs”),
the fovea is usually located relatively inferiorly. It fits with the hy­
pothesis, that a movement of BM into the inferior direction led to the
overhanging of BM at the superior disc pole and to the inferior location
of the fovea.
A sagittal rotation of the optic disc is usually seen in highly myopic
eyes, most often with the superior disc pole rotated in direction to the
fovea. Interestingly, the fovea is located in these eyes relatively inferi­
orly, usually slightly inferior to a line drawn perpendicularly to the
maximal disc diameter through the disc center. Also in eyes with a
normal-shaped optic disc, the fovea is usually located about 0.5 mm
inferior to a line drawn perpendicularly to the maximal disc diameter
Fig. 7. Optic disc photographs showing the change in disc shape and the enlargement of parapapillary gamma zone with a vertical disc ovalization in an adolescent
(A) and with a horizontal disc ovalization in a 5-year-old girl (B), with increasing myopia after 3-year follow-up. Green dot: Bruch’s membrane opening; Cyan: disc
border at baseline; Yellow: disc border at follow-up.
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Progress in Retinal and Eye Research xxx (xxxx) xxx
through the disc center (Jonas et al., 1989c). Since this line is rotated
downward in highly myopic eyes with a disc rotation around the sagittal
axis, the spatial relationship between the fovea and the optic disc is
preserved, despite the disc rotation. This observation would fit with the
notion of BM as a biomechanical important structure for the retinal and
optic disc anatomy and for the form and shape of the globe (Jonas et al.,
2017b).
3.1. Optic disc shape in myopia
In myopic eyes, the optic disc is significantly more ovally configured,
and more obliquely oriented than in any other group (How et al., 2009;
Jonas et al., 1988c; Tay et al., 2005; Xu et al., 2007a; You et al., 2008).
The vertically oval shape of the optic disc increases during myopization
in adolescence (Guo et al., 2015, 2018a; Hwang et al., 2012a, b; Naka­
zawa et al., 2008; Kim, T.W., et al., 2012; Samarawickrama et al., 2011)
(Figs. 1 and 7). The reason for the ovalization of the optic disc shape in
moderately myopic eyes may be a shift of BMO leading to an over­
hanging of BM on one side of the optic disc. The overhanging part of BM
covers a semilunar part of the lamina cribrosa and prevents it to be
assessable upon ophthalmoscopy. The disc thus appears to have an oval
shape (Zhang et al., 2019) (Fig. 1). The same holds true for optic disc
with a horizontally oval shape (Fig. 7).
The oval disc shape in highly myopic eyes, after adjusting for
perspective ophthalmoscopical artefacts (caused by the nasal location of
the optic disc), indicates that the axial elongation-related stretching of
the optic disc occurs asymmetrically, with a stronger effect in the di­
rection of the longest disc diameter and a weaker effect in direction of
the shortest disc diameter. Interestingly, the shape of the optic disc in
highly myopic eyes is not identical to the shape of BMO in highly myopic
eyes (Zhang et al., 2019). It may suggest that the forces leading to the
enlargement of the BMO partially differ from those responsible for the
enlargement of the optic disc. It has been discussed that the main force
for the enlargement of the BMO (and for the development of secondary
BM defects in the macular region) is the enlargement of BM in the
midperiphery of the fundus (Dong et al., 2019a; Jiang et al., 2017; Jonas
et al., 2017b). This peripheral BM enlargement leads mainly to a sagittal
elongation of the eye. Although the coronal globe diameters as
Y.X. Wang et al.
compared to the sagittal diameter increase markedly less (Jonas et al.,
2017c), the increase in the coronal diameters may lead to an increase in
tension within BM, mainly at the posterior pole. In a first step, the BMO
may enlarge, and if the corresponding decrease in BM tension is not
sufficient, new BM defects may open up in the macular region.
The optic disc, i.e., the lamina cribrosa, is only indirectly connected
to BM via the peripapillary choroidal border tissue (Jonas, R.A., and Hou
et al., 2020). During the formation of gamma zone, the peripapillary
choroidal border tissue elongates and gets thinner so that one may as­
sume that only a fraction of the tension within BM is transferred on the
optic disc (Jonas, R.A., and Hou et al., 2020). The forces which may be
prevalent at the optic disc include those caused by the (presumably)
secondary stretching of the posterior sclera (perhaps secondary to the
primary event, i.e. the backward pushing of the posterior BM), the
tension caused by the stretching of the peripapillary choroidal border
tissue which is the only connection between BM (as the biomechanical
most important part of the inner shell of the eye) and the sclera (i.e., the
peripapillary scleral flange) (Jonas, R.A., and Hou et al., 2020; Ren et al.,
2009), and the potential backward pull by the optic nerve (probably
mainly by the optic nerve dura mater) in adduction in extremely myopic
eyes (Demer, 2016; Fan et al., 2017; Wang, X., et al., 2016a, b, 2017).
Most of these forces and anatomic structures have not yet fully been
incorporated in models of the biomechanics of the ONH (Wang, X., et al.,
2017). In the study by Wang and colleagues, the biomechanical model
calculated that the forces exerted on the optic disc by an eye
movement-related backward pull of the optic nerve led to a high optic
nerve sheath traction force of the same order of magnitude as extra­
ocular muscle forces. The ONH deformation may also depend on the
tortuosity or slackness of the optic nerve in the orbit (Wang, X., et al.,
2019). Interestingly, the vertical optic disc rotation as assessed on
fundus photographs did not differ markedly between exotropic eyes,
non-strabismic eyes and esotropic eyes in a non-highly myopic group
(Shang et al., 2019a). It suggested that the disc rotation around the
vertical axis was not markedly influenced in non-highly myopic eyes by
a potential backward pull of the optic nerve on the optic disc structures
in adduction. One may infer that the potential backward pulls by the
optic nerve on the ONH may be present predominantly in highly myopic
eyes. Further studies may address whether strabismic eyes versus
non-strabismic eyes, and highly myopic eyes versus non-highly myopic
eyes differ in the tortuosity or length of the intraorbital part of the optic
nerve.
3.2. Optic disc shape in glaucoma
The disc shape did not differ between various types of primary and
secondary open-angle glaucoma in non-highly myopic eyes (Jonas and
Papastathopoulos, 1996), while in highly myopic eyes, the axial elon­
gation was associated with disc shape. Since the intrapapillary glaucoma
susceptibility has been reported to increase with a longer distance of the
region to the central retinal vessel trunk (Jonas and Fernández, 1994),
the disc shape may indirectly influence the pattern of glaucomatous
neuroretinal rim loss and perimetric defects.
4. Neuroretinal rim size and color
The neuroretinal rim is the optic disc part containing the optic nerve
fibers (Airaksinen and Drance, 1985; Araie et al., 2017; Betz et al., 1981;
Britton et al., 1987; Chauhan et al., 2015). Its area is positively corre­
lated with the disc and optic cup size (Britton et al., 1987; Caprioli and
Miller, 1987; Jonas et al., 1988a; Varma et al., 1994). The reasons for the
correlation with the disc size are at least twofold: First, in small discs, the
rim cannot be larger than the disc is small; and second, eyes with large
discs tend to have a higher number of optic nerve fibers (Quigley et al.,
1991; Jonas et al., 1992a), parallel to a higher number and total area of
lamina cribrosa pores (Jonas et al., 1991a).
In eyes with non-glaucomatous optic nerve damage, the rim does not
8
Progress in Retinal and Eye Research xxx (xxxx) xxx
get smaller but diminishes in height or sagittal thickness, which can be
defined as the distance between the top of the rim and the reference line
through the ends of BM. With loss of nerve fibers within the rim, the rim
color changes from pinkish to pale as it is typically the case in non-
glaucomatous optic nerve damage (Hayreh, 1972a; Hitchings, 1978;
Robert et al., 1982) (Fig. 8).
In glaucoma, the rim gets smaller, preferentially in the temporal
inferior sector and temporal superior disc sectors in the early and me­
dium advanced stages of GON (Jonas et al., 1988g). Special attention
should therefore be paid to these disc regions in the diagnosis of early
glaucoma. In contrast to non-glaucomatous optic nerve damage, glau­
coma does not lead to a marked pallor of the remaining rim. It shows
that if the rim is pale, the probability for a non-glaucomatous optic
neuropathy increases. It has remained elusive why GON is characterized
by the loss of rim, and complementarily, by the increase in optic cup
size. Except for GON, a loss of rim occurs only in optic nerve damage due
to giant cell arteritis (Hayreh et al., 1998a; Sebag et al., 1986). In the
latter, the occlusion of the posterior ciliary arteries leads to a necrosis
and collapse of the lamina cribrosa with a secondary entry of vitreous
into the retro-laminar part of the optic nerve (Hinzpeter and Naumann,
1976). Neuroretinal rim loss in association with enlargement and
deepening of the optic cup are thus almost pathognomonic for GON.
Future studies may address the causes for the morphological difference
in the ONH appearance between GON and non-glaucomatous optic
neuropathy.
In moderately myopic eyes with a shift of BMO into the temporal
direction, with an overhanging of BM into the nasal intrapapillary
compartment and a temporal gamma zone, the neuroretinal rim area as
assessed by ophthalmoscopy tends to be relatively small, parallel to the
relatively small optic as assessed upon ophthalmoscopy (Zhang et al.,
2019). In highly myopic eyes without optic nerve damage, the neuro­
retinal rim is large, in association with the secondary enlargement of the
discs (secondary macrodiscs in highly myopic eyes). Due to the rela­
tively pale color of the rim in highly myopic eyes and due to the reduced
spatial contrast between the rim height and the cup bottom, the delin­
eation between the rim and cup can be difficult in highly myopic eyes
(Dichtl et al., 1998; Jonas et al., 2017a; Xu et al., 2007a).
5. Neuroretinal rim shape
In non-glaucomatous eyes, independently of the axial length, the rim
shape often follows the so called ISNT-(Inferior-Superior-Nasal-Tempo­
ral)-rule: It tends to be widest inferiorly, followed by the superior disc
region, the nasal disc part, and finally the temporal disc region (Jonas
et al., 1988a). The smallest part of the rim is located in the temporal 60◦
of the discs in almost all non-glaucomatous eyes, while in a substantial
percentage of eyes the rim can be wider superiorly than inferiorly (Jonas
et al., 1988a) (Fig. 8). The most important letter in the ISNT-rule is
therefore the “T”. With respect to the difference in the rim width be­
tween the inferior region and the superior region (and also the nasal
region), studies reported that in 21%–63% of non-glaucomatous eyes
the sequence of the disc sectors may be different from the sequence
inferior – superior – nasal-temporal (Harizman et al., 2006; Maupin
et al., 2020; Poon et al., 2017; Pogrebniak et al., 2010; Sihota et al.,
2008).
The rim shape in its sequence inferior – superior – nasal-temporal
corresponds with:
- the thickness of the peripapillary retinal nerve fiber layer (RNFL)
which usually is thickest temporal inferiorly, followed by the tem­
poral superior region, and which often is the thinnest in the temporal
region in the so called papillo-macular bundle (Dichtl et al., 1999;
Jonas et al., 1989c, 1999; Jonas and Dichtl, 1996; Jonas and Schiro,
1993; Varma et al., 1996). Correspondingly, the mean ratio of
temporal-superior RNFL thickness peak to the temporal-inferior
RNFL thickness peak was 1.08 in a sample of 667 healthy Chinese
Y.X. Wang et al.
eyes (unpublished data); - the ophthalmoscopical visibility of the
RNFL in the sequence of temporal inferior, temporal superior, nasal
superior, nasal inferior, and eventually temporal (Jonas et al., 1989c;
Jonas and Schiro 1993); - the diameter of the retinal arterioles which
are widest in the inferior temporal arcade, followed by the superior
temporal arcade, the nasal superior arcade, and finally the nasal
inferior arcade (Jonas et al., 1989d); - the location of the foveola
about 0.5 ± 0.3 mm inferior to a horizontal line drawn though the
disc center (Jonas et al., 1989c); - the anatomy of the lamina cribrosa
with the largest lamina cribrosa pores and the least amount of
inter-pore connective tissue in the inferior and superior regions as
compared to the temporal and nasal sectors (Dandona et al., 1990;
Jonas et al., 1991a); and
- the distribution of the optic nerve fibers, as stratified by their
thickness, in the retrobulbar region, with the thickest fibers inferi­
orly and superiorly, and the thinnest fibers in the temporal part of the
optic nerve (Jonas et al., 1990b, 1992a; Mikelberg et al., 1989).
Fig. 9. Optic disc photographs showing a normal disc (0) and optics with different stages of glaucomatous optic nerve damage (Stage1–5) as classified by the shape of
the neuroretinal rim (blue arrow).
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Progress in Retinal and Eye Research xxx (xxxx) xxx
Fig. 8. Optic disc photographs showing the shape of
neuroretinal rim, in a normal eye (left) and in an eye
with non-glaucomatous optic nerve damage (right).
The neuroretinal rim (between black arrows) follows
the ISNT-rule with the smallest part in the temporal
horizontal sector of the optic disc, in both the normal
eye and the eye with non-glaucomatous optic nerve
damage. The eye with the non-glaucomatous optic
nerve damage shows a normal shape and size of the
neuroretinal rim, increased disc pallor, flattening of
the optic cup, physiologic parapapillary alpha zone
(red arrows) and a decreased visibility of the retinal
nerve fiber layer. The peripapillary ring as the outer
border of the optic disc and of the neuroretinal rim is
marked with green arrows.
5.1. Neuroretinal rim shape in glaucoma
In glaucoma, neuroretinal rim is lost in all sectors of the optic disc
with regional preferences depending on the stage of the disease (Jonas
et al., 1993). This sequence of disc sectors is inferotemporal, super­
otemporal, temporal horizontal, nasal inferior and finally nasal superior.
In early glaucoma, the rim is lost preferentially in the temporal disc
sector and temporal superior disc regions, leading to so called rim
notches which, on an average, are located about 15◦ temporal to the
vertical optic disc axis (Betz et al., 1981; Hitchings and Spaeth, 1976,
1977; Hitchings and Wheeler, 1980; Jonas et al., 1993; Pederson and
Anderson, 1980; Quigley et al., 1981a, b; Radius et al., 1978; Tuulonen
and Airaksinen, 1991) (Figs. 8 and 9). With further progression of GON;
the rim gets lost predominantly in the temporal region, so that the
ISNT-rule can get being fulfilled again. In the pre-final stage of glau­
coma, there is some rim left usually in the nasal superior disc region,
corresponding to a rest of visual field temporal inferiorly (Jonas et al.,
Y.X. Wang et al.
1993). It suggests that the temporal inferior disc region and temporal
superior disc sector are of special importance for the early glaucoma
diagnosis. Overall, the glaucomatous loss of rim occurs in all regions at
any stage of the disease, as long as rim is left. Factors which may be
associated with this pattern of glaucomatous neuroretinal rim loss are:
- the physiologic configuration of the rim being broader at the inferior
and superior disc poles than at the nasal and temporal poles (Jonas
et al., 1988a); - the morphology of the inner surface of the lamina
cribrosa with the larger pores and the higher ratio of pore to
inter-pore connective tissue area in the inferior and superior regions
as compared to the temporal and nasal regions; a high ratio of pore
area to total area is considered to predispose to glaucomatous nerve
fiber loss (Dandona et al., 1990; Jonas et al., 1991a); - the glau­
comatous backward bowing of the lamina cribrosa to the outside
mainly in the inferior and superior disc regions as shown on scanning
electron microscopic photographs of glaucomatous eyes (Quigley
and Addicks, 1981); - the anatomy of the lamina cribrosa which is
thicker in the disc periphery where the nerve fiber bundles have a
slightly more bent course through the lamina cribrosa (Dichtl et al.,
1996) and where they are lost earlier than in the center of the optic
disc; - the optic nerve shrinkage-associated exposure of the posterior
peripheral lamina cribrosa surface directly to the CSF space, without
being buffered any longer by the solid optic nerve tissue (Jonas et al.,
2003, 2004); - the regional distribution of thin and thick retinal
nerve fibers with thin nerve fibers coming from the foveola, passing
mainly through the temporal aspect of the optic disc (Jonas et al.,
1992a; Minckler, 1980) as compared to the thick optic nerve fibers
which originate predominantly in the fundus periphery, lead to the
inferior, superior and nasal disc regions and are more glaucoma
sensitive.
- the distance from the central retinal vessel trunk exit on the lamina
cribrosa is an additional variable for the pattern of glaucomatous rim
loss (Jonas and Fernández, 1994; Jonas et al., 2001). The larger the
distance to the central retinal vessel trunk exit on the lamina cribrosa
is, the more pronounced is the loss of neuroretinal rim and the
perimetric defect in the corresponding visual field quadrant (Wu
et al., 1995). Taking into account the slightly eccentric location of
the retinal vessel trunk in the nasal upper quadrant of the vertically
oval optic disc (Jonas et al., 1991a), one can infer that the progres­
sive sequence of rim loss in glaucoma is partially dependent upon the
distance of the region to the retinal vessel trunk; the further away the
region from the retinal vessel trunk, the more likely it is to be
affected by rim loss. As a corollary, glaucoma eyes with an atypical
location of the retinal vessel trunk or an unusual optic disc form were
found to exhibit an abnormal glaucomatous rim configuration (Jonas
and Fernández, 1994).
The minimum rim width of at BMO (BMO-MRW) has been intro­
duced as a new measurement parameter of the rim width and is based on
identifiable anatomic configurations assessed on three-dimensional OCT
images. It measures the minimum rim width as distance between the
edge of BM and the internal limiting membrane (Reis et al., 2012b).
Parallel to the peripapillary circular RNFL thickness, the BMO-MRW
showed a significant decline with ageing in normal participants, with
a 4.0% loss per decade of life and with the age-related change occurring
most markedly in the inferior region and least pronounced in the tem­
poral region (Chauhan et al., 2015). The BMO-MRW was found to be
especially important in myopic eyes with an indistinguishable rim on
two-dimensional images. Using the BMO-MRW instead of the traditional
optic rim width measures assessed on optic disc photographs might
improve the diagnostic precision of the ISNT rule in glaucoma diagnosis
(Park et al., 2018). Interestingly, the BMO-MRW as compared to other
OCT-based parameters such as the RNFL thickness map and the retinal
ganglion cell layer thickness map had a better performance in glaucoma
discrimination, in particular in myopic eyes with so called tilted discs
10
Progress in Retinal and Eye Research xxx (xxxx) xxx
(Chauhan et al., 2013; Malik et al., 2016; Rebolleda et al., 2016).
Upon ophthalmoscopy in clinical routine and on conventional
fundus photographs, the shape of the neuroretinal rim in glaucomatous
eyes may be used to stage the amount of optic nerve damage (Jonas
et al., 1988g, h) (Fig. 9). In a stage 1, the rim has lost its physiologic
shape and the rim width in the inferior sector and/or in the superior
sectors equals the rim width in the temporal horizontal sector. In a stage
2, rim notches are clearly detectable, more often in the temporal inferior
region than in the temporal superior region. The rim notches are located
at about 15◦ temporal to the vertical disc axis (Jonas et al., 1988g). In a
stage 3, rim has occurred predominantly in the temporal horizontal disc
region, so that the rim notches are no longer clearly delineable. In a
stage 4, rim is left only in the nasal superior region, while in stage 5, all
rim is lost. This or similar methods of GON staging as based on the rim
shape are independent of disc size. A more differentiated system of a
morphologic staging of GON has been proposed by Spaeth and col­
leagues (Bayer et al., 2002; Henderer et al., 2003; Spaeth et al., 2002,
2006). Generally, none of such staging systems have been introduced
into clinical routine.
In contrast to GON, non-glaucomatous optic nerve damage,
including the age-related loss of optic nerve fibers, is usually not asso­
ciated with a loss of neuroretinal rim, except for giant cell arteritis
induced optic nerve atrophy (Balazsi et al., 1984; Hayreh et al., 1998a;
Sebag et al., 1986). As a corollary, the rim shape is not markedly
changed in eyes with non-glaucomatous optic neuropathy.
5.2. Neuroretinal rim shape in myopia
Also in highly myopic eyes with secondary macrodiscs without GON,
the rim shape follows the ISNT-rule. In a similar manner, the pattern of
glaucomatous rim loss is similar in highly myopic eyes as it is in non-
highly myopic eyes (Wang et al., 2007; Kim et al., 2014).
6. Optic cup size and shape, and cup/disc ratios
Complementary to the neuroretinal rim, the optic cup is the
remaining part of the optic disc. Cup size is positively correlated with
disc size and rim size (Bengtsson, 1976; Jonas et al., 1988a). Minicups in
minidiscs are thus glaucomatous, while macrocups in macrodiscs can be
physiological (Jonas et al., 1990a). Non-glaucomatous optic nerve
damage as in contrast to GON does not show an enlargement of the optic
cup.
A primary macrocup in a primary macrodisc in non-highly myopic
eyes can be differentiated from a secondary macrocup in a secondary
macrodisc in highly myopic eyes in which the axial elongation-
associated enlargement of the optic disc is accompanied by an
enlargement of the optic cup, with the rim preserving its physiological
shape according to the ISNT-rule. Another type of secondary macrocup
is the glaucoma-related enlarged optic cup in glaucomatous eyes.
The optic cup shape is in normal eyes horizontally oval (Jonas et al.,
1988a). The interplay between the horizontally oval cup and the verti­
cally oval disc leads to the ISNT-rule of the rim shape, with the rim being
wider inferiorly and superiorly than nasally and temporally. The cup
shape depends on the disc shape.
An indirect measure for the cup is the cup/disc diameter ratio (CDR)
which traditionally has been used to describe the ONH and to semi-
quantify the amount of GON. In normal eyes, the horizontal CDR is
larger than the vertical CDR, since the cup normally has a horizontal
oval shape and the disc a vertical oval shape. Correspondingly the rim is
wider inferiorly and superiorly than nasally and temporally, and the
ratio of the horizontal-to-vertical CDR is larger than 1.0 (Jonas et al.,
1989a). In less than 7% of normal eyes the horizontal CDR is smaller
than the vertical one. Since glaucoma affects in its early to medium
advanced stage preferentially the inferior and superior disc regions, the
vertical CDR increases more than the horizontal CDR in eyes with pro­
gressing GON, so that the ratio of the horizontal-to-vertical CDR can get
Y.X. Wang et al.
reduced to less than 1.0 (Jonas et al., 1988a). It also indicates that the
vertical as compared to the horizontal CDR is more important in the
diagnosis of GON.
Since the optic cup size is one of the determinants of the CDR and
since the cup size depends on the disc size, the CDR shows a strong
dependence on disc size. In a normal population, the CDR can range
between 0.0 in microdiscs and almost 0.9 in macrodiscs (Jonas et al.,
1988f; Jonas et al., 1989e; Jonas et al., 1990a). If the CDR is used to
describe the status of GON, one may add a rough estimate of the disc size
to allow a more precise interpretation of the CDR value.
As ratio of cup diameter to disc diameter, CDR is independent of the
magnification by the optic media of the examined eye and of the fundus
camera or other devices. Methods to correct for the ocular and camera
magnification may not have to be applied. The quotient of the
horizontal-to-vertical-CDR is additionally independent of the size of the
optic cup and disc.
The optic cup depth is positively correlated with the cup size, and
indirectly with the disc size (Jonas et al., 1988a). In non-glaucomatous
optic nerve damage, the cup depth decreases, due to a loss in height of
the rim. In glaucoma, the cup deepens in dependence of the IOP and the
type of glaucoma. Studies have suggested that the optic cup is deepest in
glaucomatous eyes with high minimal values of IOP (e.g., in
juvenile-onset primary open-angle glaucoma (Jonas and Gründler,
1996a). The cup is shallow in non-highly myopic eyes with the so called
age-related atrophic type of primary open-angle glaucoma (Caprioli,
1993; Geijssen and Greve, 1987; Jonas and Papastathopoulos 1995a, b;
Spaeth et al., 1976, 1995; Spaeth, 1992). The cup depth is reversely
correlated with the prevalence and size of parapapillary beta zone
(Jonas et al., 1992b). In particular in eyes with the juvenile-onset type of
primary open-angle glaucoma with high minimal and maximal IOP
values, a deep cup occurs together with a relatively small beta zone. In
addition, some eyes with the focal type of normal-pressure glaucoma can
show a deep cupping and a relatively small beta zone (Jonas and
Gründler, 1996a, b).
In highly myopic eyes, the cup depth is shallow so that the spatial
contrast between the height of the rim and the depth of the optic cup is
reduced (Jonas et al., 1997; Xu et al., 2007a). It is one of the reasons why
the detection of GON in highly myopic eyes can be difficult.
7. Lamina cribrosa
The lamina cribrosa forms the bottom of the optic cup (Girkin et al.,
2019; Quigley et al., 1983; Kim et al., 2018; Reynaud et al., 2016). In
eyes with small optic discs and normal optic nerve, the complete pos­
terior surface of the lamina cribrosa is covered and supported by the
solid tissue of the optic nerve. In highly myopic eyes with secondary
macrodiscs, the lamina cribrosa is elongated and markedly thinned
(Jonas et al., 1992c, 2003, 2004). Even if the optic nerve is normal, the
peripheral region of the posterior surface of the lamina cribrosa is no
longer buffered by the solid optic nerve tissue but directly faces the
retrobulbar CSF space. A similar situation develops in non-highly
myopic eyes with GON in which due to the shrinkage of the optic
nerve the peripheral region of the lamina cribrosa is directly facing the
CSF space. In association with the glaucoma-related thinning of the
lamina cribrosa, the peripheral part of the lamina cribrosa can locally
bulge backward into the CSF space. It leads to the so called acquired
ONH pits (Javitt et al., 1990; Faridi et al., 2014; Kimura et al., 2014;
Kiumehr et al., 2012; Moghimi et al., 2019; You et al., 2013). In highly
myopic eyes, such pits may be less likely to develop, since the lamina
cribrosa is presumably stretched and tight.
The thinning of the lamina cribrosa in highly myopic secondary
macrodiscs decreases the distance between the intravitreal compart­
ment with the IOP and the retrobulbar compartment with the CSF
pressure, so that, with an unchanged translaminar cribrosa pressure
difference, the translaminar cribrosa pressure gradient steepens (Jonas
et al., 2003, 2004). The translaminar cribrosa pressure difference is the
11
Progress in Retinal and Eye Research xxx (xxxx) xxx
difference of the IOP minus the orbital CSF pressure (Berdahl et al.,
2008a, b; Burgoyne et al., 2005; Jonas et al., 2003, 2004; Morgan et al.,
1995, 1998; Ren et al., 2010). In association with stretching-associated
morphological changes in the lamina cribrosa, the increased
trans-lamina cribrosa pressure gradient may be one of the reasons for the
presumed increased glaucoma susceptibility of highly myopic eyes
(Jonas et al., 2003, 2004, 2017a; Xu et al., 2007a, b).
8. Central retinal vessel trunk
The lamina cribrosa is pierced through by the central retinal vessel
trunk which is usually located in the nasal upper quadrant close to the
lamina cribrosa center (Jonas et al., 1991a, 2001). Potentially acting as a
stable element against a mechanical deformation of the lamina cribrosa,
the central retinal vessel trunk may influence the local susceptibility for
glaucomatous optic nerve fiber loss within the lamina cribrosa. Studies
suggested that the loss in neuroretinal rim and visual field increased
with the distance to the exit of the central retinal vessel trunk on the
lamina cribrosa surface (Jonas and Fernández, 1994; Wu et al., 1995).
Correspondingly, eyes with open-angle glaucoma and a temporal cil­
ioretinal artery retained longer central visual field (and temporal neu­
roretinal rim) as compared to eyes without a temporal cilioretinal artery
(Lee et al., 1992). An abnormal position of the central retinal vessel can
be associated with an abnormal shape of the rim and an abnormally
located loss in visual field in glaucomatous eyes (Fig. 10). Interestingly,
the position of the central retinal vessel trunk in the lamina cribrosa is
associated with the location of parapapillary beta zone in the para­
papillary region (Jonas et al., 1992b).
The position of central retinal vessel trunk moves nasally along with
the myopic elongation of the globe (Lee et al., 2018a). Nasalization of
vessel trunk may also be a biomarker for central visual field loss and for
a more rapid visual field progression in glaucoma (Wang, M., et al.,
2017; Shon et al., 2020). A longitudinal study suggested that eyes with a
positional shift of the vessel trunk were at a higher risk of glaucoma
progression (Radcliffe et al., 2014). In an experimental monkey study,
retinal blood vessels were pulled toward to the optic disc after an IOP
elevation induced by laser photocoagulation (Kuroda et al., 2017). The
retinal blood vessel shift was more frequently observed in with a fast
glaucoma progression as compared to eyes with a mild glaucoma pro­
gression (Radcliffe et al., 2014).
The pathogenic reasons for the spatial association between vessel
trunk location and rim loss have remained unclear so far. Since the
central retinal artery inside of the lamina cribrosa does not supply
branches to the lamina cribrosa, a vascular etiology may be unlikely. It
has been discussed that the vessel trunk inside of the lamina cribrosa
may act as a stable element against the glaucoma-related deformation of
the lamina cribrosa and may indirectly the optic nerve fibers from
deformation-related damage. Correspondingly, eyes with advanced
glaucomatous optic disc cupping show an elevation, i.e. less compres­
sion, of the part of the lamina cribrosa where the vessel trunk is located
(Quigley and Addicks, 1981).
The lamina cribrosa is more condensed and more bowed to the back
in the inferior and superior disc regions than close to the center of the
lamina cribrosa where the retinal vessels emerge (Quigley et al., 1981a,
b). If the vessel trunk is, as usually, decentered into the superior nasal
quadrant of the optic disc, the inferotemporal disc region without sup­
port by the vessel trunk is larger than the superior nasal disc sector.
Consequently, the inferotemporal sector can be deformed to a greater
extent than the superior nasal disc region in glaucomatous eyes. It could
explain the greater frequency of neuroretinal rim notches in the infe­
rotemporal disc region than in the superotemporal sector in eyes with a
normal disc shape and a normal position of the vessel trunk exit (Jonas
et al., 1988g). As an alternative to this mechanical theory, one could also
speculate that in the close vicinity of the retinal vessel trunk the vascular
supply to the adjacent tissue is better than in the periphery. A vitally
important participation of branches of the central retinal vessels in the
Y.X. Wang et al.
nourishment of the optic nerve fibers in the lamina cribrosa, however,
has not been demonstrated yet (Hayreh 1969; Lieberman et al., 1976).
The central retinal vein within the central retinal vessel trunk shows
a pulse-synchronous pulsation which can ophthalmoscopically be visu­
alized in about 80–90% of normal eyes (Harder and Jonas 2007; Jonas
2003a, b, c; Jonas and Harder 2007). These movements within the
lamina cribrosa may play a role in the biomechanics of the lamina cri­
brosa. The cause for the retinal vein pulsations is potentially a time-shift
in the pulse waves of the orbital CSF pressure and IOP, with the pulse
wave coming from the heart first arriving in the CSF space and a bit later
in the eye (choroid) (Kain et al., 2010). The time difference may lead to
the situation that the CSF pressure is shortly higher than the IOP, so that
a pressure wave travels through the central retinal vein from the ret­
rolaminar compartment into the intraocular compartment. In patients
with increased CSF pressure, increased orbital tissue pressure, or in eyes
with a presumably increased trans-lamina cribrosa venous outflow
resistance (due to glaucomatous changes in the lamina cribrosa), the
central retinal vein no longer shows spontaneous pulsations (Walsh
et al., 1969). In these situations, the pulsations can be induced by gently
increasing the IOP during ophthalmodynamometry. It then also allows
an estimation of the central retinal vein pressure. The physiology and
pathophysiology of the central retinal vein pulsations and its pressure
has not fully been explored yet (Balaratnasingam et al., 2007, 2009;
Heimann et al., 2020; Matthé et al., 2019; Morgan et al., 2004, 2005,
2008, 2009; Stodtmeister et al., 2018).
It was hypothesized that the positional change of the vessel trunk and
central vasculature represented the change of the inner retinal structures
and outer bear-loading structures, especially the lamina cribrosa and
peripapillary sclera. During the axial elongation in childhood myopia,
the central retinal vessel trunk is moved mostly into the nasal direction,
often combined with an enlargement of gamma zone or even before
gamma zone develops. The change in the location of the retinal vessel
trunk is associated with a change in the position of the central retinal
vasculature (Lee et al., 2018a).
The central retinal vessel trunk in the lamina cribrosa also changes
its position in association an IOP increase (Wang et al., 2020a; Zhang
et al., 2020). Interestingly, optic discs differed in their morphology in
dependence of the direction the central retinal vessel trunk moved
during the IOP rise. To mention an example, discs with a trunk move­
ment towards the nasal direction (as could be observed in most eyes),
usually showed an almost circular disc shape. Optic discs with a tem­
poral shift of the central retinal vessel trunk tended to have a larger optic
cup and showed a larger angle kappa between the temporal-superior
vascular arcade and the temporal-inferior vascular arcade. Optic discs
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Progress in Retinal and Eye Research xxx (xxxx) xxx
Fig. 10. Optic disc photograph demonstrating an
abnormal position of the central retinal vessel corre­
sponding with an abnormal shape of the rim in glau­
comatous eyes.
Left image: A glaucomatous eye with the central
retinal vessel trunk (asterisk) located inferiorly,
together with an abnormal shape of the glaucomatous
rim, with the widest part (abnormally) in the tempo­
ral inferior region, in closest vicinity to the central
retinal vessel trunk, and the smallest rim part in the
nasal superior disc sector, with the longest distance to
the central retinal vessel trunk. Right image: Optic
disc photograph of a glaucomatous eye with an
abnormal position of the central retinal vessel trunk
(asterisk) located in the temporal inferior disc sector,
and an abnormal shape of the glaucomatous rim, with
the widest part (abnormally) in the temporal inferior
region, in closest vicinity to the central retinal vessel
trunk, and the smallest rim part in the nasal superior
disc sector, with the longest distance to the central
retinal vessel trunk.
with an inferior shift usually showed a tilted or rotated shape with a
gamma zone (Figs. 11 and 12). The direction of the vessel trunk (or
lamina cribrosa) shift may be related with topographic and biome­
chanical factors of the ONH, and may be involved in the process of
remodeling of the ONH during the development of axial myopia and
glaucoma (Figs. 11 and 12).
9. Peripapillary border tissues
The ONH canal is formed by the BMO as its inner layer, the choroidal
opening as its middle layer, and the opening in the peripapillary scleral
flange as its outer layer (Fig. 1). The peripapillary scleral flange is the
continuation of the inner part of the posterior sclera to the lamina cri­
brosa, while the outer part of the posterior sclera continues into or
merges with the optic nerve dura mater. The peripapillary scleral
opening contains the lamina cribrosa. Both the choroidal opening and
the peripapillary scleral flange opening are delineated from the ONH
canal tissue by the peripapillary choroidal border tissue (Jacoby) and
the peripapillary scleral flange border tissue (Elschnig) (Anderson 1969,
1970; Bücklers 1929; Elschnig 1900, 1901; Hayreh 1974b; Hayreh and
Vrabec 1966; Hogan et al., 1971; Jacoby 1905; Jonas RA and Holbach
2020; Kuhnt 1879; Salzmann 1912) (Fig. 6). Upon light microscopy, the
scleral flange border tissue appears to be a continuation of the optic
nerve pia mater and continues into the peripapillary choroidal border
tissue which connects to the end of BM at the level of the BMO (Jonas
and Holbach, 2020). The scleral border tissue is crisscrossing with
collagenous fibers coming from the peripapillary scleral flange and
continuing into the lamina cribrosa. It appears as if the suspension of the
whole intrapapillary tissue including the lamina cribrosa with the optic
nerve fibers attached to the lamina cribrosa is strengthened by this
perpendicular crisscrossing of fibers of the scleral flange border tissue
running in sagittal direction, and the scleral flange – lamina cribrosa
fibers running in a coronary direction (Jonas and Holbach, 2020). The
choroidal border tissue connects the scleral flange border tissue with the
BM end. Besides the scleral spur in the anterior segment of the eye, the
choroidal border tissue is thus one of the only two structures which
connects the inner shell of the eye, consisting of the choroid, BM, RPE
and retina, with the outer shell, i.e., the sclera. Both border tissues may
thus have biomechanical importance. Both peripapillary border tissues
can also be detected on OCT B-scans, matching with histological findings
(Strouthidis et al., 2010) (Fig. 6).
The merging line of the choroidal border tissue with the BM end is
the histological correlate of the peripapillary ring which upon
ophthalmoscopy surrounds the optic nerve (Jonas et al., 2014a). The
Y.X. Wang et al.
Fig. 11. The shift of central retinal vein (blue) and artery (red) trunks may represent the shift of the lamina cribrosa pores (green), in both distance (length of the
line) and direction (direction of the line), after an acute intraocular pressure elevation.
choroidal border tissue additionally may be associated with the
choroid-ONH blood barrier, since the choroid contains with the cho­
riocapillaris fenestrated capillaries with leakage of fluorescein and
blood proteins such as albumins, while the intrapapillary compartment
is free of fluorescein leaking vessels. The location and composition of the
presumed choroid-ONH blood barrier has not been found yet.
9.1. Border tissue in myopia
In eyes with axial elongation, the choroidal border tissue elongates
due to the development of parapapillary gamma zone (Jonas and Hol­
bach, 2020). The increased distance between the end of BM and the
optic disc leads to a lengthening and thinning of the choroidal border
tissue, which may even rupture in some highly myopic eyes. In such a
case, BM may no longer be firmly and tautly connected to the optic disc.
It may lead to and explain an undulation of BM observed upon histology
and on OCT images in some highly myopic eyes (Jonas et al., 2018a).
The volume of the choroidal border tissue is mostly independent of the
axial elongation, since the increase in its length is associated with a
decrease in its thickness. The importance of the axial
elongation-associated elongation and thinning of the choroidal border
tissue and also the importance of a rupture and detachment of the per­
ipapillary choroidal border tissue from the BM end for the biomechanics
of the lamina cribrosa has remained elusive yet.
The scleral flange border tissue can get shorter in eyes with axial
elongation in association with the axial elongation-associated thinning
of the lamina cribrosa (Fig. 6).
9.2. Border tissue in glaucoma
The choroidal border tissue is not affected by GON; while the scleral
flange border tissue may change in association with the glaucoma-
associated thinning of the lamina cribrosa (Jonas et al., 2003).
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Progress in Retinal and Eye Research xxx (xxxx) xxx
9.3. Terminology
In previous studies, various terms have been used for the different
structures of the ONH. The peripapillary border tissue of the choroid has
also been termed the “border tissue of Jacoby”, and the peripapillary
border tissue of the peripapillary scleral flange has been termed the
“border tissue of Elschnig”. The term “scleral “flange” refers to the
peripapillary scleral flange and is thus different from the peripapillary
border tissues. The ophthalmoscopical equivalent of the upper end of the
peripapillary choroidal border tissue when attaching to the end of BM is
the peripapillary ring or “wall of the optic disc” (Jonas et al., 2014a).
The deeper part of the peripapillary choroidal border tissue and the
border tissue of the peripapillary scleral flange can be seen on OCT
images of the ONH of some eyes (Fig. 6).
10. Optic disc hemorrhages
Hemorrhages located at the optic disc border in the retinal nerve
fiber layer have a splinter-shaped configuration (Furlanetto et al., 2014;
Jasty et al., 2020; Kim and Park, 2017; Shukla et al., 2020). In the
Beijing Eye Study including individuals aged 40+ years, disc hemor­
rhages were found in approximately 1.2% of the examined eyes (Wang,
Y., et al., 2006). In 19% of these eyes, the disc hemorrhages were
associated with GON, and 9% of the glaucomatous eyes showed a disc
bleeding. In a reverse manner, the association between the presence of
disc hemorrhage and GON was highly significant (P < 0.001; odds ratio:
9.3). Interestingly, glaucoma eyes with elevated IOP and glaucoma eyes
with normal IOP did not vary significantly in the frequency of disk
hemorrhages (P = 0.44). Fitting with these observations, two other
epidemiological studies reported about a prevalence of disc bleedings of
approximately 1% in non-glaucomatous eyes (Klein et al., 1992; Healey
et al., 1998). Other investigations showed the strong relationship be­
tween the occurrence of a disc hemorrhage in a glaucomatous eye and
the risk of progression of GON as detected within the next two months by
a widening of a localized retinal nerve fiber layer, loss of neuroretinal
rim, increase in perimetric loss or widening of parapapillary beta zone
Y.X. Wang et al.
(Akagi et al., 2017, 2018; Bak et al., 2020; Budenz et al., 2006; Cho and
Kee, 2020; De Moraes et al., 2011; Diehl et al., 1990; Drance et al., 1977;
Drance, 1989; Founti et al., 2020; Hou et al., 2020; Jonas and Xu, 1994;
Kitazawa et al., 1986; Kim, Y.W., et al., 2020; Lee et al., 2020a; Lee, J.S.,
et al., 2019; Leske et al., 2003, 2007; Seol et al., 2019; Shukla et al.,
2020; Siegner and Netland, 1996; Skaat et al., 2016). Described first by
researches such as Drance and Begg (Drance and Begg, 1970; Drance
et al., 1977), disc hemorrhages are thus of high importance for glaucoma
diagnosis (Airaksinen et al., 1981a; Drance, 1989; Healey et al., 1998;
Jonas and Xu, 1994; Katz and Hoyt, 1995; Kitazawa et al., 1986; Klein
et al., 1992). The prevalence of disc bleedings increases from early GON
stages to medium advanced stages, while in eyes with absolute glau­
coma and no neuroretinal rim left, disc hemorrhages were only rarely, if
at all, observed (Jonas and Xu, 1994). It suggests that the presence of
neuroretinal rim is a condition sine qua non for the development of
glaucomatous disc hemorrhages. The disc hemorrhages in glaucomatous
eyes are usually located close to the site of (progressing) damage, e.g.,
close to a localized retinal nerve fiber layer defect, a neuroretinal rim
notch or a lamina cribrosa defect (Airaksinen et al., 1981a, b, 1984;
Airaksinen and Tuulonen, 1984; Drance et al., 1977; Mistry et al., 2020;
Rasker et al., 1997, Siegner and Netland, 1996; Sugiyama et al., 1997;
Susanna et al., 1979). The ophthalmoscopic visibility of a glaucomatous
disc hemorrhages lasts about 2–3 months (Heijl, 1986).
The prevalence of disc bleedings has been reported to vary between
the different types of open-angle glaucoma, with disc hemorrhages
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Progress in Retinal and Eye Research xxx (xxxx) xxx
Fig. 12. Eyes with the central vessel trunk movement
into different directions upon an acute elevation of
intraocular pressure (IOP).
Upper: An acute IOP rise-associated retinal vessel
trunk movement towards the nasal direction, like in
most eyes, may occur mostly in optic discs with a
normal round shape.
Middle: Eyes with an acute IOP rise-associated retinal
vessel trunk movement into the temporal direction
tend to have a larger cup and a larger angle kappa
between the temporal-superior vascular arcade vein
and the temporal-inferior vascular arcade.
Lower: Eyes with an acute IOP rise-associated retinal
vessel trunk movement into the inferior direction
tended to tilted or rotated, and showed a gamma zone.
being found most often in eyes with focal normal-pressure glaucoma and
less often in eyes with juvenile-onset primary open-glaucoma, age-
related atrophic primary open-angle glaucoma, and highly myopic pri­
mary open-angle glaucoma (Jonas and Budde, 2000b; Jonas and Grün­
dler, 1996a,b; Nicolela and Drance, 1996; Sakata et al., 2020; Spaeth,
1994). The disc bleedings can be detected however, in all types of the
chronic open-angle glaucomas, and differences between the various
glaucoma groups in the prevalence of detected disc hemorrhages were
mostly not statistically significant. Also, selection artefacts in these
hospital-based studies might have had a confounding effect as suggested
by a longitudinal study of Diehl, Quigley and colleagues (Diehl et al.,
1990). This follow-up examination revealed fewer normal-pressure
glaucoma patients developing disc hemorrhages than could be ex­
pected given the initial prevalence. Correspondingly, the
population-based Beijing Eye Study did not reveal a difference in the
prevalence of disc hemorrhages between glaucoma eyes with elevated
IOP and glaucoma eyes with normal IOP (Wang, Y., et al., 2006). The
size of the disc hemorrhages was larger in eyes with normal-pressure
glaucoma than in eyes with high-pressure glaucoma. The larger size of
the disc bleedings in glaucoma eyes with low IOP may be due to a larger
vessel transmural pressure difference in eyes with low IOP as compared
to eyes with high IOP. The larger hemorrhage size in eyes with low IOP
may be the cause for a higher chance for them to be detected and may
indirectly lead to a higher prevalence of detected hemorrhages in
glaucoma eyes with low IOP as compared with glaucoma eyes with high
Y.X. Wang et al.
IOP.
Besides glaucoma, disc hemorrhages can also occur in circumstances
unrelated to glaucoma, such as an acute posterior vitreous detachment
from the ONH (Hitchings et al., 1976; Jonas and Ritch 2012), and retinal
vein outflow disorders among other reasons.
Causes for the development of disc hemorrhages in glaucoma have
remained elusive. Several pathologic mechanisms leading to disc hem­
orrhages in glaucomatous eyes have been discussed and include local
ischemia, a blood-retinal barrier damage due to an autoregulatory
dysfunction, a stretching of the ONH capillaries, and a damage caused
by the remodeling of the ONH including the lamina cribrosa (Lee et al.,
2017a; Grieshaber et al., 2006; Quigley et al., 1981a). Lee and col­
leagues discussed that GON-related reactive proliferative gliosis leads to
fibrous glial scars, which may exert a traction force leading to a
disruption of capillaries at the border between the healthy and damaged
retinal nerve fiber layer region, eventually resulting in splinter-shaped
peripapillary hemorrhages. Remodeling and deformation of the lamina
cribrosa beams in glaucomatous ONH could additionally insult the
capillaries surrounding the lamina cribrosa pore and lead to round
blotch-shaped hemorrhages in the optic cup. Interestingly, eyes after an
ocular contusion with a sharp and high IOP rise did not show disc
hemorrhages (Königsreuther and Jonas, 1994). It may suggest that rapid
IOP spike-related movements of the lamina cribrosa may not be the
cause of disc hemorrhages. From a pathogenic point of view, the ques­
tion arises whether disc hemorrhages have their origin in the arterioles,
venules, or the capillaries of the peripapillary radial network on the
surface of the peripapillary retina (Cousins et al., 2020). The finding that
disc hemorrhages are not in spatial correlation with cotton-wool spots
contradict the notion that disc hemorrhages occur in association with an
ischemic event. It has also been discussed that the ophthalmoscopically
detected disc hemorrhages represent the extreme of disc bleedings in a
spectrum of hemorrhages including also microscopical bleedings unde­
tectable upon ophthalmoscopy.
Fig. 13. Fundus photographs showing parapapillary alpha zone (white dots), beta zone (yellow dots) in a moderately-myopic eye (left), and parapapillary gamma
zone (green dots) and delta zone (blue dots) in a highly-myopic eye (right).
15
Progress in Retinal and Eye Research xxx (xxxx) xxx
11. Parapapillary alpha, beta, gamma and delta zones
In the parapapillary region, four zones can be differentiated (Jonas
and Naumann, 1989a; Jonas et al., 1989e, 1992b, 2011, 2012, 2018b;
Fantes and Anderson, 1989; Kubota et al., 1993; Dai et al., 2013)
(Figs. 13 and 14).
11.1. Alpha zone
Alpha zone is present in almost all eyes and shows an irregular hy­
perpigmentation and hypopigmentation due to irregularities in the
parapapillary RPE (Fantes and Anderson, 1989; Jonas et al., 1992b;
Kubota et al., 1993). It is the most peripheral one of all zones. Upon
histology, alpha zone is characterized by the presence of BM and RPE,
with the latter being irregularly structured. Alpha zone is the largest and
most frequently located in the temporal horizontal sector, followed by
the inferior temporal area and the superior temporal region, while it is
smallest and most rarely to be found in the nasal region. Alpha zone is
present in almost all normal eyes and is thus more common than beta
zone, gamma zone or delta zone (Jonas and Naumann 1989a; Jonas
et al., 1989e; Jonas and Xu 1993b).
11.2. Beta zone
Beta zone is defined by the presence of BM and absence of RPE (Jonas
et al., 1989e, 1992d). In the part of beta zone located closest to the optic
disc border, the choriocapillaris is closed and retinal photoreceptors are
missing (Fantes and Anderson, 1989; Jonas et al., 1992b, 2011, 2012;
Kubota et al., 1993). In an intermediate region of beta zone, the cho­
riocapillaris is open and photoreceptors are absent. In the peripheral
part of beta zone, the choriocapillaris is open and photoreceptors are
present, but the RPE (by definition) is missing. If one longitudinally
extrapolates these findings obtained in a cross-sectional study, they may
Y.X. Wang et al.
Fig. 14. A schematic figure illustrating parapapillary alpha zone (Bruch’s membrane present, retinal pigment epithelium irregular), beta zone (Bruch’s membrane
present, retinal pigment epithelium absent), gamma zone (Bruch’s membrane absent), and delta zone (part of gamma zone, corresponding to an elongated and
thinned peripapillary scleral flange). Gamma zone sometimes includes few large choroidal vessels. The peripapillary border tissue of the choroid connects the end of
Bruch’s membrane with the peripapillary border tissue of the scleral flange, and it is covered only by the retinal nerve fibers. The peripapillary border tissue of the
scleral flange is the continuation of the optic nerve pia mater.
suggest that during beta zone development there is first a loss of RPE
cells, followed by a loss of photoreceptors and finally a closure of the
choriocapillaris. Corresponding to the histological anatomy, beta zone
represents an absolute scotoma in perimetry, and alpha zone a relative
scotoma (Jonas et al., 1991d; Meyer et al., 1997; Rensch and Jonas
2008). Due to the mostly closed choriocapillaris, beta zone appears as a
hypofluorescent area in angiography (O’Brart et al., 1997). Beta zone is
the largest and most frequently located in the temporal horizontal
sector, followed by the inferior temporal area and the superior temporal
region, while it is the smallest and most rarely to be found in the nasal
region (Jonas and Naumann 1989a).
The occurrence and size of beta zone are correlated with the glau­
comatous loss of neuroretinal rim inside of the optic disc, glaucomatous
visual field loss, decreasing diameter of the retinal arteries in eyes with
glaucoma, and a decreasing diameter of the retrobulbar part of the optic
nerve as measured sonographically (Anderson, 1983; Araie et al., 1994;
De Moraes et al., 2017; Horn et al., 1997, Jonas and Naumann 1989a;
Jonas et al., 1992b; Manalastas et al., 2018; Miki et al., 2017; Park et al.,
1996; Quigley et al., 1994; Skaat et al., 2016; Sugiyama et al., 1997;
Tezel et al., 1996, 1997a,b; Tuulonen et al., 1996; Uchida et al., 1998). A
large beta zone, also called “halo glaucomatosus” when encircling the
optic disc, is often associated with a marked degree of fundus tessella­
tion, a shallow glaucomatous disc cupping, a relatively low frequency of
disc hemorrhages and detectable localized defects of the retinal nerve
fiber layer, a mostly concentric loss of neuroretinal rim, and normal or
almost normal intraocular pressure measurements (Jonas et al., 1992b).
The location of beta zone is spatially correlated with the location of
neuroretinal rim loss inside of the optic disc, and both are correlated
with the longest distance to the central retinal vessel trunk in the lamina
cribrosa (Jonas et al., 2001). Cho and Park found in eyes with glau­
comatous eyes with a single localized retinal nerve fiber layer defect that
76% of the eyes had beta zone located in the same hemi-field as the
nerve fiber layer defect was present (Cho and Park, 2013). In another
study, the hemi-field with a more rapid visual field progression was
spatially correlated with the location of largest beta zone in a longitu­
dinal observation (Teng et al., 2011). The shape or the micro-structure
of beta zone may also serve as element in the morphological glaucoma
evaluation. In the study by Song et al. an eccentric type beta zone as
compared with a concentric beta zone was related with glaucoma pro­
gression in myopic eyes (Song et al., 2018). Eyes with a more irregular
margin of beta zone tended to progress more rapidly than eyes with a
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Progress in Retinal and Eye Research xxx (xxxx) xxx
smoother margin (Ha et al., 2020). Related with the microstructure of
beta zone, a curved BM as the beta zone bed was related with the
presence of glaucoma, while a straight BM related with the absence of
glaucoma (Hayashi et al., 2012).
Both, beta zone enlargement and rim loss, are associated with the
longest distance to the central retinal vessel trunk in the lamina cribrosa
(Jonas et al., 2001). While the spatial association between the central
retinal vessel trunk and the glaucomatous loss of neuroretinal rim may
perhaps be explained by a mechanical aspect, with the vessel trunk
stabilizing the adjacent part of the lamina cribrosa against deformation,
the spatial association between the vessel trunk location and beta zone
in the parapapillary region has not been discussed yet. An enlargement
of beta zone was also observed in an investigation on experimental
glaucoma in monkeys (Hayreh et al., 1998b).
From a practical point of view, the diagnostic value of beta zone for
the diagnosis of glaucoma varied among studies. The population-based
Beijing Eye Study suggested that the Beta zone as defined by OCT was
present in 73% of normal participants aged 50+ years, which suggested
the presence of beta zone to be a relatively poor indicator to glaucoma
(Zhang et al., 2018). When comparing clinical studies on the association
between beta zone and glaucoma, one may take into account that most
clinical studies used fundus photographs on which beta zone was not
differentiated from gamma zone.
With respect to the etiology of beta zone, a study applying the dark
room prone provocative test suggested that an acute IOP elevation led to
a folding and centrifugal sliding of the peripapillary RPE and, after IOP
reduction, to a rebound centripetal movement of the RPE with return to
the original formation (Wang, Y.X., et al., 2015) (Fig. 15). These findings
may suggest that the development of beta zone with loss of RPE cells
may be associated with a mechanical stress of the RPE at the disc border
in association with changes in IOP.
Size, shape and frequency of alpha zone and beta zone do not differ
significantly between normal eyes and eyes with nonglaucomatous optic
nerve atrophy (Jonas et al., 1991c; Jonas and Hayreh, 1999). Both zones
are significantly larger and beta zone occurs more often in eyes with
glaucomatous optic nerve atrophy than in normal eyes (Jonas and
Naumann, 1989a; Jonas et al., 1989e; Tezel et al., 1996, 1997a,b).
11.3. Gamma zone
Gamma zone is located between beta zone (or alpha zone in the case
Y.X. Wang et al.
Fig. 15. A schematic 3D figure showing the morphological changes of optic nerve head upon acute intraocular pressure rise. A centrifugal sliding of the peripapillary
retinal pigment epithelium and a lateral movement of the lamina cribrosa (suggested by the movement of lamina cribrosa pores and the central retinal vessel trunks)
were observed after acute elevation of intraocular pressure (Jiang et al., 2015; Wang et al., 2015, 2020a; Zhang et al., 2020)..
of an absence of beta zone) on its peripheral side, and the peripapillary
ring on its central side (Dai et al., 2013; Guo et al., 2018a,b; Hu et al.,
2020; Jonas et al., 2011, 2012, 2017a,c, 2018b; Kim et al., 2020; Kim,
M., et al., 2018; Lee, E.J., et al., 2017b; Lee, K.M., et al., 2018a,b; Miki
et al., 2017; Sakaguchi et al., 2017; Sawada et al., 2018; Shang et al.,
2019b; Yoo et al., 2016). In highly myopic eyes, gamma zone may
include in its central part (i.e., in direction to the optic disc) the para­
papillary delta zone. Gamma zone is characterized by the absence of BM
and RPE, so that gamma zone neither contains choriocapillaris or deep
retinal layers (Jonas et al., 2012). It consists of few large choroidal
vessels in its deep layer and retinal nerve fibers and large retinal vessels
in its inner layer. In some eyes, the BM border may be located more
peripherally than the border of the choroidal tissue so that a small
crescent of choroidal tissue may be located in the peripheral part of
gamma zone, uncovered by BM (Jonas et al., 2012).
Gamma zone may develop due to two mechanisms. In non-highly
myopic eyes, BMO may shift, usually, in direction to the macula, so
that at the nasal disc border, the end of BM overhangs into the intra­
papillary region (Zhang et al., 2019). At the temporal disc border, BM is
subsequently missing, so that gamma zone is present. The shifting of the
three layers of the optic nerve canal (BMO choroidal opening, peri­
papillary scleral flange opening) leads to an oblique orientation of the
ocular optic nerve canal in dependence of the direction of the shift of the
BMO (Girkin et al., 2017; Hong et al., 2019). The direction of the pre­
sumed BM shift may also determine the location of the widest extension
of gamma zone. The shift of BM may also explain why some myopic eyes
have a choroidal crescent in the peripheral part of gamma zone, with BM
moving primarily and with the choroid being passively drawn and
staying a bit behind. In most (medium myopic) eyes, gamma zone is
widest in the temporal inferior region, corresponding to BM over­
hanging into the nasal superior disc quadrant. Eyes with formerly called
“tilted optic discs” show an overhanging of BM superiorly and an infe­
rior gamma zone, so that one may assume that the main direction of the
BM shift was in these eyes from superior to inferior. Fitting with the
notion of a shift of BM as cause for the disc shape in these eyes with a
“tilted disc”, the foveola is located more inferiorly than in eyes with a
normal optic disc shape. In eyes with a so called “inversio situs papillae”,
BM is overhanging at the temporal disc border with a subsequent gamma
zone in the nasal parapapillary region. Correspondingly, eyes with an
“inversio situs papillae” show a large angle kappa, i.e., the temporal
superior retinal vessel arcade and the temporal inferior vascular arcade
leave the optic disc first into nasal superior direction and nasal inferior
direction, respectively before turning into the temporal direction. Fitting
with the notion of a shift of BM as cause for the disc shape in these eyes
17
Progress in Retinal and Eye Research xxx (xxxx) xxx
with an inversio situs papillae, the fovea-disc distance is reduced.
The cause for the presumed BM shift has remained unproven yet. It
has been discussed that the process of axial elongation is governed by a
new production and enlargement of BM in the midperiphery of the
fundus (Jonas et al., 2017b). It leads to a thinning of the midperipheral
retina and a decreased density of the RPE in that region, and to a change
of the eye shape from a spherical structure to an oblong structure (Jonas
et al., 2016a; 2017d, e, 2020a). In contrast, the retinal thickness, RPE
density, BM thickness and BM thickness at the posterior pole is unaf­
fected allowing a normal, best corrected central visual acuity (Jonas
et al., 2014b, 2016a, b; Panda-Jonas et al., 2020).
In highly myopic eyes, the BMO enlarges, what eventually leads to a
circular gamma zone. The reason for the enlargement of the BMO may
be an increase in the tension within BM perhaps caused by the
enlargement of BM in the midperiphery of the fundus not only in the
sagittal direction, but also in the coronal directions (Jonas et al., 2017b).
One may discuss that high myopia may be defined by a cut-off value of
axial length at which the BMO starts to enlarge (Jonas, 2005; Xu et al.,
2010).
Gamma zone is dependent mostly on axial length, and it is not, or not
profoundly, associated with glaucoma (Dai et al., 2013; Jonas et al.,
2012). In a histomorphometric study, the prevalence of gamma zone
started to increase, and did so steeply, at an axial length of about
26.0–26.5 mm (Jonas et al., 2012).
Gamma zone (and delta zone) leads to an enlargement of the para­
papillary region in highly myopic eyes. Since gamma zone does not
contain choriocapillaris or medium sized choroidal vessels, OCT angi­
ography visualizes only the superficial peripapillary retinal capillary
system in gamma zone. These anatomic characteristics may be taken
into account when OCT-angiographic findings in myopic eyes with
gamma zone are interpreted (Lee et al., 2020b; Park et al., 2019; Suwan
et al., 2018).
11.4. Delta zone
Some eyes with gamma zone show in the central part (i.e., in di­
rection to the optic disc) of gamma zone an elongation and thinning of
the peripapillary scleral flange (Dai et al., 2013; Jonas et al., 2012). This
central part can be called delta zone. It directly borders the peripapillary
ring at its central side (Jonas et al., 2014a). Since the peripapillary
scleral flange ends where the optic nerve dura mater merges with the
posterior scleral, and since the peripapillary arterial circle Zinn-Haller is
usually located at the dura mater-sclera merging line, the peripapillary
arterial circle can ophthalmoscopically delineate delta zone from the
Y.X. Wang et al.
remaining peripheral gamma zone (Jonas et al., 2013b). Delta zone
consists of the retinal nerve fiber layer in its inner layer, and the peri­
papillary scleral flange in its outer layer. It has remained unclear
whether the retinal nerve fiver layer is covered by an inner limiting
membrane, since the Müller cells, forming the inner limiting membrane
as their basal membrane, are missing in gamma and delta zone. The
peripapillary scleral flange forms the anterior border of the orbital CSF
space, and it is the biomechanical anchor of the lamina cribrosa. In
highly myopic eyes, the scleral flange elongates and thins in a
compensatory manner, keeping its volume mostly unchanged (Jonas
et al., 2003, 2004). Since the geometric dimensions of the scleral flange
may have a marked influence on its biomechanics including its influence
on the lamina cribrosa, the elongation and thinning of the peripapillary
scleral flange may be one of the reasons for the increased susceptibility
for glaucomatous optic nerve damage in highly myopic eyes (Jonas
et al., 2017a; Xu et al., 2007b). Correspondingly in a clinical study, a
larger disc size and a larger delta zone were the two factors associated
with an increased prevalence of glaucomatous or glaucoma-like optic
nerve damage (Jonas et al., 2017a).
12. Peripapillary arterial circle of Zinn-Haller
The peripapillary arterial circle of Zinn-Haller is located approxi­
mately at the merging line of the optic nerve dura mater with the pos­
terior sclera at the peripheral end of the peripapillary scleral flange
(Jonas and Jonas, 2010). The myopia-associated elongation of the per­
ipapillary scleral flange increases the distance between the arterial circle
and the lamina cribrosa which is nourished by the arterial ring. The
lengthening of the scleral flange with the secondary enlargement of the
distance between the arterial circle and the lamina cribrosa may be
another reason for the increased glaucoma susceptibility of highly
myopic eyes.
13. Morphological differentiation between glaucomatous optic
neuropathy and non-glaucomatous optic nerve damage
Any optic nerve damage, of glaucomatous and of non-glaucomatous
etiology, is associated with a loss in the thickness and oph­
thalmoscopical visibility of the peripapillary retinal nerve fiber layer
and a generalized (Frisén and Claesson, 1984; Jonas et al., 1989d,
1991c; Jonas and Naumann, 1989b; Jonas and Xu, 1993a) and focal
(Rader et al., 1994; Papastathopoulos and Jonas, 1995, 1998; Ratkin
and Drance, 1996) reduction in the diameter of the retinal arterioles.
The retinal arteriolar thinning correlates with the loss of retinal nerve
fiber layers and other parameters indicating the amount of optic nerve
damage (Hayreh, 1974c; Jonas et al., 1999). In GON as compared to the
non-glaucomatous optic nerve damage, the neuroretinal rim area gets
reduced and the rim shape changes, the optic cup deepens (and en­
larges), parapapillary beta zone develops and enlarges, and disc hem­
orrhages can occur. In contrast in non-glaucomatous optic nerve
damage, the neuroretinal rim remains mostly unchanged, and only the
height of the rim, due to the loss of the nerve fiber layer, decreases; the
optic cup gets more shallow due to the decrease in the rim height; and
the parapapillary region does not show changes (Bianchi-Marzoli et al.,
1995; Drance and King, 1992; Fard et al., 2019; Fortune et al., 2016;
Hayreh and Jonas, 2000a,b; Ing et al., 2016).
An exception of these findings may be some patients with intrasellar
or suprasellar tumors who show a glaucoma-like optic disc morphology
in eyes with a normal IOP (Qu et al., 2011). It has been discussed, that in
these patients the tumor located close to the inner aperture of the ocular
optic nerve canal might have blocked the access of the CSF to the orbit,
so that the orbital CSF pressure was abnormally low, leading to an
increased trans-lamina cribrosa pressure difference (Jonas et al., 2015).
Another exception of the findings is giant cell arteritis-induced optic
nerve damage, in the case of which the optic cup deepens and enlarges,
in association with an infarct in, and subsequent disruption of, the
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Progress in Retinal and Eye Research xxx (xxxx) xxx
lamina cribrosa with shifting of vitreous into the optic nerve tissue
(Hinzpeter and Naumann, 1976). A similar histology of the ONH has
been described for eyes after an acute angle-closure glaucoma attack in
the case of Schnabel’s cavernous optic atrophy.
In the prelaminar area, the retinal nerve fibers are physiologically
supported by astrocytes. In GON, axonal loss is accompanied by a
disruption of the glial architecture, which acts as a frame structure. The
glial architecture disruption may lead to the reduction of the neuro­
retinal rim. In contrast, in non-glaucomatous optic nerve damage, the
glial architecture is not markedly affected by the loss of retinal nerve
fibers in the prelaminar compartment what may be the reason why the
neuroretinal shape and size is not profoundly affected and changed in
eyes non-glaucomatous optic nerve damage (Lee et al., 2020).
14. Biomechanical aspects
The anatomic structures described above are important for the
biomechanics of the ONH and of the eye. The movement of any of these
structures may lead to a stress and strain on the neighboring structures
of the globe. Some aspects are:
- The IOP (or more precisely, the transcorneal pressure difference)
with its pulse-synchronous undulations exerts a force on the anterior
surface of lamina cribrosa and beyond and it is one of the de­
terminants of the trans-lamina cribrosa pressure difference.
- The orbital CSF pressure with its pulse-synchronous undulations
exerts a force on the posterior surface of lamina cribrosa and beyond
and it is one of the determinants of the trans-lamina cribrosa pressure
difference. The pressure undulations of the CSF pressure and IOP
may not be in phase. It leads to the
- Pulse phase-depending undulations of trans-lamina cribrosa pressure
difference, due to the time shift between the pressure wave arriving
inside of the orbital CSF space and the pressure wave arriving inside
of the eye. The undulations of the trans-lamina cribrosa pressure
difference may physiologically be necessary to allow the retrograde
axoplasmic flow enter the eye, and to allow the orthograde
axoplasmic flow leave the eye. They may also lead to pulse-
synchronous movements of the lamina cribrosa in the sagittal
direction.
- The spontaneous pulsations of the central retinal vein may lead to
pulse-synchronous movements of the central part of the lamina cri­
brosa in the coronal plane.
- The IOP rise-induced backward movement of the lamina cribrosa
and a lateral movement of the lamina cribrosa pores may stretch the
retinal ganglion axons in the intrapapillary compartment, leading
indirectly to a pressure on the parapapillary tissue (Jiang et al., 2015;
Wang, Y.X., et al., 2015, 2020a) (Fig. 15). It may also potentially
explain the up-rolling of the RPE as potential etiology of beta zone)
- The thickness of the parapapillary choroid decreases during an acute
IOP rise, leading to a change in the position of the BMO and its
adherent structures.
- An IOP rise exerts a force on the optic disc leading to a movement of
the lamina cribrosa in the coronal plane (Wang, Y.X., et al., 2020a).
- The optic nerve dura mater may pull backward the merging line of
the peripapillary scleral flange/posterior sclera in highly myopic
eyes, leading first to a peripapillary suprachoroidal cavitation (Dai
et al., 2015b; Demer, 2016; Q.S. You et al., 2013), and then poten­
tially to a peripapillary staphyloma. The backward pull may also
exert forces on the lamina cribrosa (Wang, X., et al., 2017).
- Other forces that may potentially have an influence on the biome­
chanics of the ONH include the shear stress from the vitreous body
during eye movements, a stress from the ocular pulse amplitude-
associated and arterial blood pressure fluctuation-related choroidal
swelling (Jin et al., 2018), and forces in association with the
accommodative process.
Y.X. Wang et al.
- During myopization in adolescence, the BMO may shift, most often
into the direction to the fovea, leading to a stretching of the peri­
papillary choroidal border tissue on the nasal side (centripetally, in
direction into the intrapapillary compartment) and at the temporal
side (centrifugally in direction away from the optic disc). The reason
for the BMO shift may be a new production and enlargement of BM in
the midperiphery of the fundus in the process of axial elongation
(Jonas et al., 2017b). Any stretching of the peripapillary border tis­
sue of the choroid will directly be transferred onto the lamina cri­
brosa, since the choroidal border tissue is connected with the
peripheral end of the lamina cribrosa.
- The inner shell of the eye, consisting of the choroid, ciliary body and
iris, BM, RPE, retina and vitreous body, is connected to its outer shell,
i.e. the sclera, only at two locations: anteriorly at the scleral spur, and
posteriorly at the peripapillary border tissue of the choroid. The
importance of the biomechanical role of the peripapillary choroidal
border tissue has not fully been explored yet.
- The eye performs movements with marked acceleration and decel­
eration. It may lead to a hurling of the inner ocular shell against the
outer shell (i.e. the sclera), buffered by the choroid. In that model,
the choroid would play a similar role as the outer CSF space plays for
buffering body movements-induced shifting of the brain against the
skull. The hurling of the inner ocular shell leads to a stress and strain
in the peripapillary choroidal border tissue which is the only
connection between the inner shell and the outer shell in the pos­
terior hemisphere of the globe.
- The potential enlargement of BM in the equatorial regions, also
leading to an increase in the coronal diameters of the globe may lead
to a strain in BM at the posterior pole, leading to an enlargement of
the BMO in highly myopic eyes (usually beyond an axial length of
approximately 26.0 mm–26.5 mm). This BMO enlargement leads to a
centrifugal stretch on the peripapillary choroidal border tissue, and
to the development of a circular gamma zone.
- The collagenous fibers of the peripapillary border tissue of the per­
ipapillary scleral flange crisscross with the collagenous fibers of the
scleral flange which continue into those of the lamina cribrosa. The
biomechanics of this anchoring of the scleral flange/lamina cribrosa,
running in the coronal plane, with the sagittally orientated peri­
papillary border tissues has remained unexplored.
- If in highly myopic eyes with a large gamma zone the peripapillary
choroidal border tissue (connecting the BM end with the end of the
lamina cribrosa) ruptures, the strain within BM may get released,
leading to an undulation of BM in its vicinity (Jonas et al., 2018a). A
similar morphology can be detected close to macular BM defects in
eyes with myopic maculopathy.
- The development of BM defects in the macular region may lead to a
release in the strain of BM around the BMO of the optic nerve, with a
secondary reduction in the strain in the peripapillary choroidal
border tissue.
- The potential enlargement of BM in the equatorial regions in axial
myopization may lead to an increase in the strain within the sclera,
most marked at the posterior pole. It may cause not only to a
reduction in the posterior sclera thickness, but also an enlargement
of the peripapillary scleral flange opening (i.e. the optic disc), with a
secondary stretching, elongation and thinning of the lamina cribrosa.
It may have marked importance for the biomechanics of the lamina
cribrosa, in particular with respect to the increased prevalence of
glaucomatous or glaucoma-like optic neuropath yin high myopia.
- The potential enlargement of BM in the equatorial regions in axial
myopization may lead to a backward movement of the BM at pos­
terior pole, leading to a compression and thinning of the choroid at
the posterior pole.
- A large gamma zone in the temporal parapapillary region, increasing
the distance between the retinal ganglion cell nuclei and the optic
disc border, may lead to a stretching of the retinal ganglion cell axons
in the papillo-macular region, and eventually to their loss,
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Progress in Retinal and Eye Research xxx (xxxx) xxx
potentially explaining the development of central scotoma in highly
myopic eyes without maculopathy (Bikbov et al., 2020).
- In particular in highly myopic eyes, additional forces may play a role,
such as an increased pressure of the potentially compressed retro­
bulbar orbital fat, an increased backward pull by the four rectus
muscles the insertion position of which has moved forward due to the
forward displacement of the anterior segment of the highly axially
elongated globe, and biomechanical sequels of localized scleral
staphylomas.
15. Myopia
Pathologic myopia has been estimated to become, or already to be,
one of the most common causes of irreversible blindness worldwide
(Bikbov et al., 2020; Flaxman et al., 2017; Wong et al., 2020; Xu et al.,
2006). While myopic macular changes are eye-catching features of
pathologic myopia, optic nerve changes in highly myopic eyes can
sometimes not fully been taken into account. Hospital-based and
epidemiological investigations however have demonstrated a marked
increase in the prevalence of optic nerve damage in eyes with longer
axial length in highly myopic eyes (Jonas et al., 2017a, 2020b; Xu et al.,
2007b). It may suggest that a considerable part of the group highly
myopic patients may lose vision due to a high myopia-associated optic
nerve damage. The optic nerve damage in highly myopic eyes can be
clearly glaucomatous in the case of an elevated IOP, it can be glau­
comatous or glaucoma-like in highly myopic eyes with an IOP in the
statistically normal range, and it can be non-glaucomatous. As in
non-highly myopic eyes, the glaucomatous and “glaucoma-like” optic
nerve damage in highly myopic eyes is characterized by an abnormal
size and shape of the neuroretinal rim parallel to an abnormal size and
shape of the optic cup (Jonas et al., 2017a). The border between the
optic cup and neuroretinal rim may best be characterized by a slight but
definite kinking of the retinal vessel. If such a vessel kinking is found
close to or at the optic disc border in the inferior or superior disc sector,
the likelihood of a glaucomatous or glaucoma-like optic nerve damage is
high. Since studies have not shown yet that the optic nerve damage in
highly myopic normotensive eyes is dependent on the IOP (and that a
reduction in IOP is therapeutically helpful), it may be more prudent to
describe the optic nerve damage in these eyes as “glaucoma-like” (Jonas
et al., 2017f,g).
15.1. Diagnostic problems in detection optic nerve damage in a myopic
ONH
Reasons for the difficulties in detecting an optic nerve damage in a
highly myopic ONH are:
- that the spatial contrast between the neuroretinal rim height and
optic cup depth is decreased reduced since the myopia-related
stretching of the lamina cribrosa leads to a flattening of the optic
cup; - that longer axial length makes the optic cup to appear to be
flattened; - that the color contrast between the pinkish neuroretinal
rim and the pale optic cup is reduced; - that the ophthalmoscopical
examination of the retinal nerve fiber layer thickness is hampered
due to the bright underground in the parapapillary region; - that the
OCT-based determination of the peripapillary retinal nerve fiber
layer thickness often is unreliable due to irregularities in the para­
papillary region in profile and color; and
- that visual field defects are often not specific for an optic nerve
damage but may also be due to myopic macular changes and irreg­
ularities in the globe shape.
Some of these problems may be avoided if the retinal ganglion cell-
inner plexiform layer thickness outside of macular patchy atrophic areas
is measured by OCT. Within the patchy atrophic regions, usually con­
taining a smaller defect in BM and a larger defect in the RPE layer and
Y.X. Wang et al.
photoreceptor layer, the retinal surface area is enlarged potentially
leading to a geometrically explained thinning of the retinal ganglion cell
layer and inner plexiform layer (Jonas et al., 2013c). Another possibility
is the assessment of the radial peripapillary capillary network by
OCT-angiography and the assessment of the retinal nerve fiber layer
texture (Ang et al., 2018; Sung et al., 2018; Tan et al., 2019).
The difficulties in detecting an optic nerve damage in highly myopic
eyes is combined with an even greater problem in detecting progression
of optic nerve damage in high myopia. It may be explored in futures
studies whether the assessment of the outer isopters of the visual field
and whether the measurement of the retinal ganglion cell-inner plexi­
form layer thickness outside of macular patchy atrophic areas are useful
to detect a progression of the optic nerve damage in highly myopic eyes.
15.2. Process of axial elongation
Myopia-related changes in the ONH may be caused by the process of
axial elongation in myopia and its morphological sequels. While the
mechanism underlying myopic axial elongation has not been fully un­
covered yet, one of the theories has suggested that BM is main structure
making the globe longer during the process of emmetropization in the
transition of moderate hyperopia in children older than two years to
emmetropia in adolescents and young adults. Myopization might be an
overshooting of the process of emmetropization (Jonas et al., 2017b).
The hypothesis considers that the globe gets axially elongation by the
enlargement (and new production) of BM in the equatorial and
retro-equatorial region while the foveal region is primarily untouched.
Such a mechanism would explain the histologic observations that the
retinal thickness and the RPE cell density decrease in the equatorial and
retro-equatorial region with longer axial length, that the RPE cell den­
sity, retinal thickness and choriocapillaris thickness in the macular re­
gion are unaffected by axial length, that the overall choroidal thickness
in the macula decreases with longer axial length, and that the best
corrected visual acuity is independent of axial length (if eyes with
maculopathy and optic neuropathy are excluded) (Dong et al., 2019b;
Jonas et al., 2014b, 2016a, b; 2017a, d, 2020a; Panda-Jonas et al.,
2020). Such a mechanism would include the backward movement of the
posterior BM, leading to shift of the BMO of the ONH into the direction
towards the fovea, and the thinning of the posterior choroid by a
compression effect between the posterior BM being pushed backward
and the sclera (Spaide et al., 2008; Wei et al., 2013; Zhang et al., 2019).
The hypothesis also includes an increase in the strain within BM
since the enlargement of BM in the equatorial and retro-equatorial re­
gion would also lead to a slight increase in the horizontal and vertical
globe diameters increasing the tension (or strain) within BM at the
posterior pole. In a first step, it might lead to an enlargement of the BMO
in the ONH, and in a second step, if the BMO enlargement was not
sufficient to reduce the strain within BM to the development of addi­
tional BM defects in the macular region (category 3 and 4 of myopic
maculopathy) (Jonas et al., 2017b; Ohno-Matsui et al., 2015). The BMO
enlargement would occur mostly in highly myopic eyes, with a cut-off
value of an axial length of approximately 26.0–26.5 mm (Zhang et al.,
2019).
15.3. Myopia-related changes of the ONH
The myopia-related changes of the ONH include (Jonas et al.,
2020b):
- a shift of BMO, usually into the temporal direction, leading to an
overhanging of BM into the intrapapillary compartment at the nasal
disc border, and a lack of BM in the temporal parapapillary region
(then called gamma zone). If the BMO shift occurs more in the
inferior direction, the ophthalmoscopically visible optic disc gets a
horizontally oval shape with an inferior gamma zone (so called
“tilted disc”). Fitting with the notion of BM as driving structure, the
20
Progress in Retinal and Eye Research xxx (xxxx) xxx
location of the fovea is more inferior in eyes with an inferior gamma
zone than in eyes with a superior gamma zone (own data). As a
corollary, eyes with a so called “inversio situs papillae”, character­
ized by the temporal retinal vessels leaving the optic disc in the nasal
direction, BM is overhanging into the intrapapillary compartment at
the temporal disc border, and there may be a small gamma zone in
the nasal parapapillary region. The development of gamma zone due
to the shift of the BMO occurs usually in moderately myopic eyes.
- an enlargement of the BMO in highly myopic eyes, with an axial
length of more than 26.0–26.5 mm. The BMO enlargement may be
due to an increased strain within BM, potentially caused by the BM
enlargement in the equatorial region, leading also (to a minor de­
gree) to an enlargement of the eye in the coronal plane. Due to the
BMO enlargement, the overhanging BM edge retracts from the
intrapapillary compartment so that eventually a circular gamma
zone develops. The enlargement of the BMO can be followed by the
development of additional BM defects in the macular region. Highly
myopic eyes with a larger BMO as compared to highly myopic eyes
with a smaller BMO tend to have less macular BM defects.
- an elongation and thinning of the peripapillary scleral flange within
gamma zone in highly myopic eyes. The elongated and thinned
scleral flange can be called delta zone. The border between delta
zone and the remaining peripheral gamma zone can be roughly
marked by the peripapillary arterial circle of Zinn-Haller, which
usually runs in the region of the merging line of the optic nerve dura
mater with the end of the scleral flange (Jonas and Jonas, 2010;
Jonas et al., 2013b). The peripapillary scleral flange is anterior end
of the orbital CSF space, and is internally covered only by the retinal
nerve fiber layer, without any additional retinal or choroidal tissue
(except for some large choroidal vessel in few eyes). Since the peri­
papillary scleral flange is the biomechanical anchor of the lamina
cribrosa, any change of the scleral flange, in particular a thinning,
will have biomechanical consequences for the lamina cribrosa
including the axons passing through.
- an elongation and thinning of the lamina cribrosa in highly myopic
eyes, potentially due to an enlargement of the peripapillary scleral
opening. The enlargement of the scleral flange opening may be
caused by an increased strain within the sclera caused by the
expanding BM. The changes in the lamina cribrosa may potentially
lead to a shearing effect on the lamina cribrosa pores and the axons
passing through them. In addition, the lamina cribrosa thinning de­
creases the distance between the intraocular compartment with the
IOP and the retrobulbar compartment, i.e., the orbital CSF space,
with the orbital cerebrospinal fluid pressure. With pressures forming
the trans-lamina cribrosa pressure difference, the trans-lamina cri­
brosa pressure gradient will get steeper if the distance between both
compartments decreases. A steeper pressure gradient may be a risk
factor for damage of the axons when passing through the lamina
cribrosa.
- an increased distance between the lamina cribrosa and the peri­
papillary arterial circle of Zinn-Haller which is located roughly at the
merging line of the optic nerve dura mater with the posterior sclera
at the peripheral end of the peripapillary scleral flange, and which
nourishes the lamina cribrosa tissue. The increased may perhaps be
an additional reason for an increased glaucoma susceptibility in high
myopia.
- an elongation of the peripapillary border tissue of the choroid
(Jacoby) which connects the peripapillary border tissue of the scleral
flange (Elschnig) with the end of BM (Jonas, R.A., and Hou et al.,
2020). Since with the development of gamma zone BM recedes away
from the disc border in the temporal region of myopic eyes, the
distance between the BM end and the peripapillary border tissue of
the scleral flange enlarges, i.e. the choroidal border tissue gets
elongated and thinned. Since the choroidal border (besides the
scleral spur in the anterior ocular segment and besides the vulnerable
retinal nerve fibers) is the only connection between the inner shell of
Y.X. Wang et al.
the eye (including the retina, BM and choroid) and the outer shell
(including the sclera, the peripapillary scleral flange and the lamina
cribrosa), any change in the choroidal border tissue will have con­
sequences for the biomechanics of the ONH and of the whole globe. If
the choroidal border tissue in highly myopic eyes gets overextended,
it may rupture potentially leading to a corrugation of BM with its
then loose end (Jonas et al., 2018a).
- a widening of the aperture of the peripapillary border tissue of the
scleral flange in the framework of an enlargement of the lamina
cribrosa. Since the scleral flange border tissue crisscrosses with the
collagenous fibers running from the scleral flange into the lamina
cribrosa will thus be of importance for the sagittal fixation of the
lamina cribrosa, any change of the scleral flange, including its
thinning in the framework of a thinning of the peripapillary scleral
flange, will have an effect on the biomechanics of the lamina
cribrosa.
15.4. Increased prevalence of glaucoma in high myopia
These and other myopia-related morphological changes may be
connected with the increased prevalence of glaucomatous or glaucoma-
like optic neuropathy, with the clinical risk factors of an enlarged optic
disc and presence and enlarged delta zone (Jonas et al., 2017a). It fits
with the notion of the peripapillary scleral flange (delta zone) as a
biomechanical structure of the lamina cribrosa, and fits with the changes
of the lamina in association with an enlargement of the optic disc.
Interestingly, presence and size of gamma zone (after subtraction of
delta zone) was not markedly associated with glaucoma in high myopia,
fitting with the notion, that it is the peripapillary scleral flange which is
primarily connected with the lamina cribrosa. It may clinically be of
importance that in extremely elongated eyes, the prevalence of glau­
comatous or glaucoma-like optic neuropathy can increase to values
higher than 50%. It suggests that at least some highly myopic patients
may lose vision not only due to myopic macular changes but also due to,
or primarily due to, optic nerve changes.
15.5. Non-glaucomatous optic nerve damage in high myopia
In addition to the glaucomatous or glaucoma-like optic neuropathy,
there may be a non-glaucomatous optic nerve damage occurring in
highly myopic eyes with a large temporal gamma zone and which is
characterized by deep central and paracentral scotomas which cannot be
explained by macular changes (Bikbov et al., 2020). One may discuss
that a large gamma zone increases the disc fovea distance so that retinal
ganglion cell axons which a straight course from the fovea to the optic
disc border get elongated, stretched and finally damaged. This mecha­
nism would hold true only for retinal nerve fibers which do not have
curved course to the optic disc and the course of which get straightened
before a stretching of the fibers would occur.
15.6. Definition of high myopia
A definition of high myopia by a cut-off value in axial length of
myopic refractive error has not generally been agreed upon. The current
consensus threshold value for high myopia is a spherical equivalent
refractive error − 6 diopters (Flitcroft et al., 2019). Such a definition has
been based on a functional point of view, since − 5.00 diopter of un­
corrected myopia results in an estimated uncorrected visual acuity of
6/172, a level meeting the threshold for blindness (<3/60 in the better
eye), and it has been d on an overall evidence-based consensus pointed
to a threshold of − 6.00 D for high myopia (Flitcroft et al., 2019; Morgan
et al., 2012). From a morphological point of view, high myopia may be
defined by an enlargement of the BMO, independently of additional,
pathological changes in the macular region or ONH (Jonas, 2005; Zhang
et al., 2019). An enlargement of the BMO may be the first step in the
development of axial elongation-related morphological changes in the
21
Progress in Retinal and Eye Research xxx (xxxx) xxx
posterior ocular segment, before secondary macular BM defects may
develop. A BMO enlargement occurs usually beyond an axial length of
about 26.0–26.5 mm or a myopic refractive error of approximately more
than − 6 to − 8 diopters (Jonas, 2005; Zhang et al., 2019). In a parallel
manner, the prevalence of a glaucomatous or glaucoma-like optic neu­
ropathy increased with a myopic refractive error of − 6 to − 8 diopters
(Xu et al., 2007b).
Since the globe elongates in childhood and adolescence, the cut-off
value for high myopia in children and adolescents may be defined in
dependence of the age of the individual, and it may be based on nor­
mograms, according to which a final axial length of more than
26.0–26.5 mm or a myopic refractive error of more than − 6 to − 8 di­
opters may eventually be reached in adulthood (Pärssinen et al., 2014;
Pärssinen and Kauppinen 2019; Tideman et al., 2018).
16. Future developments
Future research may be directed to address biomechanical aspects of
the anatomical structures of the ONH in health and disease, with special
reference to glaucoma and axial myopization and both together. It in­
cludes to assess the biomechanical importance of the peripapillary
border tissues, the physiologic and pathological role of the undulations
in the trans-lamina cribrosa pressure difference, the sequels of the
lamina cribrosa movements in sagittal direction and in the coronal
plane, the importance of the retro-lamina CSF pressure for the trans-
lamina cribrosa pressure difference and gradient in the pathogenesis
of GON, the biomechanical role of BM for the ocular optic nerve canal
including the connection between the BM end and the peripapillary
choroidal border tissue, the importance of an IOP rise-related movement
of the lamina cribrosa in the coronal plane, the potential association
between a large temporal gamma zone with a non-glaucomatous optic
nerve damage in highly myopic eyes with paracentral scotomas,
potentially caused by a stretching of the retinal ganglion cell axons in
the papillo-macular bundle, and other aspects listed above.
The differences between a non-glaucomatous myopic eye and a
glaucomatous myopic eye in the etiology of the optic nerve damage and
the development of axial myopia and in the diagnosis of on optic nerved
damage in that situation may also be explored. In particular, clinical
investigations may improve the OCT strategies and techniques to
enhance the diagnostic precision to detect and stage optic nerve damage
in highly myopic eyes (Tan et al., 2019). It is necessary to apply longi­
tudinal studies to explore structural biomarkers that predispose a highly
myopic to the development of a glaucomatous and non-glaucomatous
optic neuropathy (Wang et al., 2020b; Jeoung et al., 2020).
Future research may also address the etiology of parapapillary beta
zone and its associations with GON, including the cause for the spatial
relationship between the neuroretinal rim loss inside of the disc and
enlargement of beta zone outside of the disc, and the association of both
parameters with the longest distance to the central retinal vessel trunk in
the lamina cribrosa. It may also include longitudinal studies assessing
the OCT-detectable histologic changes during the development and
progression of beta zone in glaucomatous eyes, addressing the question
which structure is first affected: the RPE with a loss, the choriocapillaris
with a closure, and/or the photoreceptors. Research may also explore
whether alpha zone in normal eyes is similar or different from alpha
zone in glaucomatous. Future studies may also examine whether the
glaucoma-like optic nerve damage in highly myopic eyes with a loss of
neuroretinal rim and widening of the optic cup are dependent on the IOP
(Jonas et al., 2017e; Lin et al., 2020).
Author statement
Ya Xing Wang: Conceptualization; Data curation; Investigation;
Formal analysis: not applicable; Funding acquisition: not applicable;
Roles/Writing - original draft; Writing - review & editing.
- Songhomitra Panda-Jonas: Conceptualization; Data curation;
Y.X. Wang et al.
Investigation; Formal analysis: not applicable; Funding acquisition: not
applicable; Roles/Writing - original draft; Writing - review & editing.
- Jost B Jonas: Conceptualization; Data curation; Investigation;
Formal analysis: not applicable; Funding acquisition: not applicable;
Roles/Writing - original draft; Writing - review & editing.
Funding
None.
Financial interest
Jost B. Jonas, Songhomitra Panda-Jonas: Europäische Patent­
anmeldung 16 720 043.5 and Patent application US 2019 0085065 A1
„Agents for use in the therapeutic or prophylactic treatment of myopia
or hyperopia).
Acknowledgement
Supported in part by National Natural Science Foundation of China
#81570835 (China) and Beijing Municipal of Health Reform and
Development Project, #2019-4 (Beijing, China).
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