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Underlying conditions not the same among dry eye patients
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Diagnosing and treating dry eye is frustrating for clinicians, patients and researchers alike. Dry eye syndrome represents a group of diseases characterized by ocular surface exposure leading to symptoms such as dryness, burning, foreign body sensation, photophobia and blurry vision.
During the past decade, research has led to a number of dry eye discoveries. We have learned that dry eye is not solely caused by a lack of tear volume but also a deficiency in one or more of the tear components causing a disruption in the tear film and inadequate lubrication of the ocular surface. A key concept we have learned is that the lacrimal gland, meibomian glands and ocular surface should be considered as a single, highly interacting unit.
Researchers have also identified interrelationships between hormones, mucin, oils, growth factors, retinoids, cytokines as well as goblet cells, the surface epithelium and the effects of blinking. We now understand that any two dry eye sufferers may have different underlying conditions, and we must differentiate between them. We are at a time when proper diagnostic tools are becoming necessary to properly match the right treatment to the right patient.
Determining tear film stability
Tear film stability is a detector of both aqueous-deficient and evaporative dry eye. Stability of the tear film is influenced by blinking, the character of the tear film and the health of the ocular surface.
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A common measurement of tear film stability is tear film break-up time (TFBUT). Traditionally TFBUT was measured with large or varying amounts of sodium fluorescein (approximately 40 µL). As a result, the test was not reproducible, and values for dry eye patients were determined to be less than 10 seconds. In recent years, small micro quantities of unpreserved sodium fluorescein (5 µL) have been used to measure TFBUT. As a result, the accuracy and reproducibility of this test has been dramatically enhanced. With the technique, TFBUT has been determined to be less than 5 seconds in dry eye patients.
It has been established that a correlation exists between ocular discomfort, tear film break-up time and blinking. Studies show that within 1 second of TFBUT, 73% of dry eye patients experience awareness or ocular discomfort, which may stimulate a blink — decreasing symptoms as well as replenishing the tear film and providing protection to the ocular surface. If blink rate is altered as a result of visual tasking (i.e., reading, watching TV or staring at a computer screen), symptoms and signs of dry eye may be exacerbated.
A protected ocular surface exists when TFBUT matches or exceeds the time between blinks (inter-blink interval). In contrast, an unprotected ocular surface occurs when TFBUT is less than the inter-blink interval, temporarily exposing the ocular surface and causing ocular discomfort and the development of keratitis and redness.
The Ocular Protection Index (OPI) quantifies the interaction between the inter-blink interval and TFBUT. Studies have shown that the average blink rate is approximately 12 times per minute, or once every 5 seconds. If patients fit this average and their TFBUT is 3 seconds, their ocular surface is unprotected for 2 seconds between each blink. An agent would produce a clinically significant improvement if it extended the TFBUT to continually protect the ocular surface — in this case, if it lengthened TFBUT by 2 seconds to match the inter-blink interval.
Diagnostic staining
Sodium fluorescein, lissamine green and rose bengal are common dyes used to diagnose dry eye and assess the intactness of the pre-corneal tear layer and integrity of the ocular surface. Sodium fluorescein is a classic dye, which selectively stains areas of epithelial damage. The use of a yellow filter and a cobalt blue illumination along with the slit lamp enhances the visibility of the stained cells.
Rose bengal, and its more modern alternative, lissamine green, stain dead and degenerated cells on the ocular surface, particularly the conjunctiva. The staining characteristics of rose bengal and lissamine green are comparable, but the tolerance of lissamine green is much better, thus it serves as a reliable alternative to the uncomfortable rose bengal in diagnosing and assessing dry eye. All three of these dyes can be used to assess the therapeutic effect of dry eye agents on preventing and treating ocular surface damage.
Measuring tear production
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In a clinical setting, tear production is commonly measured by the Schirmer’s test, while in a research setting, it can also be measured by fluorophotometry. The Schirmer’s test is based upon the absorption of tears by a piece of filter paper placed in the inferior fornix over a set period of time. This test can be performed with or without an anesthetic. The element of reflex tearing can often devalue the results of testing performed without an anesthetic.
While the use of an anesthetic should minimize reflex tearing, it does not eliminate the fact that the natural physiological state of the eye and tear film is being altered. As the Schirmer’s test is relatively disruptive to this natural state, a more effective, less disruptive way to gain similar information is through the use of fluorophotometry.
Fluorophotometry uses the decay of fluorescein in the tear film caused by the turnover of tears to give a truer indication of tear production and tear turnover rate. Both of these tests help determine the functional status of the lacrimal glands and assess the therapeutic effect of agents that stimulate lacrimation or decrease lacrimal gland inflammation.
Assessing symptoms
Clinicians often use patient-reported symptoms of dry eye in making a dry eye diagnosis. However, a puzzling feature of dry eye is that symptoms do not always correlate with signs. The degree of ocular discomfort does not always correlate with severity of dry eye as measured by corneal or conjunctival staining, TFBUT or tear production.
Studies have shown the least severe discomfort may exist in patients with the most severely stained ocular surface. Although it is not entirely clear why this discrepancy exits, evidence suggests that the progressive nature of the disease reduces corneal sensitivity either by the impairment of nerve interventions or by the presence of inflammation. Thus, in later stages of dry eye, signs can be present while symptoms are frequently absent.
The symptoms of dry eye are also greatly influenced by environmental factors such as humidity, air flow and visual tasking. If your patients work at computers or are frequently in air-conditioned or heated rooms, worse or more frequent dry eye symptoms may be present. You may also see an increase in the prevalence of dry eye symptoms during months with lower humidity.
Effects of oral antihistamines
Signs and symptoms of dry eye are also caused by the anti-muscarinic action of oral antihistamines, which decrease the aqueous layer of the tear film. Studies have shown that in as little as 4 days of dosing with Claritin (loratadine, Schering) both dry eye symptoms and signs, including increased corneal and conjunctival staining, and TFBUT worsen. Decreased tear flow and tear volume as measured by fluorophotometry and Schirmer’s test are also seen.
Dry eye pipeline
Currently, treatment options consist of lubricating eye drops or punctal plugs/occlusion, which attempt to mimic or replace a patient’s natural tears or their residence time. But these efforts are often unsuccessful or provide brief relief of symptoms. As we better understand the underlying causes of dry eye, we are able to develop pharmaceutical agents aimed at treating the disease.
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Recently, Restasis (cyclosporine ophthalmic suspension‚ Allergan) was approved for the treatment of dry eye due to ocular inflammation. Restasis presumably works by decreasing the inflammatory process in dry eye allowing, over time, the ocular system to return to a more “normal” state.
In clinical trials, Restasis significantly improved Schirmer I scores, which may show decreased inflammation of the lacrimal glands and thus increased basal tears.
Researchers have shown that a deficiency in conjunctival mucin exists in dry eye states, suggesting a potential therapeutic value of mucin secretagogues. Two such secretagogues are currently under investigation. The compound 15(S)-HETE (hydroxy-eicosatetraenoic acid) is currently being investigated for its ability to stimulate secretion of mucin.
Another secretagogue being investigated is a synthetic purinoceptor P2Y2 agonist, INS365, which stimulates the production of chloride and fluid secretion and increases mucin secretion from goblet cells. Studies have shown that INS365 increases tear secretion and decreases the loss of corneal epithelial integrity in dry eye patients. Researchers are expecting the therapeutic effect of these secretagogues to show an improved TFBUT and decreased corneal and conjunctival staining.
Artificial tears are designed to mimic the natural component of tears and maintain the function of the tear film that may be lacking in dry eye patients. Thus, artificial tears should help maintain protection of the ocular surface (increase OPI), create a smooth surface to allow light refraction and clear vision and provide relief from symptoms of dry eye.
Until recently, the dwell time of artificial tears was short, providing very temporary relief of signs and symptoms. Newer, more viscous polymers are aimed at improving retention time and drop comfort and preventing evaporation from the ocular surface without causing blurred vision or stickiness. For example, the artificial tear Systane (polyethylene glycol 400, propylene glycol, HP guar, borate, Alcon) combines with the natural tears and uses the gelling properties of its HP guar ingredient, creating a cross-linked scaffold to increase dwell time. It spreads over the cornea and conjunctiva, holding the demulcent system on the eye to lubricate between blinks, enhance tear film stability and allow repair of the epithelial surface. This microenvironment protection, provided by an improved polymer, may facilitate epithelial cell repair processes. The effect of agents such as this can be assessed by measuring OPI over time after instillation.
For Your Information:`
- John Pietrantonio, OD, is director of eye services at East Boston Neighborhood Health Center and affiliated clinical professor of optometry at the New England College of Optometry. He can be reached at Ophthalmic Research Associates Inc., 863 Turnpike St., N. Andover, MA 01845; (978) 685-8900; fax: (978) 689-0020. Dr. Pietrantonio has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any of the companies mentioned.