Dry Eye Update 2003
New developments in research and diagnosis lead to more treatment options for dry eye and contact lens-related dry eye.
BY KELLY K. NICHOLS, OD, MPH, PHD, AND JASON J. NICHOLS, OD, MS, MPH

The field of dry eye (DE) continually changes as a result of basic and clinical research into the etiology, course and treatments of the disease. New directions in research, understanding and development can at times leave even those intimately involved in the field dazed and confused. In spite of important progress, the pharmaceutical and contact lens industries need to do even more to help alleviate basic DE and contact lens-related dry eye (CL-DE), which afflicts millions of people in the United States and countless millions more globally.

Aging, Hormones and Dry Eye

Recently there has been increasing interest regarding the effect of hormones on females. Menopause and hormone replacement therapy (HRT) have become common phrases in both the professional literature and the mass media. The role of aging and hormones on numerous ocular disorders (cataract, dry eye and macular degeneration) has been studied more rigorously in recent years.

Clinical diagnostic tests demonstrate changes in tear composition and stability with aging, even in patients without ocular surface disease (OSD). Total tear volume and tear production decrease and tear osmolarity increases with aging, which indicates that tear film function declines throughout life.

Over the past few decades, there has been considerable debate regarding the ocular effect of systemic hormones. It has been reported that postmenopausal women suffer more frequently from DE than healthy younger women. While the etiology of postmenopausal DE is unclear, the influence of hormones is strongly suspected to play a role.

Research has shown that androgens, estrogens and progestins may significantly influence the structure and function of many ocular tissues, which include DE-related structures such as the lacrimal gland and ocular surface. While the conjunctiva is reported to be sensitive to estrogen in menstruating and pregnant women, the presence of estrogen receptors on the ocular surface and in the lacrimal gland is not established. In contrast, the lacrimal gland has receptors for androgen and prolactin, both of which have proven to affect tear production. In addition, it is thought that estrogen and glucocorticoids have an indirect regulatory role in maintaining the tear film.

Topical hormones have been used experimentally for treating DE. In one study, estrogen was applied in a gel formulation topically to the ocular surface in women with post-menopausal DE symptoms, and an improvement resulted both in symptoms and in a few clinical tests. In a similar trial using a placebo control group, topical 17B-oestradiol ophthalmic drops were applied to the ocular surface in the treatment group. Symptoms, tear production and tear stability improved in the treatment group. The authors concluded that the topical drops successfully treated DE and that the blood-eye barrier prevented systemic estrogens from acting on the conjunctiva. In contrast, another study found a statistically significant difference in conjunctival cell cytological maturation in patients on HRT compared to those not on HRT, which indicates that systemic HRT plays a role in maintaining the ocular surface.

Research published over the last 10 years shows a strong association between androgens and DE. Women with primary and secondary Sjögren's syndrome have been shown to be androgen deficient. Androgens also play a significant role in maintaining the meibomian glands. Androgen receptor mRNA and proteins have been found in the meibomian glands, and androgens have been shown to regulate lipid production. It is postulated that decreasing androgen support to the meibomian glands, both with normal aging and in cases of androgen-deficient Sjögren's patients, results in decreased lipid production, tear film instability and evaporative dry eye. Topical or systemic androgen administration reportedly increases lipid production, and topical androgen eye drops are currently under development and evaluation.

The effect of HRT on DE is not as clear. A recent study reported that estrogen HRT for menopause may play a role in DE development. In this study of over 25,000 postmenopausal women, those taking estrogen HRT were more likely to have DE symptoms than women taking estrogen-progestin combination therapy or those not using HRT. The meibomian glands may be target sites for estrogen, which reduces gland activity and lipid output, and results in DE. This may seem contradictory to the common view that HRT eases the irritation caused by drying of mucus membranes. If estrogen does de-regulate the meibomian glands in postmenopausal women, certainly HRT would not relieve dry eye as some may have speculated. Ask your patients on HRT about DE symptoms, as HRT may be associated with the disease.

Tests for Dry Eye

Although most clinicians rely on patient-reported symptoms for a DE diagnosis, there are many tests available for assessing tear function. These include the Schirmer test, phenol red thread test, fluorescein and rose bengal staining, tear break-up time (TBUT), meibomian gland and tear debris assessments and tear meniscus height measures. Although each test has advantages and disadvantages, most of these tests lack test-retest repeatability. In addition, studies generally show a lack of association between test signs and patient-reported symptoms, which questions the validity of present DE clinical testing. There is a need for additional DE tests that are repeatable and that correlate well with patient symptoms.

Figure 1. Corneal fluorescein staining and tear break-up in a patient with moderate dry eye.

There are tests that are costly and more laboratory-based. These assess tear film osmolarity, lactoferrin and fluorescein dye disappearance (flourophotometry).

No commercially available instruments measure tear film osmolarity, although five years ago Advanced Instruments, Inc. (Norwood, MA) produced a nanoliter osmometer which was commercially available on a limited basis at a cost of approximately $15,000. The instrument uses freezing point depression osmometry in which a sample's last ice crystal is detected using CCD imaging and software and correlated to its melting point temperature using a precision thermistor. The instrument is accurate to within ± 4 mOsm, and is reportedly quite sensitive to DE. One difficulty in measuring tear film osmolarity is in obtaining a tear sample; however, this instrument requires only 200 nanoliters of tears, which makes sample collection more feasible. We have succeeded with this instrument in our laboratory, and it appears to have a high sensitivity to patient symptoms. A new osmometer is currently under development at Advanced Instruments, which is ultimately intended for commercial availability in clinical practice and research.

Lactoferrin is an iron-binding protein produced by the lacrimal gland in the aqueous tears. It is thought to modulate inflammation, control cell growth and possess anti-microbial properties. The Touch Tear Lactoferrin MicroAssay is a commercially available instrument that measures tear lactoferrin concentration. Touch Scientific, Inc., recently partnered with CIBA Vision, which will market the instrument (Corneal Science Corporation). Our laboratory has found the instrument difficult to use. Both the expense of the instrument (about $15,000) and the time/effort required for use may limit clinical application.

Fluorophotometry was originally developed to measure leakage of fluorescein from the retina to the vitreous, but the technique is also used on the anterior segment of the eyes. We know of only one commercially available instrument (The Fluorotron Master, Ocumetrics, Inc.), which has been used to assess corneal pH, epithelial permeability, endothelial permeability and tear turn-over (both during contact lens wear and in the normal open-eye state). A recent study showed a significant reduction in tear film secretion in patients with presumed DE disease. The authors report that the instrument is simple to use and is reliable. We have no personal experience with the instrument, but it is reportedly very useful clinically and takes measurements in about 15 seconds. The cost is around $50,000.

Treatments for Dry Eye

The available topical treatments for DE ­ lubricant eye drops and ophthalmic ointments ­ are palliative. Punctal occlusion is a potential treatment, but its success in alleviating symptoms and in improving signs has not been systematically reported in the literature even for non-contact lens wearing patients.

Increased knowledge of DE disease etiology has stimulated the development of targeted treatments. One group of potential agents are anti-inflammatories, specifically topical cyclosporin A and topical corticosteroids. A second approach is to use a topical P2Y2 purinergic receptor agonist. This has been reported to increase chloride and fluid secretion from the conjunctival accessory lacrimal glands and to promote mucin production by the conjunctival epithelial cells.

Assessing the success of potential treatments in DE patients depends largely on study design and the definition of DE used. With numerous diagnostic tests and surveys to choose from, selecting the patient sample and the outcome variables can have a significant impact on the study results. Food and Drug Administration studies are currently underway for numerous potential medications to treat DE (Table 1).

Allergan received FDA approval in late 2002 for its Restatis (cyclosporine ophthalmic emulsion, 0.05%). After an unsuccessful trial of cyclosporine vs. vehicle, Restasis demonstrated statistically significant and clinically relevant increases in Schirmer wetting vs. vehicle (Refresh artificial tears) at six months. Numerous other positive results have been published regarding cyclosporine's effect on the ocular surface. One reported that six-month treatment with topical cyclosporine in Sjögren's and non- Sjögren's DE patients resulted in increased goblet cell numbers and decreased epithelial cell turnover. The authors postulated that the reduced ocular surface inflammation may help regulate epithelial proliferation. Another study found that the use of topical cyclosporine resulted in fewer visits to eyecare practitioners, improved symptoms and patient satisfaction, as well as fewer prescriptions for ancillary DE medications (artificial tears).

Allergan recently marketed a new artificial tear drop, Refresh Endura. Some speculate that it is the vehicle from the first cyclosporine clinical trial previously mentioned. Most of the doctors and patients we have spoken to about Refresh Endura have been satisfied with the drop, which the company says contain oil in the form of microscopic droplets.

Also in clinical trials is topical P2Y2 purinergic receptor agonist, INS365 (Inspire Pharmaceuticals), and Phase III results are in the process of submission to the FDA. An additional Phase IIIb study is evaluating INS365 in a controlled environment and is in the last stage of data collection. Responses from the FDA are expected within the next year. If the responses are positive, the medication may arrive at market in late 2003 or early 2004. The manufacturer says that INS365 promotes aqueous production by the accessory lacrimal glands and may also affect the meibomian glands. A recent study also showed that INS365 may promote corneal integrity by inducing production of a mucin-like glucoprotein in the DE rabbit model. With the results of these studies pending, the next year should prove interesting in the dry eye pharmaceuticals arena.

In addition to developmental medical therapy, several other management options exist for DE. Salagan oral tablets (pilocarpine) increase aqueous tear production, and they are currently available. However, this oral drug has systemic side effects, such as increased perspiration, which limits its use for mild to moderate DE.

Both punctal occlusion and artificial tears can be useful, but do not offer a total solution. Artificial tears can be costly, messy and time consuming. Patients often discontinue artificial tears once they use the samples they receive at the office. Patients with more severe DE will use artificial tears numerous times daily, and they notice if a dose is missed. Artificial tear usage patterns often help assess DE severity. Punctal occlusion tends to be more successful in aqueous deficient DE. The plugs have a life span of about six months. They can create a "cesspool" effect in DE, and any inflammatory mediators in the tear film can further irritate the ocular surface due to lengthened exposure time. In addition, the exposed cap of a Freeman-type punctal plug can irritate the conjunctiva. Patients generally adapt within a week if they experience any sensation following plug insertion. Intracanalicular plugs are inserted below the punctum and have been rarely associated with bacterial infection and granuloma formation, both of which require further medical treatment.

Dry Eye and Contact Lenses

Tear film and contact lens interactions continue to challenge practitioners and researchers. In 1993-1994, the National Eye Institute (NEI) and key industry corporations sponsored workshops on DE syndrome. The report from the workshops indicated that CL-DE is a subclassification of DE syndrome. As with DE in general, much is unknown about the epidemiology and etiology of CL-DE. NEI and industry organizations sponsored a similar meeting in 2001 that emphasized symptoms, quality of life assessment and clinical tests used for the classification and diagnosis of DE.

Figure 2. Lissamine green conjunctival staining in a patient with severe dry eye.

CL-DE Symptoms Symptom assessments are key in determining a general DE diagnosis. Many believe that DE and CL-DE are very much symptom-based diseases. Ocular symptoms associated with DE and CL-DE include ocular fatigue, discomfort, redness, itching, dryness, irritation, crusting of lids, scratchiness, epiphora, discharge, blurry vision, pain, photophobia, blinking abnormalities and foreign body sensation. Each may vary in frequency and intensity depending on the severity of the disease. Studies have, however, consistently shown that "dryness" and "discomfort" are the most frequent complaints of contact lens wearers, who report these symptoms more frequently than non-lens wearers. These symptoms have also been found to increase during a day's wear of lenses.

Several surveys are available for evaluating CL-DE. Some surveys are generic in their assessment of DE (McMonnies Questionnaire), and focus on clinical factors that include age, gender, symptoms, previous DE treatments, medication use, environmental stimuli and medical conditions associated with DE (arthritis, Sjögren's syndrome, thyroid disease). Other surveys are more specific to contact lens wearers and focus on symptoms associated with the disease (Contact Lens Dry Eye Questionnaire). Still other surveys relate to quality of life dimensions (the Refractive Status and Vision Profile survey and the National Eye Institute Refractive Error Quality of Life instrument).

Epidemiology and Outcomes As many as 50 percent of the 35 million contact lens wearers in the United States (up to 17 million lens wearers) experience DE symptoms during lens wear. One survey of U.S. practitioners found that 12 to 21 percent of contact lens wearers had DE symptoms severe enough to reduce their wearing time, and 6 to 9 percent of lens wearers became intolerant due to dryness symptoms. A Gallup Poll study in 1991 found that 11 percent of ammetropes are contact lens dropouts, primarily due to discomfort and dryness. A 1993 survey of 199 contact lens dropouts also found that the vast majority of these patients discontinued lens wear due to discomfort and dryness. Finally, a 1999 study found that after five years of lens wear, about 12 percent discontinue contact lenses permanently, with discomfort and dryness accounting for the majority of discontinuations. This study also showed that 49 percent of discontinuing patients had been refit at least one time, and they all had reduced wearing times. Estimates suggest that most of these patients return to spectacle wear, with a smaller number proceeding to refractive surgery.

This data shows that CL-DE leads to a reduction in wearing time and/or possibly a discontinuation of contact lens wear. However, the mechanism of these outcomes is poorly understood and needs further study. Knowing potential risk factors and the disease mechanism may allow clinicians to offset any potential for discomfort, ocular surface desiccation and disease, and ultimate failure of contact lens wear in these patients.

Mechanism of Disease The pre-ocular tear film (POTF) is a complex, thin film that protects and maintains the cornea, which allows for good vision. This "functional unit" can normally tolerate environmental stresses and demands, but a contact lens disrupts the tear film and divides it into two layers -- the pre- and post-lens tear film (Table 2). The pre-lens tear film probably consists anteriorly of the superficial lipid layer, with a base layer that is more aqueous. The post-lens tear film likely consists anteriorly of aqueous with a mucin gradient near the corneal epithelium. Although researchers are just starting to unravel the mysteries associated with these complex layers, they believe it is important that the layers continue to perform the normal functions of the POTF for non-contact lens wearers to allow for successful contact lens wear. Current basic investigations are examining the physical (thickness and structure) and biochemical compositions (inflammatory mediators) of these layers during normal lens wear.

When discussing the mechanisms of CL-DE, consider the relation between three key variables--symptoms, the contact lens and the tear film. CL-DE may have its direct etiology in the superficial lipid layer of the tear film, which prevents evaporation of the tear film (Figure 3). In the short term, contact lens wear may cause alterations in the blink reflex, which normally spreads a smooth, even lipid layer over the ocular surface. In the long-term, some forms of lens wear may keratinize the meibomian glands, which leads to a further instability of the lipid layer. The end result of either of these factors is an altered lipid layer, which results in evaporation and increased osmolarity of the tear film. Alteration of the superficial lipid layer and pre-lens tear film may also lead to visual disturbances associated with an unstable tear film.

Following evaporation of the pre-lens tear film, a soft contact lens may start to dehydrate, then absorb the post-lens tear film in order to rehydrate. Studies suggest that soft contact lenses of high water content dehydrate more than low water content lenses, and thinner lenses dehydrate faster than thicker ones. Clinicians may theoretically argue that if high water lenses tend to maintain their hydration on the eye, they must absorb the post-lens tear film, which dries the eye and desiccates the ocular surface. With an altered lipid layer, the lens continues to dehydrate, which exacerbates the cycle of absorption, depletion and evaporation. Depletion of the post-lens tear film is the final outcome associated with this cycle, which may potentially cause ocular surface problems, reduced tear exchange and a build-up of inflammatory mediators on the ocular surface. This is a theoretical mechanism for CL-DE, but studies have yet to confirm a relation between symptoms and lens dehydration.

Clinical Implications of Contact Lens-Related Dry Eye Reduced post-lens tear film thickness has implications for daily or extended wear. The cycle of evaporation, dehydration and tear depletion is probably related to the symptoms of dryness and discomfort, and dehydration generally results in changes in hydrogel lens fitting characteristics. Studies have shown that minus-powered lenses tend to increase in minus power and plus-powered lenses tend to increase in plus power due to lens dehydration. Further, dehydrated lenses tend to "steepen," which reduces lens movement and leads to "tight-lens syndrome." This lens adherence may occur in up to 50 percent of extended wear patients.

Contact lens dehydration also has implications in terms of mechanical desiccation of the cornea (the "smile" or arcuate staining patterns seen in thin high water hydrogel contact lenses). Post-lens tear film depletion is also associated with a reduced tear exchange from behind the contact lens. This may increase the potential inflammatory response due the mediators present in the post-lens tear film. There are also physiological considerations of contact lens dehydration, such as reduced lens oxygen transmissibility as oxygen is more transmissible in water. This is especially important during overnight wear of a contact lens, when the corneal epithelium is particularly vulnerable to adhesion by infectious agents.

Contact Lens Fitting in DE Patients In light of this proposed mechanism, it is important to consider several factors when managing patients with CL-DE symptoms. Because higher water content lenses dehydrate faster than lower water content lenses, silicone hydrogel lenses may be advantageous in managing CL-DE as these lenses have particularly low water contents (Bausch & Lomb's PureVision is 36 percent water and CIBA Vision's Focus Night & Day is 24 percent water). Practitioners can also control lens thickness with conventional soft lenses. Group I lenses provide some relief to patients because they are low water, nonionic and dehydrate the least.

Contact lens dehydration could be associated with other environmental stimuli (forced heating, air conditioning and arid conditions). These can be more difficult for practitioners to manage, although it is still important to consider each of these factors in managing CL-DE patients. Management options include tear supplements, eliminating environmental factors or stopping lens wear if removing an environmental stimulus is not feasible. Also, practitioners should encourage regular blinking during sustained visual activity, such as reading or computer use. It is vital that new lens materials and treatments be developed to prevent CL-DE failure.

Conclusion

The POTF is the host environment for contact lenses in-vivo. An inadequate POTF quantity or quality usually interferes with successful contact lens wear. Conversely, contact lens wear can disrupt the quantity, quality or spreading of the POTF, which impedes its ability to properly perform its many functions. The POTF must produce optically smooth and clean anterior corneal and contact lens surfaces, provide a rinsing system for removing debris from the cornea and from between the cornea and contact lens, create a reservoir and passageway for gases such as oxygen and carbon dioxide, maintain the proper osmotic equilibrium and pH, combat infection via bacteriostatic and bacteriocidal agents, wet the contact lens and the eye, create a capillarity and surface tension to help hold lenses in place and maintain the level of contact lens hydration.

	Figure 3. Contact lens-related dry eye model.

The total average volume of the POTF is about one-fifth of a drop, and it is secreted at the rate of about one-thirtieth of a drop per minute. These small volumes have to fulfill all of the described functions, which is a demanding task even with a good POTF. When the quantity or quality is reduced, the task of fulfilling all of these functions becomes more difficult.

Practitioners should evaluate the POTF by clinical tests and also consider factors that can influence it (aging, hormones, environmental conditions, certain medical conditions and some systemic or topical ocular medications). Medications that tend to decrease aqueous production include anti-anxiety agents, anticholinergics, antihistamines, phenothiazines and oral contraceptives.

There are no silver bullets for managing CL-DE. Because symptoms are so important, we recommend that you ask all patients if they feel they have dry eyes when they wear contact lenses, especially at the end of the day. One 1989 study asked practitioners to rank their preferences for managing CL-DE. The top-rated management option was the use of rewetting drops. This was followed by recommending reduced wearing time, using unpreserved lens care products, refitting the patient (in a low water soft contact lens or a GP lens), using lid scrubs and finally, refitting in a thicker lens. Note that this study concluded before the widespread use of punctal plugs and the availability of silicone hydrogel lenses. Two recent studies evaluated the use of low water content lenses and thick lenses in managing CL-DE symptoms. They found that patients preferred thick lenses, but not necessarily high water content lenses, in terms of reduced symptoms. However, some still feel the verdict remains out on the use of low water content lenses for CL-DE.

References are available upon request to the editors of Contact Lens Spectrum. To receive references via fax, call (800) 239-4684 and request document #90. (Have a fax number ready.)

Dr. Kelly Nichols is assistant professor of clinical optometry at The Ohio State University College of Optometry in the area of dry eye research.
Dr. Jason Nichols is a senior research associate at the Ohio State University College of Optometry.