INNERVATION OF THE ANTERIOR 13

SEGMENT
-----------------------_._--- ---­

G. Ruskell and J.G. Lawrenson

13.1 INNERVATION OF THE CORNEA
The cornea is innervated by the ophthalmic
division of the trigeminal nerve. The naso­
ciliary branch of the ophthalmic nerve is the
source of all somatic sensory nerves of the
eye. Branches from the nasociliary nerve
either pass directly to the eye as long ciliary
nerves or pass through the ciliary ganglion
and enter the eye together with postgangli­
onic parasympathetic fibres in several short
ciliary nerves. Long and short ciliary nerves
commonly join before penetrating the sclera
in a ring around and close to the optic nerve.
They advance in the suprachoroid and enter
the ciliary body where sensory fibres, des­
tined for the cornea, separate from the much
larger parasympathetic content of the ciliary
nerves. Shortly after their separation the sen­
sory fibres enter the sclera as numerous fine
nerves, often using the same conduits as the
anterior ciliary arteries and venules, and
advance radially to the corneal stroma (Fig.
13.1). Most cross from sclera to cornea in the
outer half, the more superficial of them often
having first reached the episclera. A few
small fibre bundles enter conjunctival epi­
thelium within 1 mm of the cornea and
continue into corneal epithelium rather than
the stroma (Zander & Weddell, 1951; Lim &
Ruskell, 1978) (Fig. 13.2). A suggestion that
access for all corneal nerve fibres is via this
route (Lim & Ruskell, 1978) is now know to
be false.
A circumcorneal arrangement of nerves is
demonstrable in gross preparations, using
such stains as methylene blue or acetylcho­
linesterase. This arrangement is composed of
an episcleral pericorneal plexus and a sub­
conjunctival plexus or bundles (Attius, 1912;
Zander & Weddell, 1951); the two are inter­
connected. A few scleral branches may pass
superficially and contribute to the pericor­
neal arrays and subsequently tum forward
into the cornea at a superficial level - those
Figure 13.1 Meridional section through the ante­
rior segment of the coat of the eye. The 'vermi­
form' structure leaving the ciliary muscle (c) and
penetrating the sclera (s) is a ciliary nerve branch
destined for the cornea via the episclera. An
anterior ciliary vein occupies the same conduit
(magnification X 25).

Contact Lens Practice. Edited by Montague Ruben and Michel Guillon.

Published in 1994 by Chapman & Hall, London. ISBN 0 412 35120 X

226 Innervation of the anterior segment

Figure 13.2 Anterior view of the eye showing the

distribution of corneal nerves. A segment is
removed to reveal the cornea in section. In an
adjacent segment opposite the limbus at (a) the
epithelium is removed to show the distribution of
stromal nerves. In the segment opposite (b) epi­
thelial nerves are added with the broken lines
representing the principle stromal nerves;
examples of penetration of Bowman's layer are
arrowed. Penetration is again shown in the cor­
neal section (larger arrows), and direct access of a
nerve fibre bundle from the conjunctiva to the
corneal epithelium is indicated at (c). The drawing
Figure 13.3 Nerves of the corneal stroma of a
is based on the nerve pattern seen in rabbit and
rabbit stained with acetylcholinesterase. They
human cornea (modified from Ruskell, 1989).
radiate from the darkened limbal tissue below
(magnification X 34).

passing directly into the corneal epithelium

are an example of this. However, most of the
pericorneal nerves tend to follow the course
of limbal blood vessels and are predomi­
nantly autonomic and vasomotor. The claim
that a fraction of the nerves entering the
cornea come from sources other than the
ciliary nerves (Attius, 1912) has not been
confirmed (Zander & Weddell, 1951). The
superficial circumferential pattern termi­
nates at the corneal margin and nerve distri­
bution in the cornea itself is predominantly
radial. But, as can be seen in Figure 13.3,
branches of the principal nerves disperse in a
variety of directions.
The 50-80 precorneal nerve trunks contain
a mixture of myelinated and, more numer­
ous, unmyelinated fibres, enclosed by a
perineurium and packed with endoneurial
collagen (Fig. 13.4). Only the nerve fibres
progress into the cornea and any myelin
quickly terminates. The initial path of nerve
fibre bundles in the cornea may be seen with
the biomicroscope as dull white spikes for a
fraction of a millimetre and sometimes sub­
stantially longer. Their visibility is presum­
ably due to light reflection from the Schwann
cell sheaths of larger fibre bundles, rather
than to the persistence of myelin.
Unmyelinated nerve fibre bundles contain
between one and eight axons and as many as
20 bundles are initially grouped together in
the larger corneal nerves. Much overlapping
occurs and junctions between nerves are
quite common. Some penetrate to the centre
of the cornea and beyond. This arrangement
explains why sensitivity, although reduced,
 Innervation of the cornea 227
and Weddell (1951). Beading also Occurs
along axons of the plexus nerves. The axo­
plasm is composed largely of neurofilaments,
and mitochondria occur at infrequent inter­
vals; this pattern is interrupted at the beads
which are packed with mitochondria and
often contain a few vesicles (Fig. 13.6). Mat­
suda (1968) claimed that beads or varicosities
fall into two groups - one with and the other
without vesicles - and he attributed different
functions to them. However, it remains
unclear whether or not the difference in form
is attributable to sampling from single rather
than serial sections; the latter might reveal
similar organelles in all beads. As nerves
penetrate deeper into the cornea they tend to
flatten between or within stromal lamellae
(Fig. 13.7).
Nerves from the subepithelial plexus
pass superficially and penetrate Bowman's
layer to enter the epithelium (Fig. 13.8).
Schwann cells are shed before or during
their passage through this layer. Generally
they consist of small groups or leashes of
naked axons that turn into the plane of the
epithelium at basal cell level close to or on
Figure 13.4 Transverse section through an epis­
cleral nerve shortly before entering the cornea. It
contains three myelinated fibres (one with a
Schwann cell nucleus is arrowed) and numerous
unmyelinated nerve fibre bundles. A thick
perineurium encloses the nerve (magnificataion X
5300).

persists in all areas of the cornea subsequent

to large, full-penetration, perilimbal inci­
sions (Schirmer & Mellor, 1961). All nerves
move to a more superficial position to
become confined to the anterior third of the
stroma, and a subepithelial plexus of nerves
is formed. Single nerve fibres issue from the
large radial nerves or the plexus, often at
right angles, and divide a number of times. 5
These are assumed to terminate in the Figure 13.5 Varicose axons immediately underly­
stroma. In our preparations the single axons ing Bowman's layer. They appear to run singly
are beaded (Fig. 13.5) and not in the fonn of and presumably terminate in this position. Whole
simple fine threads as described by Zander mount, gold chloride (magnification X 720).
228 Innervation of the anterior segment
Figure 13.6 Nerve fibre bundles of the corneal
stroma close to the limbus. Note the prominence
of Schwann cell sheaths (s), a substantial variation
in axon diameters and the presence of small
agranular vesicles in some axons (arrows) (magni­
fication X 22 700).
Figure 13.7 A nerve fibre bundle, remote from the
limbus, is flattened in the plane of the cornea
(magnification X 6300).
the basement membrane (Fig. 13.9). They
usually divide into smaller groups upon
entry and run a lengthy and surprisingly
straight course, maintaining their position
close to the basement membrane. Single
axons separate from the bundle and termi­
nate locally.
Figure 13.8 A nerve fibre bundle entering Bow­
man's layer (top left) from the stroma. Each of the·
five axons in the bundle contains mitochondria;
one is practically filled with them, another (aster­
isk) appears to have swollen and contains few
organelles, and the uppermost axon, which is
tuming into Bowman's layer, also contains
vesicles. The lowermost axons are ensheathed by
a Schwann cell (s) and the bundle is accompanied
by fibroblast processes (f) that continue into Bow­
man's layer. The random orientation of collagen
fibrils of Bowman's layer is discernible (arrow)
(magnification X 17 000).
The relationship between axons and the
basal epithelial cells varies. Single or mul­
tiple axons may lie between the cell and its
basement membrane or between cells. Oth­
ers deeply invaginate the cells, lying within a
fold of the plasma membrane; the axon or
axons are tightly enclosed as are the apposed
cell membranes forming the channel con­
necting the axon chamber to the surface of
the cell (Fig. 13.10). The channel commonly
displays a series of sharp convolutions and it
is bridged by gap junctions and desmosomes
(Fig. 13.11). Some axons tum superficially
towards the corneal surface (Fig. 13.12).
Schimmelpfennig (1982) found evidence that
axons passing towards the surface are
numerous, but in our experience they have a
relatively low frequency and the bulk of
epithelial axons remain close to the basement
membrane.
An agreed morphological or biochemical

Figure 13.9 Varicose axons with a common direc­
tion at basal cell level. Each of the four strands
may represent more than a single axon. Note that
they mainly pass between basal cells but some­
times appear to traverse cells (arrows). The dense
dark spot (asterisk) indicates an axon orientated
perpendicular to the plane of the cornea. Whole
mount, gold chloride (magnification X 680).
Figure 13.10 Two epithelial axons sectioned at
varicosities and packed with mitochondria. They
invaginate a basal cell, and the periaxonal spaces
are exposed to the cell surface through a short
narrow channel (arrow) (magnification X 12 800).
subdivision of corneal nerve terminals in
man has not been found. Substance P (Tervo
Innervation of the cornea 229
et al., 1982; Stone & Kuwayama, 1985) and
calcitonin gene-related peptide (Stone &
McGlinn 1988; Uusitalo et al., 1989) immu­
noreactive nerves of trigeminal origin are
described in the human cornea. They are
present in the stroma and in the epithe­
lium. However, it is unlikely that the two
reactions indicate separate groups of sen­
sory fibres, because it is known that both
neuropeptides occur in the same neuron in
experimental animals (Lee et al., 1985; Gul­
benkian et al., 1986). The specific local
functional roles of the neuropeptides is not
known. The proportion of nerves showing
these reactions is a small fraction of the
total corneal innervation, and presumably
sensory nerves of a different character may
be present.
Whether or not the human cornea has
sympathetic innervation remains uncer­
tain. A histochemical technique providing
evidence for a sympathetic innervation in
subprimate mammalian species fails to do
so when applied to monkey and human
Figure 13.11 Two more examples ofaxons invagi­
nating a basal cell. The axons are sectioned at
intervaricose level and contain mainly neurofila­
ments and microtubules. The circuitous channel
on the left; linking the periaxonal space to the cell
base is bridged by a desmosome (arrow). h. basal
hemidesmosome (magnification X 41 700).

Fi~re 13.12 Axon with several agranular vesicles.
near the surface of the cornea; the lighter cell
above was adjacent to a squamous surface cell
(magnification X 37 500).
corneas (Ehinger, 1964, 1971; Laties & Jaco­
bowitz, 1966), yet application of a modified
version of the technique is claimed to give
a positive result in man (Toivanen et al.,
1987). On the other hand, neuropeptide-Y­
like immunoreactive nerves closely parallel
sympathetic nerve distribution in the eye,
and none could be found in human corneas
(Stone, 1986).
Cataract surgery and other procedures
requiring incision of the limbus incur the
severance of a large fraction of the nerves
serving the cornea, and in penetrating
keratoplasty the nerves of the donor cornea
are totally severed and destroyed. The
capacity of nerves to regenerate in these
circumstances is limited. Progress of rein­
nervation may be inferred from sensitivity
monitoring following the lesion. Corneal
touch sensitivity close to a limballesion is
reduced to half the normal level and subse­
quent testing shows little improvement
(Draeger, 1984). Recovery of sensitivity fol­
lowing corneal grafts is practically nil in
some cases and slow and fractional in oth­
ers (Ruben & Colebrook, 1979; Lyne, 1982).
These observations parallel the very few
nerves seen in corneal grafts obtained less
than three years after operation (Tervo et
al., 1985), yet in a single clear cornea with a
29-year-old graft, epithelial innervation
was almost normal, whereas few stromal
nerves had regenerated.
The possibility that the maxillary nerve is
the source of some corneal nerves cannot be
discounted. Fibres from a maxillary root to
the ciliary ganglion found in monkeys, con­
tinue in the short ciliary nerves (Ruskell,
1974). Their terminations within the eye
remain unknown but the cornea is a likely
target.
13.2 INNERVATION OF THE TRABECULAR
MESHWORK
Because the Ciliary muscle inserts into the
uveal part of the trabecular meshwork, any
nerve fibres present may represent looping
or misdirected fibres properly belonging to
the ciliary muscle. But fibres of terminal
form have been located well forward of the
muscle, and the possibility of a function
specific to the trabeculae cannot be
ignored. They are present in the uveal and
scleral trabeculae and immediately beneath
the inner wall of the canal of Schlemm in
monkeys (Ruskell, 1976), but their fre­
quency is low (Fig. 13.13). Of the sympa­
thetic, parasympathetic (of pterygopalatine
ganglion origin) and sensory terminals
found, only the latter were found regularly.
In man, sympathetic adrenergic nerves are
usually absent (Ehinger, 1971) or few
(Stone, 1986) (assuming that fibres immu­
noreactive to neuropeptide Yare sympa­
thetic). Moderate numbers of substance
P-like immunoreactive fibres, and there­
fore probably sensory, are present (Stone &
Kuwayama, 1985). The frequency and
apparent variability of trabecular terminals
hinders consideration of their possible
roles and does not permit disciplined
speculation. This must await more detailed
and comprehensive study.

Figure 13.13 Two axons, ringed and separated by
a Schwann cell process, within a trabecula, A few
vesicles are present in the larger axon (arrow). The
nuclei of two trabecular endothelial cells are
shown (n) (magnification X 9900).
13.3 INNERVAnON OF THE CONJUNCTIVA
It has now been established that the conjunc­
tiva receives a tripartite nerve supply; con­
juctival nerve fibres are classified as sensory,
sympathetic or parasympathetic. The sen­
sory nerves are trigeminal in origin and
reach the conjunctiva principally via
branches of the ophthalmic nerve. The tradi­
tional view is that the inferior conjunctiva is
served, additionally, by the infra-orbital
branch of the maxillary nerve (Duke-Elder &
Wybar, 1961). However, Oduntan (1987),
tracing Wallerian degeneration following
maxillary neurectomy in monkeys, ques­
tioned the constancy of the maxillary contri­
bution, which when present was found to be
minor.
There is some evidence that the bulbar and
limbal conjunctiva receive their sensory sup­
ply via ciliary nerve branches that penetrate
the sclera from an intra-ocular position ante­
riorly in monkeys (Ruskell & Simons, 1990).
Presumably, nervous activity arising from
stimulation of the bulbar conjunctiva would
therefore, in part, be transmitted through the
eye.
Evidence for a sympathetic innervation of
the conjunctiva was presented by Ehinger
(1971) who demonstrated catecholaminergic
Innervation of the conjunctiva 231
and, by implication, sympathetic fibres in
relation to conjunctival blood vessels. Fur­
ther evidence for a sympathetic supply issu­
ing from the superior cervical ganglion has
been obtained from degeneration studies in
monkeys (Macintosh, 1974), from tracer
experiments in rabbits (Ten Tusscher et al.,
1988), and combined immunohistochemical
and denervation studies in rats (Luhtala et
al., 1991).
Parasympathetic nerve fibres of facial
nerve origin are known to innervate the eye
and orbital structures (Ruskell, 1965, 1970).
Such fibres, relaying in the pterygopalatine
ganglion (PPG), are known to project to con­
junctival blood vessels (Macintosh 1974;
Ruskell, 1985; Ten Tusscher et al., 1988).
Vasoactive intestinal polypeptide (VIP) has
been identified as a neurohumour localized
in ocular parasympathetic nerve endings of
PPG origin (Uddman et al., 1980) and it is
known to be a potent vasodilator in the eye
(Nilsson & Bill, 1984). The concentration of
VIP in the rabbit conjunctiva was reduced
following PPG lesions (Butler et al., 1984) but,
surprisingly, conjunctival nerves displaying
VIP immunoreactivity have not been identi­
fied so far in man (Miller et al., 1983).
The general form and distribution of con­
junctival nerve fibres and their terminals in
man is similar to that described in monkeys
(Macintosh, 1974; Ruskell, 1985,: Oduntan,
1987). Nerves of various calibres, containing
both myelinated and unmyelinated fibres
and invested with a perineural sheath (Fig.
13.14), are present within the deep fibrous
layer of the conjunctiva, where they fre­
quently lie adjacent to conjunctival blood
vessels. In addition, single and small groups
of nerve fibres (with or without a perineu­
rium) and nerve terminals are widely distrib­
uted throughout the substantia propria, with
greatest concentration close to the basal epi­
thelial layer (Fig. 13.15) and within the
adventitia of blood vessels (Fig. 13.16).
Although nerves fibres terminate at all levels
of the substantia propria but few enter the
232 Innervation of the anterior segment
epithelium - those that do are confined to the
basal layer (Fig. ·13.17). Nerve endings are
located in the walls of arterioles and capillar­
ies where sympathetic parasympathetic and
sensory terminals have been identified
(Macintosh, 1974). The presence of a sensory
supply to conjunctival blood vessels is sup­
ported by studies on the distribution of the
neuropeptides substance P and calcitonin
gene related peptide (Stone & Kuwayama,
1985; Stone & McGlinn, 1988; Luhtala et al.,
1991). These biologically active peptides are
known to localize in ocular sensory nerves
(Stone et al., 1987).
Accounts of conjunctival innervation
describe two forms of nerve termination ­
free nerve endings and corpuscular (com­
pact) nerve endings. The term 'free nerve
ending' describes terminals showing the Figure 13.15 A subepithelial unmyelinated nerve
minimal degree of structural specialization, fibre bundle including a large axon terminal vari­
where an axon ends blindly with sparse cosity (arrowed) underlying limbal conjunctival
epithelium (e). The varicostiy contains several
cellular wrappings. Free nerve endings arise mitochondria (magnification X 16 257).
from both unmyelinated and myelinated

axons, and account for the mode of termina­

Figure 13.14 Electron micrograph of a mixed
nerve from deep in conjunctival stroma. An
incomplete perineural sheath encloses a single
myelinated nerve fibre (n) and several unmyeli­
nated fibres (magnification X 9661).
tion of all autonomic fibres and the majority
of sensory fibres. A feature of the axon termi­
nal is the presence of beads or varicosities
(Figs 13.15 and 13.17). Varicosity content
cannot generally be used to distinguish sen­
sory from autonomic terminals, but those
containing small granular vesicles are, in our
experience, highly suggestive of sympathetic
terminals (Ruskell, 1981).
Nerve endings of corpuscular form repre­
sent the terminal morphology of a proportion
of human conjunctival sensory nerves,
although surprisingly they are not found in
the conjunctiva of other primates. They were
first described in the mid-nineteenth century
(Krause, 1859), and subsequent accounts
express various opinions as to the precise
morphology and relative incidence of these
complex nerve endings (see Duke-Elder &
Wybar, 1961 for a summary). Corpuscular
nerve endings are distributed throughout
the bulbar conjunctiva (Fig. 13.18), where

Figure 13.16 Unmyelinated nerve fibre bundles
(arrowed) adjacent to a conjunctival capillary. v,
vascular endothelium; P. pericyte; f, fibrocyte
processes (magnification X 11 216).
they are most numerous in the upper tempo­
ral quadrant (Ciaccio, 1874; Oppenheimer et
al., 1958). In addition, they are commonly
found at the eyelid margin (Munger &
Hulata, 1984) and at the limbus (Lawrenson
& Ruskell, 1991) where they show a close
association with the conjunctival palisades of
Vogt. Corpuscles are often found within the
connective tissue ridges which make up the
palisades (Fig. 13.19). Each corpuscle is usu­
ally served by a single nerve fibre (Fig.
13.20), which loses its myelin sheath upon
entering the corpuscle. This afferent fibre
subsequently branches to give rise to a vari­
able number of axon terminal varicosities
containing an accumulation of mitochondria.
Both terminal and preterminal axons are sur-
Innervation of the conjunctiva 233
Figure 13.17 Intra-epithelial axon terminal vari­
cosity (arrowed) enclosed by a basal epithelial cell.
Note compound melanosomes (asterisks) within
epithelial cells (magnification X 19 501).
rounded by Schwann-like supporting cells,
and the whole corpuscle is enclosed by a thin
fibrocyte capsule (Figs. 13.21 and 13.22).
The sensory innervation of the conjunctiva
provides the mucous membrane with the
ability to detect changes in its environment.
The sensory receptors are capable cf
responding to the sensory modalities of
touch, pain, warmth and cold. Although sub­
ordinate to the cornea in its sensitivity to
touch and pain, the conjunctiva appears to
be superior in differentiating temperature
(Kenshalo, 1960). Terminal form within the
conjunctiva cannot as yet be related to func­
tion, although free nerve endings in the skin
have been implicated in the mediation of a
full range of modalities. The function of
234 Innervation of the anterior segment
Figure 13.18 Three corpuscular nerve endings
(arrowed), assumed to be sensory receptors, in the
bulbar conjunctiva at varying distances from the
goblet cell-containing epithelium (magnification
X 182).
corpuscular nerve endings found within the
conjunctiva has been considered by various
investigators and suggestions include
mechanoreception (Krause, 1859) and cold
reception (Strughold & Karbe, 1925). In con­
trast, Oppenheimer and co-workers (1958)
claimed that rather than representing spe­
cific receptors, such nerve endings are the
product of cyclic degenerative and regenera­
tive changes taking place within sensory
nerve terminals. However, our own observa­
tions of a normal appearance of axoplasm in
all or most of these putative receptors dis­
courages acceptance of this dismissal of their
functional relevance. Furthermore, a recent
study of the limbal touch sensitivity (Lawren­
son & Ruskell, 1993) has provided some
indirect evidence of a role for corpuscular
Figure 13.19 Corpuscular receptor in the limbal
conjunctiva. The corpuscle is located within a
stromal elevation which forms a palisade of Vogt
(magnification X 469).
nerve endings in mechanoreception. The
palisade zone was found to have a higher
touch sensitivity than the adjacent conjunc­
tiva, which may be related to the concentra­
tion of sensory corpuscles in this zone.
Sensory nerves of the conjunctiva mediate
a local inflammatory response to a variety of
noxious stimuli (Lewis, 1937). This phenom­
enon, known as neurogenic inflammation, is
characterized by vasodilation and increased
permeability, which are thought to be medi­
ated specifically by sensory nerves contain­
ing the neuropeptide substance P and
calcitonin gene-related peptide (Unger &
Butler, 1988). These neuropeptides can act on
blood vessels, or indirectly by stimulating
the release of vasoactive substances from
mast cells. The vascular sympathetic and
parasympathetic terminals are responsible
for vessel constriction and dilation respec­
tively.
....
Figure 13.20 Whole-mount gold chloride prepara­
tion of a corpuscular receptor showing the afferent
nerve fibre (n) and connective tissue capsule (c).
Detail within the corpuscle is obliterated by the
dense staining pattern (magnification X 540).
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