ArticlePDF Available

Definition of the Ocular Surface


Abstract and Figures

The ocular surface is a very important part of the eye. It consists of the conjunctiva and the cornea, together with elements such as the lacrimal gland, lacrimal drainage apparatus and associated eyelid structures. This part of the eye has unique properties and is associated with special physiological mechanisms, for example tear production and drainage, as well as predisposition to specifi c diseases. Certain diseases affect only this part of the eye, due to its functional requirement for vision, exposed anatomical location and its proximity to the nasal mucosa and sinuses. For these reasons, diseases such as allergic keratoconjunctivitis affecting the ocular surface primarily are common. This chapter summarizes important terms and root words used in conjunction with the ocular surface in the scientific literature. Understanding of the nomenclature is essential for any research discussion or clinical practice related to the ocular surface.
Content may be subject to copyright.
Defi nition of the Ocular Surface 1
Section I: Anatomy and
Physiology of the Ocular Surface
2 Ocular Surface
Defi nition of the Ocular Surface 3
De nition of the Ocular Surface
Louis Tong,a Wanwen Lan and Andrea Petznick
The ocular surface is a very important part of the eye. It consists of the
conjunctiva and the cornea, together with elements such as the lacrimal
gland, lacrimal drainage apparatus and associated eyelid structures.
This part of the eye has unique properties and is associated with special
physiological mechanisms, for example tear production and drainage,
as well as predisposition to specifi c diseases. Certain diseases affect
only this part of the eye, due to its functional requirement for vision,
exposed anatomical location and its proximity to the nasal mucosa and
sinuses. For these reasons, diseases such as allergic keratoconjunctivitis
affecting the ocular surface primarily are common.
This chapter summarizes important terms and root words used
in conjunction with the ocular surface in the scientific literature.
Understanding of the nomenclature is essential for any research
discussion or clinical practice related to the ocular surface.
The ocular surface, an integrated unit comprising the cornea, conjunctiva,
lacrimal glands and eyelids, was fi rst described by Thoft in 1987 (Thoft
1978). Gipson extended the description of the ocular surface system
in her Friedenwald lecture in 2007 (Gipson 2007): ‘the ocular surface...
includes the surface and glandular epithelia of the cornea, conjunctiva, lacrimal
gland, accessory lacrimal glands, meibomian glands and their apical (tears) and
basal (connective tissue) matrices; the eyelashes with their associated glands of
Moll and Zeis; those components of the eyelids responsible for the blink and the
Singapore Eye Research Institute, Singapore National Eye Centre, Duke-NUS Graduate Medical
School, 11 Third Hospital Avenue, 168751, Singapore.
Is this OK?
The Corresponding has not been specified here. Is that
required? If yes, kindly specify.
4 Ocular Surface
nasolacrimal duct’. Together, these components are interconnected through
a continuous epithelium, as well as the nervous, vascular, immune and
endocrine systems. Figure 1 illustrates a cross-sectional view showing some
components of the ocular surface system. The lacrimal functional unit is
defi ned by the 2007 International Dry Eye Work Shop (2007) as ‘an integrated
system comprising the lacrimal glands, ocular surface (cornea, conjunctiva and
meibomian glands), lids, and the sensory and motor nerves that connect them’. The
anatomical components of the lacrimal functional unit will be described
under ‘Lacrimal glands’ below.
Figure 1 This fi gure shows a cross-sectional view of the ocular surface system with the
continuous epithelium highlighted in pink and the tear fi lm in blue.
General Appearance of the Ocular Surface
In the normal ocular surface, the cornea occupies the approximate centre
of the exposed surface. The outer limit of the cornea adjacent to the bulbar
conjunctiva is the limbus. At both sides of the limbus are two triangular
sclero-conjunctival areas, visualised as the white part of the sclera. When
a person is looking straight ahead, the lower eyelid height is normally 1–2
mm higher or lower than the lower corneal limbus (see section on Cornea),
whereas the superior eyelid is normally 1–2 mm higher than the visual axis
but just lower than the superior corneal limbus (Lens et al. 2007).
The upper and lower eyelids meet at the medial (inner) and lateral
(outer) canthi which are the angles of the palpebral fi ssures. The medial
Color image of this figure appears in the color plate section at the end of the book.
Lacrimal gland
Accessory lacrimal gland
Meibomian gland
Tear lm
Defi nition of the Ocular Surface 5
canthus is near to the nose, whereas the lateral canthus is located temporally.
The medial canthus is usually positioned slightly lower than the lateral
canthus. The positions of the canthi have signifi cance in oculoplastic surgery.
They facilitate the fl ow of the tear fi lm from the lateral to medial direction,
and are youthful-looking aesthetically.
The Eyelids
The eyelid or palpebral refers to a movable fold of skin, muscle and cartilage
that can be closed or opened over the eyeball. The upper and lower eyelids
form a covering over the globe protecting against excessive light or injury.
When the eyelids are open, the margins or the palpebral fi ssures form an
almond-shaped structure (Lens et al. 2007).
The eyelid structure consists of four layers. The fi rst or outermost
layer includes the skin, eyelashes and associated glands. The second layer
comprises the muscular layer, namely the orbicularis oculi, the circular
sphincter-like muscles responsible for closing the eyelids. The third fi brous
layer, important for mechanical stability of the eyelid, consists mainly of the
tarsal plate. The innermost layer of the eyelid is the palpebral conjunctiva.
The fi rst two layers are sometimes termed anterior lamella of the eyelid,
whereas the last two layers are termed posterior lamella of the eyelid. In
oculoplastic surgery, a substantial full- thickness eyelid defect may need to
have the anterior and posterior lamellae reconstructed separately, as these
lamellae have different mechanical requirements.
The orbicularis oculi are innervated by cranial nerve VII. When there
is pathology of cranial nerve VII, such as in Bell’s palsy, the eyelids may
not be able to close. On the other hand, some conditions irritate the ocular
surface, resulting in secondary blepharospasm and tonic contraction of
orbicularis muscle. The levator palpebrae muscles are innervated by a
branch of the cranial nerve III. In the event that the cranial nerve III function
is compromised, there may be drooping of the upper eyelid or, in more
extreme cases, inability to open the lid.
Palpebral Fissures
The fusiform lid fi ssure represents the shape of a spindle. However, the
curvature of the upper eyelid fi ssure is often greater than that of the lower
eyelid. Certain dynamic features of the palpebral fi ssures are unique: when
the eyes are blinking or closing, the inferior eyelid moves only minimally
and almost all the movement is done by the descending sweep of the upper
lid. To facilitate this downward motion of the upper eyelid, the medial and
lateral insertions of the palpebral ligaments are lower than the level of the
pupil, and as a result, the upper eyelid is quite bowed.
6 Ocular Surface
The piriform lid fi ssure (like a pear lying fl at on the side) is similar
to the fusiform one, except that the maximal height of the interpalpebral
ssures is not aligned with the vertical diameter of the cornea but slightly
lateral to that.
Eyelid Margin
The mucocutaneous junction, or gray line, is located just posterior to the
eyelashes. The gray line demarcates the eyelid into anterior and posterior
lamellae, and contains the muscle of Riolan (Wulc et al. 1987, Lipham et
al. 2002). This is also called the Marx’s line and can be visualised with
uorescein dye. Along the posterior lid margin, the single or double row
of meibomian gland orifi ces is found. This forms the white line, which
corresponds to the free border of the tarsal plate, where the bulk of the
meibomian gland elements islocated.
Tarsal Plate
The tarsal plate or tarsus is a thin fl at plate of dense connective tissue (one
in each eyelid), which supports the eyelid structure. The tarsus extends from
the orbital septum to the lid margin. The upper tarsal plate has a D shape
structure lying on its side and is much larger than the lower tarsal plate. The
height is 11 mm centrally, whereas the corresponding height in the lower
oblong tarsus is only 5 mm. Each tarsus is about 3 cm long and 1 mm thick.
The meibomian glands (refer to ‘Tear producing glands: meibomian glands’)
are located within the tarsus (Jester et al. 1981, Obata 2002).
The eyelashes are hairs growing at the edge of the eyelids. They are
positioned in the anterior portion of the lid margin, lined by skin epithelium.
The eyelashes are surrounded by the glands of Zeis (modifi ed sebaceous
glands) and the glands of Moll (modifi ed sweat glands) (Stephens et al.
1989). The eyelashes help to keep foreign particles from entering the ocular
surface system, as well as increase the sensitivity of the eye to touch. Refer
to Table 1 for the terms related to the eyelids or eyeball.
Gross Anatomy and Corneal Limbus
The cornea is an avascular, transparent tissue that provides the majority
of optical power to refract the light entering the eye. It is generally ovoid
Defi nition of the Ocular Surface 7
in nature, with a steeper or shorter radius of curvature in the vertical than
the horizontal plane. It occupies a central position in the ocular surface
and consists of several layers including the epithelium, stroma and
A general overview on the corneal structure is shown in Fig. 2. The
stroma is separated from the epithelium and endothelium by the Bowman’s
membrane and Descemet’s membrane respectively.
Table 1 This table summarizes words related to the eyelids or eyeball.
Eyelid-related defi nitions Examples of use of term
Fusion of the upper to the lower eyelids
Blepharo- Related to the eyelid Blepharospasm
Blepharitis Eyelid infl ammation Anterior,
Blepharo-conjunctiva Related to the eyelid and conjunctiva Blepharo-conjunctivitis
Enophthalmos Decreased palpebral fi ssures associated
with posterior movement of the eyeball
into the orbit
Traumatic enopthalmos
Epiblepharon Congenital horizontal fold of skin over
the upper eyelid which can result in
inward-turning of the eyelashes of the
medial upper eyelid, common in people
of Asian origin
Exophthalmos Increased palpebral fi ssures associated
with bulging of the eyeball from the
Intermittent, specifi c
Entropion Abnormal inward-turning of the eyelid
Cicatricial, involutional,
Ectropion Abnormal outward-turning of the eyelid
cicatricial, paralytic,
punctual, mechanical,
Lagophthalmos Condition of inadequate eyelid closure Nocturnal, paralytic
Marx’s line Refers to the muco-cutaneous junction at
the eyelid margin
Ptosis Drooping of the eyelids Involutional or paralytic
Symblepharon Condition where the palpebral
conjunctiva of the upper or lower
eyelids fusing with the bulbar
conjunctiva of the eyeball
Anterior, posterior,
Trichiasis Condition where backwardly directed
lashes cause irritation, usually due to
scarring of the eyelids
Please check
8 Ocular Surface
The surgical limbus is an important landmark for surgical incisions as
well as the anatomical position of ocular surface progenitor or stem cells
important for regeneration of the corneal epithelium (Lens et al. 2007). The
surgical limbus can be differentiated into a bluish zone anteriorly, and a
more whitish zone posteriorly. The line dividing the two zones corresponds
to the Schwalbe’s line, which is the termination of the Descemet’s membrane
(see below) (Preziosi 1968).
Corneal Epithelium
The epithelium is the outermost layer of the cornea. The corneal epithelium
is approximately 50 µm thick (Li et al. 1997, Haque et al. 2004) and is
composed of fi ve to seven cell layers. The stratifi ed epithelium of the cornea
is non-keratinized and composed of several morphologically distinct layers
of cells including two to three layers of superfi cial attened squamous
cells, several layers of wing cells and a single layer of columnar basal cells
(Beuerman and Pedroza 1996).
Bowman’s Layer
The Bowman’s layer, produced by the corneal epithelium, is a thin layer
separating the corneal epithelium from the stroma. It is usually 10–17 µm
thick (Li et al. 1997, Hayashi et al. 2002)and comprises collagen fi brils found
in random distribution. Damage to the Bowman’s layer may confound
adherence of corneal epithelium to the stroma and disrupt structural
integrity of the ocular surface (Wilson and Hong 2000).
Corneal Stroma
The stroma accounts for approximately 90% of the total corneal volume. It is
predominantly composed of hydrated fi brils of collagen, glycoproteins (such
Figure 2 This fi gure shows a schematic illustration of the different layers of the
cornea (not drawn to scale).
Color image of this figure appears in the color plate section at the end of the book.
Defi nition of the Ocular Surface 9
as fi bronectin and laminin) and proteoglycans (Linsenmayer et al. 1998).
It has the tendency to imbibe fl uid and controlled dehydration is essential
to maintain transparency of the cornea. Damage to the cellular limiting
layers, with subsequent fl uid infl ux, interferes with the orderly fi brillar
arrangement of the stromal lamellae increasing light scatter, resulting in loss
of transparency of the cornea (Maurice 1957). Infi ltration of the cornea with
immune cells such as macrophages can also reduce corneal transparency.
Descemet’s Membrane
The Descemet’s membrane, which is a basement membrane secreted by the
endothelium, separates the stroma from the endothelium. The Descemet’s
membrane is approximately 10 µm thick in an adult human cornea and its
thickness increases throughout life (Joyce 2003).
Corneal Endothelium
The corneal endothelium is a cellular monolayer of approximately 5 µm
thickness and 15 to 20 µm width (Binder et al. 1991). Endothelial cells
forming this layer are joined by interdigitations and leaky tight junctions.
In order to keep the cornea dehydrated, the endothelial cells serve as a
pump which removes fl uid by active transport from the corneal stroma to
the aqueous (Maurice 1972). The number of endothelial cells in humans
decreases with age (Joyce 2003). Following injury, the non-replicative
endothelium in humans repairs the endothelial wound by enlargement
and migration of existing cells rather than mitosis (Chan-Ling et al. 1988b,
Joyce 2003). Refer to Table 2 for terms related to the cornea.
The conjunctiva is a thin, transparent tissue that lines the inner surface of
the eyelids, fusing with the eyelid epithelium at the eyelid margin and the
corneal epithelium at the limbus. It covers the sclera up to the limbus and
is continuous with the corneal epithelium. The conjunctiva consists of six
or more non-keratinized epithelial cell layers near the limbus and can be
up to 12 layers near the fornix (Wanko et al. 1964). The conjunctival fold
(cul-de-sac) is open at the palpebral fi ssure and is closed when the eyelids
are apposed.
The conjunctiva is divided into 3 parts: The forniceal conjunctiva,
bulbar conjunctiva and palpebral conjunctiva. These will be described in
the sections below.
10 Ocular Surface
Bulbar Conjunctiva
This is the part of the conjunctiva that lines the globe of the eye. It consists
of 2 parts: the limbal conjunctiva which is fused with the episclera at the
limbus, and the scleral conjunctiva which extends from the limbus to the
forniceal conjunctiva.
Forniceal Conjunctiva
This is the intermediate portion of the conjunctiva which is not attached
to the eyelids or the eyeball. This lines the bottom of the conjunctival sac
(fornix) and joins the bulbar and palpebral portions.
Table 2 This table summarizes words related to the cornea.
Cornea-related defi nitions Examples of use of term
Corneal degeneration Acquired age-related condition of
the cornea
Fuchs’ endothelial dystrophy,
Inherited developmental disease
of the cornea
Fuchs’ dystrophy,
keratoconus, lattice
Corneal ectasia/melt/
Abnormal thinning of the cornea Post-LASIK corneal ectasia
Corneal epitheliopathy Pathology of the corneal
Punctate corneal
Abnormal spots or indentations
in the corneal endothelium
infi ltrates
Abnormal deposits in the cornea
Corneal striae/folds Abnormal lines in the cornea
Condition with a defect in
the corneal epithelium. Often
associated with infection
Bacterial keratitis, fungal
keratitis, Chlamydia
Keratitis Infl ammation of the cornea Infectious, marginal keratitis
Keratoconjunctivo- Related to the cornea and the
Keratolysis Thinning or melting of cornea Paracentral, rheumatoid
Keratopathy Any disease of the cornea Band, exposure, lipid,
lamentous keratopathy
Keratomalacia Melting of the cornea usually
related to xerosis
Is this OK?
Defi nition of the Ocular Surface 11
Palpebral Conjunctiva
The palpebral conjunctiva lines the posterior surface of the eyelids. It is
divided into 3 portions: the marginal conjunctiva which extends from the
margin of the eyelids to the tarsus, the subtarsal conjunctiva which extends
over the tarsal plate and the orbital conjunctiva which extends from the
tarsus to the fornix (Lens et al. 2007).
The lacrimal caruncle is the reddish structure or eminence that is found in
the medial angle of the eye. It contains sebaceous and sweat glands.
The plicasemilunaris is asmall crease of the bulbar conjunctiva found at the
medial canthus (Arends and Schramm 2004). It produces a watery/mucoid
secretion with fatty substances that traps dirt and foreign particles from the
ocular surface to form rheum. The rheum forms the crust from the canthus
during sleep. Refer to Table 3 for terms related to the conjunctiva.
Table 3 This table summarizes words related to the conjunctiva.
Conjunctiva-related defi nitions Examples of use of term
Blepharoconjunctiv Related to eyelid and
Conjunctivalisation Abnormality of the cornea
where the epithelium resembles
that of the conjunctiva. Usually
related to limbal stem cell
defi ciency
Conjunctivitis Infl ammation in the conjunctiva,
usually infectious in nature, but
sometimes due to rare immune-
mediated conditions
Ligneous, bacterial, viral,
allergy-based, chlamydial,
Keratoconjunctivitis Infl ammation involving the
cornea and conjunctiva
Allergic keratoconjunctivitis
—atopic and vernal
keratoconjunctivitis sicca
(dry eye disease)
A special type of conjunctivitis
where a ‘membrane’ is
visualised over the ocular
Diphtheritic, pseudo-
membranous conjunctivitis
12 Ocular Surface
The sclera is a tough fi brous coat of the eye composed of mainly collagen
and elastic fi brous tissue. It has 3 poorly defi ned layers from superfi cial to
deep, called the episclera, the sclera proper and the lamina fusca (Lens et
al. 2007). Refer to Table 4 for defi nitions of some conditions involving the
Table 4 This table summarizes words related to the sclera.
Sclera-related defi nitions
Episcleritis Infl ammation of the episclera
Scleritis Infl ammation of the sclera
Sclerokeratitis Infl ammation of the sclera and cornea
Scleromalacia Degenerative thinning of the sclera, commonly associated
with rheumatoid arthritis and collagen diseases
Preocular Tear Film
The tear fi lm is a mixture of ocular surface secretions from the main lacrimal
and accessory lacrimal glands, meibomian glands and the corneal and
conjunctival epithelium. The tear fi lm, as part of the ocular surface system,
has several roles that include the provision of a smooth refractive surface,
protection of the ocular surface with its antibacterial and immune functions,
supply of oxygen and removal of metabolites such as carbon dioxide,
lubrication, and clearance of cells, debris and foreign bodies in conjunction
with the eyelids (Van Haeringen 1981, Tiffany 2008).
The preocular tear fi lm is the fi rst structure that incident light encounters
on reaching the eye; so the air-tear interface is the fi rst refractive surface
for focusing of light rays. Irregularities of the tear fi lm therefore affect
quality of vision. The tear fi lm in human eyes is structured in three layers:
the outer lipid layer, the intermediate aqueous layer and the inner mucin
layer. However, the aqueous and mucin layers have been described as a
continuum (Chen et al. 1997, Spurr-Michaud et al. 2007). The lipid layer of
the tear fi lm is secreted by the meibomian glands. This layer can be evaluated
by interferometry, and may be deranged in meibomian gland disease. There
have been studies which suggest that this layer consists of an outer layer
of neutral lipids and an inner layer of amphipathic polar lipids (Linsen
and Missotten 1990). The functions of this layer include the prevention of
aqueous tear evaporation and aiding the spreading of the tear fi lm.
The aqueous layer of the tear fi lm is basally secreted by the Kraus
and Wolfring accessory lacrimal glands, and refl ex secretion is by the
Defi nition of the Ocular Surface 13
main lacrimal gland. This layer forms the main bulk of the volume of
the tear fi lm.
The mucin layer is secreted by the goblet cells and also the corneal and
conjunctival epithelial cells (Asbell and Lemp 2006). This layer merges with
the glycocalyx of the conjunctival epithelial cells. The glycocalyx, being
anterior to the corneal epithelium, holds the tear fi lm on to the ocular
surface via membrane-spanning mucins attached to the microvilli and
small fi laments of the outermost superfi cial epithelial cells (Beuerman and
Pedroza 1996, Gipson 2007).
Tear Meniscus
The upper and lower tear menisci are strips of tear found on the upper and
lower lid margins respectively. They account for 75–90% of the total tear
volume on the ocular surface (Mishima et al. 1966, Holly 1985). During
blinking, tears are distributed from the menisci onto the ocular surface
(Lens et al. 2007).
The radius of curvature of the tear menisci has been found to be directly
correlated to the total tear volume (Yokoi et al. 2004), and the absence of
tear menisci is associated with dry eye disease. In ocular surface practice,
the menisci may be evaluated using the anterior segment optical coherence
tomography (Qiu et al. 2010).
Tear Turnover
Tear turnover is defined as the percentage decrease in fluorescein
concentration of tears per minute and is clinically used to assess the lacrimal
functional unit as well as tear quality (Mishima et al. 1966, Nelson 1995).
Reduced tear turnover is usually associated with ocular irritation and
infl ammation (de Paiva and Pfl ugfelder 2004).
Tear Production
There are multiple factors governing tear production. Tear production may
be classifi ed as basal, refl ex and emotional.
The lacrimal refl ex is the process where tear is produced after irritation
of the cornea and conjunctiva. This is in contrast to the basal tear production
which is constant in the resting state and added to the refl ex production in
the stimulated state. Psycho-emotional tears are related to emotional states
such as sadness, anger or happiness (Murube 2009).
14 Ocular Surface
Lacrimal Glands
The main lacrimal gland is located in the upper, outer quadrant of the
orbit and is made up of two lobes, the palpebral and orbital lobes. It is
composed of acinar, ductal and myoepithelial cells. The main lacrimal
gland is approximately 15 to 20 mm long, 10 to 12 mm wide and 5 mm thick
(Lorber 2007). The lacrimal gland is innervated by the smallest branch of
the ophthalmic nerve, the lacrimal nerve (Burton 1992). Any stimulation
to the ocular surface activates afferent sensory nerves in the cornea and
conjunctiva, which then activate afferent sympathetic and parasympathetic
nerves that subsequently stimulate the lacrimal gland to secrete proteins,
electrolytes and water (Zoukhri 2006).
With age, the morphology of the lacrimal gland changes and infi ltration
of infl ammatory cells into the lacrimal gland tissue occurs. This, in turn,
leads to infl ammation of the tissue and reduces protein and tear production
(Draper et al. 1998, Nagelhout et al. 2005).
Accessory Lacrimal Glands
The smaller accessory glands of Krause and Wolfring are part of the lacrimal
system and are located close to the superior fornix of the conjunctiva. Their
microanatomy is identical to that in the main lacrimal gland (Lemp and
Wolfl ey 1992).
Meibomian Glands
The meibomian glands are large, tubuloacinar structures embedded within
the tarsal plate of the eyelids (Jester et al. 1981, Obata 2002). There are about
32 glands in the upper eyelid and 25 in the lower eyelid (Greiner et al. 1998).
The sebaceous meibomian glands consist of branched, round-shaped acini
that secrete lipids into a long single duct.
The meibomian gland lipids, also referred to as meibum, comprise waxy
esters, sterols, cholesterol, polar lipids and fatty acids which are transported
towards the ductal orifi ce by blinking (Lemp and Wolfl ey 1992). The muscle
of Riolan at the gray line of the eyelid margin may also regulate meibomian
gland secretion. Once the lipids are secreted into the ocular surface, they
form the superfi cial lipid layer of the tear fi lm.
Goblet Cells
Conjunctival goblet cells are specialized glandular epithelial cells. They are
integrated in the conjunctiva epithelium and secrete gel-forming mucin
(Gipson 2004). The highest density of conjunctival goblet cells in humans
Defi nition of the Ocular Surface 15
is found in the nasal and nasal inferior area of the conjunctiva (Kessing
1968, Rivas et al. 1991). The number of goblet cells decreases in humans
in some conditions such asa loss of vascularisation after chemical injury,
or infl ammation in the ocular surface, e.g. conjunctivitis (Tseng et al. 1984,
Grahn et al. 2005). The innermost mucin layer of the tear fi lm is hydrophilic,
accounting for its adherence to the ocular surface.
Tear Drainage
The nasolacrimal drainage system consists of the lacrimal puncta,
canaliculus, lacrimal sac and nasolacrimal duct. This is the tear drainage
pathway from the lacrimal lake to the nasal cavity. The lacrimal lake is the
space or recess between the eyelids at the nasal commissure of the eye. The
tears collect from the upper and lower tear menisci and the preocular surface
into the lacrimal lake before draining into the lacrimal punctum.
The concept of the lacrimal pump is that the orbicularis oculi muscle
creates a pressure on the lacrimal sac. On relaxation, there is a negative
pressure which draws tears from the lacrimal lake into the sac via the
Lacrimal Puncta
The lacrimal puncta are small openings located on the medial aspect of the
eyelid margins and sit on an elevated structure called the papilla lacrimalis.
The openings are usually directed posteriorly against the globe.
Lacrimal Canaliculus
The lacrimal canaliculi are the tubular structures linking the lacrimal
puncta to the lacrimal sac. There is a vertical 2mm segment and a horizontal
8mm segment in each canaliculus. The upper canaliculus and the lower
canaliculus join to form the common canaliculus.
The common canaliculus enters the lacrimal sac obliquely forming the
valve of Rosenmüller, which prevents backfl ow of tears from the sac to
the canaliculi. Sometimes, the common canaliculus dilates slightly before
entering the lacrimal sac, forming the sinus of Maier.
Lacrimal Sac
This structure sits on the part of the bony orbit called the lacrimal fossa.
The superior part of the sac is the fundus and the inferior part of the sac,
16 Ocular Surface
the body, is where it extends to the osseous opening of the nasolacrimal
canal which contains the nasolacrimal duct.
Nasolacrimal Duct
The nasolacrimal duct consists of a superior (intraosseous) portion travelling
within the maxillary bone and a shorter inferior (membranous) portion
along the nasal mucosa. The duct ultimately opens into the inferior meatus
of the nasal cavity under the inferior nasal turbinate. There may be a valve
of Hasner at the opening of the nasolacrimal duct just before the tear drains
into the nasal cavity (Snell and Lemp 1998). Refer to Table 5 for terms related
to the lacrimal apparatus or unit.
Table 5 This table summarizes words related to lacrimal production and drainage.
Lacrimal-related defi nitions Examples of use of term
Dacryo-adenitis Infl ammation of the lacrimal
Granulomatous, tuberculoid,
lacrimal sac abscess
Pus-fi lled infected swelling in
the lacrimal sac
Dacryocystogram Imaging of the nasolacrimal
Dacryocystor-hinostomy Surgical procedure where
anastomosis is established
between nasal cavity and
lacrimal sac
Epiphora Excessive tearing onto the
face, i.e. caused by obstructed
drainage of tears
Lacrimal cysts Congenital displacement of
the lacrimal tissue resulting
in subconjunctival cysts
Lacrimal sacmucocele/
Swelling of the lacrimal
sac due to congenital
malformation or, if infected,
called lacrimal sac abscess
The Blood Supply of the Ocular Surface
The cornea is avascular except for the limbal area, which has a similar blood
supply as the conjunctiva. The blood supply to the conjunctiva is mainly
derived from the anterior ciliary and the palpebral artery branches. The
palpebral arteries also supply the eyelids and associated structures. The
corresponding veins drain these structures. The main lacrimal gland is
supplied by the lacrimal artery derived from the ophthalmic artery, with
veins draining to the superior ophthalmic vein (Snell and Lemp 1998).
Defi nition of the Ocular Surface 17
The Lymphatics of the Ocular Surface
The conjunctival and eyelid lymphatic vessels drain to the submandibular
lymph glands medially and to the superfi cial preauricular nodes laterally.
After certain types of infection or inflammatory processes, corneal
lymphatics can be observed (Tang et al. 2010, Nakao et al. 2011, Zhang et
al. 2011).
The cornea is the most densely innervated structure in the human body. The
nerve branches supplying the cornea are derived from the long posterior
ciliary nerves, which are from the ophthalmic and maxillary division of the
trigeminal nerve. At the peripheral cornea, the nerves from the conjunctiva,
episclera and sclera penetrate the cornea at various depths.
The nerve fi bers become unmyelinated when they penetrate the cornea
and run parallel to its surface. The corneal nerves turn abruptly 90 degrees
and proceed towards the corneal surface where they branch into the dense
subepithelial plexus (Marfurt et al. 2010). Unsheathed nerve endings arise
from the subepithelial plexus and continue superfi cially into the wing
and squamous cell layers of the epithelium (Beuerman and Pedroza 1996,
Müller et al. 2003).
Conjunctiva, Eyelids and Lacrimal Gland
The conjunctiva and eyelids are innervated by the ophthalmic and maxillary
branches of the trigeminal nerve (cranial nerve V). Refer to “Lacrimal gland
section” for lacrimal gland innervation.
Immune Privilege of Cornea
Since the cornea is avascular, the corneal stroma is normally not accessible
to the immune system. However, components of the innate immunity, such
as dendritic cells, have access to the limbal region. The corneal epithelial
cells possess pathogen recognition receptors, form a barrier to pathogens
and constitute an important part of innate defence of the ocular surface
(Kiel 2010).
In addition, components of the immune system, such as the complement
system and immunoglobulins, are present in the tear fi lm, thereby exposing
the corneal epithelium to these elements of the immune system. During
18 Ocular Surface
infl ammation of the cornea or when the cornea epithelium is breached by
trauma or microbes, cytokines and immune cells such as neutrophils and
macrophages will have access to the deeper layers of the cornea.
Mucosal Associated Lymphoid Tissues/Conjunctiva
Associated Lymphoid Tissues
The mucosal associated lymphoid tissue (MALT) is an important component
of the immunity in many mucosa of the body, for example, the Peyer’s
patches in the intestinal mucosa. Embedded into the palpebral conjunctiva
are lymphoid aggregates, the conjunctival associated lymphoid tissues
(CALT), which are an ocular surface form of MALT. The CALT are composed
of T and B lymphocytes, macrophages, plasma cells and dendritic cells
(Knop and Knop 2005) and serve as an induction site for immune defence
responses of the ocular surface (Astley et al. 2003, Liang et al. 2010).
The ocular surface is a well-integrated unit comprising the different parts
summarized above. Being a relatively exposed anatomical unit, the ocular
surface is prone to infections that can seriously affect the quality of lifestyle
of patients. In this chapter, we have summarized the main functions of
these different units and their associated commonly encountered clinical
diseases. We hope that this will help readers better understand the ocular
surface and its related pathology.
We would like to thank Lee Man Xin for aid in diagrams and research
relevant for the review.
Arends, G. and U. Schramm. 2004. The structure of the human semilunar plica at different
stages of its development—a morphological and morphometric study. Ann Anat 186:
Asbell, P.A. and M.A. Lemp. 2006. Dry eye disease: the clinician’s guide to diagnosis and
treatment. New York, Thieme Medical Publishers.
Astley, R.A., R.C. Kennedy and J. Chodosh. 2003. Structural and cellular architecture of
conjunctival lymphoid follicles in the baboon (Papio anubis). Exp. Eye Res. 76: 685–
Beuerman, R.W. and L. Pedroza. 1996. Ultrastructure of the human cornea. Microsc. Res.
Tech. 33: 320–335.
Binder, P.S., M.E. Rock, K.C. Schmidt and J.A. Anderson. 1991. High-voltage electron
microscopy of normal human cornea. Invest Ophthalmol. Vis. Sci. 32: 2234–2243.
Defi nition of the Ocular Surface 19
Burton, H. 1992. Somatic Sensations from the eye. Adler’s Physiology of the Eye. W. M. Hart.
St. Louis, Mosby-Year Book 71–100.
Chan-Ling, T.L., A. Vannas and B.A. Holden. 1988b. Long-term changes in corneal endothelial
morphology following wounding in the cat. Invest Ophthalmol Vis. Sci. 29: 1407–1412.
Chen, H.B., S. Yamabayashi, B. Ou, Y. Tanaka, S. Ohno and S. Tsukahara. 1997. Structure
and composition of rat precorneal tear fi lm. A study by an in vivo cryofi xation. Invest
Ophthalmol. Vis. Sci. 38: 381–387.
de Paiva, C.S. and S.C. Pfl ugfelder. 2004. Tear clearance implications for ocular surface health.
Exp. Eye Res. 78: 395–397.
Draper, C.E., E. Adeghate, P.A. Lawrence, D.J. Pallot, A. Garner and J. Singh. 1998. Age-related
changes in morphology and secretory responses of male rat lacrimal gland. J. Auton.
Nerv. Syst. 69: 173–183.
Gipson, I.K. 2004. Distribution of mucins at the ocular surface. Exp. Eye Res. 78: 379–388.
Gipson, I.K. 2007. The ocular surface: the challenge to enable and protect vision: the
Friedenwald lecture. Invest Ophthalmol. Vis. Sci. 48: 4390; 4391–4398.
Grahn, B.H., S. Sisler and E. Storey. 2005. Qualitative tear fi lm and conjunctival goblet cell
assessment of cats with corneal sequestra. Vet. Ophthalmol. 8: 167–170.
Greiner, J.V., T. Glonek, D.R. Korb, A.C. Whalen,E. Hebert, S.L. Hearn, J.E. Esway and C.D.
Leahy. 1998. Volume of the human and rabbit meibomian gland system. Adv. Exp. Med.
Biol. 438: 339–343.
Haque, S., D. Fonn, T. Simpson and L. Jones. 2004. Corneal and epithelial thickness changes
after 4 weeks of overnight corneal refractive therapy lens wear, measured with optical
coherence tomography. Eye Contact Lens 30: 189–193.
Hayashi, S., T. Osawa and K. Tohyama. 2002. Comparative observations on corneas, with special
reference to Bowman’s layer and Descemet’s membrane in mammals and amphibians.
J. Morphol. 254: 247–258.
Holly, F.J. 1985. Physical chemistry of the normal and disordered tear fi lm. Trans. Ophthalmol.
Soc. UK 104: 374–380.
Jester, J.V., N. Nicolaides and R.E. Smith. 1981. Meibomian gland studies: histologic and
ultrastructural investigations. Invest Ophthalmol. Vis. Sci. 20: 537–547.
Joyce, N.C. 2003. Proliferative capacity of the corneal endothelium. Prog. Retin Eye Res. 22:
Kessing, S.V. 1968. Mucous gland system of the conjunctiva. A quantitative normal anatomical
study. Acta. Ophthalmol. 95: 91.
Kiel, J.W. 2010. The Ocular Circulation. San Rafael, Morgan and Claypool Publishers.
Knop, E. and N. Knop. 2005. The role of eye-associated lymphoid tissue in corneal immune
protection. J. Anat. 206: 271–285.
Lemp, M.A. and D.E. Wolfl ey. 1992. The Lacrimal Apparatus. Adler’s Physiology of the Eye,
Mosby Year Book 18–28.
Lens, A., S.C. Nemeth and J.K. Ledford. 2007. Ocular Anatomy and Physiology. Basic Bookshelf
for Eyecare Professionals Series, Slack Incorporated.
Li, H.F., W.M. Petroll, T. Moller-Pedersen, J.K. Maurer, H.D. Cavanagh and J.V. Jester. 1997.
Epithelial and corneal thickness measurements by in vivo confocal microscopy through
focusing (CMTF). Curr. Eye Res. 16: 214–221.
Liang, H., C. Baudouin, B. Dupas and F. Brignole-Baudouin. 2010. Live conjunctiva-associated
lymphoid tissue analysis in rabbit under infl ammatory stimuli using in vivo confocal
microscopy. Invest Ophthalmol. Vis. Sci. 51: 1008–1015.
Linsen, C. and L. Missotten. 1990. Physiology of the lacrimal system. Bull. Soc. Belge Ophtalmol.
238: 35–44.
Linsenmayer, T.F., J.M. Fitch, M.K. Gordon, C.X. Cai, F. Igoe, J.K. Marchant and D.E. Birk.
1998. Development and roles of collagenous matrices in the embryonic avian cornea.
Prog. Retin Eye Res. 17: 231–265.
Lipham, W.J., H.A. Tawfi k and J.J. Dutton. 2002. A histologic analysis and three-dimensional
reconstruction of the muscle of Riolan. Ophthal. Plast. Reconstr. Surg. 18: 93–98.
20 Ocular Surface
Lorber, M. 2007. Gross characteristics of normal human lacrimal glands. Ocul. Surf. 5:
Marfurt, C.F., J. Cox, S. Deek and L. Dvorscak. 2010. Anatomy of the human corneal innervation.
Exp. Eye Res. 90: 478–492.
Maurice, D.M. 1957. The structure and transparency of the cornea. J. Physiol. 136: 263–286.
Maurice, D.M. 1972. The location of the fl uid pump in the cornea. J. Physiol. 221: 43–54.
Mishima, S., A. Gasset, S.D. Klyce, Jr. and J.L. Baum. 1966. Determination of tear volume and
tear fl ow. Invest Ophthalmol. 5: 264–276.
Müller, L.J., C.F. Marfurt, F. Kruse and T.M. Tervo. 2003. Corneal nerves: structure, contents
and function. Exp. Eye Res. 76: 521–542.
Murube, J. 2009. Hypotheses on the development of psychoemotional tearing. Ocul. Surf. 7:
Nagelhout, T.J., D.A. Gamache, L. Roberts, M.T. Brady and J.M. Yanni. 2005. Preservation of
tear fi lm integrity and inhibition of corneal injury by dexamethasone in a rabbit model
of lacrimal gland infl ammation-induced dry eye. J. Ocul. Pharmacol. Ther. 21: 139–148.
Nakao, S., S. Zandi, Y. Hata, S. Kawahara, R. Arita, A. Schering, D. Sun, M.I. Melhorn, Y. Ito,
N. Lara-Castillo, T. Ishibashi and A. Hafezi-Moghadam. 2011. Blood vessel endothelial
VEGFR-2 delays lymphangiogenesis: an endogenous trapping mechanism links lymph-
and angiogenesis. Blood 117: 1081–1090.
Nelson, J.D. 1995. Simultaneous evaluation of tear turnover and corneal epithelial permeability
by fl uorophotometry in normal subjects and patients with keratoconjunctivitis sicca
(KCS). Trans. Am. Ophthalmol. Soc. 93: 709–753.
Obata, H. 2002. Anatomy and histopathology of human meibomian gland. Cornea 21:
Preziosi, V.A. 1968. The Periphery of Descemet’s Membrane: A Study by Light Microscopy.
Arch. Ophthalmol. 80: 197–201.
Qiu, X., L. Gong, X. Sun and H. Jin. 2011. Age-related Variations of Human Tear Meniscus
and Diagnosis of Dry Eye With Fourier-domain Anterior Segment Optical Coherence
Tomography. Cornea 30: 543–549.
Rivas, L., M.A. Oroza, A. Perez-Esteban and J. Murube-del-Castillo. 1991. Topographical
distribution of ocular surface cells by the use of impression cytology. Acta. Ophthalmol.
(Copenh) 69: 371–376.
Snell, R.S. and M.A. Lemp. 1998. Clinical Anatomy of the Eye. Malden, Blackwell Science.
Spurr-Michaud S., P. Argueso and I. Gipson 2007. Assay of mucins in human tear fl uid. Exp.
Eye Res. 84: 939–950.
Stephens, L.C., T.E. Schultheiss, K.J. Vargas, D.M. Cromeens, K.N. Gray and K.K. Ang.
1989. Glands of the eyelids of rhesus monkeys (Macaca mulatta). J. Med. Primatol. 18:
Tang, X.L., J.F. Sun, X.Y. Wang, L.L. Du and P. Liu. 2010. Blocking neuropilin-2 enhances
corneal allograft survival by selectively inhibiting lymphangiogenesis on vascularized
beds. Mol. Vis. 16: 2354–2361.
The International Dry Eye Disease Workshop. 2007. The defi nition and classifi cation of dry
eye disease: report of the Defi nition and Classifi cation Subcommittee of the International
Dry Eye WorkShop. Ocul. Surf. 5: 75–92.
Thoft, R.A. 1978. Role of the ocular surface in destructive corneal disease. Trans. Ophthalmol.
Soc. UK 98: 339–342.
Tiffany, J.M. 2008. The normal tear fi lm. Dev. Ophthalmol. 41: 1–20.
Tseng, S.C., L.W. Hirst, A.E. Maumenee, K.R. Kenyon, T.T. Sun and W.R. Green. 1984. Possible
mechanisms for the loss of goblet cells in mucin-defi cient disorders. Ophthalmology
91: 545–552.
Van Haeringen, N.J. 1981. Clinical biochemistry of tears. Surv. Ophthalmol. 26: 84–96.
Wanko, T., B.J. Lloyd, Jr. and J. Matthews 1964. The Fine Structure of Human Conjunctiva in
the Perilimbal Zone. Invest. Ophthalmol. 3: 285–301.
Defi nition of the Ocular Surface 21
Wilson, S.E. and J.W. Hong. 2000. Bowman’s layer structure and function: critical or dispensable
to corneal function? A hypothesis. Cornea 19: 417–420.
Wulc, A.E., R.M. Dryden and T. Khatchaturian. 1987. Where is the gray line? Arch. Ophthalmol.
105: 1092–1098.
Yokoi, N., A.J. Bron, J.M. Tiffany, K. Maruyama, A. Komuro and S. Kinoshita. 2004. Relationship
between tear volume and tear meniscus curvature. Arch. Ophthalmol. 122: 1265–1269.
Zhang, H., X. Hu, J. Tse, F. Tilahun, M. Qiu and L. Chen. 2011. Spontaneous lymphatic
vessel formation and regression in the murine cornea. Invest Ophthalmol. Vis. Sci. 52:
Zoukhri, D. 2006. Effect of infl ammation on lacrimal gland function. Exp. Eye Res. 82:
... In the present study, we found 61 signals associated with eye disorders, accounting for 25% of the positive signals, and 38 signals anatomically related to the ocular surface, including "conjunctival, " "corneal, " "lid, " "lash, " and "lacrimal" 28 . In previous phase 2b and phase 3 clinical trials that included patients with moderate to severe AD (SOLO1 and SOLO2), the dupilumab treatment groups had a greater incidence of conjunctivitis (7.3% in dupilumab 300 mg every week group and 9.7% in dupilumab 300 mg q2w group) than the placebo group (2.2%) after 16 weeks of treatment 29 . ...
Full-text available
Dupilumab is a dual inhibitor of interleukin-4 and interleukin-13 and is mainly used to treat moderate-to-severe atopic dermatitis. Post-marketing safety data related to dupilumab have been accumulated, and it has been found that ocular surface diseases are closely associated with dupilumab treatment. The aim of this study was to detect dupilumab-related signals and to determine the safety characteristics of dupilumab with respect to eye disorders using real-world big data. Data on dupilumab use until December 29, 2019 were collected. The data were mined by calculating three indices: proportional reporting ratios, reporting odds ratios, and information components. The detected signals were classified using the primary system organ class in MedDRA terminology. Among 21,161,249 reports for all drugs, 20,548 reports were recorded for dupilumab. A total of 246 signals in the preferred terms were detected for dupilumab. Among the 246 positive signals obtained, 61 signals were related to eye disorders, which accounted for the largest percentage (24.8%), and 38 signals were anatomically related to the ocular surface. Dupilumab may cause extensive eye disorders; however, the underlying mechanisms and risk factors remain unclear. Our findings may facilitate broad safety screening of dupilumab-related eye disorders using real-world big data.
The eye is a unique and intricate organ with a persisting challenge to uphold optical clarity and sustain satisfactory neural retina function. The immune defenses in the eye occur at varying microenvironments including the corneal and conjunctival epithelia, uveal pigmented connective tissue, and even the highly protected neural retina. Ocular macrophages have been implicated in homeostasis and number of pathological conditions. In this chapter, the present understanding of ocular immunology with the distribution, phenotype, and the physiological role of the various ocular immune cells is discussed with their implication on ocular pathologies. Various novel strategies for potential macrophage targeting of drug in intraocular diseases are also discussed.KeywordsEyeIntraocular drug deliveryMacrophageOcular immunologyOphthalmic
The conjunctiva can be damaged by numerous diseases with scarring, loss of tissue and dysfunction. Depending on extent of damage, restoration of function may require a conjunctival graft. A wide variety of biological and synthetic substrates have been tested in the search for optimal conditions for ex vivo culture of conjunctival epithelial cells as a route toward tissue grafts. Each substrate has specific advantages but also disadvantages related to their unique physical and biological characteristics, and identification and development of an improved substrate remains a priority. To achieve the goal of mimicking and restoring a biological material, requires information from the material. Specifically, extracellular matrix (ECM) derived from conjunctival tissue. Knowledge of the composition and structure of native ECM and identifying contributions of individual components to its function would enable using or mimicking those components to develop improved biological substrates. ECM is comprised of two components: basement membrane secreted predominantly by epithelial cells containing laminins and type IV collagens, which directly support epithelial and goblet cell adhesion differentiation and growth and, interstitial matrix secreted by fibroblasts in lamina propria, which provides mechanical and structural support. This review presents current knowledge on anatomy, composition of conjunctival ECM and related conjunctival disorders. Requirements of potential substrates for conjunctival tissue engineering and transplantation are discussed. Biological and synthetic substrates and their components are described in an accompanying review.
Full-text available
To investigate the potential inhibitory effects of RNA interference-mediated knockdown of neuropilin-2 (NP2) on inflammation-induced corneal hemangiogenesis and lymphangiogenesis, and whether selective inhibition of lymphangiogenesis on vascularized recipient beds before transplantation improves the graft survival. Mouse lymphatic endothelial cells were transfected with the plasmid expressing artificial microRNA (amiRNA) against mouse NP2, and the down-regulation of VEGF-C-induced NP2 expression by NP2 amiRNA was evaluated by real-time PCR and western blot assays. Next, NP2 amiRNA or negative control amiRNA was injected intrastromally into BALB/c mouse model of suture-induced corneal neovascularization three days after surgery. Corneas were harvested 1 week after suture placement and the formation of lymphatic and blood vessels as well as the recruitment of macrophage was evaluated by immunohistochemical staining. The neovascularized graft beds treated by NP2 amiRNA or control then served as recipients of orthotopic corneal transplants, and age-matched C57BL/6 donors were used. Corneal allografts were examined twice a week for 8 weeks, and graft clarity was quantified by means of an opacity score. VEGF-C-induced NP2 expression at both mRNA and protein levels was significantly suppressed by NP2 amiRNA in mouse lymphatic endothelial cells. Intrastromal administration of NP2 amiRNA reduced corneal lymphangiogenesis by 45% versus control (p=0.015), but corneal hemangiogenesis (p=0.815) and the recruitment of CD11 antigen-like family member B (CD11b)-positive macrophage (p=0.589) were unchanged. Kaplan-Meier survival analysis revealed a better graft survival rate in the vascularized recipient beds pre-treated by NP2 amiRNA in comparison to controls (p=0.014). Knockdown of NP2 improves corneal graft survival by selectively inhibiting lymphangiogenesis in vascularized beds before transplantation. Thus our results open new treatment options for transplant rejection and other lymphatic disorders.
This presentation describes the unique anatomy and physiology of the vascular beds that serve the eye. The needs for an unobstructed light path from the cornea to the retina and a relatively fixed corneal curvature and distance between refractive structures pose significant challenges for the vasculature to provide nutrients and remove metabolic waste. To meet these needs, the ocular vascular beds are confined to the periphery of the posterior two thirds of the eye and a surrogate circulation provides a continuous flow of aqueous humor to nourish the avascular cornea, lens and vitreous compartment. The production of aqueous humor (and its ease of egress from the eye) also generates the intraocular pressure (IOP), which maintains the shape of the eye. However, the IOP also exerts a compressing force on the ocular blood vessels that is higher than elsewhere in the body. This is particularly true for the intraocular veins, which must have a pressure higher than IOP to remain patent, and so the IOP is the effective venous pressure for the intraocular vascular beds. Consequently, the ocular circulation operates at a lower perfusion pressure gradient than elsewhere in the body and is more at risk for ischemic damage when faced with low arterial pressure, particularly if IOP is elevated. This risk and the specialized tissues of the eye give rise to the fascinating physiology of the ocular circulations. Table of Contents: Introduction / Anatomy / Blood flow measuring techniques / Ocular perfusion pressure, IOP and the ocular Starling resistor effect / Ocular blood flow effects on IOP / Local control of ocular blood flow / Neural control of ocular blood flow / Summary
Purpose. The purpose of this article is to review available information regarding development, structure, and function of Bowman's layer in the cornea. Disease-related abnormalities of Bowman's layer are described. A hypothesis is advanced to explain the development and maintenance of Bowman's layer. Methods. Literature review and hypothesis formulation based on previous studies. Results. Information is presented that supports the hypothesis that Bowman's layer forms as a result of cytokine-mediated interactions occurring between corneal epithelial cells and keratocytes that include chemotactic and apoptotic effects on the keratocytes. This hypothesis suggests that Bowman's layer results from such interactions beginning in early development and continuing into adulthood in humans and other animals, such as chickens. Conclusions. Bowman's layer may be a visible indicator of ongoing stromal-epithelial interactions in the human and have no critical function in corneal physiology. Bowman's layer is commonly destroyed in diseases such as advanced bullous keratopathy where stromal-epithelial interactions may be interrupted. Bowman's-like layers often form in response to epithelium, for example when epithelial plugs extend into the stroma in corneas with radial keratotomy incisions.
A study by light microscopy of the periphery of Descemet's membrane was carried out using unconventional methods for the preparation of the specimen. The results showed a fiber system contiguous to the anterior limitation of the trabecular meshwork or of Schwalbe's ring when present. It was concluded that there is a possibility of this fiber system being connected with a specific functional region.
The aim of the DEWs Definition and Classification Subcommittee was to provide a contemporary definition of dry eye disease, supported within a comprehensive classification framework. A new definition of dry eye was developed to reflect current understanding of the disease, and the committee recommended a three-part classification system. The first part is etiopathogenic and illustrates the multiple causes of dry eye. The second is mechanistic and shows how each cause of dry eye may act through a common pathway. It is stressed that any form of dry eye can interact with and exacerbate other forms of dry eye, as part of a vicious circle. Finally, a scheme is presented, based on the severity of the dry eye disease, which is expected to provide a rational basis for therapy. these guidelines are not intended to override the clinical assessment and judgment of an expert clinician in individual cases, but they should prove helpful in the conduct of clinical practice and research.
Purpose: To study the feasibility of measuring total corneal thickness, as well as the thickness of the epithelium and Bowman's layer, using a novel in vivo confocal microscopy through-focusing (CMTF) methodology. Methods: The central cornea was scanned from the epithelium to endothelium at an average focal plane speed of 32 microns/sec for rabbits, and 64 microns/sec for humans. Scans were initially video-recorded and later digitized. From digital images, CMTF intensity curves were generated by calculating the average pixel intensity in the central 180 x 180 pixel region (285 microns x 285 microns) of each image in the scan, and plotting as a function of z-depth. Peaks in this intensity profile were then empirically correlated to unique corneal layers using a program which interactively displayed images corresponding to the mouse cursor position along the intensity profile curve. Sublayer thickness values were then calculated from the z-axis positions of the relevant peaks in the intensity curve. Ten normal rabbits and seven human volunteers were evaluated in the study. Both CMTF and ultrasonic pachymetry (UP) measurements were performed on rabbit eyes to determine the agreement between CMTF and UP. Results: Distinct epithelial, basal lamina, and endothelial peaks were identified for all 10 rabbit eyes. The mean central corneal thickness in the rabbit was 381.6 +/- 27.3 microns by CMTF and 384.4 +/- 28.7 microns by UP. The mean difference in central corneal thickness between CMTF and UP was -2.8 +/- 7.1 microns which was not statistically significant (p > 0.2 by paired t-test). Central epithelial thickness in the rabbit measured by CMTF was 47.7 +/- 2.2 microns. The average coefficients of variation for repeated scans were 2.5% and 0.7% for epithelial and corneal thickness, respectively. The standard errors for both epithelial and corneal thickness were less than 1.5 microns for all rabbits. The reproducibilities for epithelial and corneal thickness measurements were 2.2 microns and 2.6 microns, respectively, calculated as the square root of the within group variances of One-Way ANOVA. Intensity profiles for human corneas showed strong epithelial and endothelial peaks, as well as smaller peaks corresponding to the basal-epithelial nerve plexus and the denser anterior layer of stromal keratocyte nuclei. The mean central corneal thickness in the human was 532.1 +/- 18.8 microns; central epithelial thickness was 50.6 +/- 3.9 microns; central Bowman's layer thickness was 16.6 +/- 1.1 microns. The average coefficients of variation for repeated scans were 5.9%, 13.2%, and 1.6% for epithelial, Bowman's layer, and corneal thickness, respectively. The standard errors for all measurements were less than 2.4 microns. The reproducibilities for epithelial, Bowman's layer, and corneal thickness measurements were 3.2 microns, 2.3 microns, and 10.0 microns, respectively. Conclusions: CMTF is a novel, reproducible technique for obtaining epithelial and corneal thickness measurements during clinical in vivo confocal microscopy of the cornea. More importantly, this methodology provides the first objective, quantitative approach for measurement and analysis of depth and thickness of corneal sub-layers which may prove uniquely valuable in temporally assessing corneal function.
Mucin genes, both secreted (MUC2, MUC5AC, MUC5B, MUC7) and membrane associated (MUC1, MUC4, MUC16), have been reported to be expressed by ocular surface epithelia. The purpose of this study was to comprehensively assay the mucin content of human tear fluid using multiple antibodies for each mucin and to develop a sensitive, semi-quantitative method for the assay of mucins in tears. Tear washes were obtained by instillation of saline onto the ocular surface, followed by collection from the inferior fornix. Tear proteins were separated in 1% agarose gels, transferred to nitrocellulose membrane by vacuum blotting and probed with multiple antibodies recognizing MUC1, MUC2, MUC4, MUC5AC, MUC5B, MUC7 and MUC16. Binding was detected using chemiluminescence, and quantity was determined by densitometry. Serial dilutions of pooled tears from normal individuals were assayed to determine the linear range of detectability. MUC1, MUC4, MUC16, MUC5AC and low levels of MUC2 were consistently detected in human tear fluid, while MUC5B and MUC7 were not. Use of several antibodies recognizing different epitopes on the same mucin confirmed these findings. The antibodies to mucins bound to serial dilutions of tears in a linear fashion (r2 > 0.9), indicating the feasibility of semi-quantitation. MUC5AC in tear fluid had an increased electrophoretic mobility compared to MUC5AC isolated from conjunctival tissue. This study provides clear evidence that the mucin component of tears is a mixture of secreted and shed membrane-associated mucins, and for the first time demonstrates MUC16 in tear fluid. Immunoblots of tears using agarose gel electrophoresis and chemiluminescence detection provide a semi-quantitative assay for mucin protein that will be useful for comparisons with tears from diseased eyes or after pharmacological intervention.
To determine the age-related variations in the human tear meniscus using Fourier-domain anterior segment optical coherence tomography (FD-ASOCT) and evaluate its application in dry eye screening and diagnosis. One hundred forty-six patients with dry eye and 160 healthy controls were enrolled in this prospective, randomized, case-control study and grouped according to age: group A (0-19 years), group B (20-39 years), group C (40-59 years), and group D (>60 years). Tear meniscus height, tear meniscus depth, and tear meniscus cross-sectional area (TMA) were measured using FD-ASOCT (RTVue-100); corneal fluorescein staining, tear film breakup time, Schirmer I test, and a dry eye questionnaire were also estimated. Tear meniscus values were significantly correlated with clinical examination results and dry eye syndrome. Mean tear meniscus height, tear meniscus depth, and TMA values of patients with dry eye were significantly lower than those of the controls (P < 0.05). Tear meniscus values were negatively correlated with age in healthy Chinese subjects. Intraindividual variations in optical coherence tomography results were small in each group. Accuracy of dry eye diagnosis by FD-ASOCT was approximately 70%, and the clinical diagnostic critical point became lower with increasing age. Significant differences were observed in the tear meniscus borderline, TMA, and tear transparency between the 2 groups. FD-ASOCT provides blur-free imaging and precise measurement of the tear meniscus, which is consistent with clinical examinations. Therefore, FD-ASOCT is expected to become a valuable technique in dry eye screening and diagnosis.
Lymphatic dysfunctions are associated with many diseases, ranging from cancer metastasis to transplant rejection, for which there is little effective treatment. To date, there is no natural model with which to study lymphatic regression. This study was conducted to investigate whether murine cornea, an extensively exploited tissue for vascular studies, derives its lymphatic-free status from a natural regression mechanism. The differential behaviors between the lymphatic and blood vessels under normal development and inflammation conditions are also compared. Normal mouse eyeballs or whole-mount corneas encompassing the entire course of corneal development and maturation and adult inflamed corneas were used for immunofluorescent microscopic studies. The data demonstrated, for the first time, that mouse cornea was endowed with a significant number of lymphatic vessels that underwent spontaneous formation and regression during a critical period after birth, which was not observed for blood vessels. Because lymphatic growth can be reactivated in the adult cornea after inflammatory stimulation, the cornea thereby becomes the first tissue ever identified to have a full range of lymphatic plasticity. These novel findings not only provide a new concept in defining the cornea and its related diseases, they also reveal a completely natural model with which to study both lymphatic regression and formation. It is hoped that further studies will divulge novel and potent pro- or anti-lymphatic factors to treat lymphatic disorders inside and outside the eye.