Pain in and around the Eye

Gross Anatomy

The sensory innervation of the eye originates at the trigeminal ganglion. Most of the sensory axons directed to the eye run with the first division of the trigeminal ganglion, the ophthalmic nerve, which enters the superior orbital fissure and branches into the nasociliary, frontal, and lachrymal nerves. The nasociliary nerve sends out two long ciliary nerves that reach the eyeball and pierce the sclera. These nerves contain the major sensory output of the globe. Other branches of the nasociliary nerve are the infratrochlear nerve, which covers the medial aspect of the lids, nose, and lachrymal sac, and the external nasal nerves, as well as a branch coming from the ciliary ganglion. This parasympathetic ganglion, located within the orbit, sends to the eye numerous short ciliary nerves that carry parasympathetic postganglionic fibers. These short ciliary nerves also contain trigeminal sensory nerve fibers and postganglionic sympathetic axons originating from the superior cervical ganglion. The second branch of the ophthalmic nerve is the frontal nerve, which sends the supraorbital nerve to innervate the upper eyelid and frontal sinus and the supratrochlear nerve to innervate the forehead and upper eyelid. The third branch of the ophthalmic nerve, the lachrymal nerve, innervates the lachrymal gland and some areas of the conjunctiva and skin of the upper lid. It also receives postganglionic parasympathetic nerve fibers from the pterygopalatine ganglion ( Fig. 60-1 A).

The second major branch of the trigeminal ganglion, the maxillary nerve, carries sensory fibers from the eye through the infraorbital nerve, which is regarded as a continuation of the maxillary nerve; the infraorbital nerve enters the eye through the inferior orbital fissure and contributes to innervation of the conjunctiva and skin of the lower eyelid. This area receives additional innervation from the nasociliary nerve ( Fig. 60-1 A).

Trigeminal sensory nerve fibers end at the connective tissue, epithelia, and blood vessels of the orbit, uvea, ciliary body, extraocular muscles, choroid, scleral spur, lids, sclera, cornea, and conjunctiva. The retina itself does not receive direct trigeminal sensory innervation.

Architecture of Peripheral Ocular Sensory Nerves

The sensory nerves that innervate the various structures of the eye can be classified morphologically by their diameter and the presence of a myelin sheath and specialized structures around the nerve terminals. The majority of peripheral branches directed to the eye are thin myelinated or unmyelinated fibers that branch extensively and terminate as free nerve endings that have small enlargements (varicosities) along their terminal course. These varicosities are often incompletely surrounded by Schwann cells. This type of innervation is typically seen in the cornea ( Fig. 60-1 B–G). Under the electron microscope, some ocular sensory terminals exhibit a large number of mitochondria, whereas others show fewer mitochondria but both granular and small agranular vesicles ( , 1982b; ).

All myelinated axons reaching the cornea lose their myelin sheath when they penetrate the corneal stroma. Around 70 radially oriented stromal nerve trunks enter the human cornea and branch extensively to form the midstromal and subepithelial plexuses ( Fig. 60-1 B). The limbus and peripheral part of the cornea are innervated by more superficial nerve fascicles originating at the limbal plexus, an extension of the subconjunctival plexus ( ). Branches of the subepithelial plexus ascend vertically and traverse Bowman’s membrane, where they turn 90 degrees ( Fig. 60-1 B and E). Between Bowman’s layer and the basal epithelial cells, one parent stromal nerve branches into up to 20 long bundles (leashes or hairpin nerves) that ran parallel to the corneal surface from the periphery to the center ( Fig. 60-1 B, C and D). Sub-basal nerve filaments running into the leash branch repetitively and anastomose to form the sub-basal plexus. Altogether, the nerve fibers of the sub-basal plexus follow a curvilinear trajectory within the whole cornea and form a gentle spiral (vortex) located inferonasal to the apex of the cornea ( Fig. 60-1 C). From the sub-basal plexus, single fibers split off, turn 90 degrees vertically, and penetrate between the epithelial cells ( Fig. 60-1 E). These terminals end at variable levels as bulbous single endings ( Fig. 60-1 E and F) or branch into a small number of short collaterals, as occurs with most cold nerve terminals ( , , , , ).

Corneal axons appear morphologically homogeneous when they are visualized by classic histological or electron microscopy techniques. However, immunocytochemical staining shows the presence of different neuropeptides within the cell soma and the peripheral axons of corneal sensory neurons, thus suggesting a functional heterogeneity ( ). The deep nerve fiber bundles maintain a rather constant position and configuration within the cornea, whereas the intraepithelial terminals experience an extensive rearrangement that takes place in less than 24 hours. This suggests that active extension plus retraction of nerve terminals is occurring continuously in the most superficial layers of the corneal epithelium ( ). The number of corneal nerve terminals (around 600/mm ² ) decreases gradually with age in animals and humans ( , , ). Stromal and sub-basal corneal nerve filaments, but not corneal nerve terminals, can be visualized in the living eyes of human subjects by confocal microscopy, thus allowing correlation of morphological disturbances in nerves with clinical symptoms (Vesaluoma et al 2000, , ) ( Fig. 60-1 G).

The conjunctiva and eyelids, as well as the episclera and chamber angle, but not the cornea, receive some sensory fibers with encapsulated terminals in addition to their neuropeptide-containing thin, naked nerve terminals ( ). The choroid and iris are also richly innervated, mostly by naked, thin sensory nerve fibers.

Ocular Primary Sensory Neurons

The cell bodies of the ocular sensory afferents, most of which are of small or medium size, are located in the ipsilateral trigeminal ganglion and chiefly clustered in its ophthalmic (medial) region. Neurons innervating the cornea represent about 1.5% of the total number of neurons of the ganglion ( ). The axons of these pseudo-unipolar neurons divide into a peripheral branch that projects to the peripheral target tissues and a central branch that enters the brain stem to reach the trigeminal sensory complex.

Despite its relatively small size, the cornea receives a significant proportion of the ocular innervation (315,000–600,000 nerve terminals, 300–400 times more than in the skin) ( ). Based on the size and the presence of a myelin sheath in the peripheral axons, corneal trigeminal neurons can be classified as myelinated (20% in the mouse) and unmyelinated (80% in the mouse) ( , ). This feature is also reflected in the conduction velocity of the corresponding peripheral axons (see below).

Trigeminal ganglion neurons contain a large number of peptides, including the tachykinins substance P (SP) and neurokinin A, calcitonin gene–related peptide (CGRP), vasoactive intestinal peptide, neuropeptide Y, galanin, cholecystokinin, gastrin, somatostatin, opioid peptides, pituitary adenylate cyclase–activating peptide, neuronal nitric oxide synthase, secretoneurin, and chromogranin B–derived peptides (PE-11). The presence and functional role of the different peptides in the subpopulation of ocular sensory neurons have not been fully documented. However, it is well established that about 50% of the corneal neurons in the trigeminal ganglion are immunoreactive to CGRP, 20% of which also contain SP and neurokinin A, and all of them are directly involved in ocular neurogenic inflammation (Tervo et al 1982a, , ; for review see Tervo et al 1982b, , ).

Functional Types of Ocular Sensory Neurons

Corneal Neurons

The majority of the corneal sensory nerve fibers, about 70%, are polymodal nociceptors. They are activated by near-noxious or noxious mechanical energy, heat, chemical irritants, and a large variety of endogenous chemical mediators released by damaged corneal tissue and resident and migrating inflammatory cells or leaking from limbal vessels ( , , , ). Some of the polymodal nociceptor fibers belong to the group of thin myelinated (Aδ) nerve fibers, but most of them are of the C-fiber type. Polymodal nociceptors respond to their natural stimuli with a continuous, irregular discharge of nerve impulses that persist as long as the stimulus is maintained. Polymodal nociceptors have a mechanical threshold slightly lower than that of mechanonociceptors (see below), and when stimulated with heat, they begin to fire at temperatures higher than 39–40°C. A fraction of polymodal fibers (around 50%) also increase their firing rate when the corneal temperature is reduced to below 29°C ( , ). Many chemical agents known to excite the polymodal nociceptors of other territories (prostaglandins, bradykinin, capsaicin, mustard oil) also activate ocular nociceptors. Acidic solutions (pH 5.0–6.5) or gas jets containing increasing concentrations of CO ₂ (carbonic acid formation at the corneal surface decreases local pH) evoke an impulse discharge in corneal polymodal nociceptors ( ; ; ; ) ( Fig. 60-2 A). There is evidence that the transient receptor potential channel TRPV1 and possibly also the TRPA1 channel mediate the chemical sensitivity of corneal polymodal fibers.

About 15%–20% of the peripheral axons innervating the cornea, all thin myelinated fibers, respond only to mechanical force on the order of magnitude close to that required to damage corneal epithelial cells. Accordingly, they belong to the mechanonociceptor type. The axons of this class of receptor fire one or a few nerve impulses in response to either brief or sustained indentations of the corneal surface and often also when the stimulus is removed. Thus they are phasic sensory receptors that signal the presence of the stimulus and, to a very limited degree, its intensity and duration. The threshold force required to activate mechanonociceptors is low (about 0.6 mN), far below the force that activates mechanonociceptor fibers in the skin. However, this intensity might be sufficient to damage unkeratinized corneal epithelium. Mechanonociceptors in the cornea are probably responsible for the acute, sharp sensation of pain produced by touching the corneal surface. The aftersensations of pain elicited by noxious stimuli are probably explained by the more sustained activity of polymodal nociceptors (see Fig. 60-2 B).

Another category of corneal nerve fibers that represents 10%–15% of the total population consists of cold-sensitive thermal receptors. These are Aδ and C fibers that discharge spontaneously at rest, increase their firing rate when the normal temperature of the corneal surface (around 33°C) is reduced, and are transiently silenced on warming ( , , , ). Accordingly, cold thermoreceptor activity increases with drops in temperature produced by evaporation of the corneal surface, blowing of cold air onto the cornea, or the application of cold and hyperosmolar solutions. Menthol also activates and/or sensitizes ocular cold thermoreceptors. They are able to detect and encode the intensity of a stimulus by its impulse frequency within very small temperature ranges, 0.5°C or less ( , , ), thus explaining the perception of reductions in corneal temperature of such magnitude to elicit a conscious sensation of cooling ( ) and/or dryness ( ) ( Fig. 60-2 C). Spontaneous and cold-evoked impulse activity depends critically on the expression of TRPM8 because genetic deletion of this channel in mice makes corneal cold nerve terminals silent and unresponsive to cooling ( ).

Finally, it has been suggested ( ) that the cornea possesses mechanically insensitive, “silent” nociceptors ( ). Although experimental evidence for the presence of such nociceptors in the cornea is only indirect, they have been identified in virtually all other somatic tissues. Thus it seems likely that such nociceptors also exist in the cornea.

Sensory Neurons of Other Ocular Structures

Electrophysiological studies dedicated to identifying sensory receptor types in ocular structures other than the cornea are scarce. Nevertheless, they have shown that the same main functional classes of sensory afferents identified in the cornea and episclera (i.e., mechanonociceptors, polymodal nociceptors, and cold receptors) are also present in the bulbar conjunctiva ( ), the scleral surface ( ), and the iris and ciliary body ( , ). Cold fibers with response properties similar to the thermal receptors present in the cornea and limbus are also found in the iris and posterior sclera. It has been hypothesized that such scleral cold receptors that are not exposed to changes in environmental temperature could contribute to the detection of changes in choroidal and retinal blood flow and thereby contribute to reflex blood flow regulation rather than to the production of conscious thermal sensations ( ). Likewise, endings in the chamber angle with the appearance of mechanosensory terminals have been associated with neural regulation of intraocular pressure ( , ).

Figure 60-3 schematically depicts the functional types of sensory endings identified electrophysiologically in the various structures of the cat’s eye. Polymodal nociceptor and mechanonociceptor fibers have large receptive fields and are present in most ocular structures. Cold receptors have small receptive fields and are relatively abundant in the cornea and perilimbal area, where they exhibit spot-like receptive fields (for review see ). A few large, fast-conducting nerve fibers also innervate the perilimbal episclera ( ). They respond to weak mechanical stimulation and presumably contribute to non-noxious touch sensations evoked by gentle mechanical stimulation of the ocular surface, as those produced by blinking ( ).

Higher-Order Ocular Neurons

Sensory information from the eye, carried centripetally by trigeminal ganglion neurons, reaches the ipsilateral trigeminal brain stem nuclear complex (TBNC) in the lower brain stem and connects with second-order neurons located mainly at the rostral trigeminal subnucleus interpolaris/caudalis (Vi/Vc) transition and more caudally in laminae I–II neurons of the subnucleus caudalis/upper cervical spinal cord (Vc/C1) junction region, as well as in the adjacent bulbar lateral reticular formation ( , , , ). A few neurons with an ocular and periocular origin are present in the principal nucleus, and a very sparse number are confined to a few locations along the ventral border of the pars oralis and interpolaris of the spinal trigeminal nucleus ( ) ( Fig. 60-4 ).

Electrophysiological recordings have shown that about one-third of the ocular neurons found in the trigeminal subnucleus caudalis are intermingled with cutaneous low-threshold mechanoreceptive units and respond to eye stimulation. Most of them also receive convergent cutaneous input from periorbital skin. Ocular neurons have been further classified as nociceptive-specific (NS) neurons when responding only to noxious mechanical stimulation and as wide–dynamic range (WDR) neurons when they are also recruited by low-force stimuli ( , ).

It has been proposed that there exists a modality-specific distribution of corneal–conjunctival neurons within the TBNC. Neurons of the subnucleus interpolaris/caudalis are activated by all modalities of stimuli, whereas those within the superficial laminae of the subnucleus caudalis/cervical cord transition respond only to heat and chemical irritation, hence suggesting that the input to this region is restricted to polymodal nociceptor neurons ( , , ). A specific set of neurons that are inhibited by wetting and excited by drying the ocular surface have been identified at the interpolaris/caudalis transition area. They may receive input from cold thermoreceptors of the ocular surface and be involved in reflex tearing and fluid homeostasis of the ocular surface ( , , ). Corneal inflammation evoked by ultraviolet irradiation or intravitreal endotoxin sensitizes neurons at Vc/C1 but not at the Vi/Vc area, thus supporting the view that Vc/C1 ocular neurons are in charge of the sensory discriminative aspects of ocular pain and hyperalgesia whereas those of Vi/Vc mediate ocular-specific reflexes (lacrimation, blinking) ( ). The trigeminal complex conveys nociceptive messages to several brain stem and thalamic relays that activate a number of cortical areas responsible for ocular pain sensations and reactions. Second-order ocular neurons of the TBNC carrying nociceptive information from the eye and periocular structures project to the contralateral thalamus; NS and multimodal corneal neurons reach the dorsolateral and caudal regions of the thalamic posterior nucleus, respectively ( ). The zona incerta area and the superior salivatory/facial nucleus region also receive corneal input ( ).

Non-visual sensory representation of the eye in the cortex has been described in areas 3b and 1, in the lateral sulcus mainly on the contralateral side. In area 3b, ocular neurons are located along the lip of the lateral sulcus together with those that represent the nose, ear, and scalp. Ocular neurons that are activated by stimulation of the contralateral side have also been identified in the secondary somatosensory cortex (SII). The receptive fields are several times larger than those for area 3b neurons. The face is represented most superficially in the sulcus, with the hand, foot, and trunk being located deeper in the sulcus in a rostrocaudal sequence. A systematic representation of the face and body that extends laterally from SII on the lower bank of the lateral sulcus and forms the “ventral somatic” area has also been described ( , ). Cortical processing is sustained by reciprocal interactions with thalamic areas and also by direct modulation of their prethalamic relays. Processing of nociceptive input by ocular neurons of the TBNC is modified by the activation of descending controls from the pontine parabrachial area and the nucleus raphe magnus and mediated by γ-aminobutyric acid A (GABA _A ) receptors ( , ).

Activity in Ocular Primary Afferent Neurons following Noxious Stimulation

When injurious mechanical forces, noxious temperatures, or chemical irritants act on the ocular surface, polymodal nociceptor fibers fire nerve impulses at a frequency that increases rapidly with the amplitude of the stimulus and attains a maximum when overt cell damage is produced. Removal of the noxious stimulus transiently interrupts this activity, but it reappears few seconds later as a long-lasting, irregular low-frequency firing ( , ) representative of sensitization. Sensitization to new stimuli is additionally reflected in the lower threshold value required to activate the impulse response and the higher-frequency discharge evoked by a given intensity of the stimulus ( , ) ( Fig. 60-5 ) and is produced by the large variety of chemicals released locally by cells directly damaged by injury, such as potassium ions, protons, arachidonic acid metabolites, and others ( ). In addition, injury triggers an acute inflammatory response in the damaged tissue, and inflammatory cells, including neutrophils, macrophages, dendritic cells, and lymphocytes, enter the cornea from the limbal vessels to the stroma and epithelium. In the epithelium surrounding the wound, γδT cells, macrophages, and platelets contribute cytokines, chemokines, and growth factors in the early phases of tissue injury. Inflammatory mediators modify the probability of opening of the membrane ion channels of nociceptive nerve terminals, either directly or indirectly, through membrane receptor proteins that activate intracellular messenger pathways. This results in the changes in the membrane excitability of polymodal nociceptors that characterize sensitization (see Chapter 1, Chapter 2, Chapter 3 ). Anti-inflammatory drugs reduce the sensitization of polymodal nociceptors ( ).

Long-lasting local inflammation produces more permanent changes in nociceptive terminals, including modified expression of the existing receptor molecules and expression of new ones. Such effects seem to be mediated by cytokines (for instance, interleukin-6 [IL-6]) and growth factors, in particular, nerve growth factor (NGF) ( ), which during inflammation is produced in larger amounts by fibroblasts, thus increasing its levels in the injured cornea ( ). NGF induces acute sensitization of nociceptive sensory endings and long-lasting hyperalgesia. Acute NGF-evoked sensitization is the consequence of TrkA-mediated phosphorylation and translocation of TRPV1 to the cell membrane ( ), whereas its long-lasting sensitizing effects are most probably based on changes in protein expression. These changes could be mediated by internalized NGF/TrkA complexes that are transported to the trigeminal ganglion and activate gene expression or by modifying axonal translation of local mRNA and subsequent up- or down-regulation of voltage-sensitive sodium and potassium channels ( ). Another growth factor, glial-derived neurotrophic factor (GDNF), is also expressed following trauma and/or inflammation. GDNF acts on the subpopulation of non-peptidergic primary nociceptive neurons by altering the expression of neuronal receptor and ion channel molecules ( , ). Hence, growth factors appear to have a long-term influence on the responsiveness of ocular nociceptor neurons after injury and inflammation, as occurs with the peripheral sensory neurons of other tissues ( ).

The nerve impulses generated at corneal sensory endings by noxious stimuli propagate centripetally but also antidromically invade other non-stimulated branches of the parent axon ( ). The polymodal nociceptor endings of the cornea, unlike the cold-sensitive ones, possess sufficient density of sodium ion channels to sustain the propagation of antidromic nerve impulses down to the most distal part of the nerve terminal ( ; ). This property is possibly important to enable the depolarization-induced release of neuropeptides contained in the endings of distant nerve branches that were not directly exposed to the stimulus but became invaded by antidromic action potentials. These neuropeptides amplify and extend the local inflammatory reaction to intact ocular structures not directly affected by the stimulus (neurogenic inflammation). In this manner inflammation may spread after small corneal lesions to non-injured areas of the cornea and conjunctiva and extend even to the iris and ciliary body through the collateral branches of the corneal polymodal nociceptors that reach these structures. In the uvea, this neurogenic release of neuropeptides produces local vasodilation, plasma extravasation, and migration of immune cells, which ultimately leads to the excitation/sensitization of distant iris/ciliary body nociceptors and to the pain sensations, hyperalgesia, reflex tearing, and photophobia accompanying the widespread inflammatory response of the anterior segment of the eye evoked by localized corneal injuries ( ).

The uveal region is innervated mainly by its own mechanonociceptors and polymodal nociceptors that respond directly to high-threshold mechanical, thermal, and chemical stimuli ( ). These nociceptors are presumably the origin of the pain reported when the iris is touched accidentally during ocular surgery or, more often, when argon laser pulses are applied to the posterior uvea.

Intense, sustained ocular pain is also observed in parallel with the rapid rise in intraocular pressure that takes place in congestive glaucoma, which may lead to ischemia of the anterior segment of the eye. However, artificial increases in intraocular pressure in the eye of normal cats resulted in only transient impulse discharges in most corneal, scleral, and iridal sensory fibers ( ). This discrepancy can probably be explained by the fact that in a non-inflamed eye, very high intraocular pressure is required to effectively stimulate the mechanosensory and polymodal fibers that innervate the eye coats whereas the uveal inflammation that develops during congestive glaucoma leads to sensitization of nociceptors and could thereby increase excitability to mechanical stimulation and produce sustained firing.

Cold receptors of the cornea and conjunctiva have traditionally been considered low-threshold thermoreceptors not directly involved in ocular pain. In more recent times they have been postulated to behave as ocular surface humidity detectors because their continuous, ongoing activity exerts a tonic stimulatory action on lacrimal gland basal tear secretion ( ). Moreover, their exquisite sensitivity to temperature enables them to encode the oscillations in temperature that take place during interblink tear film evaporation, thus signaling surface wetness. This ability of cold thermoreceptors to measure ocular surface evaporation coupled with their sensitivity to changes in osmolality ( ) makes them particularly suited to encode in their firing frequency the drying of the ocular surface that occurs during exposure to dry environments, decreased aqueous tear secretion, or excessive tear evaporation. It is conceivable that the increased activity in ocular cold receptors contributes to the conscious and qualitatively distinct sensations of dryness experienced in these conditions ( ).

Clinical Testing of Ocular Sensitivity

Exploration of the sensitivity of the cornea or conjunctiva to mechanical stimulation is normally performed by gently touching the ocular surface with a wisp of cotton and observing the blink reflex or by comparing the subjective sensation with that evoked from the fellow eye. A more quantitative approach is obtained by using a calibrated hair of variable length (the Cochet-Bonnet esthesiometer). The gas esthesiometer ( ) uses an air jet of adjustable flow and temperature that may contain CO ₂ in a variable concentration to reduce local pH, which allows separate mechanical, thermal, or chemical stimulation of a limited area of the corneal or conjunctival surface. With these procedures, changes in corneal sensitivity in relation to age, sex, pregnancy, iris color, use of contact lenses, various types of ocular surgeries, or corneal diseases such as herpesvirus infection, keratitis, iritis, uveitis, diabetes, or glaucoma have been detected in multiple clinical and experimental studies ( Box 60-1 ) (for review see , ).