While the goal of a simple, objective, and unambiguous test for dry eye remains elusive, new and emerging clinical tests for dry eye are increasingly specific and quantitative, moving us further toward that goal.
Traditional clinical tests for dry eye, including the Schirmer test, ocular surface staining, tear film breakup time (TFBUT), and meibomian gland grading, all provide useful diagnostic information. However, these tests are also subjective and notoriously variable, exhibiting significant observer-to-observer and test-to-retest differences in results. Room drafts and test strip irritation affect Schirmer test results; timing and practitioner judgment impact the grading of ocular surface staining; and TFBUT results and meibomian gland grading can be remarkably variable and subjective.
In contrast, new and developing dry eye tests focus increasingly on identifying specific biomarkers and taking precise, noninvasive measurements. While none of these has yet displaced traditional dry eye tests, the new tests add objectivity, reproducibility, and new insights into disease progression and treatment efficacy.
Elevated tear osmolarity is well established as a defining characteristic of dry eye disease.1 In normal subjects, tear osmolarity is low and nearly identical to blood osmolarity (290 milliosmoles per liter), indicating that tears are in proper homeostasis. Dry eye patients, on the other hand, have elevated (> 316 mOsm/L) and unstable tear osmolarity. In patients with dry eye, tear osmolarity can vary both over time and between eyes.2 Indeed, a dry eye can test with different osmolarity scores within minutes, and an inter-eye difference greater than 8 mOsm/L is itself diagnostic of dry eye. The critical thing to recognize is that the variability of osmolarity values is a hallmark of the disease process, not an inadequacy of the technology (TearLab™ Osmolarity System [TearLab Corp]).
Recent studies have established the analytical reproducibility of TearLab™ osmolarity determinations and demonstrated clearly that variable results in dry eye patients are biological in origin. In the first part of one study, trained and untrained operators (all masked) measured in vitro tear samples across a dynamic range from 295 to 377 mOsm/L. The untrained operators were physicians, nurses, and technicians with no previous experience using the technology.3 In the second part of the study, the trained and untrained operators collected and measured 178 in vivo tear samples from the inferior lateral menisci of study volunteers.
In the study, in vitro osmolarity was highly reproducible: the average difference between trained and untrained observers testing the same specimen was only 5.3 + 4.5 mOsm/L. This was a roughly 1.5% difference between the operators, with a correlation coefficient (r2) of 0.95. The repeatability of in vivo results was found to scale with disease severity. In the 86 normal study subjects, the mean osmolarity measured by all untrained operators was 297 + 8 mOsm/L; the mean value for trained operators was 296 + 9 mOsm/L. The average absolute difference in testing the same eye, trained vs untrained, was 5.9 + 4.9 mOsm/L—essentially the same as the in vitro performance.
In the 92 dry eye subjects, the mean osmolarity determined by untrained observers was 318 + 17 mOsm/L vs the mean value measured by trained observers, which was 315 + 18 mOsm/L. The mean absolute difference between trained and untrained testers examining the same eye was 16.4 + 14.5 mOsm/L. This study demonstrates the technology’s relative stability, and it highlights an inherent challenge in dry eye disease: that osmolarity is not just high but variable in affected patients.
An advantage of the test, however, is that tear osmolarity has also been demonstrated to reduce and stabilize in conjunction with symptom improvement in response to therapy.4 With a clear understanding of what variability indicates in this test, clinicians who treat dry eye should find it extremely useful—both as an initial diagnostic and as a gauge of treatment success.
Testing tear osmolarity has added a great deal to my practice, giving me not just a diagnostic and monitoring tool but a way to track and encourage patient compliance with therapy. Because it is a quantitative test, patients can understand and relate to it; and they find it satisfying and motivating to keep track of their osmolarity number. The test is also simple and quick to perform, and can be easily delegated to a technician.
Like the TearLab Osmolarity System, the InflammaDry™ test (Rapid Pathogen Screening) is a rapid, point-of-care assay that measures a tear film component indicative of dry eye. InflammaDry detects elevated levels of matrix metalloproteinase-9 (MMP-9), a marker for inflammation found in the tears of dry eye patients.
In the normal tear film, the level of MMP-9 is between 3 and 40 ng/mL; an MMP-9 level greater than 40 ng/mL is indicative of ocular surface inflammation. Because it is a nonspecific marker of inflammation, patient history and other clinical signs are necessary to confirm a diagnosis of dry eye, but other inflammatory conditions affecting the eye (eg, corneal ulceration, allergic conjunctivitis, rosacea, or Sjogrens syndrome) are generally not difficult to rule out.
Dry eye, on the other hand, is often hidden, and patients with significant symptoms may have few or no signs of the condition. Likewise, patients may have fairly developed signs but report mild or no symptoms. An objective, albeit nonspecific, test like InflammaDry can add important diagnostic information.
The InflammaDry test, moreover, is inexpensive, highly portable, and easily administered by a nurse or technician. In an FDA clinical trial, InflammaDry demonstrated 85% sensitivity and 94% specificity.5
While estimates vary, evidence suggests that most dry eye is evaporative or has a significant evaporative component; and evaporative dry eye results from deficient or dysfunctional meibomian gland-produced lipids. As more attention is focused on the treatment of meibomian gland dysfunction (MGD) to remedy evaporative dry eye, more sophisticated lipid diagnostic technology is also becoming available. In addition to meibomian gland grading and expression, which evaluate gland patency and lipid quality, tear film interferometry has been developed to visualize and measure the tear film lipids as they spread over the ocular surface.
The LipiView® Ocular Surface Interferometer (TearScience) is a tabletop device that illuminates the tear film and records and measures the interference pattern of the reflected light. This “interferogram” is captured and analyzed by software included with the device, allowing lipid layer thickness to be determined with nanometer accuracy. If the lipid layer is too thin or the tear film composition abnormal, then the associated LipiFlow® Thermal Pulsation System treatment may be advised, provided the meibomian glands remain expressible. LipiView offers valuable data to practitioners; its current use is limited chiefly by the cost of the equipment and billing issues (ie, patients must pay out of pocket for the test).
OCT and Topography
While still largely a research tool, high-resolution optical coherence tomography (OCT) shows promise for imaging and measuring tear film thickness in the clinic. OCT is noninvasive, highly accurate, and has successfully documented tear film changes in response to punctal occlusion and cyclosporine therapy.6,7 Since OCT does not require contact with the ocular surface or the use of dyes, it may be less affected by reflex tearing than traditional tear film assessments.
The idea of using topography data to characterize ocular dryness is not new, but commercial technology is beginning to focus seriously on this application. I presented data at ARVO in 2002 in which I correlated the raw data from Shack-Hartmann wavefront analysis with a standard clinical evaluation of dry eye.8 A decade later, the Keratograph 5M (Oculus) now comes equipped with robust dry eye screening software, including noninvasive keratographic tear breakup time, interferometry, meibography, and automated bulbar and limbal redness assessment.
While few comprehensive ophthalmology practices own a confocal microscope, it is becoming an increasingly useful tool for studying corneal nerves. It is, for example, being applied to find and monitor diabetic peripheral neuropathy. The nerves can be captured with high fidelity and reliability: tracking software now allows practitioners to image and return to the same nerve over multiple visits.
Ongoing research should be able to tell us more about what kind of diagnostic information can be gleaned from serial nerve imaging. Will changes in corneal nerves precede clinical signs and symptoms of dry eye, allowing for earlier intervention? A close, long-term look at corneal nerves may have much to tell us about the progressive course of dry eye.
THE BOTTOM LINE
Rapid diagnostic devices like TearLab and InflammaDry and noninvasive, quantitative imaging technologies like the TearScience LipiView interferometry and the OCULUS Keratograph topography, meibography, interferometry, and automated bulbar and limbal redness assessment all contribute a measure of objectivity to the diagnosis of dry eye disease. Combined with traditional clinical tests for dry eye, these devices add important detail to dry eye diagnostic capabilities. In the future, high-resolution anterior segment OCT and even confocal microscopy may become a routine part of the dry eye workup.
Marguerite B. McDonald, MD, FACS, is a clinical professor of ophthalmology at the NYU Langone Medical Center in New York, NY, and an adjunct clinical professor of ophthalmology at Tulane University Health Sciences Center in New Orleans, LA. She was assisted in the preparation of this manuscript by Refractive Eyecare contributing editor, Danielle Sweete, MSc.
1. Lemp MA, Baudouin C, Baum J, et al. The definition and classification of dry eye disease: report of the definition and classification subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf. 2007;5(2):75-92.
2. Tomlinson A, Khanal S, Ramaesh K, et al. Tear film osmolarity: determination of a referent for dry eye diagnosis. Invest Ophthalmol Vis Sci. 2006 Oct;47(10):4309-15.
3. McDonald M, Geffen D, Goldsmid M, Owen J. Relative amplitude of analytical and biological instability in tear osmolarity measurements. Data presented at the European Society of Cataract and Refractive Surgeons Annual Meeting, Milan, Italy, September 2012.
4. Sullivan BD, Crews LA, Sönmez B, et al. Clinical utility of objective tests for dry eye disease: variability over time and implications for clinical trials and disease management. Cornea. 2012 Sep;31(9):1000-8.
5. Data on file, Rapid Pathogen Screening. Protocol 100310.
6. Wang J, Shousa MA, Perez VL, et al. Ultra-high resolution optical coherence tomography for imaging the anterior segment of the eye. Ophthalmic Surg Lasers. 2011;42:S15-S27.
7. Wang J, Cui L, Shen M, et al. Ultra-high resolution optical coherence tomography for monitoring tear meniscus volume in dry eye after topical cyclosporine treatment. Clin Ophthalmol. 2012;6:933-8.
8. Cervino A, McDonald MB, Klyce SD. Shack-Hartmann pattern as aid in the diagnosis and evaluation of dry eye: a retrospective study. Poster presented at the ARVO Annual Meeting, Ft. Lauderdale, FL, May 2002.