NEUROBIOLOGY OF DISCOMFORT AND PAIN

Contact lenses interact with some of the most richly innervated areas of the body, such as the cornea, lid margin, and to a lesser extent the conjunctiva, and so it perhaps is not surprising that the eye can detect and sometimes react to the presence of the contact lens. The sensory (afferent) nerves (i.e., those that react to ‘‘pain’’ stimuli), which are derived from the ophthalmic and maxillary regions of the trigeminal ganglion, give rise to numerous intraepithelial terminals, some of which may extend to within a few micrometers of the ocular surface. The sensory nerves of the cornea consist of polymodal receptors (which can react to near-noxious or noxious mechanical energy, heat, cooling, chemical irritants, and by a large variety of inflammatory mediators), mechano-nociceptors(which respond to mechanical forces of a magnitude close to that required to damage corneal epithelial cells), and cold- sensitive thermoreceptors (which react to temperature drops produced by evaporation of tears at the corneal surface, or application of cold and hyperosmolar solutions). Activation of these nociceptors is via specific ion channels; however, there appears to be no linear relationship between channel activation and contact lens discomfort.

Postreceptor propagation of the sensory nerve signal travels from the source through trigeminal ganglion to terminate in multiple spatially discrete zones along the rostrocaudal axis of the trigeminal brainstem sensory complex (TBSC) of the central nervous system. In this region, sensory nerves terminate mainly in the ventral aspect of the transition region between caudal interpolaris of the spinal trigeminal nucleus and caudalis of the same region (Vi/Vc) or at the spinomedul- lary junction (Vc/C1). Evidence suggests that ocular sensory neurons at Vi/Vc or Vc/C1 serve different functions in ocular homeostasis and sensation. Drying or detection of cold at the ocular surface stimulates the Vi/Vc region only. Transection of the spinal trigeminal tract at Vi/Vc eliminates pain sensation upon corneal stimulation, but a sense of corneal touch remains. Pharmacologic blockade of only Vi/Vc prevents reflex lacrimation evoked by chemical stimulation of the ocular surface. The ascending projections from second-order ocular neurons in the TBSC to higher brain centers are not well known and no systematic mapping study has been reported, even though the complex nature of many ocular perceptions, such as dryness, grittiness, itch, irritation, and fatigue, suggests interactions across multiple psychophysical channels that require integration at higher brain centers.

Contact lens wear may, or may not, alter nerve fiber density, tortuosity, branching, beading, thickness, or reflectivity. The large changes in morphology of the subbasal nerve plexus in the cornea during orthokeratology (OK) lens wear increase the threshold to sensation. Changes in corneal sensitivity with contact lens wear have been reported widely, but the underlying mechanism is not known, and the outcomes of studies may be very dependent on the type of instrument used to test sensitivity. The fact that tactile/pneumatic stimulus of the cornea after soft contact lens wear is reduced, but no associated change occurs in symptoms of discomfort during lens wear, suggests that the touch response in the cornea, and, hence, propagation of the stimulus through Vc/C1, is not associated with CLD. This then may implicate the cooling, osmolality differences detected through the Vi/Vc region. An alternate hypothesis, but not necessarily mutually exclusive, is the possibility of mechanical stimulation of the nociceptors in the lid wiper region of the eyelids. Stimulation of subacute inflammation of the ocular surface during lens wear may occur, and nerves can respond to the production of a variety of inflammatory mediators, including cytokines and arachidonic acid metabolites. The key neurotransmitters involved in the transmission of ocular sensations in human cornea and conjunctiva have been identified as substance P and calcitonin gene-related peptide (CGRP). No change in tear levels of substance P was found in a group of contact lens wearers compared to nonwearers, which may indicate no role for substance P in CLD. No reports on changes to CGRP were found. Conversely, the neurotrophin nerve growth factor (NGF) appears to be upregulated in CLD. As NGF is involved in survival and maintenance of sympathetic and sensory neurons, its upregulation suggests that nerves either are being damaged (and so need extra NGF for repair) or being altered in other ways during CLD.

Much more research needs to be performed to enable a comprehensive outline of the neurobiology of CLD. Better integration of the research from the peripheral and central
nervous system, with observations of nerve morphology/ structural changes, and the biochemistry of the system could only be beneficial to our understanding of CLD. An important first step would be to design experiments to determine which tissue (e.g., corneal or lid margin) is the primary sensory location of CLD.