Ординатура / Офтальмология / Английские материалы / Dry Eye and Ocular Surface Disorders_Pflugfelder, Beuerman, Elliot Stern_2004

Table 1 Frequently Reported Complaints of Dry Eye Patients

Irritation symptoms

Burning or stinging

Gritty or scratchy sensation

Sandy sensation

Soreness

Dryness

Sensitivity to cold, or to air drafts

Itching

Pain or burning in the middle of the night, or upon awakening

Tearing/discharge symptoms

Mucus discharge

Tearing

Vision symptoms

Vision fluctuation

Vision that improves with tears

Blurred vision

Light sensitivity

patients use to describe their eye irritation symptoms (Table 1), mean that a single complaint cannot be used to screen patients for dry eye. Although symptoms or a history of ocular irritation are not sufficient to arrive at a diagnosis, they may be used as indicators of dry eye.

Responses to several different questionnaires suggest that some common patterns underlie the symptoms experienced by dry eye patients [3–9]. Two complaints provide important clues that patients may be suffering from dry eye: exacerbation of irritation by environmental stress, and exacerbation of irritation by activities that require prolonged visual attention. For example, patients with dry eye are often intolerant of drafts from air conditioners, smoky environments, and the low humidity of airplane cabins, and they typically report worsening symptoms when reading or viewing a video display terminal because their blink rate decreases, resulting in increased tear film evaporation and ocular surface desiccation [10]. The severity of eye irritation symptoms significantly correlates with results of objective tests of lacrimal keratoconjunctivitis (LKC, also known as keratoconjunctivitis sicca) such as the fluorescein clearance test, fluorescein or rose bengal staining scores, and computerized videokeratoscopic surface regularity indices [8,11–13].

It is essential to obtain a complete history of the patient’s medication use to identify any agents that may decrease tear secretion (Table 2). A history of dry mouth (xerostomia), dental and gum disease, or arthritis, all symptoms found with Sjögren’s syndrome, or a history consistent with other autoimmune disorders, may be associated with dry eye disease (Table 3).

Source: Information from Refs. 14–18.

Table 3 Autoimmune Disorders

Associated with Sjögren’s Syndrome

Rheumatoid arthritis

Systemic lupus erythematosus

Progressive systemic sclerosis

Scleroderma

Polyarteritis nodosa

Polymyositis

Lymphocytic interstitial pneumonitis

Hashimoto’s thyroiditis

Thrombocytopenic purpura

Hypergammaglobulinemia

Waldenström’s macroglobulinemia

Raynaud’s phenomenon

Dermatomyositis

Interstitial nephritis

Chronic hepatobiliary cirrhosis

Figure 2 A modified Belmonte gas esthesiometer. (A) Air and CO2 gas tanks. (B) Control module. (C) The distance from the tip of the instrument to the cornea is 4 mm.

instrument delivers a temperature-controlled 2-s pulse of air or an air/CO2 mixture through a 0.5-mm-diameter metal tube 4–5 mm away from, and perpendicular to, the corneal surface. Mechanical sensations due to contact are assessed by increasing the air flow. Chemical sensation is evaluated by increasing the CO2 concentration in the gas jet, which is converted to carbonic acid on the corneal surface, decreasing its pH [31,34], followed by observation of the polymodal receptor response. Mechanical and chemical stimulation thresholds of the normal cornea ranged from 79 to 121 mL/min and from 21% to 31% CO2, respectively [30–32,35]. Both mechanical and chemical corneal sensation decreased after instillation of the pungent substance capsaicin, which depletes the sensory nerve endings of substance P and causes anesthesia [32].

The noncontact aesthesiometer delivers a 0.5-mm-diameter stimulus of atmospheric air to the cornea for 0.9 s [36], which produces a localized area of cooling [37]. Using this technique, contact lens wearers and LASIK patients showed decreased sensitivity and higher thresholds than subjects with normal corneas [38,39]. Similar findings were obtained with the Cochet-Bonnet esthesiometer [40–45]. However, no correlation between mean sensitivity thresholds

of the noncontact aesthesiometer and the Cochet-Bonnet tests were found for normal subjects [46].

B.Assessment of Lacrimal Gland Function

The Schirmer test, originally described in 1903 [47], remains the most commonly used technique for assessing tear secretion. It is performed with or without topical anesthesia by placing a standardized folded Whatman filter paper strip over the lid margin at the junction of the medial and lateral third of the lower lid. Aqueous tear production is measured by the millimeters wetted during the test period, usually 5 min (Fig. 3) [48]. A cutoff value of 5.5 mm wetted in 5 min for the Schirmer I test (without anesthesia) diagnosed aqueous tear deficiency in 83% of dry eye patients tested [49]. For the Schirmer test with anesthesia (the Schirmer II test), which minimizes reflex tearing, a measurement of less than 10 mm of wetting in 5 min was defined as abnormal [50].

The Schirmer test has been criticized for its variability and poor reproducibility. A study of the reproducibility and kinetics of the Schirmer test with

Figure 3 A Schirmer test strip placed over the lower eyelid. The arrow and line indicate the portion of the strip wetted by tears.

and without topical anesthesia in normal subjects found an initial rapid phase of Schirmer strip wetting followed by a progressive reduction in wetting rate [51]. Results were variable when the test was repeated, and variability was greater after topical anesthesia. This was attributed to residual reflex components, perhaps resulting from varying degrees of ocular surface anesthesia. A different study reported greater tear flow for young girls than young boys, and that tear flow decreased with age [52], whereas another study found no correlation between Schirmer I test scores and age [53].

An evaluation of the Schirmer I test using a diagnostic cutoff of 1 mm/min found 25% sensitivity and 90% specificity for diagnosis of dry eye, using patient history, symptoms, and clinical examination (i.e., deficient inferior tear meniscus, excess debris in the tear film, and/or a viscous tear film) as diagnostic criteria for dry eye [54]. Another recent study noted significant differences in Schirmer I values between patients with aqueous tear deficiency, patients with meibomian gland disease, and normal subjects [7]. All normal eyes and eyes with meibomian gland disease had Schirmer I values greater than 5 mm in both eyes, whereas only 5% of eyes with Sjögren’s syndrome LKC and 33% of eyes with non-Sjögren’s LKC had Schirmer I values greater than 5 mm.

Another measure of tear secretion employs a special cotton thread impregnated with the pH indicator phenol red (phenolsulfonphthalein), which is inserted into the temporal side of the lower conjunctival sac for 15 s (Fig. 4) [55]. When tears wick into the thread, phenol red turns from yellow to bright orange because tears are slightly alkaline. The length of thread wetted measures aqueous tear production. The cotton thread is not irritating, so topical anesthesia is not required. Better reproducibility than Schirmer tests with or without anesthesia has been reported, as well as greater specificity for diagnosis of dry eye [56].

Fluorophotometric techniques have also been used to quantitate tear secre-

tion and tear volume. Measurements of tear secretion using a commercial fluorophotometer showed significantly less secretion in dry eye patients (0.2 L/min)

than in healthy subjects (1.2 L/min) [57]. Measurement of physiological tear flow using a quantitative fluorophotometer found a rate of 1.2 L/min, similar to the value of 0.6–0.8 L/min measured by Schirmer test strips, with no significant

difference between age groups, genders, or fellow eyes [58]. Fluorophotometry is not commonly used in clinical practice because the equipment is expensive and the technique lacks standardization.

C.Evaluation of the Tear Meniscus

Reflective meniscometry uses photographs or video images of an illuminated target reflected off the meniscus to measure the radius of tear meniscus curvature, which is related directly to tear volume [59]. The video system provides images of human menisci over prolonged periods of time [60]. Changes in the meniscus

Figure 4 Cotton thread measurement of tear secretion. Tears wicking up the thread turn the pH indicator in the thread to red (arrow), facilitating measurement of distance wicked.

radius can be used to monitor effects of conventional tests, such as the cotton thread or the Schirmer tests, on the tear reservoir [61]. In a study of 45 normal and 32 dry eyes, the tear meniscus radii of curvature were significantly lower in dry eyes than in normal eyes, and correlated significantly with corneal fluorescein staining scores and grading of interference colors of the precorneal lipid layer [59]. Reflective meniscometry also correlates significantly with conventional tear meniscus height measurements taken with a micrometer-equipped slit lamp [62].

D.Tear Film Osmolarity

Elevated tear film osmolarity was recognized by the NEI/Industry workshop on dry eye as a global measure of tear film deficiency [27]. It is a sensitive test for identifying dry eye [63,64], although elevated osmolarity is often a secondary effect of decreased tear secretion due to lacrimal gland disease, or of increased tear film evaporation resulting from exposure, blink abnormalities, or meibomian gland disease [65–67]. Collecting a sufficient volume of tears to perform an accurate and reproducible measurement of tear osmolarity without causing reflex tearing has been one of the obstacles to widespread application of this test. Collection of microliter tear sample volumes with small-diameter glass pipettes allows measurement of osmolarity without causing reflex tearing [68]. However, no instrument to measure tear osmolarity is commercially available.

E.Tear Protein Analysis

The antimicrobial protein lysozyme was initially discovered in mucosal secretion by Fleming in 1922 [69]. It degrades peptidoglycan, found only in bacterial cell walls, causing susceptible bacterial cells to lyse. Over the next 30 years, the lysozyme content of tears was studied using a variety of methods. A common method for measuring tear lysozyme employs a uniform suspension of Micrococcus lysodeikticus, a lysozyme-sensitive bacterium, in an agarose gel. Enzyme molecules applied to a central well diffuse radially through the gel during incubation and lyse the bacteria, clearing a zone around the well. A greater lysozyme concentration in the tear sample produces a larger zone of clearance. Lysozyme accounts for 20–40% of total tear protein, and its concentration decreases with age [14] and in dry eye patients [70]. Tear lysozyme concentration was reported to be a more sensitive test for the diagnosis of dry eye than either the Schirmer test or rose bengal staining, with a sensitivity and specificity of greater than 95% [49]. Filter paper strips or cellulose sponges have been used to collect tear specimens [71], but adsorption of lysozyme to these materials can lead to errors in measurement. The main disadvantage of tear lysozyme as a diagnostic test for dry eye is its lack of specificity. Decreased tear lysozyme levels

have been found in herpes simplex virus (HSV) keratitis, bacterial conjunctivitis, smog irritation, and malnutrition [72–76].

Lactoferrin is a tear protein with antioxidant and antibacterial properties secreted by lacrimal glands. Its concentration in tears has been used as a measure of lacrimal function. Tear lactoferrin concentrations measured by ELISA correlated with the clinical severity of LKC as assessed by symptoms, biomicroscopic findings, Schirmer test scores, rose bengal staining, and tear breakup time [77]. Another study found that tear lactoferrin concentrations correlated well with symptoms of ocular irritation, but not with tear breakup time or rose bengal staining [78].

The tear concentration of epidermal growth factor (EGF), also secreted by lacrimal glands, decreased with age and after sensorineural stimulation [79]. Tear EGF concentration was lower in women than in men of similar age [80].

F.Measurement of Tear Clearance

Delayed clearance (turnover) of fluorescein dye instilled onto the ocular surface has been reported for the two most commonly encountered dry eye conditions, aqueous tear deficiency and meibomian gland disease [7]. Tear fluorescein clearance can be assessed visually in the inferior tear meniscus, on Schirmer strips (Fig. 5), or fluorometrically [7,11,81,82].

Fluorescein clearance measures the rate of tear turnover. At 15 min after instillation of 5 L of 2% sodium fluorescein into the inferior conjunctival cul-de-sac, the fluorescein-stained tear fluid is collected under direct observation from the inferior tear meniscus with a porous polyester rod or glass capillary pipette. Fluorescein concentration is measured with a commercial fluorometer [11]. Tear turnover can also be assessed directly in vivo using a Fluorotron Master fluorometer (Ocumetrics, Mountain View, CA) [83,84].

Figure 5 Schirmer strip method for tear clearance evaluation. The color of the fluorescein on the Schirmer strip is compared visually with known concentrations of fluorescein.

Figure 6 For fluorescein tear clearance evaluation, the color of the lateral inferior tear meniscus is visually matched to the 0–6 color scale.