Sudi Patel

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	Keratoconjunctivitis sicca, or dry eye disease (DED), is a multifactorial disorder of the tears and the ocular surface characterised by symptoms of discomfort, tear film instability and sometimes inflammation.

 Among the most common conditions encountered by eye care professionals, estimates of DED prevalence vary from 7.4% to 33.7% worldwide.

 Even using a very restrictive definition, the disease is reported to affect almost 5 million Americans aged 50 years and older; tens of millions more experience episodes of dry eye, typically when exposed to adverse environmental factors such as low humidity.

	Traditionally, the tear film has been described as having three distinct layers (Figure 1): an outermost lipid (oily) layer; an aqueous (watery) layer that makes up 90% of the tear film volume; and a mucin layer that coats the corneal surface.

	However, it is now recognised that, rather than having three distinct layers, the tear film has a surface lipid component and then phases of aqueous with differing concentrations of mucins suspended throughout (Figure 2). In addition, mucins in the tear film have a much more active role in maintaining tear-film stability than was once thought.

	DED is prevalent in patients with autoimmune diseases, which affect around 8% of the population; 78% of patients with autoimmune diseases are women. DED also affects postmenopausal women and elderly people. The prevalence of DED is estimated to be anywhere from 7.4% to 33.7% depending which study is cited, how the disease is diagnosed and what population is surveyed. The Beaver Dam population-based study found the DED prevalence rate to be 14% in adults aged 48 to 91 years. The study also found that DED affects more women (16.7%) than men (11.4%). Reliable epidemiological studies, the large Womenâs Health Study and the Physicianâs Health Study, indicate that the prevalence of symptomatic dry eye in people over the age of 50 in the United States is about 7% in women and 4% in men. These numbers translate into approximately 3.2 million women and 1.05 million men with DED. Estimates of those affected by DED of any severity amount to approximately 20 million or more in the United States alone.

	International epidemiological studies report similar or higher rates around the world. The prevalence of DED is approximately 7.4% in Australia, with significantly increased prevalence in older patients and a significant decrease in tear production in women aged 50 to 59 years. In Indonesia, dry eye prevalence is around 27.5%, with increased prevalence associated with age, cigarette smoking and pterygium. In Taiwan, the prevalence of DED is 33.7% in a tested elderly population, with significantly more women than men reporting dry eye symptoms. The prevalence of dry eye is also estimated at 25% in Canada and 33% in Japan. However, the prevalence and incidence of DED might be under-reported, as patients might fail to recognise the symptoms of DED or to report the problem to a physician.

	Many contact-lens wearers experience dry eyes at some point, with many discontinuing or limiting lens wear.

	Common symptoms experienced by the patient vary but can include foreign body sensation, discomfort, dryness, stinging and blurred vision. The diverse array of dry eye symptoms and their effect on quality of life has prompted the use of numerous patient questionnaires, such as the ocular surface disease index (OSDI),

 to objectively quantify symptom improvement in response to treatment.

	In recent years, advances in cataract and refractive surgery have dramatically improved patientsâ postoperative quality of vision. The benefits of these advances may be lost, however, when the ocular surface deteriorates even slightly. During clear corneal cataract surgery, which now accounts for 73% of cataract surgery according to this yearâs trends survey by the American Society of Cataract and Refractive Surgery, many of the corneal nerves are cut. With typical cataract surgery, the primary incision may be about 3.0 mm in width and the paracentesis about 1.0 mm in width, giving a total arc length of 4.0 mm of full-thickness corneal incisions. If we add to this the incisions for astigmatic correction, such as limbal relaxing incisions, or the three-incision technique of bimanual cataract surgery advocated by some surgeons, the cutting of corneal nerves is even more severe.

	Often when patients present with cataracts, surgeons are so focused on planning for the surgical procedure that they overlook dry eye symptoms. It is important to preoperatively assess patients for concurrent problems, especially dry eye, and moderate to severe dry eye needs to be addressed prior to surgery. Even patients with no history of dry eye commonly experience dry eye after surgery: a recent study conducted by Cal Roberts and Eleanor Elie found that a clinically significant proportion of patients report experiencing at least some dry eye symptoms after cataract surgery.

	Turning to refractive surgery, it is widely accepted that the act of cutting (with a microkeratome) or ablating (via a laser) the corneal nerves during refractive surgery leads to an iatrogenic dry eye syndrome in nearly all patients. It is now the standard of care to treat all patients for dry eye for at least a few months after corneal refractive surgery until the corneal nerves have had a chance to regenerate.

	In both cataract and refractive surgery there is a growing necessity to measure tear volume and prescribe tear-enhancing products preoperatively and, postoperatively, it is also useful to investigate the patientsâ tear volume.

	The successful development of pharmaceutical agents targeting DED requires a definitive demonstration that the drug can induce a significant improvement in signs and symptoms of the disease. To this end, reproducible and sensitive assessment of dry eye is central to the drug development process.

	Tear quantity or volume is measured seldom in ophthalmic practice and almost never in general medical practice. Until now, doing so has been time consuming and somewhat bothersome for the patient. Several methods, including the Schirmer test (dated from 1905), the phenol red thread (PRT) and tear meniscus height, are available for checking tear volume. Tear clearance tests are also available but these have had low uptake rates by clinicians.

	Regarding the Schirmer test, much of the difficulty in defining wetting limits for diagnostic purposes can be summarised by a statement paraphrased from Cho:

 âSchirmer values are too variable, such that no definite limit for normal tear production can be determined.â Despite significant efforts, only a very small number of studies have found a wetting cut-off point that correlates with another sign or symptom of dry eye. Furthermore, the range of values is such that, regardless of cut-off point, false negative and/or positive identification of dry-eyed patients is common.

	The PRT test, which was introduced in 1982,

 was developed to overcome many of the disadvantages of the Schirmer test described in the previous section, including high variability, poor reproducibility and low sensitivity for detecting dry eyes.

 Phenol red is pH sensitive and changes from yellow to red when wetted by tears.

	The Lacrymeter is an updated version of the PRT: it is a soft, gentle, minimally invasive product in the form of a thread that soaks up the tear fluid present at the ocular surface over a period of seconds. The colour of the thread changes from yellow to red in response to the tears, and the length of thread that has changed colour correlates with tear volume and flow.

	Methodologically, the lacrymeter is similar to the Schirmer test, although there are some potential advantages that include the fact that there is little to no sensation from the lacrymeter, thus less potential for reflex. Furthermore, the test time is only 30 s per eye (the Schirmer test requires 5 minutes), the eyes remain open and are free to blink and no anaesthetic is required.

	Despite these advantages, a previous test that resembles the lacrymeter has rarely been used in clinical practice or clinical development. Two possible reasons for this are that the threads can be difficult to handle because of their light and flexible nature and that they are only manufactured in Japan, making their supply costly and often requiring special ordering. However, an Israeli company (Fepasaet Group Ltd) has now developed the lacrymeter, which is more accessible and cheaper than other similar devices.

	The lacrymeter test does not require an anaesthetic. The patient must not instill drops 1 hour before the examination; however, contact lenses can be worn during the test.

	Although the PRT and lacrymeter tests are not standard clinical tests, they have the potential to be embraced as such because of their many advantages over the traditional Schirmer I test. Several studies have found the PRT test to be more repeatable than the Schirmer test (with and without anaesthestic) as well as more reliable in diagnosing dry eye.

 compared 66 normal eyes and 14 dry eyes using both Schirmer I and PRT, performed on successive days in 28 eyes. Comparing normal with dry eyes, the following data were reported: PRTâ=â20.3âÂ±â8.7 mm vs 8.1âÂ±â8.0 mm (

â<â0.005); Schirmerâ=â10.0âÂ±â7.9 mm vs 14.6âÂ±â9.8 mm (

â=â0.33). Based on these data, the authors concluded that the likelihood of a false positive was 3% using PRT and 18% using Schirmer. An estimate of the reproducibility of the measurements was achieved through comparison of data collected on two successive days. The Pearson coefficient was 0.89 for PRT and only 0.39 for Schirmer. Patel 

 concluded that the PRT test could accurately differentiate aqueous-deficient dry eye subjects from non-dry-eye subjects although, in his study, the thread was left in place for 120 s. In the same study, it was concluded that the PRT test could not differentiate between dry eye and non-dry eye if aqueous-deficient and lipid-deficient dry-eyed individuals were combined.

	From a limited number of studies, it generally appears that the PRT outperforms the Schirmer test in the areas of reproducibility and reliability. Global data interpretation, however, must proceed with caution, as several of the studies addressing repeatability were performed on non-dry-eyed subjects, thus calling into question the utility of the findings with respect to use in a dry-eyed population. Nichols

 analysed reliability and correlation of clinical measurements of dry eye and found that positive correlations do exist between (a) Schirmer and fluorescein staining, (b) PRT and both fluorescein and rose bengal staining and (c) Schirmer and PRT.

 suggest that the poor correlation between tests results from the fact that each test utilises a different mechanism to assess the ocular surface. Therefore, owing to the multifactorial nature of dry eye, many mechanisms may not apply to an individual dry-eye patient. Saleh 

 further demonstrated that, in a cataract population being screened for surgery, neither Schirmer nor PRT results agreed with symptoms (28 of 103 patients were symptomatic of dry eye based on questionnaire) and that PRT results showed no correlation with Schirmer results.

	It has been suggested that the ability of the PRT to differentiate aqueous dry-eyed from non-dry-eyed subjects is because of its ability to first absorb the tears naturally present in the lacrimal lake and then to measure the replenishment of fluid into the lake as a result of basal flow and/or mild stimulation. Subjects with aqueous deficiency cannot replenish their fluid as quickly, so less wetting of the thread occurs.

 have argued that the PRT test should take longer than 15 s as they and others have demonstrated that wetting is not linear: the threads they employed reached equilibrium in 120 s. Further adding complexity to our understanding of what is being measured is the possibility that the composition of the tear fluid can influence wetting length. Both lipids and mucins can influence flow and it has been demonstrated that, unlike simple migration of saline through a thread, variable tear composition likely increases the variability of both PRT and Schirmer measurements.

	It is argued that leaving the thread in for a longer time will increase the accuracy of the test. For example, the measuring scale for PRT has a resolution of 1 mm; thus, if mean migration in 15 sâisâ9.2 mm, then the resolving powerâ=â100âÃâ1/9.2â, â11%. If the test runs for 60 s and mean wetting is 18 mm, then resolving power is reduced to 5.6%, increasing the ability to detect change or differences among test patients. Perhaps finding the time that provides the optimal balance between sufficient time for wetting and minimal irritation (which causes reflex tearing) is key.

	In summary, although rarely used at present, the PRT and the lacrymeter offer advantages over the Schirmer test with respect to increased measurement reproducibility. To this end, they might provide both better diagnostic utility as well as serving as a more meaningful tool for therapeutic drug evaluation. The test, however, still demonstrates variability and compromised reproducibility because of patient variation in the volume, depth and shape of the lacrimal lake, the temperature of the environment in which the test is performed and the variation in tear composition between patients. The threads might be somewhat difficult to handle and insert, thus necessitating appropriate training. The testing time is vital and should not be less than 30 seconds.

	With the lacrymeter, the ophthalmologist and the general practitioner have a new tool to measure tear volume, which is essential for selecting the appropriate treatment for a patient with symptoms of dry eye.

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