CHAPTER
39
Development of the ear
inferior. The endolymphatic appendage elongates and its tip expands
INNER EAR
into an endolymphatic sac that is connected to the pars superior by a
narrow endolymphatic duct.
The production of a precisely positioned and functionally well-tuned Two plate-like diverticula, one vertical and one horizontal, emerge
inner ear depends on genetic patterning and a cascade of transcription from the dorsal part of the pars superior. The epithelia in the centre of
signals expressed by numerous tissues, including the developing inner each outgrowth coalesce to form a fusion plate; the central part of this
ear and its surrounding periotic mesenchyme, the adjacent hindbrain, plate is eventually resorbed, leaving the anlagen of the semicircular
neural crest and notochord (Ohyama et al 2010, Sienknecht 2013). canals. The vertical plate gives rise to the anterior and posterior semi-
The first signs of inner ear development are visible shortly after those circular canals, which share a common crural attachment to the utricu-
associated with the developing eyes. Two patches of ectodermal thicken- losaccular chamber, and the horizontal plate gives rise to the lateral
ing, the otic placodes, appear lateral to the hindbrain at stage 9. Each semicircular canal. A small expansion, the ampulla, forms at one end
placode invaginates as an otic pit, adjacent to rhombomeres 5 and 6 of of each semicircular canal.
the hindbrain and dorsal to the second pharyngeal cleft. During stage The central part of the utriculosaccular chamber, which now repre-
12, the pit is pinched off from the surface ectoderm to form a simple, sents the membranous vestibule, becomes divided into a small ventral
hollow epithelial sac, the otic vesicle (otocyst or auditory vesicle) saccule and a larger dorsal utricle, mainly by horizontal infolding
(Fig. 39.1). extending from the lateral wall of the chamber towards the opening of
Regions of the vesicle differentiate into prosensory domains, which the endolymphatic duct. In this way, communication between the


give rise to the membranous labyrinth and the vestibulocochlear (stato- utricle and saccule is restricted to a narrow utriculosaccular duct. The
acoustic) ganglia of the eighth cranial nerve. The first morphological latter becomes acutely bent on itself; its apex is continuous with
evidence of this differentiation is visible during stage 14 (approximately the endolymphatic duct. While this is happening, the membranous
33 days), when the otic vesicle loses its initial piriform shape. A tubular labyrinth rotates so that its long axis, which was originally vertical,
diverticulum, the endolymphatic appendage, develops from its dorso- becomes more or less horizontal.
medial rim. The remainder of the vesicle, the utriculosaccular chamber, The ventral tip of the pars inferior begins to elongate. A medially
differentiates into an expanded pars superior and a narrower pars directed evagination, the cochlear anlagen, is evident in the ventral part
A 4.3mm ANTEROLATERAL C 11.0mm LATERAL VIEW D 20.0mm LATERAL VIEW Fig. 39.1 A–F, The stages in the development of
VIEW the membranous labyrinth from the otocyst, at the
Neural tube Otocyst Endolymphatic Posterior Anterior (superior) Posterior embryonic stages and aspects indicated. Note the
diverticulum semicircular semicircular duct semicircular relationship of the vestibular (orange) and cochlear
Anterior (superior) duct duct (yellow) parts of the vestibulocochlear nerve.
semicircular duct Crus
Absorption focus commune
B 6.6mm LATERAL VIEW Crus commune
Endolymphatic Lateral Lateral
diverticulum semicircular duct
semicircular duct
Developing Developing cochlea Utricle
cochlea Saccus
Saccule
endolymphaticus
Cochlear duct
Anterior
semicircular duct
Posterior
semicircular duct
Ductus
endolymphaticus
Lateral
semicircular duct
Utricle
Ampullae of
semicircular
ducts
Ductus reuniens
Saccule
Cochlear duct
658 E 30.0mm LATERAL VIEW F MEDIAL VIEW


External ear
659
93
RETPAHC
of the utriculosaccular chamber in a 7–9 mm (approximately 35 days) mainly to the outer hair cells in the organ of Corti, where they are
embryo. The proximal region of this cochlear duct continues to increase associated with modulation of hearing. In utero, the fetus receives sound
in length and its distal region becomes progressively more coiled. When by bone conduction; interaural sound differences are not established
the duct has achieved its final length and spiral configuration, its proxi- until birth, whether preterm or term.
mal part becomes constricted, forming the ductus reuniens by which
the saccule remains connected to the cochlea. The cochlea is initially
patterned into several prosensory domains. The central domain will MIDDLE EAR (TYMPANIC CAVITY AND
give rise to the organ of Corti. Molecular signals regulating the induc- PHARYNGOTYMPANIC (AUDITORY) TUBE)
tion and differentiation of the organ of Corti are complex (Kelly and
Chen 2009). Relatively little is known about the mechanisms establish-
All the components of the outer and middle ears develop from the first
ing sensory and non-sensory territories in the cochlear duct; there is
and second pharyngeal arches. The pharyngotympanic tube and tym-
evidence that bone morphogenetic protein (BMP) signalling is required
panic cavity are lateral extensions of the early pharynx (see Fig. 36.4).
(Ohyama et al 2010).
They become visible in a 4–6 mm embryo as a hollow, the tubotym-
Cells derived from the otocyst differentiate into the bipolar neurones
panic recess, lying between the first and second pharyngeal arches, with
that populate the vestibular and cochlear ganglia; sustentacular cells
a floor that consists of the second arch and its limiting pouches. The
(Wan et al 2013); the unique endolymph-producing epithelia of the
forward growth of the third pharyngeal arch causes the proximal part
stria vascularis; the absorbing epithelia of the endolymphatic sac; the
of the recess to remain narrow, forming the pharyngotympanic tube
general epithelial lining of the membranous labyrinth; and specialized


region, and also excludes the inner part of the second arch from this
cells in the six sensory patches of the inner ear (crista ampullaris of the
portion of the floor. The more lateral part of the recess eventually comes
three semicircular canals, maculae of the utricle and saccule, organ of
in contact with the first pharyngeal cleft and widens and develops into
Corti in the cochlea). Each of the sensory patches consists of mechano-
the tympanic cavity; its floor later forms the lateral wall of the tympanic
sensory hair cells and non-sensory supporting cells arranged into
cavity up to approximately the level at which the chorda tympani
mosaic patterns that are essential for normal hearing and balance. The
branches off from the facial nerve. The lateral wall of the tympanic
only cells in the mature inner ear that are not of otocyst origin are
cavity contains first and second arch elements. The first arch territory is
melanocytes in the stria vascularis, which are derived from the neural
limited to that part in front of the anterior process of the malleus, and
crest.
the second arch forms the outer wall behind this and also turns on to
The very different morphologies of the mature cristae, maculae and
the posterior wall to include the tympanohyal region.
organ of Corti reflect the differential expression of multiple genes
The tubotympanic recess at first lies inferolateral to the cartilaginous
during their development and maturation. The formation of the utricle
otic capsule; this spatial relationship alters as the capsule enlarges and
and saccule occurs during a time that coincides with the initiation of
the tympanic cavity becomes anterolateral. A cartilaginous process
hair cell planar polarity. It is important to note that the development
grows from the lateral part of the capsule to form the tegmen tympani
of core planar cell polarity in the orientation of stereocilia in the mech-
(Rodríguez-Vázquez et al 2011). The process curves caudally to form the
anosensory hair cells of the mammalian inner ear is the subject of an
lateral wall of the pharyngotympanic tube, incorporating the tympanic
extensive and conflicting literature (Deans 2013, Ezan and Montcou-


cavity and the proximal part of the pharyngotympanic tube into the
quiol 2013).
petrous region of the temporal bone. The mastoid antrum appears as a
At the same time as these changes are taking place, mesenchymal
dorsal expansion of the tympanic cavity during the sixth to seventh
cells surrounding the developing membranous labyrinth chondrify to
months (some sources place this as a later phenomenon). Exactly how
form an encasing cartilaginous otic capsule. Between 16 and 23 weeks,
middle ear cavitation occurs is poorly understood (Sienknecht 2013);
the otic capsule ossifies to form all of the bony labyrinth of the internal
it seems to involve cavitation of a neural crest mass (Thompson and
ear within the petrous temporal bone, except the modiolus and osseous
Tucker 2013).
spiral lamina, which ossify directly from connective tissue. The carti-
The middle ear ossicles are of neural crest origin, i.e. crest cells that
laginous capsule is initially incomplete and the cochlear, vestibular and
have migrated from rhombomeres 1–4 into the mesenchyme of the first
facial ganglia are temporarily exposed in the gap between its canalicular
and second pharyngeal arches. The malleus develops from the dorsal
and cochlear parts. They subsequently become covered by an outgrowth
end of the ventral mandibular (Meckel’s) cartilage of the first arch. The
of cartilage, in which the facial nerve becomes enclosed.
incus develops from the dorsal cartilage of the first arch, which is prob-
Vacuoles filled with perilymph develop in the embryonic connective
ably homologous to the quadrate bone of birds and reptiles. The origin
tissue between the cartilaginous capsule and the epithelial wall of the
of the stapes in humans remains controversial. It is thought to be
membranous labyrinth. The rudiment of the periotic cistern or vestibu-
derived mainly from an anlage situated in the cranial end of the carti-
lar perilymphatic space can be seen in the reticulum between the saccule
lage of the second pharyngeal arch, initially as a ring (anulus stapes)


and fenestra vestibuli in an 11–14 mm (approximately 42 days) embryo.
that encircles the small stapedial artery (Rodríguez-Vázquez 2005). The
The cochlear scalae (scala vestibuli and scala tympani) develop by
ossicles remain embedded in the mesenchymal roof of the tympanic
fusion of these spaces; the mechanism is uncertain (Kim et al 2011).
cavity until the eighth month of gestation, when the mesenchyme is
The two scalae gradually extend along each side of the cochlear duct; a
resorbed. As this happens, the ossicles become suspended within the
communication, the helicotrema, opens between them when they reach
developing tympanic cavity, initially by transient endodermal mesen-
the tip of the coiled duct.
teries and ultimately by supporting ligaments. They become covered
The rudiment of the eighth cranial nerve appears in the 4–6 mm
by the mucosa of the middle ear as the tympanic cavity fills with air
embryo as the vestibulocochlear (statoacoustic) ganglion that lies
after birth. Further postnatal developmental changes contribute to the
between the otocyst and the hindbrain and is initially temporarily fused
functional maturation of the middle ear.
with the ganglion of the facial nerve. Neuro blasts, whose fate is already
Two anlagen of each stapedius muscle appear close to the stapedial
specified in the ectoderm of the otic placode, delaminate from the
artery and facial nerve in second arch mesenchyme in 13–17 mm
anteroventral region of the otic vesicle, proliferate and migrate to the
embryos. Tensor tympani starts to appear near the extremity of the
site of the presumptive ganglion, where they coalesce. They differentiate
tubotympanic recess at almost the same time in first arch mesenchyme.
into mature bipolar sensory neurones and become segregated into ves-
The pyramidal eminence is formed within a condensation of mesen-
tibular and spiral ganglia, each associated with the corresponding divi-
chyme around the belly of stapedius (Rodríguez-Vázquez 2009). The
sion of the eighth cranial nerve. These neurones are unusual because


pharyngeal membrane separating the tympanic cavity from the external
they are exclusively placodal in origin, unlike neurones in most cranial
acoustic meatus develops into the tympanic membrane.
ganglia (which have a dual placodal and neural crest origin), and many
of their somata become enveloped in thin myelin sheaths. Their periph-
eral processes collectively provide the afferent innervation of the
EXTERNAL EAR
labyrinthine hair cells, relaying balance and auditory information. Tan-
talizing evidence about the transcriptional networks that encode the
positioning of sensory hair cells and spiral ganglion neurones along a The external acoustic meatus develops from the dorsal end of the first
frequency (tonotopic) gradient within the developing cochlea, and pharyngeal (hyomandibular) cleft (see Fig. 36.4). Close to its dorsal
which ensure that the two cell types make appropriate functional con- extremity, this groove extends inwards as a funnel-shaped primary
nections, is appearing in animal models (Appler and Goodrich 2011, meatus, from which the entire cartilaginous part of the meatus, and a
Appler et al 2013, Coate and Kelley 2013). The olivocochlear bundle, small area of its roof, are developed. A solid epidermal plug extends
an outgrowth of axons from neurones in the superior olivary complexes inwards from the tube along the floor of the tubotympanic recess. The
in the pons, accompanies the axons of the developing eighth cranial cells in the centre of the plug subsequently degenerate to produce the
nerve; these axons provide the inner ear with an efferent innervation, inner part of the meatus (secondary meatus). The epidermal stratum of


DEvEloPmEnT of THE EAR
660
4
noITCES
the tympanic membrane is formed from the deepest ectodermal cells Common congenital anomalies of the auricle are described in
of the epidermal plug; the fibrous stratum is formed from the mesen- Chapter 37.
chyme between the meatal plate and the endodermal floor of the
tubotympanic recess. The osseous part of the external acoustic meatus
HEREDITARY DEAFNESS
develops postnatally from the tympanic ring of the squamous part of
the temporal bone; the cartilaginous part develops much earlier and
independently of the osseous part (Ikari et al 2013). Prelingual deafness is the most common congenital anomaly, affecting
The development of the auricle is initiated by the appearance of six 2–6/1000 newborns: at least two-thirds of cases reported in the devel-
tissue elevations, the auricular hillocks, which form round the margins oped world are due to genetic factors, classified as non-syndromic (typi-
of the dorsal portion of the first pharyngeal cleft. Of the six, three are cally sensorineural and accounting for approximately 70% of cases)
on the caudal edge of the first pharyngeal (mandibular) arch and three and syndromic (which may be sensorineural, conductive or mixed and
on the cranial edge of the second pharyngeal (hyoid) arch (see Fig. accounts for approximately 30% of cases). A number of molecules
36.3A). The hillocks appear from stage 15; before then, only the most likely to be mediators of genetic hearing loss have been identified,
ventral hillock on the mandibular arch, which subsequently forms the including TGFB1, BMP4, ERK1/2 and many GPCR genes (Stamatiou
tragus, can be identified. The rest of the auricle is formed in the mes- and Stankovic 2013). The range of affected chromosomes and the spe-
enchyme of the hyoid arch, which extends forwards round the dorsal cific genes involved in sensorineural deafness is given by Hildebrand


end of the remains of the first pharyngeal cleft, forming a keel-like et al (2010). The structural abnormalities resulting from absent or aber-
elevation that is the forerunner of the helix. The contribution made by rant gene expression during the development of the ear include laby-
the mandibular arch to the auricle is greatest at the end of the second rinthine dysplasias (e.g. a reduction in the number of cochlear turns or
month; thereafter, this contribution becomes relatively reduced as an enlargement of the endolymphatic duct); disorganization of the
growth continues and, eventually, the area of skin supplied by the patterns of stereocilia in sensory hair cells and loss of cytoskeletal com-
mandibular nerve extends little above the tragus. The lobule is the last ponents in these cells; and defects in K+ recycling across gap junctions
part of the auricle to develop. between activated hair cells.
KEY REFERENCES
Appler JM, Lu CC, Druckenbrod NR et al 2013 Gata3 is a critical regulator Hildebrand MS, Hussein M, Smith RJH 2010 Genetic sensorineural hearing
of cochlear wiring. J Neurosci 33:3679–91. loss. In: Cummings Otolaryngology–Head and Neck Surgery, 5th ed.
Uses conditional knockout mice to show that the transcription factor Gata3 Philadelphia: Elsevier, Mosby; Ch 147.
(expressed in spiral ganglion neurones throughout their development) is This chapter reviews the classification and genetics of sensorineural hearing
apparently essential for the formation of precisely wired connectivity in the loss.
cochlea.
O’Rahilly R 1983 The timing and sequence of events in the development of
Deans MR 2013 A balance of form and function: planar polarity and devel- the human eye and ear during the embryonic period proper. Anat
opment of the vestibular maculae. Semin Cell Dev Biol 24:490–8. Embryol (Berl) 168:87–99.
Reviews the significance of planar polarity on vestibular system function and This paper presents the stages of human ear development.
the molecular mechanisms associated with the development of planar
Stamatiou GA, Stankovic KM 2013 A comprehensive network and pathway
polarity at three different anatomical scales (subcellular, cellular and tissue)


analysis of human deafness genes. Otol Neurotol 34:961–70.
in vestibular hair cells.
An in silico analysis of deafness genes using ingenuity pathway analysis.


Development of the ear
660.e1
93
RETPAHC
REFERENCES
Appler JM, Goodrich LV 2011 Connecting the ear to the brain: molecular Kim JH, Rodriguez-Vázquez JF, Verdugo-López S et al 2011 Early fetal devel-
mechanisms of auditory circuit assembly. Prog Neurobiol 93:488–508. opment of the human cochlea. Anat Rec (Hoboken) 294:996–1002.
Appler JM, Lu CC, Druckenbrod NR et al 2013 Gata3 is a critical regulator Ohyama T, Basch ML, Mishina Y et al 2010 BMP signaling is necessary for
of cochlear wiring. J Neurosci 33:3679–91. patterning the sensory and nonsensory regions of the developing mam-
Uses conditional knockout mice to show that the transcription factor Gata3 malian cochlea. J Neurosci 30:15044–51.
(expressed in spiral ganglion neurones throughout their development) is O’Rahilly R 1983 The timing and sequence of events in the development of
apparently essential for the formation of precisely wired connectivity in the the human eye and ear during the embryonic period proper. Anat
cochlea. Embryol (Berl) 168:87–99.
Coate TM, Kelley MW 2013 Making connections in the inner ear: recent This paper presents the stages of human ear development.
insights into the development of spiral ganglion neurons and their con- Rodríguez-Vázquez JF 2005 Development of the stapes and associated struc-
nectivity with sensory hair cells. Semin Cell Dev Biol 24:460–9. tures in human embryos. J Anat 207:165–73.
Deans MR 2013 A balance of form and function: planar polarity and devel- Rodríguez-Vázquez JF 2009 Development of the stapedius muscle and
opment of the vestibular maculae. Semin Cell Dev Biol 24:490–8. pyramidal eminence in humans. J Anat 215:292–9.
Reviews the significance of planar polarity on vestibular system function and
Rodríguez-Vázquez JF, Murakami G, Verdugo-López S et al 2011 Closure of
the molecular mechanisms associated with the development of planar


the middle ear with special reference to the development of the tegmen
polarity at three different anatomical scales (subcellular, cellular and tissue)
tympani of the temporal bone. J Anat 218:690–8.
in vestibular hair cells.
Sienknecht UJ 2013 Developmental origin and fate of middle ear structures.
Ezan J, Montcouquiol M 2013 Revisiting planar cell polarity in the inner Hear Res 301:19–26.
ear. Semin Cell Dev Biol 24:499–506.
Stamatiou GA, Stankovic KM 2013 A comprehensive network and pathway
Hildebrand MS, Hussein M, Smith RJH 2010 Genetic sensorineural hearing analysis of human deafness genes. Otol Neurotol 34:961–70.
loss. In: Cummings Otolaryngology–Head and Neck Surgery, 5th ed. An in silico analysis of deafness genes using ingenuity pathway analysis.
Philadelphia: Elsevier, Mosby; Ch 147.
This chapter reviews the classification and genetics of sensorineural hearing Thompson H, Tucker AS 2013 Dual origin of the epithelium of the mam-
loss. malian middle ear. Science 339:1453–6.
Wan G, Corfas G, Stone JS 2013 Inner ear supporting cells: rethinking the
Ikari Y, Katori Y, Ohtsuka A et al 2013 Fetal development and variations in
silent majority. Semin Cell Dev Biol 24:448–59.
the cartilages surrounding the human external acoustic meatus. Ann
Anat 195:128–36.
Kelly MC, Chen P 2009 Development of form and function in the mam-
malian cochlea. Curr Opin Neurobiol 19:395–401.


CHAPTER
40
Development of the eye
The development of the eye involves a series of inductive interactions pigmented epithelium). The area of surface ectoderm that is closely
between neighbouring tissues in the embryonic head. These are the apposed to the distal optic vesicle thickens to form the lens placode,
neurectoderm of the forebrain (which forms the sensory retina and and the mesenchymal sheath of the vesicle begins to show signs
accessory pigmented structures), the surface ectoderm (which forms the of angiogenesis. Between 33 and 35 days post ovulation, the lens
lens and the corneal epithelium) and the intervening neural crest mes placode and optic vesicle undergo coordinated morphogenesis. The
enchyme (which contributes to the fibrous coats of the eye and to lens placode invaginates, forming a pit that pinches off from the surface
tissues of the anterior segment of the eye). A broad anterior domain of ectoderm to form the lens vesicle (Fig. 40.1). The surface ectoderm
neurectoderm, characterized by the activation of several homeobox reforms a continuous layer that will become the corneal epithelium.
containing transcriptional regulators, including PAX6, RX, SIX3 and The lateral part of the optic vesicle invaginates to form a cup; the inner
OTX2, develops the potential to form optic vesicles. Subsequent interac layer (facing the lens vesicle) will become the sensory (neural) retina,
tions between mesenchyme and neurectoderm, involving expression of and the outer layer, influenced by signals from the surrounding extra
the secreted protein sonic hedgehog (SHH) at the midline, subdivides ocular mesenchyme, becomes the retinal pigmented epithelium. As a
this eyefield region into bilateral domains at the future sites of the eyes result of these folding movements, what were the apical (luminal)
(Chow and Lang 2001). Loss of SHH function causes holoprosencephaly surfaces of the two layers of the cup now face one another across a
and a range of malformations that can include cyclopia, due to incom muchreduced lumen, the intraretinal space. The pigmented layer


plete separation of the prosencephalon (Dubourg et al 2004). becomes attached to the mesenchymal sheath, but the junction between
In threedimensional culture of murine embryonic stem cells sup the pigmented and sensory layers is less firm and is the site of patho
plemented with the correct growth factors and Matrigel® (to promote logical detachment of the retina. The two layers are continuous at the
basement membrane formation), but in the absence of surface ecto lip of the cup (Fig. 40.2). The narrow part of the optic vesicle between
derm or lens epithelium, an epithelial vesicle develops and undergoes the base of the cup and the brain forms the optic stalk. As well as the
dynamic shape change to form a twolayered optic cup (Eiraku and invagination of the lateral part of the optic vesicle, the ventral surface
Sasai 2012). The tissue so formed demonstrated interkinetic nuclear of the vesicle and distal part of the stalk similarly invaginate, forming
migration and a fully stratified architecture similar to that of postnatal a wide groove, the choroid (optic) fissure, through which mesenchyme
eyes, including appropriate synapses. Similar results, i.e. production of and the hyaloid artery extend. These infoldings involve differential
retinal architecture and retinal pigment epithelial cells, have been growth and cell movement, and high levels of proliferation in the inner
reported using human embryonic stem cells (Nakano et al 2012, Zhu neuroepithelial layer.
et al 2013). As growth proceeds, the fissure closes and the artery is included in
The parallel process of lens determination appears to depend on a the distal part of the stalk. The fusion process is characterized by apop
brief period of inductive influence that spreads through the surface tosis at the margins of the fissure. Failure of the optic fissure to close is
ectoderm from the rostral neural plate and elicits a lensforming area a rare anomaly that is accompanied by a corresponding deficiency in
of the head. Reciprocal interactions that are necessary for the complete the choroid and iris (congenital coloboma) and is often associated with


development of both tissues take place as the optic vesicle forms and microphthalmia (small eyes). Reduced growth of the optic cup caused
contacts the potential lens ectoderm (Saha et al 1992, Nakano et al by mutation of the homeobox gene CHX10, important for specification
2012, Fuhrmann 2010). The vascular tissue of the developing eye forms and growth of the neural retina, is one known cause of microphthalmia
by local angiogenesis or vasculogenesis of angiogenic mesenchyme (Graw 2003). Anophthalmia, microphthalmia and coloboma are also
(Hughes et al 2000). (Accounts of the development of the eye are given associated with mutation of the SOX2 gene.
in O’Rahilly (1966, 1983).)
EMBRYONIC COMPONENTS OF THE EYE DIFFERENTIATION OF THE FUNCTIONAL
COMPONENTS OF THE EYE
The first morphological sign of eye development is a thickening of the
diencephalic neural folds at 29 days post ovulation, when the embryo The developments just described bring the embryonic components of
has seven to eight somites. This optic primordium (eye field) extends the eye into the spatial relationships necessary for the passage, focusing
on both sides of the neural plate and crosses the midline at the primor and sensing of light. The next phase of development involves further
dium chiasmatis. A slight transverse indentation, the optic sulcus, patterning and phenotypic differentiation in order to develop the spe
appears in the inner surface of the optic primordium on each side of cialized structures of the adult organ.
the brain. During the period when the rostral neuropore closes, at about The optic cup becomes patterned, from the base to the rim, into
30 days (stage 11), the walls of the neuromere diencephalon 1 (see Fig. regions with distinct functions. Several secreted factors, including bone
17.2) begin to evaginate at the optic sulcus, projecting laterally towards morphogenetic proteins (BMP), retinoic acid and SHH, and transcrip
the surface ectoderm; by 32 days, the optic vesicles are formed. Failure tional regulators, including PAX6 and PAX2, are important for specify


of the specification and development of the optic vesicle is associated ing each region (Chow and Lang 2001, Sinn and Wittbrodt 2013). The
with mutation of several transcriptional regulator genes expressed in outer layer of the optic cup remains as a thin layer of cells, which begin
the eye field and leads to anophthalmia (absence of the eye) (Graw to acquire pigmented melanosomes and form the pigmented epithe
2003). Each optic vesicle is surrounded by a sheath of mesenchymal lium of the retina at around 36 days. In a parallel process, which begins
cells derived from the head mesenchyme and neural crest; its lumen is before invagination, the cells of the inner layer of the cup proliferate to
continuous with that of diencephalon 1. By 31 days, regional differen form a thick pseudostratified neuroepithelium, the future neural retina,
tiation is apparent in each of the source tissues of the eye. The optic over the base and sides of the cup. The peripheral region around the
vesicle is visibly differentiated into its three primary parts: at the junc lip of the cup extends, and is further differentiated into the components
tion with the diencephalon, a thickwalled region marks the future optic of the prospective iris at the rim, and the ciliary body a little further
stalk; laterally, the tissue that will become the sensory (neural) retina back, adjacent to the neural retina (see Fig. 40.2). The development of
forms a flat disc of thickened epithelium in close contact with the this pattern is reflected in regional differences in the expression of
surface ectoderm; and the thinwalled part that lies between these various genes that encode transcriptional regulators and which are
regions will later form the pigmented layer of the retina (retinal therefore likely to play key roles in controlling and coordinating 661


Development of the eye
662
4
noItCeS
A B C D
E F G H
Retinal pigmented Optic Retinal pigmented Optic Early space between Position
epithelium stalk epithelium stalk neural retina and Retinal of lens
retinal pigmented pigmented Retinal
epithelium epithelium pigmented
epithelium
Choroid
fissure Optic Fusing
Hyaloid stalk choroid
Lens Lens Neural Lens Neural artery fissure Optic
cup vesicle retina vesicle retina stalk
Fig. 40.1 Development and morphogenesis of the optic cup. A–D Scanning electron micrographs of early eye development, A and C showing external
view, B and D showing longitudinal sections through the eye. B and E show the early invagination of the lens placode and the modification of the optic
vesicle to an optic cup. F and D show the formation of the lens vesicle and the two layers of the retina (nervous and pigmented). G and H show three
dimensional images of the outer aspect of the optic cup. G. Early formation of the choroid fissure along the side of the optic cup and optic stalk; the
layers of the retina are shown. H The fused choroid fissure; the position of the lens within the optic cup is shown in dotted outline. (A, B, C, D Courtesy
of Kathleen Sulik PhD, Professor, University of North Carolina.)
A B C
Mesenchyme
condensing to Pigmented layer
form sclera of retina
and choroid Trabecular Peripheral
Pigmented meshwork retina
Superficial
layer of retina
epithelium of lens
Corneal
Cavity of
Lens vesicle o Np et uic r ac lup M i bn eve tas wde ein n ec g nh i ly n em t ne se rval Optic ep Cit sh o te rr onli mu em a al Lens
layer of retina and ectoderm fissure Corneal
Cavity of Developing endothelium
Ectoderm optic stalk lens fibres
D E
Neural layer of retina
Choroidal extension Scleral spur Pigmented layer of retina
forming ciliary Ciliary processes
body and iris Scleral venous sinus
Developing Anterior chamber
aqueous Posterior chamber
chamber


Fused eyelids
Cornea
Developing
Iris stroma
vitreous
body Iris epithelium
Inferior
conjunctival
fornix
Fig. 40.2 Sections through the developing eyes of human embryos. A, Equivalent to 8 mm crown–rump length (CRL); stage 16. The thick nervous and
the thinner pigmented layers of the developing retina and the lens are shown. The two layers of the embryonic optic cup are separated by the intraretinal
space. B, Equivalent to 13.2 mm CRL; stage 17. The surface ectoderm anterior to the lens forms the corneal epithelium, whereas the corneal stroma and
endothelium will differentiate from the invading mesenchyme (of neural crest and mesodermal origin). C, Equivalent to 40 mm CRL. The development of
the anterior aqueous chamber is apparent with choroidal extensions and iris visible. The eyelids have developed and are fused; the extent of the
conjunctival fornices can be seen. D, Anterior growth of the peripheral retina, pigmented layer of the retina and mesenchymal proliferation at the anterior
part of the retina will give rise to the ciliary body and iris. The surface ectoderm anterior to the lens forms the corneal epithelium, whereas the corneal
stroma and endothelium will differentiate from invading mesenchyme (of neural crest and mesodermal origin). E, Details of the developing uveal tract.
Note the development of the anterior and posterior aqueous chambers, separated by the iris, and the attachment of the lens to the ciliary body.


Differentiation of the functional components of the eye
663
04
RetpAhC
development. Distinct sets of genes are expressed prior to and during Ciliary body
overt celltype differentiation. For example, PAX6 is expressed in the
prospective ciliary and iris regions of the optic cup; individuals hetero
The ciliary body is a compound structure. Its epithelial components are
zygous for mutations in PAX6 lack an iris (aniridia), which suggests a
derived from the region of the inner layer of the retina, between the iris
causal role for this gene in the development of the iris. The genes
and the neural retina, and the adjacent outer layer of pigmented epi
expressed in the eye are also often active at a variety of other specific
thelium. The cells here differentiate in close association with the sur
sites in the embryo, which may, in part, account for the coinvolvement
rounding mesenchyme to form highly vascularized folds that secrete
of the eye and other organs in syndromes that result from single genetic
aqueous fluid into the globe of the eye.
lesions, e.g. PAX2 mutation causes coloboma and kidney defects, reflect
The inner surface of the ciliary body forms the site of attachment of
ing the sites of expression of the gene (Graw 2003).
the lens. The outer layer is associated with smooth muscle derived from
mesenchymal cells in the choroid that lie between the anterior scleral
Developing neural retina condensation and the pigmented ciliary epithelium (p. 691).
The developing neural retina consists of an outer nuclear zone, which Iris
contains dividing neuroepithelial retinal progenitor cells, and an inner
marginal zone, which is initially devoid of nuclei. At around 37 days, The iris develops from the tip of the optic cup, where the two neuroepi
the cells of the nuclear zone invade the marginal zone, and by stage 18 thelial layers remain thin and are associated with vascularized, muscu
(44 days), the nervous stratum of the retina consists of inner and outer lar connective tissue. The muscles of the sphincter and dilator pupillae
neuroblastic layers. Cell lineage analyses have shown that seven retinal are unusual in that they are of neurectodermal origin, and develop as


cell types are all derived from a common multipotential retinal progeni a result of further growth and differentiation of the two layers of the
tor cell. Different types of retinal cells are born (cease dividing) in a optic cup. Mesenchymal cells, largely composed of neural crest cells
conserved sequence during development: ganglion cells, amacrine cells, that have migrated anterior to the lens, form the collagenrich iris
cone photoreceptors and horizontal cells develop early, whereas bipolar stroma; they overlay the pigmented epithelium of the iris, which is
cells, rod photoreceptors and Müller glial cells develop later (Cepko continuous with the ciliary body and neural retina, and is of neurecto
et al 1996). Newly born cells migrate from the apical (ventricular) dermal origin. The mature colour of the iris develops after birth and is
surface to the appropriate cell layer in the developing retina, establish dependent on the relative contributions made by the pigmented epi
ing its characteristic laminar structure. The developing ganglion cell thelium on the posterior surface of the iris and the neural crestderived
layer first separates from the neuroblastic layers by formation of the melanocytes in the mesenchymal stroma of the iris. If only epithelial
inner plexiform layer. The inner nuclear layer, containing developing pigment is present, the eye appears blue, whereas if there is an addi
amacrine, horizontal, bipolar and Müller glial cells, then separates from tional contribution from the melanocytes, the eye appears brown. Ani
the outer nuclear layer, containing the developing rod and cone photo ridia, the absence of the iris, is commonly caused by heterozygous
receptors by formation of the outer plexiform layer. Mature retinal mutations of PAX6.
neurones first appear in the central part of the retina. By the eighth
month, all the named layers of the retina can be identified. However, Lens
the photoreceptor cells continue to differentiate after birth, generating
an array of increasing resolution and sensitivity; the macula does not
The lens develops from the lens vesicle (see Figs 40.1F, 40.2A). Ini
reach maturity until 15–45 months after birth (Hendrickson and Yuo
tially, this is a ball of actively proliferating epithelium, but by stage 16,


delis 1984).
there is a discernible difference between the thin anterior (i.e. outward
The divergent differentiation of the pigmented and sensory layers of
facing) epithelium and the thickened posterior epithelium. Cells of
the retina from the initially bipotential neuroepithelium of the optic
the posterior wall lengthen and fill the vesicle (see Fig. 40.2B,C),
vesicle involves activation of regionspecific regulatory genes, e.g.
reducing the original cavity to a slit by about 44 days. The posterior
CHX10 in the presumptive neural retina and MITF in the presumptive
cells become filled with a very high concentration of proteins (crystal
pigmented epithelium (Bharti et al 2006). Patterning by gene expres
lins), which render them transparent; they also become densely
sion is an important aspect of establishing regional identity of the optic
packed within the lens as primary lens fibres. Cells at the equatorial
cup and the subsequent maturation of these respective tissues. Soluble
region of the lens elongate and contribute secondary lens fibres to the
factors from the retina elicit the polarized distribution of plasma mem
body of the lens in a process that continues into adult life, sustained
brane proteins and the formation of tight junctions in the pigmented
by continued proliferation of cells in the anterior epithelium (p. 697).
epithelium. Neural retinal differentiation is mediated by several growth
The polarity and growth of the lens appear to depend on the differen
factors, including fibroblast growth factors, SHH and retinoic acid. Basic
tial distribution of soluble factors that promote either cell division or
helixloophelix proneural transcriptional regulatory genes also play a
lens fibre differentiation, and are present in the anterior chamber and
central role in regulating retinal cell fate. However, the pigmented epi
vitreous humour, respectively. Congenital cataracts can be associated
thelium initially retains the potential to become neural retina and will
with mutations in genes that encode structural lens proteins, particu
do so if the embryonic retina is wounded, demonstrating the plasticity
larly crystallin proteins, as well as genes that encode transcriptional
of the early commitment to pigment epithelium or neural retinal fate.
regulatory factors expressed specifically in the lens, such as MAF and


The retinal vasculature forms by the aggregation of spindleshaped
PITX3, which are needed for normal lens development and which also
cells (mesenchymal cells) that emanate from the optic disc by week
influence normal growth of the globe of the eye (Graw 2003, Graw
15 and form vascular cords, consistent with vessel formation by vas
2010).
culogenesis, which give rise to the inner plexus of the retina. Vessel
The developing lens is surrounded by a vascular mesenchymal con
formation in the temporal and peripheral retina occurs by angiogen
densation, the vascular capsule, the anterior part of which is named the
esis. New vessel segments sprout from preexisting vessels and grow
pupillary membrane. The posterior part of the capsule is supplied by
tangentially by angiogenesis into the neuroepithelium (Hughes et al
branches from the hyaloid artery, and the anterior part is supplied by
2000).
branches from the anterior ciliary arteries. During the fourth month,
the hyaloid artery gives off retinal branches. By the sixth month, all of
Optic nerve
the vessels have atrophied, except the hyaloid artery, which becomes
occluded during the eighth month of intrauterine life, although its
The optic nerve develops from the optic stalk. The centre of the optic proximal part persists in the adult as the central artery of the retina.
cup, where the optic fissure is deepest, will later form the optic disc, Atrophy of the hyaloid vasculature and of the pupillary membrane
where the neural retina is continuous with the corresponding invagi appears to be an active process of programmed tissue remodelling that
nated cell layer of the optic stalk; the developing axons of the ganglion is macrophagedependent; visual impairment occurs in persistent
cells, therefore, pass directly into the wall of the stalk and convert it hyperplastic primary vitreous, a condition in which normal regression
into the optic nerve. Myelination of the axons within the optic nerve of the hyaloid vasculature fails to occur. The hyaloid canal, which carries
begins shortly before birth but the process is not completed until some the vessels through the vitreous, persists after the vessels have become


time later. The optic chiasma is formed by the meeting and partial occluded. In the neonate, it extends more or less horizontally from the
decussation of the axons within the two optic nerves in the ventral part optic disc to the posterior aspect of the lens, but when the adult eye is
of the lamina terminalis (at the junction of the telencephalon with the examined with a slitlamp, it can be seen to follow an undulating
diencephalon in the floor of the third ventricle). Beyond the chiasma, course, sagging downwards as it passes forwards to the lens. With the
the axons continue as the optic tracts, and pass principally to the lateral loss of its blood vessels, the vascular capsule disappears and the lens
geniculate bodies and to the superior tectum of the midbrain. becomes dependent for its nutrition on diffusion via the aqueous and


Development of the eye
664
4
noItCeS
vitreous humours. The lens remains enclosed in the lens capsule, a Choroid and sclera
thickened basal lamina derived from the lens epithelium. Sometimes,
the pupillary membrane persists at birth, giving rise to congenital
The choroid and sclera differentiate as inner vascular and outer fibrous
atresia of the pupil.
layers, respectively, from the neural crest mesenchyme that surrounds
the optic cup; the choroid is continuous with the leptomeningeal inter
Vitreous body nal sheath of the optic nerve, and the sclera is continuous with the outer
dural sheath of the optic nerve. The blood vessels of the choroid develop
The vitreous body develops between the lens and the optic cup as a from the fifteenth week and include the vasculature of the ciliary body.
transparent, avascular gel of extracellular substance. The precise deriv
ation of the vitreous remains controversial. The lens rudiment and the
optic vesicle are, at first, in contact, but they draw apart after closure of DIFFERENTIATION OF STRUCTURES
the lens vesicle and formation of the optic cup, and remain connected AROUND THE EYE
by a network of delicate cytoplasmic processes. This network, derived
partly from cells of the lens and partly from those of the retina, is the Extraocular muscles
primitive vitreous body. At first, these cytoplasmic processes are con
nected to the whole of the neuroretinal area of the cup but, later, they
Development of the extrinsic ocular muscles is complex, involving
become limited to the ciliary region, where, by a process of condensa
coordinated juxtaposition of specific muscle precursors, cranial motor
tion, they form the basis of the suspensory ligaments of the ciliary
nerve outgrowth and neural crest mesenchyme. During gastrulation,
zonule. The vascular mesenchyme, which enters the cup through the
when the earliest cells are migrating through the primitive node to form
choroidal fissure and around the equator of the lens, associates locally
the prechordal plate and notochordal process, they transitorily express
with this reticular tissue and thus contributes to the formation of the


myogenic markers. In stages 9 and 10 a population of prechordal mes
vitreous body.
enchyme cells migrate laterally from the lateral edge of the prechordal
plate toward the unsegemental paraxial mesenchyme each side of the
Anterior segment
notochord. After neurulation is complete, bilateral premandibular,
intermediate and caudal cavities develop adjacent to the neural tube.
Mesenchymal cells of neural crest origin migrate anteriorly around the The walls of these ‘head cavities’ are lined by flat or cylindrical cells that
optic cup and between the surface ectoderm and the lens to contribute do not exhibit the characteristics of a germinal epithelium; they were
to the development of anterior segment structures, including the ciliary previously termed preotic somites.
body, the iris, the cornea and the iridocorneal angle tissues (see Fig. As the oculomotor nerve grows towards the developing eye, at the
40.2C–E) (Gould et al 2004). The anterior chamber initially appears as level of the premandibular head cavity, the prechordal mesenchyme
a cleft in this mesenchymal tissue. The mesenchyme superficial to the becomes apparent as a condensation of premuscle cells at its ventrola
cleft forms the stroma (substantia propria) and endothelium of the teral side. This later subdivides into the blastema of superior, inferior,
cornea, and that deep to the cleft forms the stroma of the iris and medial and lateral recti and inferior oblique. Similar events occur in the
the pupillary membrane. Tangentially, this early cleft extends as far as intermediate head cavity which is associated with the trochlear nerve
the iridocorneal angle, where communications are established with the and premuscle cells forming superior oblique, and the caudal head
scleral venous sinus (canal of Schlemm). Mesenchymal cells of neural cavity (abducens nerve and lateral rectus) (see Figs 12.4 and 35.7).
crest origin lying at the angle of the anterior chamber differentiate to The early myogenic properties of the prechordal mesenchyme have
form a specialized meshwork of trabecular beams (collagen fibrils been demonstrated experimentally; if transplanted into limb buds, the


covered by cells); the open spaces of the meshwork become open to the cells are able to develop into muscle tissue (Wachtler and Jacob 1986),
anterior chamber as the beams develop. The canal of Schlemm devel however, the timing of expression of myosin heavy chain isoforms is
ops deep to the trabecular meshwork and is derived from mesodermal different from that of limb myoblasts. Myotube formation starts later
mesenchyme. Initially a vascular structure lined by endothelial cells, and progresses at a slower pace than in the limb, and coexpression of
the canal acts as an aqueous sinus from the fifth month of gestation MyHCI/1st and MyHCI/2nd are both seen from the earliest stages of
(McMenamin 1989). The forwardgrowing optic cup rim differentiates development in contrast to only MyHCI/1st in the limb. These early
into the ciliary epithelium and the iris; the posterior chamber is formed myoblasts retain their distinct differences from other skeletal muscles
between the iris, the lens capsule, the zonular suspensory fibres and the as they mature: they are smaller and loosely arranged, and belong to
ciliary processes. The ciliary processes produce the aqueous humour very small motor units (Porter and Baker 1996, PedrosaDomellöf et al
that flows through the pupil and is drained in the iridocorneal angle, 2000). Their final attachment to the eye is specified by neural crest
mainly by the trabecular meshwork and the canal of Schlemm. In this formation of the sclera, extraocular muscle tendons and the orbit. In
way, the walls of the anterior and posterior segment chambers furnish cases of anophthalmia the relative location and structure of extraocular
both the sites of production, and the channels for circulation and re muscles can be identified (PedrosaDomellöf et al 2000, Bohnsack et al
absorption, of the aqueous humour (p. 687). The FOXC1 and PITX2 2011).
transcriptional regulatory genes are expressed in the neural crest cells
migrating into the presumptive anterior segment, and regulate differen
Eyelids
tiation of the anterior segment tissues. Anterior segment dysgenesis,


involving malformation of the iris, cornea and angle, occurs when
these genes are mutated (e.g. Axenfeld–Rieger syndrome) and is often The eyelids are formed as small cutaneous folds of surface ectoderm
associated with raised intraocular pressure and glaucoma (Gould et al with a core of neural crest mesenchyme (see Fig. 40.2D). During the
2004). middle of the third month, their edges come together and unite over
the cornea to enclose the conjunctival sac; they usually remain united
until about the end of the sixth month. When the eyelids open, the
Cornea
conjunctiva lining their inner surfaces and covering the scleral region
of the eye fuses with the corneal epithelium. Transforming growth
The cornea is induced in front of the anterior chamber by the lens and factor alpha (TGFα) and several other growth factors regulate the
optic cup. The corneal epithelium is formed from surface ectoderm. The mesenchyme–epithelium interactions and cell migration that are
primordial corneal endothelium lining the front of the anterior chamber required for eyelid formation; keratinization is thought to play an
is formed from mesenchymal cells derived from the neural crest (see important role in lid separation. The eyelashes and lid glands, i.e. seba
Fig. 40.2C,D,E). Mesenchymal cells migrate between these layers and ceous glands associated with the eyelashes and tarsal (Meibomian)
differentiate to form specialized fibroblasts (keratocytes) that secrete glands, develop from ectoderm, as do the lacrimal and accessory lac
the extracellular matrix of the corneal stroma. A regular array of collagen rimal glands. Orbicularis oculi, which closes the eyelids, develops on
fibres (lamellae) is established between these two layers and serves to each side from skeletal myoblasts from the second pharyngeal arch that
reduce scattering of light entering the eye. The most anterior region of invade the eyelids. The muscles that widen the palpebral fissure develop
the stroma (Bowman’s layer) develops as an acellular zone packed with within the orbit from mesenchymal cells; the superior and inferior


collagen fibrils that confer strength on the layer. From the third month, tarsal muscles are smooth muscle, whereas levator palpebrae superioris
the endothelium is organized as a monolayer of cells and develops a is striated muscle that is attached to each upper eyelid by a tendon
strong, laminated basal lamina (Descemet’s membrane) adjacent to the derived from the neural crest (Plock et al 2005). (For a detailed time
stroma. The endothelium maintains corneal transparency by regulating table for upper eyelid development in staged human embryos and
the water content of the stroma (p. 689). fetuses, see Byun et al (2011).)


665
04
RetpAhC
Key references
Lacrimal apparatus Hartnett et al 2014). At full term, the eye is 65% of its adult size. It
grows rapidly for the first year, slightly slower until 3 years and then
more slowly until puberty. There is proportionately less growth of ante
The ectodermal epithelium of the superior conjunctival fornix prolifer
rior, compared to posterior, structures and the globe of the eye becomes
ates and gives rise to a series of tubular buds that form the alveoli and
more spherical. The neonatal lens is more spherical than that of the
ducts of the lacrimal gland. The buds are arranged in two groups: one
adult, which helps to compensate for the relative shortness of the eye.
forms the gland proper and the other forms its palpebral process (de
The visual acuity of neonates is estimated to be 20/400 and can reach
la CuadraBlanco et al 2003). The lacrimal sac and nasolacrimal duct
20/30–20/20 by 2–3 years of age; there is a general trend for infants to
are derived from ectoderm in the nasomaxillary groove (between the
be farsighted (Olitsky et al 2011). The visual pathways, lateral genicu
lateral nasal process and the maxillary process of the developing face)
late body and occipital visual cortex are patterned postnatally by expo
(see Fig. 36.11). The ectoderm thickens to form a solid cord of cells, the
sure to visual stimuli. Visual loss with no structural anomaly of the eye,
nasolacrimal ridge, which subsequently sinks into the mesenchyme and
amblyopia, is caused by abnormal visual stimulation during infancy
becomes canalized during the third month to form the nasolacrimal
and early childhood (up to 6–7 years of age) (Ruiz de Zárate and
duct. The lacrimal canaliculi arise from the cranial extremity of the cord
Tejedor 2007). Neonatal extraocular muscle coordination is usually
as buds that establish openings (puncta lacrimalia) on the margins of
achieved by 3–6 months of age and persistent deviation of an eye


the lids. The inferior canaliculus isolates a small part of the lower eyelid
requires evaluation. Preterm infants have reduced reflex and tear secre
to form the lacrimal caruncle and plica semilunaris.
tion, and tears may not be present with crying until more than 3 months
of age (Olitsky et al 2011).
Neonatal and infant eye
Lowbirthweight and preterm infants are at risk of developing retin
opathy of prematurity, a proliferative retinopathy (Kashani et al 2014,
KEY REFERENCES
Fuhrmann S 2010 Eye morphogenesis and patterning of the optic vesicle. O’Rahilly R 1983 The timing and sequence of events in the development of
Curr Top Dev Biol 93:61–84. the human eye and ear during the embryonic period proper. Anat
This paper considers the factors involved in the patterning of the optic Embryol (Berl) 168:87–99.
vesicle into neural retina and pigmented retinal epithelium. This paper presents the stages of human eye development.
Graw J 2010 Eye development. Curr Top Dev Biol 90:343–86. PedrosaDomellof F, Holmgren Y, Lucas CA et al 2000 Human extraocular
This paper presents the transcription factors in eye development and muscles: unique pattern of myosin heavy chain expression during
discusses their relevance to human eye disorders. myotube formation. Invest Ophthalmol Vis Sci 41:1608–16.
This paper presents a study of extraocular muscle development in human
Kashani AH, Drenser KA, Capone Jr A 2014 Retinopathy of prematurity. In:
embryos and fetuses.
Yanoff M, Duker J (eds) Ophthalmology, 4th ed. Oxford: Elsevier, Saun
ders; Ch. 6.20, pp. 535–40. Saha MS, Servetnick M, Grainger RM 1992 Vertebrate eye development. Curr
This chapter reviews the genetic factors and molecular causes of retinopathy Opin Genet Dev 2:582–8.
in preterm, low birthweight infants. A review of the interactions involved in eye development and discussion of
the genes responsible for development of the eye.


Olitsky SE, Hug D, Plummer LS et al 2011 Disorders of the eye. Growth and
development. In: Kliegman RM, Stanton BF, St Geme JW et al (eds) Sinn R, Wittbrodt J 2013 An eye of eye development. Mech of Dev
Nelson Textbook of Pediatrics, 19th ed. Philadelphia: Elsevier, Saunders; 130:347–58.
Ch. 610. This paper reviews the transcription factors in development of the eye.
This chapter considers the postnatal growth of the eye.
Wachtler F, Jacob M 1986 Origin and development of the cranial skeletal
O’Rahilly R 1966 The early development of the eye in staged human muscles. Bibl Anat 29:24–46.
embryos. Contrib Embryol Carnegie Inst 38:1. This paper considers the origin of the extraocular muscles.
This paper presents the fundamental information of human eye development
in staged embryos.


Development of the eye
665.e1
04
RetpAhC
REFERENCES
Bharti K, Nguyen MT, Skuntz S et al 2006 The other pigment cell: specifica McMenamin PG 1989 Human fetal iridocorneal angle: a light and scanning
tion and development of the pigmented epithelium of the vertebrate electron microscopic study. Br J Ophthalmol 73:871–9.
eye. Pigment Cell Res 19:390–4. Nakano T, Ando S, Takata N et al 2012 Selfformation of optic cups and
Bohnsack BL, Gallina D, Thompson H et al 2011 Development of extraocu storable stratified neural retina from human ESCs. Cell Stem Cell
lar muscles requires early signals from periocular neural crest and the 10:771–85.
developing eye. Arch Ophthalmol 129:1030–41. Olitsky SE, Hug D, Plummer LS et al 2011 Disorders of the eye. Growth and
Byun TH, Kim JT, Park HW et al 2011 Timetable for upper eyelid develop development. In: Kliegman RM, Stanton BF, St Geme JW et al (eds)
ment in staged human embryos and fetuses. Anat Rec (Hoboken) 294: Nelson Textbook of Pediatrics, 19th ed. Philadelphia: Elsevier, Saunders;
789–96. Ch. 610.
Cepko CL, Austin CP, Yang X et al 1996 Cell fate determination in the ver This chapter considers the postnatal growth of the eye.
tebrate retina. Proc Natl Acad Sci U S A 93:589–95. O’Rahilly R 1966 The early development of the eye in staged human
Chow RL, Lang RA 2001 Early eye development in vertebrates. Annu Rev embryos. Contrib Embryol Carnegie Inst 38:1.
Cell Dev Biol 17:255–96. This paper presents the fundamental information of human eye development
de la CuadraBlanco C, PecesPeña MD, MéridaVelasco JR 2003 Morpho in staged embryos.
genesis of the human lacrimal gland. J Anat 203:531–6. O’Rahilly R 1983 The timing and sequence of events in the development of


Dubourg C, Lazaro L, Pasquier L 2004 Molecular screening of SHH, ZIC2, the human eye and ear during the embryonic period proper. Anat
SIX3, and TGIF genes in patients with features of holoprosencephaly Embryol (Berl) 168:87–99.
spectrum: mutation review and genotypephenotype correlations. Hum This paper presents the stages of human eye development.
Mutat 24:43–51.
PedrosaDomellöf F, Holmgren Y, Lucas CA et al 2000 Human extraocular
Eiraku M, Sasai Y 2012 Selfformation of layered neural structures in three muscles: unique pattern of myosin heavy chain expression during
dimensional culture of ES. Curr Opin Neurobiol 22:768–77. myotube formation. Invest Ophthalmol Vis Sci 41:1608–16.
Fuhrmann S 2010 Eye morphogenesis and patterning of the optic vesicle. This paper presents a study of extraocular muscle development in human
Curr Top Dev Biol 93:61–84. embryos and fetuses.
This paper considers the factors involved in the patterning of the optic
Plock J, Contaldo C, von Lüdinghausen M 2005 Levator palpebrae superioris
vesicle into neural retina and pigmented retinal epithelium.
muscle in human fetuses: anatomical findings and their clinical rele
Gould DB, Smith RS, John SW 2004 Anterior segment development relevant vance. Clin Anat 18:473–80.
to glaucoma. Int J Dev Biol 48:1015–29. Porter JD, Baker RS 1996 Muscles of a different ‘color’: the unusual proper
Graw J 2003 The genetic and molecular basis of congenital eye defects. Nat ties of the extraocular muscles may predispose or protect them in neu
Rev Genet 4:876–88. rogenic and myogenic disease. Neurology 46:30–37.
Graw J 2010 Eye development. Curr Top Dev Biol 90:343–86. Ruiz de Zárate B, Tejedor J 2007 Current concepts in the management of
This paper presents the transcription factors in eye development and amblyopia. Clin Ophthalmol 1:403–14.


discusses their relevance to human eye disorders. Saha MS, Servetnick M, Grainger RM 1992 Vertebrate eye development. Curr
Hartnett ME, Morrison MA, Smith S et al 2014 Genetic variants associated Opin Genet Dev 2:582–8.
with severe retinopathy of prematurity in extremely low birth weight A review of the interactions involved in eye development and discussion of
infants. Invest Ophthalmol Vis Sci 55:6194–203. the genes responsible for development of the eye.
Hartnett ME 2015 Pathophysiology and mechanisms of severe retinopathy Sinn R, Wittbrodt J 2013 An eye of eye development. Mech of Dev 130:
of prematurity. Ophthalmology 122:200–10. 34758.
Hendrickson AE, Yuodelis C 1984 The morphological development of the This paper reviews the transcription factors in development of the eye.
human fovea. Ophthalmology 91:603–12. Wachtler F, Jacob M 1986 Origin and development of the cranial skeletal
Hughes S, Yang H, ChanLing T 2000 Vascularization of the human fetal muscles. Bibl Anat 29:24–46.
retina: roles of vasculogenesis and angiogenesis. Invest Ophthalmol Vis This paper considers the origin of the extraocular muscles.
Sci 41:1217–28.
Zhu Y, Carido M, Meinhardt A et al 2013 Threedimensional neuroepithelial
Kashani AH, Drenser KA, Capone Jr A 2014 Retinopathy of prematurity. culture from human embryonic stem cells and its use for quantitative
In: Yanoff M, Duker J (eds) Ophthalmology; 4th ed. Oxford: Elsevier, conversion to retinal pigment epithelium. PLoS One 8:e54552.
Saunders; Ch. 6.20, pp. 535–40.
This chapter reviews the genetic factors and molecular causes of retinopathy
in preterm, low birthweight infants.


CHAPTER
41
Orbit and accessory visual apparatus
There is a strong correlation between the pattern of orbital growth
BONY ORBIT
and eyeball growth. Orbital growth is most rapid during the first
12–24 months of life and most parameters reach 86–96% of adult
The bony orbits are skeletal cavities located on either side of the root values by the age of 8 years (Escaravage and Dutton 2013). Orbital
of the nose that serve as sockets for the eyes and associated tissues. The volumes are larger in boys than in girls throughout childhood (Bentley
walls of each orbit protect the eye from injury, provide points of attach- et al 2002).
ment for six extraocular muscles that allow the accurate positioning of
the visual axis, and determine the spatial relationship between the two Roof
eyes, which is essential for both binocular vision and conjugate eye
movements.
The roof of the orbit is formed principally by the thin orbital plate of
By convention, each cavity is considered to approximate to a quadri-
the frontal bone (Fig. 41.2). It is gently concave on its orbital aspect,
lateral pyramid with its base at the orbital opening, narrowing to its
which separates the orbital contents and the brain in the anterior
apex along a posteromedially directed axis. Each orbit has a roof, floor
cranial fossa. Anteromedially, it contains the frontal sinus and displays
and medial and lateral walls. The medial walls lie approximately 25 mm
a small trochlear fovea, sometimes surmounted by a small spine, where
apart in adults and are nearly parallel. The angle between the medial
the cartilaginous trochlea (pulley) for superior oblique is attached.
and lateral walls is about 45°. The compromise between protection and
Anterolaterally, there is a shallow fossa that houses the orbital part of
ensuring a good field of view dictates that each eyeball is located anter-
the lacrimal gland. The roof slopes down significantly towards the apex,
iorly within the orbit. The eyeball thus occupies only one-fifth of the
joining the lesser wing of the sphenoid, which completes the roof. The
volume of the orbit (Fig. 41.1); the remainder of the cavity is filled with
optic canal lies between the roots of the lesser wing and is bounded


extraocular muscles, vessels and nerves that are contained within and
medially by the body of the sphenoid.
supported by orbital fat and connective tissue. In brief, the orbit trans-
mits the optic, oculomotor, trochlear and abducens nerves, and branches
Medial wall
of the ophthalmic and maxillary divisions of the trigeminal nerve, the
ciliary parasympathetic ganglion and the ophthalmic vessels. It also
contains the nasolacrimal apparatus that mediates tear drainage into The medial wall of the orbit is formed principally by the orbital plate
the nasal cavity. (lamina papyracea) of the ethmoid bone (see Fig. 41.2). This paper-
thin, rectangular plate covers the middle and posterior ethmoidal air
cells, providing a route by which infection can spread into the orbit.
The ethmoid articulates with the medial edge of the orbital plate of the
Retro-orbital fat Medial rectus Optic nerve Lateral rectus
frontal bone at a suture that is interrupted by anterior and posterior
ethmoidal foramina. Posteriorly, it articulates with the body of the
sphenoid, which forms the medial wall of the orbit to its apex.
The lacrimal bone lies anterior to the ethmoid; it contains a fossa for
the nasolacrimal sac that is limited in front by the anterior lacrimal
crest on the frontal process of the maxilla and behind by the posterior
lacrimal crest of the lacrimal bone (to which the lacrimal part of orbic-
ularis oculi and lacrimal fascia are attached). A descending process of
the lacrimal bone at the lower end of the posterior lacrimal crest con-
tributes to the formation of the upper part of the nasolacrimal canal,
which is completed by the maxilla (Fig. 41.3). During development,
the medial wall of the orbit doubles in length, with disproportionate
A enlargement of its anterior half. Growth is rapid during the first 6 years
of life and gradual between 7 years and adulthood (Isaacson and
Retro-orbital fat Medial rectus Optic nerve Lateral rectus Monge 2003).
Floor
The floor of the orbit is mostly formed by the orbital plate of the
maxilla, which articulates with the zygomatic bone anterolaterally and


the small triangular orbital process of the palatine bone posteromedi-
ally (see Fig. 41.3). The floor is thin and largely roofs the maxillary
sinus. Not quite horizontal, it ascends a little laterally. Anteriorly, it
curves into the lateral wall, and posteriorly, it is separated from the
lateral wall by the inferior orbital fissure, which connects the orbit
posteriorly to the pterygopalatine fossa, and more anteriorly to the
infratemporal fossa. The medial lip is notched by the infraorbital
groove. The latter passes forwards and sinks into the floor to become
the infraorbital canal, which opens on the face at the infraorbital
foramen; the infraorbital groove, canal and foramen contain the infraor-
B bital nerve and vessels. Proportionally more pure orbital fractures
involve the floor, particularly in the region of the infraorbital groove
Fig. 41.1 A, A T2-weighted axial magnetic resonance imaging (MRI) scan (Burm et al 1999). The classic ‘blowout fracture’ leaves the orbital rim
through the mid-orbit. B, Note optic nerve in its entirety. (Courtesy of Dr intact and typically entraps soft tissue structures, leading to diplopia,
Timothy Beale FRCR, Royal National Throat Nose and Ear Hospital, impaired ocular motility and enophthalmos; infraorbital nerve involve-
666 London.) ment leads to ipsilateral sensory disturbance of the skin of the midface.


Bony orbit
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1
4
2
1
3
7
2 5
8
4
6
3
9
7 5
6 10
A B
Fig. 41.2 An anterior view of the left orbit indicating the bones forming the walls (A) and the principal apertures (B). A, Key: 1, lesser wing of sphenoid;
2, orbital plate of ethmoid; 3, lacrimal bone; 4, orbital plate of frontal bone; 5, greater wing of sphenoid; 6, zygomatic; 7, orbital plate of maxilla. B, Key:
1, supraorbital foramen; 2, posterior ethmoidal foramen; 3, anterior ethmoidal foramen; 4, lacrimal fossa; 5, (canal for) nasolacrimal duct; 6, infraorbital
foramen; 7, optic canal; 8, superior orbital fissure; 9, inferior orbital fissure; 10, infraorbital groove.
the orbital floor, is sometimes associated with an anastomosis between
Frontal process
Orbital plate of maxilla the middle meningeal and infraorbital arteries.
Infraorbital groove,
of ethmoid
leading into canal
Nasolacrimal ORBITAL FISSURES AND FORAMINA
canal
Optic canal
Lacrimal
bone
Zygomatic bone The lesser wing of the sphenoid is connected to the body of the sphen-
oid by a thin, flat anterior root and a thick, triangular posterior
Ethmoidal root. The optic canal lies between these (see Fig. 41.2) and connects the
Inferior orbital sinuses orbit to the middle cranial fossa, transmitting the optic nerve and its
fissure meningeal sheaths, and the ophthalmic artery. The common tendinous
ring, which gives origin to the four recti, is attached to the bone near
Palatine bone, the superior, medial and lower margins of the orbital opening of the
orbital process canal (see Fig. 41.4). The diameter of the cranial opening of the optic
canal increases significantly during the fetal period and childhood into
Left sphenoidal
Zygoma adulthood.
sinus
Superior orbital fissure


The superior orbital fissure is the gap between the greater and lesser
Foramen rotundum wings of the sphenoid, bounded medially by the body of the sphenoid,
Fig. 41.3 A horizontal section through the floor of the left orbit and the and closed at its anterior extremity by the frontal bone (see Fig. 41.2).
adjacent ethmoidal and sphenoidal sinuses, viewed from above. It connects the cranial cavity with the orbit and transmits the oculo-
motor, trochlear and abducens nerves, branches of the ophthalmic
nerve and the ophthalmic veins (see Fig. 41.4).
Lateral wall
Inferior orbital fissure
The lateral wall of the orbit is formed by the orbital surface of the greater
The inferior orbital fissure is bounded above by the greater wing of the
wing of the sphenoid posteriorly and the frontal process of the zygo-
sphenoid, below by the maxilla and the orbital process of the palatine
matic bone anteriorly; the bones meet at the sphenozygomatic suture.
bone, and laterally by the zygomatic bone (see Fig. 41.2). The maxilla
The zygomatic surface contains the openings of minute canals for the
and sphenoid often meet at the anterior end of the fissure, excluding
zygomaticofacial and zygomaticotemporal nerves, the former near the
the zygomatic bone. The inferior orbital fissure connects the orbit with
junction of the floor and lateral wall, and the latter at a slightly higher
the pterygopalatine and infratemporal fossae and transmits the infra-
level, sometimes near the suture. The orbital tubercle, to which the
orbital and zygomatic branches of the maxillary nerve and accompany-
lateral palpebral ligament, the check ligament of lateral rectus and the
ing vessels (see Fig. 41.4), orbital rami from the pterygopalatine
aponeurosis of levator palpebrae are all attached, lies just inside
ganglion and a connection between the inferior ophthalmic vein and
the midpoint of the lateral orbital margin. The lateral wall is the thickest
pterygoid venous plexus. A small maxillary depression may mark the
wall of the orbit, especially posteriorly, where it separates the orbit from


attachment of inferior oblique anteromedially, lateral to the lacrimal
the middle cranial fossa. Anteriorly, the lateral wall separates the orbit
hamulus.
and the infratemporal fossa. The lateral wall and roof are continuous
anteriorly but are separated posteriorly by the superior orbital fissure,
Ethmoidal foramina
which lies between the greater wing (below) and lesser wing (above)
of the sphenoid, and communicates with the middle cranial fossa. The
fissure tapers laterally but widens at its medial end, its long axis descend- The anterior and posterior ethmoidal foramina usually lie in the fronto-
ing posteromedially. Where the fissure begins to widen, its inferolateral ethmoidal suture (see Fig. 41.2). The posterior foramen may be absent,
edge shows a projection, often a spine, for the lateral attachment of the and occasionally there is a middle ethmoidal foramen. The foramina
common tendinous ring (see Fig. 41.4). An infraorbital sulcus, which open into canals that transmit their vessels and nerves into the ethmoi-
runs from the superolateral end of the superior orbital fissure towards dal sinuses, anterior cranial fossa and nasal cavity.


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COMMON TENDINOUS RING nerve all enter the orbit through the superior orbital fissure but lie
outside the common tendinous ring. Structures that enter the orbit
The common tendinous ring is a fibrous ring that surrounds the optic through the inferior orbital fissure lie outside the common tendinous
canal and part of the superior orbital fissure at the apex of the orbit, ring. The close anatomical relationship of the optic nerve and other
and gives origin to the four recti (Fig. 41.4). The optic nerve and oph- cranial nerves at the orbital apex means that lesions in this region may
thalmic artery enter the orbit via the optic canal, and so lie within the lead to a combination of visual loss from optic neuropathy and oph-
common tendinous ring. The superior and inferior divisions of the thalmoplegia from multiple cranial nerve involvement (Yeh and
oculomotor nerve, the nasociliary branch of the ophthalmic nerve, and Foroozan 2004).
the abducens nerve also enter the orbit within the common tendinous
ring, but they do so via the superior orbital fissure (see Fig. 41.15). The
ORBITAL CONNECTIVE TISSUE AND FAT
trochlear nerve and the frontal and lacrimal branches of the ophthalmic
The orbit contains a complex arrangement of connective tissue that
forms a supporting framework for the eyeball and also influences ocular
rotations and compartmentalizes orbital fat (Fig. 41.5). Certain regions
Levator palpebrae Superior rectus Superior Recurrent have anatomical and clinical significance, including the orbital septum,
superioris orbital fissure meningeal
fascial sheath of the eye, ‘check’ ligaments, suspensory ligament and
artery
Common periosteum. The notion that orbital connective tissues function as
tendinous ring extraocular muscle pulleys and influence ocular motility has recently
IV gained widespread acceptance (Demer 2002, Miller 2007).
Superior
oblique
Lacrimal nerve
ORBITAL SEPTUM
Rim of
optic canal Frontal nerve The orbital septum is a weak membranous sheet, attached to the orbital


rim where it becomes continuous with the periosteum (see Fig. 41.5).
Dural sheath
Superior It extends into each eyelid and blends with the tarsal plates and, in the
III ophthalmic vein upper eyelid, with the superficial lamella of levator palpebrae superi-
oris. The orbital septum is thickest laterally, where it lies in front of the
Optic nerve Nasociliary nerve lateral palpebral ligament. It passes behind the medial palpebral liga-
VI
ment and nasolacrimal sac, but in front of the pulley of superior
III Lateral rectus oblique. The septum is pierced above by levator palpebrae superioris
Medial rectus and below by a fibrous extension from the sheaths of inferior rectus
and inferior oblique. The lacrimal, supratrochlear, infratrochlear and
Inferior supraorbital nerves and vessels pass through the septum from the orbit
Ophthalmic
orbital fissure en route to the face and scalp. Clinically, the septum is an important
artery
anatomical reference to differentiate pre- and postseptal (orbital)
cellulitis.
Inferior rectus Zygomatic nerve
Inferior ophthalmic vein FASCIAL SHEATH OF THE EYEBALL
Infraorbital nerve and artery
A thin fascial sheath, the fascia bulbi (Tenon’s capsule), envelops the
Fig. 41.4 The common tendinous ring: muscle origins have been
eyeball from the optic nerve to the corneoscleral junction, separating it
superimposed. The relative positions of the nerves and vessels that enter
from the orbital fat and forming a socket for the eyeball (see Fig. 41.5;
the orbital cavity by passing through the superior orbital fissure or optic
Fig. 41.6). The ocular aspect of the sheath is loosely attached to the
canal are shown. Note that the attachments of levator palpebrae
superioris and superior oblique lie external to the common tendinous ring sclera by delicate bands of episcleral connective tissue. Posteriorly, it is
but are attached to it. The ophthalmic veins frequently pass through the traversed by ciliary vessels and nerves. It fuses with the sclera and with


ring. The recurrent meningeal artery (a branch of the ophthalmic artery) the sheath of the optic nerve where the latter enters the eyeball; attach-
is often conducted from the orbit to the cranial cavity through its own ment to the sclera is strongest in this position and again anteriorly, just
foramen. Abbreviations: III, oculomotor nerve; IV, trochlear nerve; behind the corneoscleral junction at the limbus. Injection of local
VI, abducens nerve. anaesthetics via a cannula into the space between the fascia bulbi and
Tendon of levator palpebrae superioris Fig. 41.5 The contents of the orbit, sagittal
Transverse ligament of Whitnall section.
Frontal bone Tendon of superior oblique
Orbital fat and fascial septum
Orbital septum
Superior rectus
Levator palpebrae
Orbicularis oculi superioris
Superior tarsus
Optic nerve
Dura mater
Conjunctiva
Orbital septum
Maxilla
Inferior oblique Suspensory Muscle Fascial Inferior rectus
ligament sheath sheath
of Lockwood of eyeball


Orbital connective tissue and fat
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A llppss ssrr ffnn ffrrbb
Thickened part of sheath of levator Conjoint fascial sheaths of levator
palpebrae superioris palpebrae superioris and superior rectus
Muscle sheath
ssoovv
Fascial sheath nnccnn
of eyeball
ssoomm
Superior rectus
Orbital septum Levator palpebrae aattcc
superioris
ooppnn
eebb
mmrr
Superior tarsus aattcc
llrr
Inferior tarsus iirr
Optic nerve
Orbital septum mm
Orbital cavity Fig. 41.7 A coronal section through the left orbit (viewed from in front),
Fascial sheath of eyeball
cut through a plane passing 5 mm behind the posterior pole of the globe.
Inferior rectus Abbreviations: atc, adipose tissue compartments; eb, ethmoid bone; fn,
Tendon of inferior oblique frontal nerve; frb, frontal bone; ir, inferior rectus; lps, levator palpebrae
‘suspensory ligament’ is posterior Muscle sheath superioris; lr, lateral rectus; m, maxilla (bone); mr, medial rectus; ncn,
nasociliary nerve; opn, optic nerve; som, superior oblique; sov, superior
ophthalmic vein; sr, superior rectus. (With permission from Koornneef L
B 1977 The architecture of the musculo-fibrous apparatus in the human
orbit. Acta Morphol Neerl Scand 15:35–64.)
Tarsal plate Medial check ligament
Lateral palpebral ligament
by some fibres of orbicularis oculi, it attaches to the inferior tarsus as
the inferior tarsal muscle; contraction of inferior rectus in downward
Lateral check ligament
Medial gaze therefore also draws the lid downward. The sheath of levator
palpebral ligament palpebrae superioris is also thickened anteriorly, and just behind the
aponeurosis it fuses inferiorly with the sheath of superior rectus. It
extends forwards between the two muscles and attaches to the upper
Medial rectus fornix of the conjunctiva.


Other extensions of the fascia bulbi pass medially and laterally, and
Fascial sheath attach to the orbital walls, forming the transverse ligament of the eye.
of eyeball This structure is of uncertain significance, but presumably plays a part
in drawing the fornix upwards in gaze elevation and may act as a
Fascial sheath Optic nerve fulcrum for levator movements. Other numerous finer fasciae form
of muscle radial septa that extend from the fascia bulbi and the muscle sheaths
to the periosteum of the orbit, and so provide compartments for orbital
fat. They also prevent the gross displacement of orbital fat, which could
Lateral rectus interfere with the accurate positioning of the two eyes that is essential
for binocular vision.
Fig. 41.6 A, The orbital fascia, sagittal section. B, The orbital fascia,
The periosteum of the orbit is only loosely attached to bone. Behind,
horizontal section.
it is united with the dura mater surrounding the optic nerve and, in
front, it is continuous with the periosteum of the orbital margin, where
it gives off a stratum that contributes to the orbital septum. It also
the sclera (sub-Tenon’s anaesthesia) has become a popular technique attaches to the trochlea and, as the lacrimal fascia, forms the roof and
for many ophthalmic surgical procedures (Davison et al 2007). lateral wall of the fossa for the nasolacrimal sac.
The fascia bulbi is perforated by the tendons of the extraocular
muscles and is reflected on to each as a tubular sheath, the muscular Orbital connective tissue pulleys
fascia. The sheath of superior oblique reaches the fibrous pulley (troch- There is mounting evidence that challenges the traditional view that the
lea) associated with the muscle. The sheaths of the four recti are very recti are attached only at their origin and scleral insertion. The concept
thick anteriorly but are reduced posteriorly to a delicate perimysium. that orbital connective tissue sheaths elastically coupled to the orbital
Just before they blend with the fascia bulbi, the thick sheaths of adja- walls function as pulleys was initially proposed as an explanation for
cent recti become confluent and form a fascial ring. the observed orbital stability of rectus muscle paths (Miller 1989). Each


Expansions from the muscular fascia are important for the attach- pulley consists of an encircling sleeve of collagen located within the
ments they make. Those from the medial and lateral recti are triangular fascia bulbi, near the equator of the globe. Elastic fibres and bundles of
and strong, and are attached to the lacrimal and zygomatic bones, smooth muscle confer the required internal rigidity to the structure
respectively; since they may limit the actions of the two recti, they are (Demer 2002). Although the original model described a passive pulley
termed the medial and lateral check ligaments (see Fig. 41.6). Other system, the current view is that fibres from the orbital surface of the
extraocular muscles have less substantial check ligaments, and the muscle insert into the pulley sleeve to allow small longitudinal move-
capacity of any of them actually to limit movement has been ments. This ‘active pulley hypothesis’ provides a better explanation for
questioned. normal ocular kinematics (Miller 2007).
The sheath of inferior rectus is thickened on its underside and blends
with the sheath of inferior oblique. These two, in turn, are continuous
with the fascial ring noted earlier and therefore with the sheaths of the ORBITAL FAT
medial and lateral recti. Since the latter are attached to the orbital walls
by check ligaments, a continuous fascial band, the suspensory ligament The spaces between the main structures of the orbit are occupied by fat,
of the eye, is slung like a hammock below the eye, providing sufficient particularly in the region between the optic nerve and the surrounding
support such that, even when the maxilla (forming the floor of the cone of muscles (see Fig. 41.5; Fig. 41.7). Fat also lies between the
orbit) is removed, the eye will retain its position. muscles and periosteum, and is limited anteriorly by the orbital septum.
The thickened fused sheath of inferior rectus and inferior oblique Collectively, the fat helps to stabilize the position of the eyeball and
also has an anterior expansion into the lower eyelid, where, augmented also acts as a socket within which the eye can rotate. Conditions


ORBiT And ACCEssORy visuAl APPARATus
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nOiTCEs
resulting in an increased overall volume of orbital fat with associated The palpebral apertures are widened in states of fear or excitement
swelling of the extraocular muscles, e.g. hyperthyroidism (Graves’ by contraction of the superior and inferior tarsal muscles as a result
disease), may lead to forward protrusion of the eyeball (exophthalmos). of increased sympathetic activity. Lesions of the sympathetic supply
result in drooping of the upper eyelid (ptosis), as seen in Horner’s
syndrome.
EXTRAOCULAR MUSCLES
THE RECTI
There are seven skeletal extraocular (extrinsic) muscles associated with
the eye. Levator palpebrae superioris is an elevator of the upper eyelid,
and the other six, i.e. four recti (superior, inferior, medial and lateral) The four recti are approximately strap-shaped; each has a thickened
and two obliques (superior and inferior), are capable of moving the eye middle part that thins gradually to a tendon (Figs 41.8–41.9). They are
in almost any direction. Complete congenital absence of the extraocular attached posteriorly to a common tendinous ring that encircles the
muscles, thought to represent a severe form of congenital fibrosis syn- superior, medial and inferior margins of the optic canal, continues lat-
drome, has been described (Brady et al 1992). Rarely, humans have erally across the inferior and medial parts of the superior orbital fissure,
deep orbital bands consistent with supernumerary extraocular muscles and is attached to a tubercle or spine on the margin of the greater wing
(Khitri and Demer 2010). of the sphenoid (see Fig. 41.4). The tendinous ring is closely adherent
to the dural sheath of the optic nerve medially and to the surrounding
periosteum. Inferior rectus, part of medial rectus and the lower fibres
LEVATOR PALPEBRAE SUPERIORIS of lateral rectus are all attached to the lower part of the ring, whereas
superior rectus, part of medial rectus and the upper fibres of lateral


Levator palpebrae superioris is a thin, triangular muscle that arises from rectus are all attached to the upper part. A second small tendinous slip
the inferior aspect of the lesser wing of the sphenoid, above and in front of lateral rectus is attached to the orbital surface of the greater wing of
of the optic canal, and separated from it by the attachment of superior the sphenoid, lateral to the common tendinous ring.
rectus (see Fig. 41.4). It has a short narrow tendon at its posterior attach-
ment and broadens gradually, then more sharply as it passes anteriorly
above the eyeball. The muscle ends in front in a wide aponeurosis.
Some of its tendinous fibres pass straight into the upper eyelid to attach
to the anterior surface of the tarsus, while the rest radiate and pierce Inferior
oblique
orbicularis oculi to pass to the skin of the upper eyelid. A thin lamina
Position of
of smooth muscle, the superior tarsal muscle, passes from the underside eyelid
of levator palpebrae superioris to the upper margin of the superior
tarsus (see Fig. 41.20).
The connective tissue sheaths of the adjoining surfaces of levator Trochlea
palpebrae superioris and superior rectus are fused (see Fig. 41.5). Where
the two muscles separate to reach their anterior attachments, the fascia
between them forms a thick mass to which the superior conjunctival
fornix is attached; this is usually described as an additional attachment
of levator palpebrae superioris. Traced laterally, the aponeurosis of the
levator passes between the orbital and palpebral parts of the lacrimal Superior
oblique
gland to attach to the orbital tubercle of the zygomatic bone. Traced
medially, it loses its tendinous nature as it passes closely over the
Lateral wall
reflected tendon of superior oblique, and continues on to the medial
of orbit Medial
palpebral ligament as loose strands of connective tissue.
rectus
Lateral
Vascular supply Levator palpebrae superioris receives its arterial rectus
supply both directly from the ophthalmic artery and indirectly from its
Superior
supraorbital branch.
rectus


Innervation Levator palpebrae superioris is innervated by a branch of Levator
the superior division of the oculomotor nerve that enters the inferior palpebrae
superioris
surface of the muscle. Sympathetic fibres to the smooth muscle com-
ponent of levator palpebrae superioris (superior tarsal muscle) are
derived from the plexus surrounding the internal carotid artery; these
nerve fibres may join the oculomotor nerve in the cavernous sinus and
Orbital apex
pass forwards in its superior branch.
Fig. 41.8 The extraocular muscles viewed from above.
Actions Levator palpebrae superioris elevates the upper eyelid. During
this process, the lateral and medial parts of its aponeurosis are stretched
and thus limit its action; the elevation is also checked by the orbital Superior oblique muscle
septum. Elevation of the eyelid is opposed by the palpebral part of and tendon Superior rectus
orbicularis oculi. Levator palpebrae superioris is linked to superior Optic nerve
rectus by a check ligament; thus the upper eyelid elevates when the gaze in dural sheath Medial rectus
of the eye is directed upwards.
Levator palpebrae superioris
The position of the eyelids depends on reciprocal tone in orbicularis
oculi and levator palpebrae superioris, and on the degree of ocular Trochlea Common tendinous ring
protrusion. In the opened position, the upper eyelid covers the upper
part of the cornea, while the lower lid lies just below its lower margin.
The eyes are closed by movements of both lids, produced by the contrac-
tion of the palpebral part of orbicularis oculi and relaxation of levator Superior
palpebrae superioris. In looking upwards, the levator contracts and the orbital
upper lid follows the ocular movement. At the same time, the eyebrows fissure
are also usually raised by the frontal parts of occipitofrontalis to dimin-
ish their overhang. The lower lid lags behind ocular movement, so that
more sclera is exposed below the cornea and the lid is bulged a little Infraorbital
by the lower part of the elevated eye. When the eye is depressed, both canal


lids move; the upper retains its normal relation to the eyeball and still
covers about a quarter of the cornea, whereas the lower lid is depressed Inferior Inferior LateralPterygopalatineForamen
because the extension of the thickened fascia of inferior rectus and oblique rectus rectus fossa rotundum
inferior oblique pull on its tarsus as the former contracts. Fig. 41.9 The muscles of the left orbit, lateral view.


Extraocular muscles
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Each rectus muscle passes forwards, in the position implied by its The muscle passes horizontally forwards along the lateral wall of the
name, to be attached anteriorly by a tendinous expansion into the orbit to insert into the lateral surface of the sclera, approximately 7 mm
sclera, posterior to the margin of the cornea. However, before their from the limbus (see Fig. 41.8).
scleral attachment, the recti make functionally important connections
within orbital connective tissue that influence muscle action. Vascular supply Lateral rectus receives its arterial supply from the
ophthalmic artery directly and/or from its lacrimal branch.
Superior rectus
Superior rectus is slightly larger than the other recti. It arises from the Innervation Lateral rectus is innervated by the abducens nerve by
upper part of the common tendinous ring, above and lateral to the optic branches that enter the medial surface of the muscle.
canal. Some fibres also arise from the dural sheath of the optic nerve.
The fibres pass forwards and laterally (at an angle of approximately 25° Actions Lateral rectus moves the eye so that it is directed laterally
to the median plane of the eye in the primary position) to insert into (abducted). For more detailed discussion of its actions, see page 672.
the upper part of the sclera, approximately 8 mm from the limbus (see
Fig. 41.8). The insertion is slightly oblique, the medial margin more
anterior than the lateral margin. THE OBLIQUES
Vascular supply Superior rectus receives its arterial supply both
Superior oblique
directly from the ophthalmic artery and indirectly from its supraorbital
Superior oblique is a fusiform muscle that arises from the body of the
branch.
sphenoid superomedial to the optic canal and the tendinous attach-
Innervation Superior rectus is innervated by the superior division of ment of the superior rectus (see Fig. 41.4). It runs forwards to end in a
round tendon that passes through a fibrocartilaginous loop, the troch-
the oculomotor nerve that enters the inferior surface of the muscle.
lea, attached to the trochlear fossa of the frontal bone (see Fig. 41.8).


Actions Superior rectus moves the eye so that the cornea is directed Tendon and trochlea are separated by a delicate synovial sheath. The
upwards (elevation) and medially (adduction). To obtain upward move- tendon subsequently descends posterolaterally and inferior to superior
ment alone, the muscle must function with inferior oblique. Superior rectus, and is attached to the sclera in the superolateral part of the
rectus also causes intorsion of the eye (i.e. medial rotation). Because a posterior quadrant behind the equator, between the superior and lateral
check ligament extends from superior rectus to levator palpebrae supe- recti.
rioris, elevation of the eye also results in elevation of the upper eyelid.
For more detailed discussion of its actions, see page 672. Vascular supply Superior oblique receives its arterial supply directly
from the ophthalmic artery and indirectly from its supraorbital branch.
Inferior rectus
Inferior rectus arises from the common tendinous ring, below the optic Innervation Superior oblique is innervated by the trochlear nerve,
canal. It runs along the orbital floor in a similar direction to superior which enters the superior surface of the muscle.
rectus (i.e. forwards and laterally) and inserts obliquely into the
sclera below the cornea, approximately 6.5 mm from the limbus (see Actions Superior oblique is inserted into the posterior part of the
Fig. 41.9). eyeball; when it contracts, the back of the eyeball is elevated, and the
front of the eyeball is depressed (particularly in the adducted position).
Vascular supply Inferior rectus receives its arterial supply from the Superior oblique also moves the eye laterally (abducted) and intorts the
ophthalmic artery and from the infraorbital branch of the maxillary eyeball. For more detailed discussion of its actions, see page 672.
artery.
Inferior oblique
Innervation Inferior rectus is innervated by a branch of the inferior Inferior oblique is a thin, narrow muscle that lies near the anterior
division of the oculomotor nerve that enters the superior surface of the margin of the floor of the orbit. It arises from the orbital surface of the


muscle. maxilla lateral to the nasolacrimal fossa and ascends posterolaterally,
at first between inferior rectus and the orbital floor, and then between
Actions The principal activity of inferior rectus is to move the eye so
the eyeball and lateral rectus. It is inserted into the lateral part of the
that it is directed downwards (depression). It also causes the eye to
sclera behind the equator of the eyeball, in the inferolateral part of
deviate medially and extorts the eye (i.e. produces lateral rotation). To
the posterior quadrant between the inferior and lateral recti, near, but
obtain downward movement alone, inferior rectus must function with
slightly posterior to, the attachment of superior oblique (see Fig. 41.9).
superior oblique. A fibrous extension from inferior rectus to the inferior
The muscle broadens and thins, and, in contrast to the other extraocular
tarsal plate of the eyelid causes the lower eyelid to be depressed when
muscles, its tendon is barely discernible at its scleral attachment.
the muscle contracts. For more detailed discussion of its actions, see
page 672. Vascular supply Inferior oblique receives its arterial supply from the
Medial rectus ophthalmic artery and from the infraorbital branch of the maxillary
artery.
Medial rectus is slightly shorter than the other recti but is the strongest
of the group. It arises from the medial part of the common tendinous
Innervation Inferior oblique is innervated by a branch of the inferior
ring, and also from the dural sheath of the optic nerve, passing hori-
division of the oculomotor nerve that enters the orbital surface of the
zontally forwards along the medial wall of the orbit, below superior
muscle.
oblique (see Figs 41.8, 41.9). It inserts into the medial surface of the
sclera, approximately 5.5 mm from the limbus and slightly anterior to
Actions Inferior oblique is inserted into the posterior part of the
the other recti.
eyeball; when it contracts, the back of the eyeball is depressed and the
front of the eyeball is elevated (particularly in the adducted position).
Vascular supply Medial rectus receives its arterial supply from the


The muscle moves the eye laterally (abduction) and also causes extor-
ophthalmic artery.
sion. For more detailed discussion of its actions, see below.
Innervation Medial rectus is innervated by a branch from the inferior
division of the oculomotor nerve that enters the lateral surface of the
MINOR MUSCLES OF THE EYELIDS
muscle.
Actions Medial rectus moves the eye so that it is directed medially Several smooth muscles are associated with the orbit, although they are
(adducted). The two medial recti acting together are responsible for not directly attached to the eyeball. Orbitalis, the orbital muscle of
convergence of the eyes. For more detailed discussion of its actions, see Müller, lies at the back of the orbit and spans the infraorbital fissure.
page 672. Its functions are uncertain but its contraction may possibly produce a
slight forward protrusion of the eyeball. The superior and inferior tarsal
Lateral rectus
muscles are small muscle laminae inserted into the upper and lower
Lateral rectus arises principally from the lateral part of the common eyelids, and are described in more detail with the tarsal plates. All three
tendinous ring and bridges the superior orbital fissure (see Fig. 41.4); minor muscles receive a sympathetic innervation from the superior
some fibres also arise from a spine on the greater wing of the sphenoid. cervical ganglion via the internal carotid plexus.