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Dilemmas in Diagnosing Dry Eye
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Dry eye disease (DED) is one of the most common causes of ocular irritation, and can severely affect a person’s quality of life by producing discomfort and reduced vision. Frequently, a patient’s clinical history is consistent with the diagnosis of DED. Unfortunately, many patients do not exhibit clinical findings, or they demonstrate clinical
findings that do not correlate with their symptoms. A single, consistently sensitive and specific test for DED would provide the clinician with objective information when the patient’s symptoms do not correspond with the clinical appearance of the eye.
Staining Tests
Estimating the degree of punctate staining of the cornea or conjunctiva provides a structured grading system to quantify and objectively assess disease effects on the ocular epithelium. This type of test has been described with various stains such as fluorescein (Figure 1), rose bengal and lissamine green.
When viewed under blue light, the fluorescein dye reveals ocular surface damage attributable to dry eye disease and many other causes.
Source: Stephen C. Kaufman, MD, PhD
Staining tests are easy to perform, fast and inexpensive; however, factors other than those associated with DED can affect the results. Anything that has a toxic effect on the conjunctiva and corneal epithelium can result in a punctate staining pattern and elicit a false result. High or low humidity, artificial tears and time of day can also alter the test results.
Tear Production Tests
The Schirmer (Figure 2) and thread tests have been used for more than 100 years and were among the first objective tests for DED, providing a means to quantify tear production over a set period of time. Theoretically, these tests have a threshold value for diagnosis and provide a means to assess the course of the condition. Unfortunately, many factors can affect outcomes, including time of day, the patient’s head position, reflex tearing caused by a foreign-body sensation from the measuring device, and artificial tear use before the test.
The Schirmer test has been used for more than a century to measure tear production. Unfortunately, many variables can affect the test’s outcomes.
Source: Stephen C. Kaufman, MD, PhD
Tear Break-Up Time
The tear break-up time (TBUT) test is not without its confounding factors, but this fast, inexpensive test correlates well with DED in many cases. Many of the conditions that affect the Schirmer test, string test and punctate epithelial grading test, also affect the TBUT.
Tear Characteristic Tests
Tear characteristic tests analyze tears for qualities that affect DED, such as lactoferrin concentrations and tear osmolarity. Increased tear osmolarity occurs in DED because the tear solutes become concentrated in dry eye patients. This increase in solutes increases the osmolarity of the tear film.
Clinical devices are now available and are able to accurately measure the osmolarity of the tear film. One such device, developed by TearLab, uses small handheld units with disposable contact tips (Figure 3). This device requires only a 50-nL tear sample, little time and no anesthetic. TearLab literature states that an osmolarity of 308 or higher indicates DED. Peer-reviewed literature is needed to establish the device’s place in diagnosing DED.
The TearLab device for measuring tear osmolarity uses disposable contact tips and requires only a 50-nL tear sample.
Source: Stephen C. Kaufman, MD, PhD
The base unit, handheld devices and disposable tips are an expense that the clinician must accept. Also, in order to bill for this test, the clinic must be certified by a laboratory standards organization, which involves
another additional expense.
Despite the high degree of precision that this device reports, its results can be affected by anything that affects the patient’s standard tear film. Anything that alters the tear osmolarity by either drying the ocular surface or by increasing the aqueous component of the tears will influence the test results. Generally, patients are instructed to avoid any eye drops prior to testing, and if serial testing for DED progression is planned, the testing should be done at the same time each day.
Inflammation Testing
Although the previously described objective tests do provide a quantitative means to assess DED, each test also can be affected by common factors that must be controlled to achieve optimal, repeatable and accurate results. A new clinical test has been developed to objectively ascertain ocular surface inflammation by detecting metalloproteinase 9 (MMP-9) in the tears (Figure 4). MMP-9 is a nonspecific inflammatory mediator that is expressed by stressed epithelial cells. MMP-9 is elevated in DED in the presence of ocular inflammation.
Rapid Pathogen Screening manufactures this device for metalloproteinase 9, a nonspecific inflammatory mediator that is expressed by stressed epithelial cells. The disposable device, not available in the United States, yields test results in 10 minutes.
Source: Rapid Pathogen Screening, Inc.
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This testing device is available in Europe, but not yet in the United States. The individually packaged, disposable device yields a result within 10 minutes and is inexpensive in Europe. In the United States the device is manufactured by Rapid Pathogen Screening, Inc. (RPS). (A family member of the author is a consultant and investor of RPS.) The company claims a specificity of 92% and a sensitivity of 87%. The test is positive when the amount of MMP-9 detected equals or exceeds 40 ng/mL and a red line appears in the window of the handheld testing device.
Patients and clinicians become frustrated when the patient’s symptoms do not correlate well with clinical examination. This new test still needs clinical trials to fully evaluate it for diagnosing and measuring the severity of DED, but it appears promising as a tool to help to diagnose DED in patients who do not demonstrate the classic clinical finding of the condition. Although tear film dilution could decrease its sensitivity, the test is able to detect extremely small amounts of MMP-9. Ocular inflammation is not present in very mild DED so the test may be useful only in advanced mild, moderate or severe disease where ocular inflammation has developed.
Previous research has shown that elevated MMP-9 indicates which patients will respond to anti-inflammatory therapy such as corticosteroids, azithromycin, cyclosporine and doxycycline. Elevated MMP-9 levels would also warn the surgeon prior to LASIK or other ocular surgery and help to reduce the risk of complications. Furthermore, a negative test result after treatment could be used to determine treatment success and long-term follow up.
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The Best Test
From Otto Schirmer’s test to the MMP-9 tagged-antibody test, each objective test for DED has its place in the clinician’s diagnostic armamentarium. No single test can detect dry eye in all patients. Most of these test results could be considered significant when they are positive since most confounding variables contribute to negative test results, but the limitations of each test must be considered by the clinician when assessing the results.
References
- Bron AJ, Yokoi N, Gaffney AE, Tiffany AM. A Hyperosmolar Gradient in the Tear Meniscus: A Hypothesis to Explain Pathophysiological Events at the Lid Margin. Invest Ophthalmol Vis Sci. 2010;51:E-Abstract 5199.
- Nichols K, Mitchell G. Lynn, Zadnik, K. The Repeatability of Clinical Measurements of Dry Eye. Cornea. 2004;23(3):272-285.
- Lemp MA, Hamill JR Jr. Factors affecting tear film breakup in normal eyes. Arch Ophthalmol. 1973;89:103–105.
- Pflugfelder SC, Tseng SC, Sanabria O, Kell H, Garcia CG, Felix C, et al. Evaluation of subjective assessments and objective diagnostic tests for diagnosing tear-film disorders known to cause ocular irritation. Cornea. 1998;17(1):38.
- TearLab Web site. http://tearlab.com. Accessed July 7, 2011.
- Rapid Pathogen Screening Web site. http://www.rpsdetectors.com. Accessed July 7, 2011.