Features

In the first of two articles, Dr Hannah Bartlett and Dr Frank Eperjesi describe the classification of dry eye disease and discuss the very latest techniques in external eye and tear assessment and analysis.

CET module C3212: This module has now closed

Dry eye has been defined as 'a disorder of the pre-corneal tear film due to tear deficiency or excessive evaporation of tears causing damage to the interpalpebral ocular surface associated with ocular discomfort'.1

Research has shown that up to 10 per cent of the non-contact lens wearing population who are under the age of 60 have dry eye symptoms and these symptoms are even more common in older people and postmenopausal women.2 Up to 25 per cent of patients consulting eye care practitioners present with dry eye symptoms,3 as well as up to 50 per cent of the 35 million contact lens wearers in the US.4-6 A survey of US practitioners showed that 12-21 per cent of soft contact lens patients reduced their wearing time because of dry eye symptoms, and that 6-9 per cent were so symptomatic that they were unable to wear lenses at all. 7

Though not sight-threatening, dry eye syndrome (DES) is an ocular disorder that may severely reduce quality of life and efficiency at work, and that has many implications for contact lens wear. Recent years have witnessed improvements in non-invasive instruments used for the diagnosis of DES.

Part 1 of this article will review the classification of DES and then highlight recent developments in non-invasive, objective evaluation techniques, some of which could be useful in the investigation and management of DES, especially by those practitioners who have a large contact lens patient base and those who specialise in the management of DES.

We have not included the traditional tests used in the diagnosis of DES, such as the Schirmer 1 test, the phenol red test, and tear film break up time in this review. Although they can be performed easily in clinical practice, these tests are invasive and result in reflex tearing which makes it difficult to acquire information about the natural state of the tear film.

Part 2 of this article will focus on some novel artificial tear and dietary modification DES management strategies.

Classification of DES
A reduction in the aqueous component of the tear film is central to most dry eye disorders, and may result from decreased tear aqueous secretion (tear deficiency dry eye) at the lacrimal gland and/or increased tear aqueous evaporation from the palpebral aperture (evaporative dry eye) due to an overall or localised reduction in lipid layer thickness.

Tear-deficient dry eye involves a disorder of lacrimal function or failure to transfer lacrimal fluid into the conjunctival sac. This results in reduced tear flow and volume, and is associated with a decrease in secretion of lacrimal proteins.8

In evaporative dry eye, lacrimal function is normal and the tear abnormality is due to increased tear aqueous evaporation.9 The resultant increase in tear osmolarity is related to a decrease in conjunctival goblet cell density and decreased corneal glycogen.

An increase in osmotic gradient between the ocular surface and the tear film pulls water from between the epithelium cells and causes desquamation. Traditional dry eye therapies involve lowering elevated tear film osmolarity by topical application of a tear-matched, electrolyte-balanced tear solution (see Part 2 of this article).

Tear-deficiency dry eye can be further divided into two categories; Sjgren syndrome tear deficiency and non-Sjgren tear deficiency, which is also known as keratoconjunctivitis sicca (KCS). Patients with Sjgren syndrome tear deficiency will also exhibit systemic signs and clinical manifestations of autoimmune disease. Sjgren syndrome has been described as an exocrinopathy affecting the lacrimal and/or salivary glands, which is associated with rheumatoid arthritis in 70-90 per cent of cases.10

Evaporative dry eye can be associated with blepharitis,11 meibomian gland disease,1 blink disorders,12 and disorders of the lid aperture such as proptosis in thyroid eye disease.13

In summary, DES can occur in people with Sjgren's syndrome, KCS (both due tear deficiency), lid margin disease, excessive palpebral aperture size and contact lens wear (all due to excessive tear evaporation). See Figure 1 for the National Eye Institute/Industry Workshop classification of dry eye.

Investigation of dry eye
The National Eye Institute/Industry workshop on clinical trials in DES identified global criteria and tests for dry eye1 and proposed that most forms of dry eye will exhibit:

• Symptoms
• Interpalpebral surface damage
• Tear instability
• Tear hyperosmolarity.
  

And that these features are embodied in the following tests:

• Validated symptoms questionnaire
• Demonstration of ocular surface damage
• Demonstration of tear instability
• Demonstration of tear hyperosmolarity.

Validated symptoms questionnaires
Once the balance of the tear film is disturbed and the physiological functions of the tears are disordered, subjective symptoms of DES will occur.
These may include some or all of the following: a persistent dry feeling, foreign body sensation, burning, soreness, itching and sometimes photophobia.14-19

Unfortunately, there is only a weak association between symptoms elicited by questionnaires and the results of clinical tests (such as fluorescein tear break up time and Schirmer 1 tests) for DES. This may be due to the design of dry eye questionnaires. For example, some questionnaires use questions with 'yes or no' responses to determine the presence of symptoms, and do not investigate severity,14-16, 20 while one of the most widely used questionnaires designed by McMonnies determines the presence and frequency of symptoms, but groups them all together, so individual symptoms cannot be tracked separately.21 Other questionnaires investigate the frequency and intensity of individual symptoms, but obtain no information about change in symptom intensity throughout the day.22,23 The Dry Eye Questionnaire has been developed to assess ocular surface symptoms in mild to moderate dry eye patients6 and is reported to be able to characterise the frequency of ocular surface symptoms, as well as their diurnal variation, in patients with DES.24

It has recently been pointed out that completion of dry questionnaires can be time consuming and their administration may be difficult in routine clinical practice. Guillon and Maissa have shown that asking patients a combination of only three questions has the same diagnostic value as the full McMonnies questionnaire. For soft contact lens wearers: 

• How often do your eyes have symptoms of dryness?
• How often do your eyes have symptoms of scratchiness?
• Do you experience these symptoms in the company of smokers (pubs, clubs)?
  

A combination of the first two of these questions is adequate for non-contact lens wearers.25

Demonstration of ocular surface damage
Assessment of ocular surface damage often involves the instillation of a vital dye such as sodium fluorescein.

By their very nature these tests are invasive and result in reflex tearing which makes it difficult to acquire information about the natural state of the tear film; also the evaluation of ocular surface staining tends to be subjective rather than quantitative. However, vital dye staining using rose bengal, has been incorporated into international standards for the diagnosis of DES26 and other stains are regularly used in clinical practice so will be briefly discussed here.

Rose bengal is thought to stain areas of the ocular surface where the tear film is discontinuous.27 Recording employs the van Bjisterveld system, which assigns grade 0-3 for each of six areas, covering the cornea and nasal and temporal conjunctiva28 (see Figure 2). Lissamine green which stains degenerated cells and mucus29 is becoming more commonly used in DES investigation and is more readily tolerated than rose bengal,29 while fluorescein, usually viewed with yellow enhancement filters,30 is the dye most often used in clinical practice. Punctate fluorescein staining is recorded using a system of grades 0-3 for each of five corneal areas (see Figure 3). Studies have shown that patients who have no staining after a single administration of fluorescein may manifest staining after sequential administrations.31 The use of a single application of fluorescein is likely to lead to variable results.

Demonstration of tear instability

Interferometry
Lipid secreted from the meibomian glands expands and compresses with lid opening and closing. Each blink spreads the lipid over the aqueous layer and, from this thin lipid layer, the light interference phenomenon results in the formation of specular reflection images.

The technique is reported to be a good clinical screening method for quick differentiation of dry eyes from normal eyes.32 The Tearscope and Tearscope-Plus (www.keeler.co.uk) are hand-held or slit lamp-mounted instruments designed to allow these specular reflection images to be easily viewed in clinical practice (see Figure 4).

The Tearscope-Plus allows determination of tear film quantity, quality and stability quickly and non-invasively with a single whole eye view. Tear quantity is assessed with one full-length view along the tear meniscus and furthermore, using the shape of the tear meniscus cases of meibomian gland dysfunction can also be identified.

Tear quality is assessed by matching the patient's tear film with the equivalent pattern in the Guillon-Keeler Tear Film Grading System, and by viewing the tear film flow dynamics. See Figure 5 for Guillon-Keeler Tear Film Grading System.

Tear stability is assessed by directly viewing the tear film on the contact lens or corneal surface and measuring the non-invasive break up time. As well as being a useful research tool, the Tearscope-Plus system is easy to use in standard clinical practice and could be of use to the general and specialist eye care practitioner.

Kowa Co has developed the DR-1 Interferometer which can be used to view still and real time specular reflection images from circular areas on the tear surface 2mm or 8mm in diameter. Light is collected by a video camera and the images are formed on a TV monitor; the instrument is about the size of a table mounted autorefractor. Images can be classified according to their appearance into five grades of tear interference patterns and these have been shown to correlate well with dry eye severity.33

Grade 2 is described as mild dry eye and the specular images have a greyish colouration and non-uniform distribution. With Grade 3 some colours are seen and there is non-uniform distribution. In Grade 4 many colours are evident and there is a non-uniform distribution, while Grade 5 described as a severe form of tear deficient dry eye with severe superficial punctuate keratopathy (SPK) and the corneal surface is partially exposed and there is no lipid layer interference.

As yet the DR-1 is not commercially available in the UK.

Fluorophotometry
Fluorophotometry facilitates sensitive and quantitative evaluation of corneal epithelial damage through time-course changes of the intensity of fluorescence emitted from the ocular surface following fluorescein instillation.

The slit lamp-mounted Anterior Fluorometer FL-500 (Kowa Co, Japan) can be used to evaluate corneal epithelial barrier function in dry eye patients with SPK, as well as in patients with sub-clinical dry eye without signs of SPK.

Fluorescein is instilled into the conjunctival sac, washed out with saline after 10 minutes and fluorescein uptake evaluated at the centre of the cornea after a further 20 minutes.34 Fluorescein uptake is reported to be significantly higher in eyes determined to be Grade 5 by the DR-1 Interferometer than Grade 2, 3 and 4.32 The Anterior Fluorometer FL-500 can be simply used in conjunction with a slit lamp and could prove to be useful in everyday clinical practice particularly for the contact lens and/or DES specialist and in the research environment. As yet the FL-100 is not commercially available in the UK.

Demonstration of tear osmolarity
Tears are secreted as an isotonic fluid35 whose tonicity is increased slightly in the waking state by evaporation.

Several factors may contribute to this increase. Total water loss from the exposed ocular surface increases with increased surface area (as in up gaze). In the same way, a lengthening of the blink interval increases water loss. Since evaporative loss is temperature dependent, it may vary regionally across the ocular surface, as surface temperature of the open eye is highest at the limbus and lowest over the avascular area. Water loss will be influenced by airflow across the ocular surface, being increased per unit area by high airflow, and conversely, will fall with increasing ambient humidity.36

It has been suggested that hyperosmolarity is common to all forms of dry eye, and due to its sensitivity and specificity, is a gold standard test in the investigation of DES.37 Physiologists use the term osmolarity, while chemists use osmolarity with both terms meaning the same for purposes of tear testing.8 Corneal epithelial cells are damaged by hyperosmolarity in vitro9 and in vivo.38

Tear hyperosmolarity arises either as a result of evaporation in the presence of reduced tear flow, or excessive evaporation in the presence of a normal flow rate.36 Hyperosmolarity may contribute to inflammatory processes at the ocular surface by causing epithelial damage, possibly inducing cytokine release from epithelial cells.39 Ocular surface disease has been reported to be dependent upon and proportional to an increase in tear film osmolarity and the duration of the disease.40-43 Hyperosmolarity is thought to be the primary causative mechanism in this group of disorders, leading to discomfort, ocular surface damage, and inflammation.9

The Clifton osmometer has been accepted as the gold standard in the diagnosis of dry eye37 and clinically, values above 312mOsm/litre, are considered to differentiate dry eye from normal with a sensitivity of 94.7 per cent and a specificity of 93.7 per cent.41

The end point is achieved when a frozen tear sample is thawed and the final ice crystal disappears when viewed through a microscope. Samples for osmolarity testing are usually taken from the lower meniscus, however, this practice has been questioned since it is possible that meniscus hyperosmolarity is likely to be less than ocular surface hyperosmolarity and the potential for hyperosmotic change over the ocular surface underestimated.36, 41

Since dilution of the meniscus tears by inflowing tears will be greatest when lacrimal function is normal, the discrepancy between meniscus osmolarity and ocular surface tear osmolarity will be greater in evaporative dry eye than in aqueous-deficient dry eye.36

Some studies have used a 10<03BC>l pipette to obtain samples from the lower tear meniscus; it is difficult to fit the tip into the lower tear meniscus without making contact with the lid margin and/or conjunctiva and as a result, the tear sample is diluted by reflex tearing.

There seems to be a need to develop techniques that allow the measurement of osmolarity directly in the tear film. Adding to the problem of reflex tearing is the fact that some techniques require 5<03BC>l of lacrimal fluid - a relatively large volume, particularly when the average tear volume in KCS has been reported as around 4.8<03BC>l.44

A complex and clinically unwieldy technique using narrow gauge pipettes that virtually eliminated the problems of reflex tearing, while allowing samples of 0.1 to 0.4<03BC>l to be collected has been described.41 An average osmolarity value of 304 10.4mOsm/litre for normal eyes and 343 32.3mOsm/litre for KCS eyes was reported.

Although tear osmolarity testing is not widely used in clinical practice and it seems to be mainly in the research environment, there are commercially available tabletop osmometers (www.otago-osmometers.com and www. aicompanies.com) which cost about the same as a standard tabletop-mounted auto-refractor. These instruments could be of use to those eye care practitioners who specialise in dry eye problems.

Histologic tests
Mucus is known to be one of the essential factors in maintaining the stability of the tear film, either in the gel form to improve the wettability of the corneal surface or in the soluble form, giving an increase in the viscosity of the fluid phase.

Mucus is difficult to study because of its high molecular weight and tendency to form relatively insoluble complexes with other tear components. However, it may be evaluated by indirect means such as measuring the density of mucus-producing goblet cells.45 Three such methods are described in the following section.

Conjunctival impression cytology
This technique permits evaluation of epithelial and goblet cells on the conjunctival surface. Squamous metaplasia of the bulbar conjunctival surface has been reported in KCS patients, although this does not correlate with symptoms, fluorescein or rose bengal staining, or the Schirmer 1 test.46, 47

The procedure involves instillation of topical anaesthetic and placement of circular discs measuring 6-7mm in diameter on the nasal, temporal and superior bulbar conjunctiva, and the inferior palpebral conjunctiva.

Pressure (40g for bulbar, and 70g for palpebral) is applied to the discs using an ophthalmo-dynamometer for three to four seconds. The discs are removed, fixed with spray fixative, and then stained.1 The amount and type of staining indicates whether keratinised conjunctival cells are present. Keratinised cells are reported to be present in patients with dry eye and not in normal subjects. The limiting factor in this technology is the availability of reagents to identify specific cell types and not the ability to sample cells. Impression cytology is more a direct measure of the cellular damage produced by KCS than tear osmolarity.48 However, it does reveal several variations in cell structure which may not be the result of a tear film deficiency but the result of ocular surface disease. Tear osmolarity measurement reflects only changes in the aqueous environment of the surface epithelium in KCS when the tear film is excessively hypertonic. Impression cytology is a procedure that is probably too cumbersome and time consuming to be of use in clinical practice, although it would be a useful tool in research.

Conjunctival brush cytology
Brush cytology49 is a less invasive method of investigating the cell population of the conjunctival surface. After instillation of a topical anaesthetic, a modified cytobrush consisting of nylon bristles which are repellent to the negative charge of the epithelial membrane is used to sample the temporal bulbar conjunctiva only. The lack of attraction between the brush and epithelial cells facilitates the preparation of adequately cellular samples since fewer cells are retained on the brush.

Using a gentle rotational motion against the anaesthetised conjunctival surface, the cells are collected using filters and then stained. The filters can be evaluated for the presence of keratinised cells, which are a sign of dry eye; furthermore the proportion of keratinised cells may be an indicator of the stage of the condition and since the corneal and conjunctival epithelium have a reciprocal relationship, the presence of abnormal cells in a sample can be taken as an indicator of abnormalities of both the conjunctiva and the cornea.49

Although simpler and easier to carry out than impression cytology the procedure is probably still too time consuming and cumbersome to use in clinical practice, although it would seem to have a role in research.

Tear ferning test
It has been proposed that analysis of the ferning patterns produced by rapid drying conjunctival mucus scrapings50 and tear film will give information on the amount and efficacy of tear mucus and on drying fluid tears.51

Tear ferns consist of linear and branched arrays of microcrystals of shapes different from the typical crystal habit of the simple electrolytes present and are probably constrained in this form by the surrounding macromolecular matrix.52 Absence or marked reduction of ferning in dried tear fluid collected from dry eyes forms the basis for diagnosing KCS using the tear ferning test.53

Tear film assessment technique involves collection of stimulated tear samples (30 to 50l) using a micropipette from the lower conjunctival cul-de-sac.

This method is considered to be more reproducible than using glass rods or spatulas to scrap the conjunctiva and the ferning seems not to be affected by tear stimulation.54 After centrifugation to remove debris such as make-up, a small droplet is placed on a clean, grease-free microscopy slide and allowed to dry at room temperature for five to seven minutes before microscopic examination at X40 to X100. If less than five minutes is allowed before analysis the heat of the microscope will dissolve some of the ferns and if more than seven minutes is allowed, excessive sample drying will lead to altered fern classification.53 The ferning patterns can be classified as: Type I, numerous acute angle branchings without spaces between the ferns sometimes described as complete, uninterrupted arborisation; Type II, similar to Type I but with many spaces and a lower branching frequency; Type 3, showed thicker and smaller ferns with very little branching and very large spaces; Type IV, an amorphous pattern with few if any ferns.

Types I and II are seen in >80 per cent of subjects with normal tears and Types III an IV in >90 per cent of people with abnormal tears in KCS.45
Clearly, ferning is a complex phenomenon depending on many types of molecular interaction. The tear-ferning technique is sensitive to change either in the amount of mucus or proteins available, or in the number of accessible cation-binding anionic groups. If this coincides with an increase in calcium ions, such as seen in contact lens wearers with fatty deposits, these tears will tend to give poor ferning of Types II and IV (see Figure 6 for Type I, II, III and IV ferning patterns).

It seems that mucus need not be present for ferning to take place, although some macromolecular material is definitely required to direct the tendency of the tear salts to crystallise to a fern-lie pattern. This material can be protein alone, a mixture of protein and mucus glycoprotein, or mucus glycoprotein alone. A more quantitative method of fern analysis has been proposed55 whereby the total area of ferning is determined by counting the number of micrometer lattice squares covering crystals and correcting for microscope magnification, crystal density and differing densities of the two fern branching types (right-angled and acute-angled).

This technique is more reproducible compared to the simple qualitative method in that two consecutive samples were identical in only 42 per cent of cases qualitatively while the coefficient of variation was low (6.4 per cent) with the quantitative method.54

The most convincing theory for the reduction of ferning in dry eye is that of a shift in the salt-to-macromolecule ratio, although an increased amount of lipid-contaminated mucus and altered tear rheology may also contribute. The combination of raised osmolarity and reduced protein and mucin critically alters the concentrations of chemical species involved in crystallisation so that fern growth is no longer favoured.53

The ferning test has been used for diagnostic purposes and to identify the degree of DES severity but as a standardised test has yet to be developed the tear ferning test is not as yet suitable for clinical practice although it is very likely to be useful for research purposes especially if quantitative analysis is employed.

Laboratory tests of lacrimal gland function

Lactoferrin
Lactoferrin, along with lysozyme and tear specific prealbumin, is one of the major proteins synthesised and secreted by the lacrimal gland.56
Lactoferrin is an iron binding enzyme protein secreted directly by the epithelial acinar cells of the lacrimal glands.56, 57 It is one of the key molecules which modulates the inflammatory response, controls cell growth, protects against infections and allogeneic recognition reactions.58-60

Lactoferrin also acts as an antimicrobial via chelation of iron or destabilisation of bacterial membranes60 and it protects mucosal surfaces from oxidative damage.61 Tear-deficient dry eye reduces lactoferrin levels by half compared with normal eyes.
Efficiency as a diagnostic test has been shown to be greatest with reflex tear concentration (80 per cent) and lactoferrin per cent increase with reflex tearing (76 per cent) and this indicates that both these measurements produce test values which correctly identify people with and without KCS.8

Furthermore, studies have shown that by increasing lactoferrin levels through punctal occlusion or instillation of lactoferrin drops damage caused by ocular surface disease can be reversed.62

Traditional tests for lactoferrin include the objective Lactoplate test (JDC, Culembourg, Netherlands); this is an objective measure of lactoferrin concentration in the tear film and involves an immunodiffusion assay performed in an agarose gel containing rabbit anti-sera to human lactoferrin. Circular discs of filter paper are placed in the inferior conjunctival cul-de-sac where they become soaked with tears. They are placed on agar and incubated for three days.63 When tears are collected with filter paper discs, a combination of basic and reflex secretion results. No statistically significant difference in lysozyme concentration between reflex and basic tears has been demonstrated.64

One study investigating the use of this procedure revealed that lactoferrin concentration was 1.77 0.82mg/ml in patients with normal tear film and 0.80 0.70 mg/ml in patients with DES.

The authors concluded that patients with a lactoferrin concentration of less than 1.1mg/ml were likely to have DES (sensitivity 79.4 per cent, specificity 78.3 per cent).65

This method is reported to be accurate in moderate to severe DES, although it is certainly too cumbersome and time consuming for clinical practice.66 The LactoCard test (Touch Scientific, Taleigh, NC, USA) is an objective colorimetric solid phase enzyme-linked immuno-serum assay (Elisa) test that is simple to calibrate and operate.

The test is end user friendly and a convenient form of this assay in which tear samples (only 2l is required) are applied to a test card which is impregnated with antibodies that carry a chromophore. These bind to lactoferrin and a colour appears on the card. This is then scanned and its intensity measured spectrophotometrically; an easy to read scale displays the exact colour intensity and the more intense the colour, the more lactoferrin there is in the tears. The final result is a lactoferrin value in milligrams/millilitre.

The LactoCard was used to investigate lactoferrin concentrations in tears of patients with chronic signs and symptoms of KCS pre- and post punctal occlusion (the investigators did not report which puncta were occluded). Elevations in tear lactoferrin concentrations and improvements in symptoms were observed at the first follow up (two to six weeks) and second follow up (nine to 16 weeks) visits. The authors proposed that by preserving tear proteins in situ, a dynamic equilibrium between acinar cell function, ocular stress, and tear film chemistry is achieved, resulting in greater lacrimal gland functional efficiency, and eventual attainment of normal stasis.67

The LactoCard has been shown to be as accurate as the Lactoplate.66 McCollum et al compared measurement of lactoferrin concentration by the LactoCard solid phase Elisa assay with the LactoPlate radial immunodiffusion assay in tears of normal patients and those with KCS.

The LactoCard gave rapid determination of tear lactoferrin concentration in 10-15 minutes, a considerable improvement over the three days required for the LactoPlate. There was no statistically significant difference between the accuracy of the two assays in normal patients or in those patients with a diagnosis of KCS.

Both assays showed a significant decrease in tear lactoferrin concentration in patients with severe KCS. For the LactoCard a value of less than 0.90 mg/dl has been proposed as being abnormal.37

We agree with the authors of this report in that the LactoCard is a rapid and reliable means of measuring tear lactoferrin concentration and is very likely to be of use to a dry eye specialist in a clinical practice setting.

Tear lysozyme
Tear lysozyme is an enzyme secreted in the tubular and acinar structures of the main and accessory lacrimal glands68 and, like lactoferrin, has antibacterial properties.69

Tear lysozyme concentrations have been shown to be reduced in aqueous tear deficiency states.70 A rapid and simple colorimetric assay (using filter paper discs as in lactoferrin measurements) that uses a synthetic chemical substrate for the measurement of tear lysozyme has been shown to be a reliable test for diagnosing tear gland deficiency when compared with clinical examination, medical history and follow up combined with the results available one hour after tear collection.71 A decline in tear lysozyme concentration of 10mg/l/year of age is considered to be normal.72 Tear lysozyme testing using colorimetric assays is likely to be a useful research tool and may also be of clinical use to the dry eye specialist.

Tear protein analysis
Tears from patients with DES are likely to contain altered protein composition.1

The key question is which proteins are indicative of DES and are there different indicative proteins for different types of DES? These proteins can be currently evaluated using a laboratory-based Elisa assay similar to that used in lactoferrin testing, although presently a system for use in clinical practice has yet to be developed.


CLINICAL TESTS

Lid-wiper epitheliopathy testing

Symptoms due to DES sometimes occur in the absence of expected definitive ocular findings such as corneal staining and abnormal fluorescein break-up time (FBUT).73 A new clinical condition called lid-wiper epitheliopathy, recently described by Korb et al, has been demonstrated in patients with symptoms of dry eye but normal FBUT, Schirmer test values, and no fluorescein corneal staining.74

Lid-wiper epitheliopathy is a clinically observable alteration of the epithelium of the lid wiper, that portion of the marginal conjunctiva of the upper eyelid that wipes the ocular surface during blinking.73 The upper lid was everted and the lid wipers of subjects with DES symptoms but normal FBUT, Schirmer test values and an absence of corneal staining were graded for staining using the cobalt blue filter and X16 magnification, one minute after instillation of two drops of fluorescein separated by five minutes.

Fluorescein staining of the upper lid wiper is graded Grade 0 (absent) to Grade 3 (severe) for each of two characteristics, the linear area and the severity of the staining, with the final fluorescein grade being an average of the two.

Rose bengal dye is then instilled and the lid wiper viewed with white and red free light. Rose bengal staining is then graded in the same way as fluorescein staining and the final score is obtained by averaging the grades from each dye. Both dyes are required because the lid wiper involves conjunctival tissue and stratified squamous epithelium (analogous to the cornea).75

Final scores have been classified as 0.5 to 1.0 = Grade 1 (mild lid-wiper epitheliopathy); 1.25 to 2.0 = Grade 2 (moderate); 2.25 to 3.0 = Grade 3 (severe). Figure 7 shows a schematic of lid-wiper epitheliopathy grading.

Symptomatic contact lens wearers show a much higher percentage of lid wiper staining, 80 per cent opposed to only 13 per cent in an asymptomatic contact lens group.75

It has been speculated that in patients with DES the thickness of the tear film is insufficient to separate the corneal and lid wiper tissue surfaces and that the lid wiper is subjected to trauma during the entire lid movement, via the friction produced by the continual rubbing of the narrow surface area of lid wiper tissue against the corneal surface during a blink (3,000 to 15,000 blinks per day)76 and therefore it is the lid wiper and not the cornea, which exhibits the epitheliopathy.73

If artificial tears are recommended to treat DES when lid-wiper epitheliopathy is present, the product chosen should have a high lubricity so regular application will result in less friction and a smoother surface as the lid wiper moves across the ocular surface. This lessens the likelihood of mechanical damage to the lid wiper and the ocular surface while providing patient comfort. Plus, a lubricated coating and smooth surface produces less drag, thus helping to prevent further damage, allowing epithelial cells to heal.73

See Part 2 of this article for more on the properties of artificial tears.

Conclusions
We hope that this review of dry eye classification and some novel investigative techniques will be of clinical use to general eye care practitioners and those who have a large contact lens patient base and/or specialise in the treatment of DES.

Evaluating the lid margins for lid-wiper epitheliopathy will help the generalist and the specialist when clinical signs do not match the patient symptoms, particularly in mild DES, while the specialist may wish to carry out further investigations involving tear interferometry, fluorophotometry, tear osmolarity, brush cytology and lactoferrin testing to aid in the differential diagnosis and management of more severe cases of DES.

References
A list of references is available on request from william.harvey@rbi.co.uk

• Dr Bartlett is a post-doctoral research optometrist in the Ophthalmic Research Group in the School of Life and Health Sciences at Aston University and Dr Eperjesi is director of undergraduate studies for Optometry in the School of Life and Health Sciences at Aston University and a research optometrist in the Ophthalmic Research Group in the School of Life and Health Sciences at Aston University

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