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

Figure 6 Neural circuitry of the lacrimal functional unit. In the normal state, subthreshold sensory input from the ocular surface modulates secretory activity. A superthreshold sensory event on the corneal surface (environment) triggers a number of involuntary reflexes, including reflex lacrimation (tears).

In the second state of activation, the individual is painfully aware that the nerves are activated, because a number of involuntary reflexes are set in motion by a superthreshold sensory event, as highlighted in Fig. 6. These reflexes, which include reflex lacrimation, a cardiovascular reflex, the blink reflex, and Bell’s phenomenon, are all nonsuppressible and function to protect the eye from potential danger. Thus, the excess lacrimation often associated with dry eye is a reflex in response to the discomfort and pain elicited by conditions on the ocular surface. Corneal hyperesthesia has been observed in dry eye patients, as well as an inverse correlation between sensory threshold and the degree of corneal punctate epitheliopathy. This heightened sensation may be due to breakdown of the tight junctions in the apical corneal epithelium that allows greater access of environmental stimuli to the sensory nerve endings terminating in the wing cell layers of the corneal epithelium.

XIV. REFLEXES AND THE LACRIMAL FUNCTIONAL UNIT

Reflexes are the ultimate means for protection of the ocular surface and the visual organ. Involuntary reflexes are invoked as part of the response to the reception

of painful stimulation. These reflexes are kept under tight neural control, because when they are triggered, the organism may become vulnerable due to temporary visual impairment. In addition to the blink reflex, copious tear secretion from the orbital lacrimal glands is typically observed. Although meibomian glands and conjunctival goblet cells have muscarinic parasympathetic innervation, it is not clear whether reflex secretions from these glands are involved. Dorsoflexion of the neck to move the head away from the noxious stimulus and a cardiovascular reflex are among the involuntary reflexes invoked.

Interestingly, the blink reflex is bilateral in humans and primates but unilateral in most other mammals (102). Recent studies using the blink reflex to investigate learning and memory have noted the participation of N-methyl-D- aspartate (NMDA) receptors in the nucleus of the abducens nerve, which activates the orbicularis muscle when this system is under stimulus control (103). The constant irritative stimulus associated with dry eye may overdrive the orbicularis motor nucleus, resulting in the increased blink rate that is often observed in dry eye patients. Indeed, the increased blink rate in dry eye has been found to correlate with corneal hyperesthesia. Reflexes that have lost neural control, such as constant tearing in dry eye or blepharospasm (not necessarily associated with dry eye), can become clinical problems themselves.

Tear secretion is acutely regulated by stimulation of trigeminal sensory nerves on the ocular surface and adnexal tissues. During nonstressful environmental conditions, the level of sensory stimulation is relatively low. Stressful environmental conditions, such as wind gusts or low humidity, increase tear evaporation and disrupt the tear film. This results in stimulation of sensory nerve endings and a resultant coordinated secretion of factors that stabilize the tear film and protect the ocular surface. Restoration of a stable tear film improves ocular surface comfort, and the level of sensory stimulation returns to baseline. Inability of the integrated unit to respond to ocular surface stress due to conditions that are reviewed in Chapter 4 worsens tear stability, further stimulates sensory nerves and causes eye pain.

The spread of tears across the ocular surface and clearance of existing tear components into the lacrimal drainage system is as important for ocular surface health as the regulated production of tear components. These functions are regulated by motor components of the integrated unit.

XV. AGING EFFECTS

Aging can affect the lacrimal functional unit in several ways. The first is by reduced flow of afferent information due to loss of sensory axons, resulting in loss of responsiveness to environmental stimuli. Additionally, central nervous system effects of aging may be evident in synaptic components or neurotransmitter availability,

which could affect processing of input from the lacrimal functional unit . Corneal innervation exhibits significant aging effects, with a decrease in sensory threshold beginning at about the fourth decade of life (104). This may occur by dropout of the axons, either from degeneration of collaterals, or more directly from loss of ganglion cells. The latter would have broader implications, but loss of support for axonal branches would lead secondarily to lowering the density of terminals in either in the sensory or the autonomic systems. It is clear that age-related dropout of cholinergic parasympathetic nerves occurs elsewhere (105,106), although it is not well documented in the eye. All of these aging mechanisms may be acting in the parasympathetic system to decrease secretory function, increase the possibility of immune activation, and potentially set the stage for homeostatic dysfunction on the ocular surface. The blink reflex, a direct result of corneal stimulation, shows oscillations over the age of 40 and increases in duration in normal subjects over age 60, which may be due to loss of substantia nigra dopaminergic neurons (107). However, the oscillatory blink reflex is associated with dry eye regardless of age, and is likely a response to corneal irritation (108).

XVI. SUMMARY

1.The lacrimal functional unit comprises the ocular surface (including the cornea, the conjunctiva, and the meibomian glands), the main and accessory lacrimal glands, and the neural network that connects them. Its overall purpose is to maintain the clarity of the cornea and the quality of the image projected onto the retina.

2.Acting through areas of the central nervous system, a complex of sensory, sympathetic, and parasympathetic nerves links the components of the lacrimal functional unit into a homeostatic loop.

3.Acinar cells of the lacrimal gland secrete water, electrolytes, protein, and mucins into tear fluid, mostly in response to neural stimulation. Neurotransmitter receptors coupled to G proteins ultimately regulate electrolyte transporters and secretion of proteins via the Golgi complex.

4.In the lacrimal quiescence associated with Sjögren’s syndome, neurotransmitter receptors seem unable to transduce signals to downstream mediators and effectors; however, many details remain to be elucidated, and whether quiescence in non-Sjögren’s lacrimal keratoconjunctivitis occurs by a similar mechanism is unclear.

5.Under normal conditions, a subthreshold level of input from ocular surface sensory nerves is proposed to modulate secretory activity by lacrimal and meibomian glands. Under stressful conditions, or during inflammation of the ocular surface as occurs in dry eye, this elaborate neural control mechanism may be disrupted.

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