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Diagnosing Dry Eye
A battery of available tests can identify tear-film instabilities.
BY MARK B. ABELSON, M.D., GEORGE OUSLER AND RUSSELL ANDERSON

Dry eye symptoms are one of the most common reasons a patient will visit his or her ophthalmologist, and millions of Americans experience these symptoms.¹ Patients can experience a good deal of discomfort, including symptoms such as ocular burning, stinging, grittiness, foreign body sensation, photophobia and blurred vision.

For the ophthalmologist, dry eye patients have been challenging to diagnose due to the many causes of the condition and the many forms it takes. This article will look at the physiological factors that can lead to tear-film instability and subsequent dry eye, and discuss some of the available diagnostic tests clinicians can utilize to best understand and manage such conditions.

The Epidemiology of Ocular Surface Desiccation

The tear film can become destabilized through insufficiency of the aqueous (generated by the lacrimal glands), mucin (produced by goblet cells) or lipid (secreted by the meibomian glands) components of human tears. An unstable tear film tends to evaporate, drain into the puncta or physically break up more rapidly than a healthy one.

If a break forms in the tear film, which normally covers and protects the ocular surface, then before the eye has a chance to blink ocular epithelial cells will be exposed to the air. This leads to desiccation and eventual death for the exposed cells, a process that gives rise to the various discomforts associated with dry eye. Damaged or desiccated cells are less capable of holding the tear film to the surface of the eye, so the epithelium is exposed even more rapidly and dries further — in this way, dry eye constitutes a vicious cycle.

Dry eye may be generated by a systemic disease such as Sjögren's Syndrome, or may be brought on and exacerbated by environmental and lifestyle aspects, such as prolonged visual tasking, smoking, contact lens wear, certain medication and exposure to arid conditions. Symptomatic presence and severity can be influenced by any or all of the environmental factors. Also, many patients notice changes in their symptoms at different times during the day and many note a specific severity when driving at night or engaging in extended visual activities such as watching television or using a computer.

It is important to ascertain which symptoms a patient has and their severity. This knowledge can be gleaned from patient questionnaires. An ophthalmologist should educate a patient on the nature of dry eye symptoms and then encourage the individual to take note of his or her symptoms and record them. In addition to exhibiting certain symptoms, a patient will most likely present with specific clinical signs of dry eye that can be evaluated through a series of basic tests. The primary clinical aspects that can be negatively influenced in a patient with dry eye are ocular surface health, tear-film stability, ocular surface protection and tear volume.

Figure 1. Lissamine green stains desiccated epithelial cells and has demonstrated similar efficacy to rose bengal, but it does not cause the ocular irritation often associated with the latter.

Vital Dye Staining

Among the standard diagnostic procedures for dry eye, vital dye staining is perhaps the best indicator of ocular surface health. Sodium fluorescein dye is best for staining the area between surface cells, which gives an idea of the extent to which epithelial cells are drying and shrinking.

Recent research suggests that a micro-drop of fluorescein — a drop less than or equal to 5 μL — is preferable to a larger volume drop when observing fluorescein staining with a slit lamp.2 A smaller, pipette-instilled drop allows for more exact pinpointing of areas of staining and comparison of relative severity between staining regions in a given eye. Take special note of any staining in the central region of the cornea. Studies have found correlations between cell desiccation in this highly innervated area and more severe dry eye symptomatology.3

The other two main dyes used for vital dye staining tests are rose bengal and lissamine green. Both fluids stain desiccated and dying cells on the ocular surface, with rose bengal being used more often historically. However, lissamine green has exhibited much better patient acceptability and is just as effective as rose bengal in terms of completeness of staining (Figure 1).4 Rose bengal has a tendency to cause a slight burning sensation, whereas lissamine green is generally tolerable and pain-free. Ideally, a clinician would look at both fluorescein staining and lissamine staining to approximate the extent of the damage to the ocular surface.

Tear-Film Instability

The ocular surface desiccation made apparent by vital dye staining is usually preceded by some form of tear-film instability. Insufficiencies or instabilities in the tear film can stem from problems with the lacrimal glands, goblet cells or meibomian glands, and can be made worse by ocular epithelial cell damage. The accessory and primary lacrimal glands yield the aqueous portion of the tear film, which accounts for most of the tear film's volume.

Distributed throughout the aqueous are mucins that help adhere the tear film to the ocular surface, via a mesh structure called the glycocalyx. Ocular lipids are generated by the meibomian glands, which are distributed across the upper and lower lids. The lipid layer offers the eye protection from outside particles, provides lubricity that helps minimize friction when the upper lid slides across the eye during blinks and slows tear film evaporation. A deficiency in any of the tear-film layers can lead to tear-film instability, which will inevitably affect tear film break-up time (TFBUT).

Tear Film Break-up Tests

Tear film break-up time can be determined by a clinician observing through a slit lamp and can be timed with a stopwatch. This procedure, like the fluorescein staining diagnostic test, requires the instillation of a micro-drop of the fluorescent dye.2 It is even more important for the purposes of break-up time that such a small quantity be used, because the instillation of a larger drop can flood the tear film and prolong TFBUT measurements. In most cases, a drop as small as 2 μL is sufficient. The physician may instruct the patient to make a series of blinks to distribute the dye throughout the tear film, and then have the patient hold the eye open while simultaneously starting a timer. The timer — a stopwatch is sufficient — is stopped when the clinician observes the appearance of dark spots, called micelles, indicating areas in which the tear film has receded, leaving the ocular surface exposed. This process can be repeated and timed values can be averaged to determine a patient's TFBUT. A value under 5 seconds is generally agreed to constitute tear-film instability consistent with dry eye.2

There is a simpler method for determining break-up time that patients can perform themselves — this is called symptomatic break-up time (SBUT). The patient can simply use a stopwatch to measure the time that elapses between a blink and the first ocular surface awareness, ensuring that the eyes are held open during the timing. In the majority (70%) of the dry eye population, the actual tear film break-up measured by a physician will closely correspond to the occurrence of the first symptomatic sensation, so the SBUT is a good estimator of break-up time.5 The test also imbues patients with an awareness of their condition and an ability to gauge changes in it.

Another potential diagnostic tool for determining tear film stability is the tear film break-up pattern (TFBUP). This is observable simultaneously with a slit-lamp TFBUT measurement, and is an as yet experimental determination that exhibits much promise for influencing differential dry eye diagnoses. Researchers first noted that every tear film break-up occurred in a unique pattern, and that these patterns were generally reproducible in a given eye. The five patterns catalogued to date are: linear, spotting, fractured, amorphous blob and wispy.6 It has since been demonstrated that these patterns can be modified by such factors as the stimulation of reflex tearing and meibomian gland expression.7,8 Also, there is the potential of tear substitutes or other eye drops to modify TFBUP — the artificial tear Systane (Alcon) has already demonstrated the capability to do so.9

This modifiability leads researchers to believe the patterns represent either different severities or different underlying causes of dry eye, or potentially both. The amorphous blob pattern is generally found in healthier eyes with more stable tear films, while the wispy pattern is most common in patients with more advanced dry eye and rapid break-up times.10 At the very least, TFBUPs are worth noting as an aspect of a patient's dry eye on the part of clinicians, and they should gain diagnostic worth as research continues to determine their nature and their more detailed implications for tear-film stability.

Ocular Protection Index

Figure 2. The Ocular Protection Index (OPI) takes into account both how rapidly the tear film breaks up and how frequently a patient blinks in order to determine whether the ocular surface is generally exposed, allowing for desiccation. Here we see the tear film breaking prior to a blink.

An unstable tear film can result in a desiccated ocular epithelium, due to the insufficient ocular surface protection it offers. It is one thing to determine, through break-up time measurements, the instability of a patient's tear film, but another to determine to what degree this instability actually leads to an exposed ocular surface. The missing factor here is blink frequency — with every blink the tear film is replenished and spread across the surface of the eye to cover it completely. To take this into account, the ocular protection index (OPI) was developed. The OPI is calculated as a function of both TFBUT and inter-blink interval (IBI). First, a blink count must be taken — there are camera technologies capable of recording this, but for practical clinical purposes, a manual count is sufficient. Physicians can simply instruct a patient to perform a visual activity, such as watching television, and note the number of times the patient blinks in the course of a minute. To determine IBI, or the average time elapsed between blinks, one simply divides 60 seconds by the blinks per minute value. If the tear film in a given eye usually breaks up and exposes the ocular surface prior to a blink, this will be reflected in an IBI greater than the TFBUT (yielding an OPI value less than 1) (Figure 2).

On the other hand, if the TFBUT value equals or exceeds the calculated IBI, this suggests that the patient usually blinks and replenishes the tear film before it has a chance to break up. This constitutes a protected ocular surface and is implied by any OPI that is greater than or equal to 1.11

For example, if it was determined that a patient blinked only 3 times in the course of a minute, yielding an IBI of 20 seconds, and the same patient's tear film break-up time (determined using TFBUT or SBUT) was 4 seconds, this would indicate that, on average, there were 16 seconds following break-up during which the ocular surface was exposed. The resultant OPI value would be 0.2, which is less than 1 and therefore indicates an unprotected ocular epithelium. The OPI diagnostic test serves as a connector between tear-film instability and ocular surface damage by indicating whether or not the ocular surface is generally left exposed. Studies have been conducted that demonstrate the modifiability of OPI with tear substitutes, and it has subsequently become an important endpoint in many clinical trials.

Tear Volume

Finally, tear volume itself can be affected by dry eye. This is primarily tied to aqueous deficiency, and is in essence a component of tear-film stability, but is also one of the most tangible signs for patients.

The standard method for determining tear volume is by placement of a Schirmer strip in each eye for a period of 5 minutes. While the strips are not always exact in their measurements due to their tendency to induce reflex tearing, they are useful both in estimating tear flow and volume and in providing patients with a clinical sign of their condition that says "dry eye" to them.

Unfortunately, the unanaesthetized placement of strips can be relatively uncomfortable for patients as well. A clinician can make a quicker and more patient-friendly tear volume estimation by looking at the tear meniscus heights in the marginal menisci during a slit lamp exam. Generally in the 0.1 mm to 0.2 mm vicinity, these readings can help determine if a dry eye patient is potentially aqueous deficient.12 Both reflex tearing, which can be stimulated by the symptoms of dry eye stemming from ocular surface desiccation, and tear film break-up itself, can cause visual blurring. Stemming from either too much or too little tear volume, this visual impairment can be captured both with standard visual acuity (VA) charts, such as Snellen or ETDRS, and with the use of a contrast sensitivity chart. These tests can help determine what tear substitute is best for a patient — gels, for instance, tend to cause blurring, though they often offer superior symptomatic relief for more advanced dry eye patients. Studies on the new gel Systane Free (Alcon), however, suggest it generally does not blur the vision like some other marketed gels. In a recent trial comparing Systane Free to a standard gel product, Refresh Liquigel (Allergan), Systane Free caused less blurring at all six measured time points with statistical significance, and demonstrated a significantly superior overall blur profile to Liquigel.13

Technology Can Foster Results

With all of these procedures, there are more technologically advanced alternatives that almost inevitably yield more accurate results. In the case of vital dye staining and TFBUT, there are video-imaging systems with on-screen timers that can be attached to specially designed slit lamps in order to record slit lamp exams. This allows for re-evaluation of staining, break-up times and break-up patterns. In the case of OPI, it is possible to use motion-tracking cameras to mechanically record blinks and software to compute blink rate and IBI.

An apparatus called a fluorophotometer is capable of using background autofluorescence and measurements of tear-film fluorescence following the instillation of fluorescein, to determine more accurate values for both tear volume and tear turnover than Schirmer strips can yield.14 Software-driven systems are even in development that will be able to more precisely measure visual acuity. In each of these cases, however, the cutting edge diagnostic procedure or equipment is financially impractical for all but perhaps the very largest clinics, so these technologies will remain in the realm of clinical testing and research for the time being.

Early Diagnosis, Patient Education

Ophthalmologists have a variety of diagnostic approaches they can use to determine and understand a patient's tear-film instabilities and ocular surface desiccation. Physicians should encourage patients to report their symptoms and should make them familiar with the more scientific aspects of dry eye. The more actively involved and educated a patient is in the diagnostic process, the more attentive the patient will be to his or her own dry eye signs and symptoms, and the more compliant he or she will be with recommended treatment regimens.

Mark Abelson, M.D., is an associate clinical professor of ophthalmology at Harvard Medical School and is the senior clinical scientist at Schepens Eye Research Institute. George Ousler is the director of the dry eye department at ORA Clinical Research and Development. Russell Anderson is a medical writer at ORA.

References

1. Schaumberg DA, Sullivan DA, Buring JE, Dana MR. Prevalence of dry eye syndrome among US women. Am J Ophthalmol. 2003;136:318-126.

2. Abelson MB, Ousler GW, Nally LA, Krenzer K. Alternative reference values for tear film break-up time in normal and dry eye populations. Cornea. 2000;19:S72.

3. Ousler III GW, Kellerman D, Durham T, Brazzell K, Kennedy K, Abelson MB. An association between central corneal staining and dry eye symptomatology. Poster presentation at the Association for Research in Vision and Ophthalmology meeting; April 30-May 4, 2006; Fort Lauderdale, Fla.

4. Kim J, Foulks GN. Evaluation of the effect of lissamine green and rose bengal on human corneal epithelial cells. Cornea. 1999;18:328-332.

5. Nally L, Ousler GW, Abelson MB. Ocular discomfort and tear film break-up time in dry eye patients: a correlation. Poster presentation at the Association for Research in Vision and Ophthalmology (ARVO) meeting; May 2000; Fort Lauderdale, Fla.

6. Ousler GW, Lemp MA, Schindelar MR, Abelson MB. Tear film break-up patterns (TFBUP) – a method of measuring tear film stability. Poster presentation at the Tear Film and Ocular Surface meeting; 2004; Puerto Rico.

7. Hagberg KW, Ousler GW, Schindelar MR, Anderson RT, Abelson MB. Effect of reflex tearing on tear film break-up time (TFBUT) and tear film break-up patterns (TFBUP) in a population of Ashkenazi Jewish patients. Poster presentation at the Association for Research in Vision and Ophthalmology meeting; April 30-May 4, 2006; Fort Lauderdale, Fla.

8. Schindelar MR, Ousler GW, Oberoi SL, Abelson MB. Perturbation of the meibomian glands and the effect on tear film stability and tear film break-up patterns (TBUPs) in an Ashkenazi Jewish population. Poster presentation at the Association for Research in Vision and Ophthalmology meeting; April 30-May 4, 2006; Fort Lauderdale, Fla.

9. Ousler GW. Tear Film Break-Up Patterns and Systane. Presented at: The American Academy of Ophthalmology Annual Meeting; October 15-18, 2005; Chicago, Ill.

10. Ousler GW, Hagberg KW, Casavant JS, Schindelar MR, Welch DW, Abelson MB. Tear film break-up patterns in a population of dry eye patients of Ashkenazi Jewish descent. Poster presentation at the Schepens Cornea Conference; 2005; Boston, Mass.

11. Ousler GW, Emory TB, Welch D, Abelson MB. Factors that influence the inter-blink interval (IBI) as measured by the ocular protection index (OPI). Poster presentation at the Association for Research in Vision and Ophthalmology meeting; May 2002; Fort Lauderdale, Fla.

12. Lim KJ, Lee JH. Measurement of the tear meniscus height using 0.25% fluorescein sodium. Korean J Ophthalmol. 1991;5:34-36.

13. Data on File. Alcon, Inc.

14. Fahim MM, Haji SA, Koonapareddy CV, Fan VC, Asbell PA. Fluorophotometry as a diagnostic tool for the evaluation of dry eye disease. BMC Ophthalmol. 2006;6:20.