CONTACT LENS DRY EYE

Contact Lens Dry Eye: Neurotrophic Disease or MGD?

Does contact lens-related dry eye start with the corneal nerves?

By Stephanie M. Cox, OD, FAAO, & Jason J. Nichols, OD, MPH, PhD, FAAO

Most eyecare practitioners have patients who experience discomfort with their contact lenses. In fact, this is the most frequent reason for contact lens discontinuation (Richdale et al, 2007). Some practitioners first attempt to change patients’ lenses or care solution. Others choose to begin a regimen aimed at improving the tear film. However, what if contact lens dry eye starts with the nerves at the ocular surface?

What Is Normal?

Thorough descriptions of corneal innervation have appeared in previously published reviews and articles (Belmonte et al, 2004; Müller et al, 2003; Shaheen et al, 2014; Stapleton et al, 2013). Here, we provide a very brief description with the intent of this article in mind.

Nerves enter the cornea from the ophthalmic division of the trigeminal nerve. The nerves can be classified as Aδ fibers or C fibers. The Aδ fibers are thicker compared to the C fibers and appear straight. C fibers have a beaded appearance. Unlike C fibers, Aδ fibers are myelinated, but this myelination is lost approximately 1mm after entering the corneal limbus.

The nerves’ path is parallel to the corneal stromal lamellae. Within the anterior one-third of the stroma, the nerves begin to anastomose and form a plexus. Some nerves form free nerve terminals here, while others innervate keratocytes. Many nerves continue in their path by perforating Bowman’s membrane within the midperipheral stroma as C fibers and entering the corneal epithelium. They then travel toward the central cornea. The free nerve endings within the corneal epithelium—called nociceptors—sense thermal, mechanical, and/or chemical stimuli.

The type of stimuli and type of nerve determine the body’s reaction to the stimulus. Corneal nerves can be described as mechanical, cold, or polymodal. Mechanical nociceptors are stimulated by only mechanical forces. Polymodal nociceptors respond to mechanical, heat, noxious cold, and chemical stimuli. Cold nociceptors respond spontaneously and in cold conditions. Stimulation of these corneal nerves activates them to help maintain the integrity of the corneal surface and tear film. When repair to the ocular surface is needed, the nerves release neuropeptides, such as Substance P, calcitonin gene-related peptide, neuropeptide Y, and acetylcholine. These neuropeptides then promote other trophic factors involved in wound healing, such as nerve growth factor (NGF) and inflammatory mediators (Nishida, 2005). In cases of neurotrophic keratopathy, patients experience elongated healing times because the factors necessary for wound healing are not present (Sacchetti and Lambiase, 2014).

In addition to initiating corneal repair, the sensory nerves can induce blinking and tear production; this can be readily observed when these reflexes are induced by an acute stimulus, such as the presence of a foreign body in the eye. The impact of ocular surface innervation in spontaneous, habitual blinks and basal tearing is continuing to be investigated. Spontaneous blinks are impacted by the status of the ocular surface, tear film, and ocular surface sensitivity (Nakamori et al, 1997; Doughty et al, 2009; Nosch et al, 2016; Rahman et al, 2015). Evidence has also been mounting suggesting that basal tearing may be controlled, at least in part, by ocular surface innervation (Robbins et al, 2012; Parra et al, 2010).

What Is Meant by Neurotrophic Disease?

Neurotrophic disease is associated with reduced corneal sensitivity. This reduced corneal sensitivity causes the nerves to not respond to corneal insults as needed, and it causes trophic factors to not be released. Corneal defects, thereby, have elongated healing times because of the reduced presence of trophic factors needed for wound healing (Sacchetti and Lambiase, 2014).

Morphological changes in corneal nerves, as well as changes in nerve density, have been observed via confocal microscopy in subjects who have neurotrophic keratopathy (Hamrah et al, 2013; Lambiase et al, 2013; Cruzat et al, 2010). This reduced sensitivity also appears to influence blinking. The reported correlations between ocular surface sensitivity and spontaneous blink are typically significant, but they vary between positive and negative correlations (Rahman et al, 2015; Doughty et al, 2009; Nosch et al, 2016). This could be due to the fact that the blink reflex is complex and can be altered by medications, tasks, and various diagnoses. Tear production is consistently reduced in both eyes of subjects who have unilateral neurotrophic conditions, suggesting that the effects of neurotrophic disease affect aqueous production in both eyes (Heigle and Pflugfelder, 1996; M’Garrech et al, 2013; Jabbarvand et al, 2015).

This reduced corneal function in neurotrophic disease has been associated with many conditions, such as herpes simplex and zoster, lesions or insults to the trigeminal nerve(s), ocular surgeries, systemic conditions such as diabetes, and, more recently, long-term use of contact lenses (Sacchetti and Lambiase, 2014; Okada et al, 2010; Semeraro et al, 2014). The Tear Film & Ocular Surface Society Contact Lens Discomfort Workshop Subcommittee on Neurobiology points to the consistent stimuli presented with contact lens wear as having a potential impact on corneal nerve function (Stapleton et al, 2013). This consistent stimuli could be the mechanical rubbing of the contact lens on the ocular surface or the hyperosmolarity associated with the contact lens tear film (Nichols and Sinnott, 2006; Iskeleli et al, 2002).

Evidence of neurotrophic disease in contact lens wearers lies in the compromises that are seen in the tear film. Contact lens wearers have reduced tear production as measured with tear meniscus height and the phenol red thread test (Le et al, 2009; Miller et al, 2004; Chen et al, 2009); this reduced tear production is intensified in symptomatic contact lens wearers compared to asymptomatic lens wearers (Chen et al, 2011). It is possible that the overstimulation of corneal nerves referenced earlier compromises the signals from the corneal nerves for tear production.

It is also interesting that contact lens wearers who experience end-of-day dryness show an increased blink rate compared to lens wearers who do not experience dryness (Martin-Montañez et al, 2015), especially given that non-lens wearers who have dry eye also show an increased blink rate compared to controls (Nakamori et al, 1997). As described above, blink rate may not be directly linked to ocular surface sensitivity due to the many factors influencing blink rate. Therefore, these findings regarding blink rate should be considered with caution.

There are some inconsistencies with the traditional characteristics associated with neurotrophic disease. One important point to note that is inconsistent with other neurotrophic conditions is that contact lens wear is not always associated with reduced sensitivity thresholds (Stapleton et al, 2013). This inconsistency may be due to inconsistency in methods of measuring corneal sensitivity or to the limitations in measuring sensitivity thresholds. Sensitivity thresholds quantify only the stimulus intensity at which a patient or subject first experiences a sensation. This testing does not provide information about how the threshold sensation is processed or how stimuli above or below threshold are processed. Does the sensation evoke the expected, healthy response in wound healing, blink, and tear production? Confirmation of the limitations of sensitivity threshold testing have recently been established in dry eye subjects.

A report by Kaido et al (2016) recruited subjects with similarly compromised tear films and showed that symptomatic subjects had similar threshold sensitivities compared to asymptomatic subjects; however, the symptomatic subjects first blinked in response to lower-intensity stimuli and reported pain at lower-intensity stimuli compared to asymptomatic subjects. As stated previously, this study was performed in dry eye subjects, so it is unknown if such differences in threshold testing are also true in contact lens wearers.

Treatments

While this article is devoted to enlightening readers about neurotrophic disease, it is important to not dismiss meibomian gland dysfunction (MGD), dry eye disease, allergies, and other ocular surface conditions. Contact lens wear has been associated with dry eye (International Dry Eye WorkShop Report, 2007) and with MGD (Schaumberg et al, 2011). Studies have demonstrated compromise to the meibomian glands in contact lens wearers (Arita et al, 2009; Machalińska et al, 2015; Villani et al, 2011). Compromise has also been seen in the goblet cells and mucins of contact lens wearers (Doughty, 2011; García-Posadas et al, 2016).

Ocular surface disease should be treated prior to initiating any treatments for neurotrophic conditions (Sacchetti and Lambiase, 2014). For patients who have findings that suggest MGD, several treatments can be helpful. Instruct patients to supplement their diet with essential fatty acids (Bhargava and Kumar, 2015; Kokke et al, 2008) and to make environmental changes that could help reduce symptoms, such as utilizing a humidifier when possible (Geerling et al, 2011). Traditional treatment involving warm compresses with lid massage can be helpful, and the advent of new masks and devices has improved the effectiveness of these treatments compared to previous at-home versions (Arita et al, 2015). Prescription therapies may include antibacterial therapies, which help to minimize bacteria at the lid margin; liposomal sprays; and topical anti-inflammatories (Lee et al, 2014).

While steroids may be helpful in treating MGD, they should be used with caution in neurotrophic disease. They and topical nonsteroidal anti-inflammatory drugs could cause corneal melting in neurotrophic conditions (Sacchetti and Lambiase, 2014).

Artificial tears can be used in both ocular surface diseases and neurotrophic disease. However, only preservative-free versions should be used for neurotrophic disease (Sacchetti and Lambiase, 2014). Another treatment that is safe for both MGD and neurotrophic conditions is autologous serum tears, which are made from blood drawn from the patient. The blood is allowed to clot and is then centrifuged. Serum is then separated and is usually diluted. The amount of dilution can vary, as can the number of drops instilled per day. Because preservatives are not used in the compounding of serum tears, they should be kept in 3mL to 5mL bottles and frozen until ready for use. Once thawed and opened, the tears should be used within one week (Aggarwal et al, 2015; Hussain et al, 2014).

These drops work because blood contains many of the same trophic factors that are in tears. Serum tears help to improve the morphology and density of corneal nerves that have been damaged (Rao et al, 2010). While the treatment effects of serum tears are positive, there are some limitations to this option, including cost and access to the facilities necessary to compound the tears.

In addition, some patients may not be candidates due to systemic conditions, such as human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS). An alternative for these patients are albumin tears, which can be ordered from compounding pharmacies and shipped to patients. These tears contain albumin, which is a trophic factor in the tears.

Another treatment option currently available is amniotic membranes. These membranes, which contain many of the wound-healing factors that are in serum tears, are applied to the eye in-office and dissolve over time, releasing the important growth factors onto the ocular surface. Studies have not confirmed whether the same improvements in corneal nerve morphology are seen with treatment by albumin tears or amniotic membranes.

Conclusions

Interestingly, neurotrophic conditions can lead to neuropathic pain (Belmonte et al, 2004). In neuropathic pain, the sensory fibers in the cornea and their processing are altered. This alteration could be due to a number of factors, such as overstimulation in the case of contact lens wear. Neuropathic pain patients experience sensations of dryness and ocular pain even though their tear film is adequate and a clear etiology cannot be identified. To prevent neuropathic pain, the nerves at the ocular surface should be assessed and treated as soon and as effectively as possible.

Treatments involving neuropeptides and neurotrophic factors are currently under development that could help to improve the nerves of the ocular surface. It is also important to consider anti-inflammatory treatments, as nerves are influenced by inflammation. In cases in which neurotrophic epithelial defects are not present, anti-inflammatory treatments may help to preserve the integrity of the corneal nerves.

There are numerous questions left to be answered regarding treatments. When should serum tear use be discontinued? Can therapy stop once the corneal nerves regain their integrity? One study that assessed long-term use of serum tears in dry eye subjects found that symptom improvement peaked after six to 12 months of therapy (Hussain et al, 2014).

A new way of thinking about contact lens dry eye is being developed that may dramatically change how ocular surface conditions are managed. The end result will likely be more effective treatment that may be based in maintaining ocular surface health, including the health of the corneal nerves. CLS

For references, please visit www.clspectrum.com/references and click on document #248.

	Dr. Cox is a clinical assistant professor at the University of Alabama at Birmingham School of Optometry and is pursuing a PhD in Vision Science.
	Dr. Nichols is an assistant vice president for industry research development and professor at the University of Alabama-Birmingham as well as editor-in-chief of Contact Lens Spectrum and editor of the weekly email newsletter Contact Lenses Today. He has received research funding from Johnson & Johnson Vision Care.