Ординатура / Офтальмология / Английские материалы / Dry Eye and Ocular Surface Disorders_Pflugfelder, Beuerman, Elliot Stern_2004

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and it provides a framework for understanding how the system dysfunctions in dry eye patients.

A complex of sensory, sympathetic, and parasympathetic nerves links the components of the lacrimal functional unit into a homeostatic loop with the essential role of protecting and supporting the ocular surface. Acting through areas of the CNS, the tissues are linked together by specific neural input and output pathways (Fig. 1). The tissues and their neural components can be classified by function. For example, the cornea provides sensory input to the functional unit, whereas the lacrimal glands, despite their secretory function, contain all three types of neural tissues. Sensations arising from the cornea are always along the pain continuum, and corneal nerves are responsible for the patient’s perception of discomfort in dry eye (2). Indeed, a role for pain-associated fibers in the control of tear flow was recently proposed based on clinical observations (3).

III.INNERVATION OF OCULAR SURFACE COMPONENTS

A.The Cornea

Situated prominently in the palpebral fissure, the cornea is broadly subject to environmental challenges. To protect itself, the cornea has developed the most densely innervated epithelial surface in the body. This specialized innervation is sensory and the neural receptors are only of the morphologically unspecialized type, or “free nerve endings,” which terminate throughout all layers of the corneal epithelium (Fig. 2A). They are protected from direct stimulation by the zonula occludens of the outer surface cells, as well as by the tear mucin gel. Similar types of sensory nerves are present throughout the ocular surface epithelia (Fig. 2B) (4,5).

Psychophysical studies in humans have shown that sensations evoked by stimulation of the cornea are unpleasant or painful in nature (2,6). Until middle age, sensory experiences involving the cornea are infrequent for most normal individuals. In contrast, patients who develop keratoconjunctivitis more commonly experience unpleasant corneal sensations, usually described as “gritty,” “sandy,” or “itchy.” This new sensory state is often the introduction to a long unpleasant relationship with the corneal innervation, as it signals the onset of a persistent pathophysiological state. Activation of corneal sensory inputs informs the patient that a problem has arisen on the ocular surface, namely, a chronic state of inflammation and altered tear composition. Patients may attempt to moderate unpleasant corneal sensations by closing their eyes, which provides some immediate relief. Later in development of dry eye, sensory mechanisms may become compromised, which correlate with the development of ocular surface epithelial disease and dye staining (7). Contributions from the sympathetic system in this process are not well substantiated, and evidence is lacking for their role in the

cornea in dry eye. However, the excess reflex tearing experienced by patients with early dry eye suggests that the homeostatic mechanisms controlling it are altered.

Since corneal sensation is infrequent for most individuals over the span of their lives, what is the normal function of corneal nerves? It could be argued that corneal nerves lie dormant and become activated only under particular pathological circumstances. However, the brief but intense sensations of pain arising from contact of the corneal surface with a speck of dirt, a fingernail, or an eyelash indicate functionality throughout one’s lifespan. As an indication of normal corneal sensitivity, even the smooth action of the eyelids moving micrometer-sized objects across the corneal epithelial surface can be very unpleasant (8). Chronic dysfunction shifts the homeostasis of the lacrimal functional unit toward inflammation and more constant psychological suffering, but at a less intense, although still significant, level of sensory discomfort than is triggered by brief trauma of physical origin.

The cornea is largely innervated by unmyelinated axons, together with small-diameter myelinated axons. These two fiber types are uniquely associated with sensory transmission of pain stimuli. In the cornea, these axons contain both substance P and calcitonin gene-related peptide (CGRP). When released through axon activation or damage, substance P and CGRP can act upon anterior segment vascular elements, leading to neurogenic inflammation with release of immune cells from the vascular space onto the ocular surface. This may contribute to the ocular irritation symptoms of dry eye.

B.Meibomian Glands

The lipid-secreting glands of the eyelid are innervated by axons containing neuropeptide transmitters of several origins. Transmission electron microscopy has shown a network of unmyelinated axons with both granular and agranular vesicles. Although sensory input is suggested by the finding of substance P- and CGRP-positive axons (9,10), their role is unclear, as they would be expected to conduct information to the CNS. Parasympathetic fibers innervating the meibomian glands are probably more abundant. The parasympathetic neurotransmitters neuropeptide Y and vasoactive intestinal peptide (VIP) have been detected around the meibomian glands, as well as tyrosine hydroxylase associated with sympathetic axons, suggesting that both types of autonomic nerves may be involved in stimulating lipid secretion onto the ocular surface.

C.Conjunctiva

A loose network of axons traverses under the mucosal surface of the conjunctiva and lid margin (Fig. 2B). Neuropeptides of sensory, sympathetic, and parasympathetic origin have been documented in the conjunctiva by a number of studies (11). Among the numerous tear-secreting glands of the conjunctiva, neural innervation

of the accessory lacrimal glands has been the best documented (12–14). Nerve fibers immunoreactive to protein gene product and to S-100 protein were found throughout the interlobular stroma, whereas CGRPand substance P-immunore- active fibers were associated with secretory tubules, interlobular and excretory ducts, and blood vessels. However, the extent of neural control over accessory lacrimal glands has not been as clearly demonstrated as it has for orbital lacrimal glands.

Goblet cells of the conjunctival surface display a secretory response to the parasympathetic cholinergic muscarinic output from the pterygopalatine ganglion. Goblet cells have M3-muscarinic receptors on their membranes, whereas M1 and M2 receptors are found throughout the conjunctiva (15). Nerves of sympathetic origin in the conjunctiva are suggested by the presence of α1A- and β3-adrenergic receptors in conjunctival goblet cells. Interestingly, cholinergic agonists acting in concert with growth factors may control proliferation of goblet cells (16).

IV. OCULAR SURFACE NEUROPATHY IN DRY EYE

Ocular surface pain and discomfort in severe sicca disease may partially result from the well-documented neuropathy associated with Sjögren’s syndrome, which is grouped with the neuropathies associated with connective tissue disease. Clinical evidence has shown that peripheral sensory neuropathy may be an important presenting sign for Sjögren’s patients (17,18). In accordance with this, ocular surface discomfort is often the initial motivation for dry eye patients to visit the ophthalmologist. In affected individuals, antibodies are found in peripheral nerves, dorsal root ganglia, and dorsal roots, as well as inflammatory cells in the ganglia. Although the trigeminal system has not been as well studied, the ocular surface discomfort of dry eye may be a form of sensory neuropathy; however, this theory requires confirmation. Small-diameter myelinated and unmyelinated axons in the cornea are potential targets for peripheral nerve disorders, and inflammatory cells infiltrating the ocular surface are well documented in dry eye. These cells, in combination with antibodies to gangliosides and other neural proteins, could cause local degeneration of small-diameter axons and their terminals. Cranial neuropathies may be more common in Sjögren’s syndrome than is currently recognized, and the dysthesias associated with the cornea may indicate an inflammatory neuropathy within the trigeminal system (19).

V.THE TRIGEMINAL AND CNS PATHWAYS

As shown in Fig. 2a and 2b, small-caliber myelinated and unmyelinated nerves end in the epithelial tissues of the cornea, limbus, and conjunctiva on the ocular

surface, and the eyelids. The pseudo-unipolar neurons within the trigeminal or semilunar ganglion have processes with axonal properties that reach their peripheral target tissues in the eye and adnexal tissues through the first or ophthalmic division of the trigeminal ganglion, as well as the second or maxillary division. As with other ganglia, this structure is outside of the central nervous system, but the central process forming the trigeminal nerve enters the brainstem and sends axonal terminations to all levels of the spinal trigeminal ganglion. The third division or mandibular portion of the trigeminal does not appear to be involved in ocular sensations. The peripheral axons, or so-called primary afferents, end blindly among the epithelial cells of the cornea and the conjunctiva. They do not synapse with the epithelial cells nor do they have secondary sensory structures that aid in transducing stimuli; thus, they are referred to as “free nerve endings” (Fig. 2A). Their exact mechanism of action is not yet clear. However, these axons course to the spinal trigeminal nucleus, where they synapse on secondary neurons in the various nuclear regions of the spinal trigeminal nucleus, which extends from the pons to the upper cervical spinal cord. Of the ocular surface sensory inputs, the cornea is the best studied and the axons have been shown to terminate in the nucleus interpolaris and caudalis (20–22). These nuclei of the spinal trigeminal system are important because they have been uniquely associated with processing of painful stimuli (23,24). Recent tracing studies have shown that the sensory inputs from the upper eyelid in primates originate from first-division trigeminal ganglion cells and terminate entirely unilaterally in the laminae of the nucleus caudalis. The sensory terminals from the lower lid, which are of maxillary origin, are located somewhat more dorsally (25). The trigeminal system is associated with more than general somatic sensation, and the trigeminal reflexes established by these neural connections have been often used to monitor and investigate brainstem regions.

VI. CONNECTIONS FROM PARASYMPATHETIC GANGLIA TO THE OCULAR SURFACE

Small-diameter axons leave the bilaterally placed parasympathetic ganglia, located on the inferior medial aspect of the maxillary nerves, to stimulate secretion by the lacrimal gland, the meibomian glands, the conjunctival goblet cells, and perhaps by other secretory glands such as the accessory lacrimal glands, and harderian glands in rodents. As seen in Fig. 3, the small, peripherally located sphenopalatine (pterygopalatine) ganglia provide postganglionic secretory drive through activation of muscarinic receptors located on the postsynaptic membrane of the secretory glands on the ocular surface. The sphenopalatine (pterygopalatine) ganglia contain several thousand neurons and have been studied intensively because of their central role in cerebral blood flow and secretory control of the

Figure 3 The sphenopalatine ganglia. Original magnification 125.

salivary glands (26). Axonal inputs to the preganglionic neurons (Fig. 1) have been suggested to be trigeminal in nature based on the presence of substance P and CGRP. A variety of neuron types are found in the ganglia based on the distribution of neuropeptides. VIP is detected in most of these neurons, while neuropeptide Y and enkephalin have been identified in a smaller percentage (27).

The output of the parasympathetic ganglia consists largely of unmyelinated fibers that provide the postganglionic output to many ocular surface tissues including the lacrimal glands, meibomian glands, harderian glands, small vessels, and conjunctival goblet cells. These conclusions are based on the results of a number of anterograde blood and retrograde tracing studies using wheat germ agglutinin, and horseradish peroxidase in combination with wheat germ agglutinin (28–30).

VII. MAJOR FLUID SECRETING ORGANS: THE MAIN AND ACCESSORY LACRIMAL GLANDS

The main lacrimal gland resides in the superior temporal orbit. It consists of two lobes that are separated by the lateral extension of the levator muscle aponeurosis. The larger orbital lobe, about the size of an almond, is located superiorly