The TFOS International Workshop on Contact Lens Discomfort: report of the subcommittee on neurobiology

Abstract

This report characterizes the neurobiology of the ocular surface and highlights relevant mechanisms that may underpin contact lens-related discomfort. While there is limited evidence for the mechanisms involved in contact lens-related discomfort, neurobiological mechanisms in dry eye disease, the inflammatory pathway, the effect of hyperosmolarity on ocular surface nociceptors, and subsequent sensory processing of ocular pain and discomfort have been at least partly elucidated and are presented herein to provide insight in this new arena. The stimulus to the ocular surface from a contact lens is likely to be complex and multifactorial, including components of osmolarity, solution effects, desiccation, thermal effects, inflammation, friction, and mechanical stimulation. Sensory input will arise from stimulation of the lid margin, palpebral and bulbar conjunctiva, and the cornea.

Keywords: contact lens; discomfort; dry eye; neurobiology.

Figure 1

Subbasal nerve fibers. (a) Schematic representation of the human corneal epithelial innervation. Three-dimensional reconstruction from digital sections was obtained with confocal laser scanning microscopy of excised corneas. Stromal nerve bundles in the subepithelial plexus penetrate the epithelial basal lamina, turn abruptly at acute angles, and divide into multiple daughter fibers called subbasal nerves. The subbasal nerves run horizontally within the deepest part of the basal epithelial cell layer and give rise to numerous, superficially directed intraepithelial terminals. Reproduced with permission from figure 2 in Guthoff RF, Wienss H, Hahnel C, Wree A. Epithelial innervation of human cornea: a three-dimensional study using confocal laser scanning fluorescence microscopy. Cornea. 2005;24:608–613. Copyright 2005 Lippincott Williams & Wilkins. BEP, basal epithelial plexus; SEP, subepithelial plexus. (b) A subepithelial nerve fiber (short arrows) in a human cornea penetrates (circle) Bowman's layer and the epithelial basal lamina to form an “epithelial leash formation” composed of multiple radially directed subbasal nerves (long arrows) of varying diameters. The nerves in this figure (and in Figs. 2a, 3) have been stained immunohistochemically with primary antiserum against the pan-neuronal marker neurotubulin. Scale bar: 100 μm. (c) The central portion of the human subbasal nerve plexus. Nerve tracings are constructed from a montage of 575 in vivo confocal microscopy images. The SNFs radiate toward the periapical cornea, where they form a gentle whorl-like complex. Scale bar: 1 mm. Reproduced with permission from figure 3a in Lum E, Golebiowski B, Swarbrick HA. Mapping the corneal sub-basal nerve plexus in orthokeratology lens wear using in vivo laser scanning confocal microscopy. Invest Ophthalmol Vis Sci. 2012;53:1803–1809. Copyright 2012 Association for Research in Vision and Ophthalmology.

Figure 2.

Ultrastructure of human SNFs and intraepithelial terminals. (a) Perpendicular section (30 μm thick) of a human cornea. The SNFs (e.g., circle) have been sectioned perpendicular to their long axes and are located in the basal epithelium immediately superficial to the epithelial basal lamina and Bowman's layer. Scale bar: 100 μm. (b) Electron micrograph of a cross-section through a human SNF. The SNF consists at the ultrastructural level of eight individual unmyelinated axons. The axons are located within a focal widening of the intercellular cleft (arrows) between two adjacent basal epithelial cells. bl, Basal lamina. Scale bar: 1 μm. Reproduced with permission from Figure 5c in Müller LJ, Marfurt CF, Kruse F, Tervo TM. Corneal nerves: structure, contents and function. Exp Eye Res. 2003;76:521–542. Copyright 2003 Elsevier. (c) Nerve terminals in the superficial layers of the dog corneal epithelium. Subbasal nerve fibers are seen in a deeper plane of focus. Calibration bar is 50 μ.

Figure 3

Major ascending brain pathways for trigeminal sensory fibers that supply the eye. The cell somata of sensory fibers are found within the TG and project centrally to terminate in two spatially discrete regions of the trigeminal brainstem complex, the trigeminal subnucleus interpolaris/caudalis transition region (Vi/Vc) and the caudalis/upper cervical cord junction (Vc/C1). Second-order ocular neurons in Vi/Vc and Vc/C1 project to brain regions that mediate eyeblink (facial motor nucleus, VII), lacrimation (superior salivatory nucleus, SSN), and cardiovascular reflexes (nucleus tractus solitarius, NTS). Projections to higher centers such as the periaqueductal gray (PAG), PBA (PB), lateral hypothalamus (LH), posterior hypothalamus (PH), and amygdala (Am) contribute to the affective and modulatory aspects of ocular pain, while projections to posterior thalamus (posterior nuclear group, Po; ventral posteromedial nucleus, VPM) and insular cortex (Ins) mediate sensory-discriminative aspects. Note that a small group of ocular responsive neurons also are found in the contralateral Vi/Vc. The source of input to this group is not well defined. 1°, Primary afferent fibers (gray); 2°, second-order projections (red); 3°, third-order projections (blue).