continuing education

Dry Eye: Overview 2000

KELLY KINNEY NICHOLS, OD, MS
May 2000

Learn more about the etiology, diagnosis and treatment
of elusive dry eye syndrome.

Dry eye has been a hot topic over the past several years. New tests, drugs, contact lenses and products have been introduced to help diagnose and manage patients with ever-elusive dry eye. This article overviews current etiological theory, diagnosis and treatment.

Prevalence

Dry eye syndrome is a commonly diagnosed clinical disorder of the anterior ocular surface characterized by dry, irritated, stinging eyes. While the mild to moderate case of dry eye is rarely sight-limiting, the disease affects a large portion of the population. Current estimates indicate that over 10 million people in the United States suffer from dry eye syndrome. Recent studies have shown that the prevalence of patients reporting dry eye symptoms is approximately 15 to 25 percent, while severe dry eye symptoms are reported less frequently. Dry eye syndrome is more prevalent in women and in the elderly. Recently, Schein et al. reported that 10.5 percent of adults over the age of 65 years routinely purchase and use lubricant eye drops to relieve dry eye symptoms. This finding indicates that a large percentage of the population voluntarily purchases over-the-counter treatments to alleviate ocular discomfort and pinpoints a group that would benefit from a greater understanding of the disorder. With the aging United States baby boomer generation, it is expected that the prevalence of dry eye will increase as we move into the next millennium, and the eye care professional will be faced with increasing numbers of patients with dry eye syndrome. Dry eye is one of the most common anterior segment disorders encountered by eye care professionals throughout the world.

Definition

Reaching a definitive dry eye diagnosis is difficult due to our lack of understanding dry eye etiology. Researchers have made significant headway in recent years; however, we have yet to fully understand the disorder. To aid diagnosis, the National Eye Institute (NEI)/Industry report on dry eye defined dry eye as follows (Lemp, 1995):

Dry eye is a disorder of the tear film due to tear deficiency or excessive tear evaporation which causes damage to the interpalpebral ocular surface and is associated with symptoms of ocular discomfort.

While this global definition is an improvement, the report also states that ocular surface damage or symptoms may be absent in some cases of dry eye. To date, definitions of dry eye have focused on describing dry eye without emphasizing the mechanisms underlying the disease. The difficulties researchers have with the definition may be inherent in the disease process itself or due to our lack of instrumentation to adequately measure signs and symptoms. In addition, symptoms do not correlate well with objective diagnostic tests. This may be due to the poor repeatability of clinical diagnostic tests. Researchers are still in the early phases of understanding what objective findings are classically present in dry eye syndrome, as well as which symptoms correlate with the objective findings.

Masquerading disorders can often confound a dry eye diagnosis. Meibomian gland disease, blepharitis, epithelial basement dystrophy and others can mimic the signs and symptoms of dry eye. A thorough evaluation of the anterior segment is necessary, as dry eye is often a diagnosis of exclusion. The NEI/ Industry Workshop on Clinical Trials in Dry Eye (Lemp, 1995) sets forth classification of dry eye states. In the classification, evaporative dry eye is differentiated from tear-deficient dry eye. In the oil-deficient category, absent meibomian glands, obstructive meibomian gland disease and anterior and posterior blepharitis are listed as associated disorders. In this diagnostic scheme, dry eye and meibomian gland disease can be diagnosed at the same time.

In recent years, various components of dry eye have been studied extensively, including many of the diagnostic tests for dry eye. What is missing from the literature, is a "gold standard" dry eye diagnostic test to which all other tests can be compared. In the design of clinical trials, choosing appropriate outcome measures is paramount in good study design. If a "gold standard" test does not exist, defining suitable outcome measures becomes a challenge. Foremost in identifying an adequate clinical test is determining the repeatability and validity of the test.

The Tear Film

The primary function of the tear film is to provide a smooth refractive surface for the eye. The tear film also traps debris and helps remove sloughed epithelial cells, provides oxygen to the cornea, has antibiotic properties (i.e. lysozyme and IgA) and acts as a protective barrier to underlying layers. In order to maintain uniformity, the tear film must be continuous and distributed evenly across the ocular surface. Uniform tear film distribution is provided by the action of the lids, and the frequency and quality of the blinking pattern can affect the lids' ability to "spread" the tears over the ocular surface.

	Acute red eye due to soft lens drying.

Composition Holly (1977) first described the pre-ocular tear film as three distinct layers: the mucin layer, a hydrated layer of mucoproteins rich in sialomucin (glycoproteins) derived from the conjunctival goblet cells, the aqueous layer, containing dissolved inorganic salts, glucose, urea, proteins and glycoproteins from the main and accessory lacrimal glands and the lipid layer, consisting mainly of waxy and cholesterol esters secreted by the meibomian glands on the lid margin (0.1µm). The tear film thickness was thought to be due mostly to the thickness of the aqueous layer (mucin 0.02µm to 0.05µm aqueous 7µm and lipid 0.1µm).

Recently, researchers assert that the tear film is more complex and composed of an aqueous-mucin gel. These mucins are concentrated closer to the epithelial surface. Thus, the mucin and aqueous layers should not be considered two separate entities, but a series of phases. Several subtypes of sialomucins are present in the preocular (corneal and conjunctival) tear film. Mucin subtypes may play various roles in maintaining of the preocular surface. Mucin acts to stabilize the tear film by providing a hydrophilic sialomucin layer which lowers tear surface tension and allows "adherence" of the tear film to the hydrophobic corneal epithelial cell membranes. Research continues to further identify and classify the mucin subtypes and clinical findings associated with subtype deficiencies. In addition to the conjunctival epithelial cells, subtypes of sialomucin have been found in the limbal epithelial cells and to some degree in the conjunctival epithelium.

Mucin maintains tear film surface tension and tear viscosity. Research by Tiffany et al. on purified mucins found surface tension and overall viscosity were most likely not due to polymeric mucin content in tears. The authors remarked, "Tear components responsible for observed physical properties of aqueous tear fluid remain unknown. We are still far from understanding how tears work."

Amount and Thickness. About 95 percent of aqueous tears arise from the orbital and palpebral portions of the main lacrimal gland. The remainder is produced by the accessory lacrimal glands of Krause and Wolfring. The lacrimal gland produces tears at a rate of 1.2µL per minute in the resting stage. The total volume of the average tear film on the eye may range from 6µL to 8µL. The inferior cul-de-sac holds approximately 1µL to 2µL of tears. Considerable reabsorbtion of tears takes place through the conjunctival surface and the mucosal passages of the lacrimal drainage system. Tear production probably decreases during sleep and general anesthesia, while topical ocular anesthesia has also been postulated to decrease tear production.

Actual tear film thickness has come under scrutiny recently. Prydal et al., using the confocal microscope, measured tear film thickness to be approximately 40µm, six times thicker than Holly's measurement. They attributed the increased thickness to a thicker mucin layer. King-Smith and coworkers, using laser interferometry techniques, recently have shown the tear film thickness at approximately 3µm to 4 µm thick.

Dry Eye with Contact Lenses

Studies have indicated that 20 to 50 percent of contact lens wearers experience discomfort with contact lens wear. This "discomfort" is described as dryness, irritation, mild burning or stinging or a foreign body sensation. Certainly, contact lens wearers are more likely to experience ocular irritation than those who do not wear contact lenses. Contact lens wear disrupts the tear film, alters mucus production, increases evaporation of the tear film and makes the tear film chronically hypertonic. It has been postulated that thicker hydrogel lenses dehydrate less quickly, and low-water non-ionic lenses are preferred for dry eye patients. Newer materials and lenses that proclaim reduced surface drying are gaining popularity. One lens material, omafilcon, received FDA approval for dry eye.

A rigid lens with band plaque inferiorally and surface haze centrally due to poor lens wetting.

Many of the dry eye diagnostic tests often give poor results in the symptomatic contact lens patient; therefore, diagnosis of dry eye is often overlooked or labeled mild to moderate. With increased recent interest in the relation of dry eye to contact lens wear, hydrogel lens dehydration has once again become a topic of great interest. It has been suggested that a contact lens that demonstrates less surface drying may be more comfortable to the contact lens-related dry eye patient. In the past, clinicians have used low water content lenses for the dry eye patient; however, the controversy of thick vs. thin lenses, high vs. low water content and lens material group continues.

Pre- and Post-lens Tears. The tear film is divided into the pre- and post-lens tear film when a contact lens is inserted. The pre-lens tear film is important in maintaining the optical qualities of the contact lens-eye system, lubricating the front surface of the lens and maintaining lens hydration. The post-lens tear thickness has been debated. Contact lenses can adhere to the eye after overnight sleep. Could this be due to a thinned post-lens tear thickness? Some researchers believe the post-lens tear thickness is negligible, even in the open-eye situation. Other researchers have used measurements of the corneal surface and optical pachometry to estimate post-lens tear thickness at 11µm to 12µm, a value as thick as some estimates of the tear film without a contact lens. In rigid gas permeable lenses, adhesion can occur in both overnight and daily wear. Post-lens tear debris has been postulated to act like biological adhesive that can be seen behind the lens.

The composition of the polymers in the rigid lens can contribute to increased drying of the lens surface. Adding silicone to the lens matrix may cause the surface of the rigid lens to become more hydrophobic, attracting tear film lipids to the lens. Aqueous is then repelled from the areas where lipids are bound to the silicone polymers. In order to combat non-wetting in silicone lenses, compounds are added to the material, or the surface is treated to attract water. These compounds can also attract other charged molecules, which can cause protein build-up on lenses. When the tear film forms over a rigid gas permeable lens, no anterior lipid layer is found. Therefore, evaporation from the surface of the rigid lens occurs at a higher rate than in the eye without a contact lens.

Tear Film Stability. The fluorescein tear break-up test (TBUT) or non-invasive measures of break-up time such as the TearScope are used clinically to assess tear stability. Tear break-up with fluorescein is defined as the first "black spot" to appear as the tear film separates over the corneal surface when viewed with cobalt illumination. Originally it was thought that break up of the tear film occurred when the lipid layer became discontinuous and the mucus layer non-wettable. This theory has been refuted by several researchers. It is now thought that the absence or thinning of the mucus layer and the aqueous layer coming in contact with the hydrophobic cornea causes dry spots to occur. The glycocalyx layer, secreted by the epithelial cells, maintains the intact tear film by binding mucins. In contact lens wear and anterior surface disease, the mucus production can be altered, thereby changing tear film stability.

Changes in the lipid layer affect tear film stability. Disorders of the eyelids, such as meibomian gland dysfunction and blepharitis, can affect the quantity and quality of tear lipids. Altered lipids can deposit on the surface of contact lenses in conjunction with mucus and protein and will have a negative effect on tear film stability. The addition of a new or deposited contact lens to the ocular environment can also deter the lids from appropriately renewing the tear film during blinking.

Etiology of Dry Eye

Risk factors for primary dry eye include age, contact lens wear, use of medications with dry eye side effects (such as antihistamines, diuretics or oral contraceptives) and environmental conditions such as low humidity. Our understanding of how these factors affect the ocular surface is still developing. The concept of the ocular surface as a functional unit has been in existence since 1979. In recent years a greater understanding of the role of the conjunctiva, lacrimal glands, accessory glands, meibomian glands and the lids on the tear film had emerged. Numerous growth factors, hormones, cytokines and receptors for these substances have been found on the ocular surface and at the glandular level. Researchers believe dry eye symptoms result from an abnormal ocular surface with decreased ability to respond to environmental challenges.

A recent paper by Stern et al. hypothesized that the components of the ocular surface (cornea and conjunctiva), the lacrimal gland and the connecting innervation act as a functional unit. Any disruption of this unit will affect the normal modulation of the immune response and may lead to immune-based inflammation and symptoms of ocular irritation. These findings point to a critical servomechanism involving innervation of the ocular surface, lacrimal glands and lids, all of which process signals. The signals modulate the secretion of chemical substances which, in turn, direct cellular turnover of the normal ocular surface and influence repair functions in response to injury and insult.

The influence of hormones on the ocular surface and the tear film has been receiving recent attention. The lacrimal glands and the meibomian glands require bio-available androgens to support their normal function. Meibomian gland disease may be initiated by a loss of androgen support and can lead to evaporative tear loss from the eye and dry eye symptoms. It is also thought that androgens may have an effect in Sjögren's syndrome and may contribute to lacrimal gland dysfunction. The affect of androgens on both of these glands is hypothesized to be the reason for the high prevalence of dry eye in postmenopausal women seen clinically.

Meibomian Gland Disease. The role of meibomian gland disease in dry eye has been strongly debated. The meibomian glands are the primary source of the lipid layer of the tear film, the essential component in the prevention of evaporation from the ocular surface. Irregularities in meibomian gland function causing insufficient tear oil or qualitatively abnormal oil lead to increased evaporation, increased ocular surface disease and dry eye symptoms. A study of patients with meibomian gland dysfunction revealed increased patient-reported dry eye symptoms associated with more fluorescein and rose bengal staining compared to non-meibomian gland dysfunction patients (Shimazaki, et al., 1995). The treatment of meibomian gland dysfunction with long-term gland expression and lid scrubs increases the thickness of the lipid layer of the tear film (Korb and Greiner, 1994). However, no attempt was made to correlate this finding with other test results or symptoms.

Dry Eye Diagnosis

The tests used clinically to diagnose dry eye fall into two categories: tests that measure tear production and tests that evaluate tear stability. Tests commonly performed to measure tear production include the Schirmer I tear test, the phenol red thread test and the measurement of the tear meniscus height. While these tests measure the quantity of tears produced, they do not yield any information about the quality of the tears. Tear stability can be assessed by using the tear break-up time test, which is both a qualitative and quantitative measurement of dry eye. Also, tear film stability can be evaluated by examining the meibomian gland function and tear quality.

The effect of dry eye on the ocular surface is evaluated using fluorescein and rose bengal dye, and patient questionnaires develop a risk profile and evaluate symptoms. In addition to clinical tests of dry eye, there are several laboratory-type tests that are more sensitive and specific in diagnosing dry eye, such as the measurement of tear osmolarity, local tear film thinning (TearScope) and lactoferrin concentration; however, the tests require expertise in measurement, time and instrumentation.

Symptomatology. Increasing attention focuses on symptoms of ocular irritation associated with dry eye. Asking patients if their symptoms are worse in the evening may give more information than just inquiring if the patient ever has ocular discomfort, dryness or irritation. In addition, dryness and blurry vision are important symptoms in contact lens wear, especially at the end of the day.

In recent years, assessing patient-reported dry eye symptoms has become increasingly popular with clinicians due to the suspected variability in objective clinical tests for dry eye. A standardized questionnaire sensitive to transient changes in the dry eye condition to date has not been developed. As part of the case history, many clinicians ascertain patient-reported dry eye symptoms. A study by Bandeen-Roche et al. reports the most frequently reported symptom was "grittiness" followed by "burning" and "redness" in dry eye patients, while Begley et al. report "discomfort" and "dryness" as the most frequent symptoms.

Dry Eye Questionnaires. Since it was first published in 1986, the McMonnies's Dry Eye Questionnaire has been used to evaluate factors associated with dry eye. The questionnaire has been tested on normal samples, as well as samples of contact lens wearers. The questionnaire assesses risk factors, namely age, sex, contact lens wear, medication use and systemic and ocular conditions that may be associated with dry eye.

Following the initial publication, a weighted scoring scale was developed (McMonnies and Ho, 1986). The weighting scheme as proposed by McMonnies is arbitrary and based on clinical observation. Higher weights are given to a higher risk states. A total of 45 points is possible, with higher points for women, increasing age, increasing frequency of dry eye symptoms, medication use associated with dry eye and sensitivity to environmental conditions, among other factors. A dry eye index score is then calculated, which allows direct comparison of patient scores. Scores greater than 14.5 indicate dry eye. Recently, two additional dry eye surveys have been developed, the Ocular Surface Disease Index, which was used in the Allergan cyclosporin clinical trials, and the Dry Eye Questionnaire, developed by the Dry Eye Investigation (DrEI) group.

Testing

	Corneal staining due to poor corneal wetting.

Tear break-up time. Break-up of the tear film is still one of the more commonly performed dry eye diagnostic tests. Akorn Ophthalmics recently introduced the Dry Eye Test (DET), which is a new method of evaluating fluorescein tear break-up time. The DET fluorescein strips are much smaller than traditional fluorescein strips, and deliver a 1µl volume of fluorescein to the tear film. In theory, this small volume induces much less reflex tearing and delivers a consistent amount of fluorescein, increasing accuracy and repeatability. In performing the TBUT test, most researchers recommend taking two to three consecutive measurements and averaging the results. Use a separate DET fluorescein strip for each eye to ensure equal amounts of fluorescein are instilled each time the test is performed. TBUT assessment is a good clinical test to evaluate tear film stability. In cases where a decreased tear break-up time is found, carefully evaluate the meibomian glands.

The tear break-up time is often thought to be an assessment of the integrity of the mucin layer; however, studies have shown decreased tear break-up times in cases of altered lipid layer quality associated with blepharitis and meibomian gland disease. Excessive lipid contamination of the tear film and mucin layer causes local dry spots and the dry eye condition. Tear break-up time is measured clinically with fluorescein dye and a cobalt-blue filter. Tear break-up time is defined as the interval between a complete blink and the appearance of the first random black spot on the corneal surface. Tear break-up time can be influenced by many factors, including method of fluorescein instillation, palpebral aperture width and humidity level. As in fluorescein staining of the cornea and conjunctiva, a Wratten #12 filter can be used to enhance the view of the fluorescein. Measurements of ¾ 10 seconds indicate dry eye. The Report of the NEI Dry Eye Workshop recommends repeating the measurement three times and averaging the results (Lemp, 1995).

Schirmer and Phenol Red Thread. In 1903, the Schirmer test was first described as a method of measuring tear secretion. The test was performed by placing a piece of filter paper 35mm in length and 5mm in width over the inferolateral conjunctival cul-de-sac for five minutes (Schirmer, 1903). The Schirmer I test is generally considered a measurement of total (reflex and basic) tear secretion, while the Schirmer II test is regarded as a test of induced reflex secretion. An evaluation of tear production is helpful in determining if the patient has aqueous-deficient dry eye.

While both the traditional Schirmer Test and the Phenol Red Thread Test (PRTT) are largely unrepeatable, insurance companies often request a test of aqueous production. In general, a failed test (low tear production) indicates dry eye, while a non-abnormal test does not necessarily rule out a dry eye diagnosis. The Phenol Red Thread Test was developed to evaluate tear production like the traditional Schirmer Test, but without the discomfort and (as much) reflex tearing as with the Schirmer test. A recent study demonstrated that reflex tearing does occur with the PRTT. Cut-point values for the Schirmer test and the PRTT are ¾ 5mm/5 minutes and ¾ 15mm/15 seconds, respectively. In addition, the cut point for the PRTT was developed in Japan. Some literature indicates that the average result found in Japanese patients is lower than the average result in patients in the United States (Sakamoto et al., 1993) This may indicate that slightly higher results in the American population are indicative of (marginal) dry eye. The Zone Quick phenol red thread test is commercially available in the United States from Menicon, Inc.

Tear Meniscus Height. Evaluation of the tear meniscus height is a rough estimate of tear quantity, and assessing the amount of debris in the tear prism also demonstrates tear quality. Several authors have suggested that a decreased tear meniscus height indicates decreased aqueous; however, there has been minimal work to systematically classify clinical ranges in normals and dry eye patients. Studies by Mainstone et al. established a tear meniscus height for dry eye of approximately 0.25 mm in height, while normals demonstrate a height of around 0.50 mm. Therefore, a dry eye cut-point value where values ¾ 0.3 mm are considered indicative of dry eye can be utilized clinically.

Dyes. Fluorescein, rose bengal and lissamine green dyes evaluate the integrity of the ocular surface in the evaluation of dry eye. Fluorescein dye detects epithelial defects in the anterior surface of the eye. It is generally accepted that fluorescein only penetrates the corneal epithelium at sites of interrupted continuity of the epithelial surface. The inferior cornea is the most common location for fluorescein staining, followed by the nasal cornea. Staining in the normal population is seen more frequently in the morning and late afternoon.

Conjunctival staining with fluorescein is much more difficult to detect, and is enhanced with a #12 Wratten barrier filter which blocks extraneous light and highlights staining patterns. Some fluorescein conjunctival staining is common, and tends to be diffuse in pattern. Rose bengal, while staining de-vitalized cells and mucus, may also be cytotoxic to corneal and conjunctival epithelial cells. Rose bengal staining patterns are classically graded on a 0 - 3 scale proposed by van Bijsterveld, in which three regions of the interpalpebral ocular surface are assessed (the triangular wedge of the nasal interpalpebral conjunctiva, the corneal surface and the wedge of the temporal conjunctiva). The grade of each region is summed, and a score greater or equal to 3.5 indicates dry eye. Rose bengal stings slightly on instillation, which is not found with lissamine green dye. Lissamine green is suitable in staining degenerate cells, mucus and dead cells with identical staining patterns to rose bengal. Lissamine green is commonly used in place of rose bengal in evaluating dry eye.

Laboratory Tests. The three most common laboratory tests for dry eye are the measurement of tear film osmolarity, the concentration of tear film lactoferrin and impression cytology of the conjunctival epithelial cells. Recent advances in technology have made these tests more available to the clinician; however, cost of the instrumentation and unfamiliarity with test procedures have prevented wide clinical application.

Treatment

Artificial tears and appropriate lid hygiene are generally the first-line treatment for dry eye, and they are often adequate in alleviating dry eye symptoms. When choosing artificial tears for patients, practitioners should consider preservation system (preserved, transient preserved or non-preserved), viscosity (low, medium or high), form (liquid, ointment or gel), container (unit dose or bottle) and cost.

Of course, tear supplement therapy should be just one part of a holistic approach to dry eye management. Recommend lid scrubs and hot compress eyelid massage as well. Treat allergies with pre- and post-lens wear topical mast cell stablizers and/or antihistamines. Avoid low humidity environments, or use a humidifier if possible. Avoid drugs, alcohol, diuretics or other agents, and minimize use of drugs which can cause dry eye. Avoid smoke which can reduce tear break-up time. Some patients benefit from RGP lenses because these lenses do not dry out, while others prefer certain soft lens polymers such as omafilcon, which has an FDA indication for mild dry eye. Some patients with severe meibomian gland dysfunction may also require topical and/or oral antibiotics.

Although punctal occlusion does not improve symptoms for all dry eye patients, some patients show significant improvement, especially aqueous deficient patients. Punctal plugs may increase the amount of tears on the eye to hydrate a contact lens, as well as decrease dry eye symptoms prior to and after LASIK and PRK.

Conclusion

Successful diagnosis and management of dry eye patients requires step-wise treatment and adequate follow-up. Subjective symptoms often aid the clinician in monitoring improvement. With increased understanding of the etiology of dry eye on the horizon, we can expect new treatments tailored to the type of dry eye and new instrumentation to further aid the diagnosis of this complex disorder.