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

A standardized visual scale from 0 to 6 (Fig. 6) for routine clinical assessment of tear fluorescein concentration avoids the use of a fluorometer [8]. Fifteen minutes after instillation of 5 L of 2% fluorescein, the color of the lateral inferior tear meniscus is visually matched to the colors on the standardized visual scale. A score of 3 corresponds to a fluorophotometric value of 274 fluorescein units / L, the previously reported threshold between normal and symptomatic patients [11]. This technique is equivalent to fluorometric assessment of tear clearance in its correlation with irritation symptoms, ocular surface sensitivity, and the severity of ocular surface, eyelid and meibomian disease. Both methods of assessing delayed tear clearance correlate better with symptoms and signs of dry eye than the Schirmer I test. The ability of the fluorescein clearance test to distinguish healthy subjects from patients with meibomian gland disease or aqueous tear deficiency can be improved by using a correction factor based on the Schirmer I test score.

G.Assessment of Meibomian Gland Disease

Meibomian gland disease is due to atrophy of the glandular acini or to obstruction of the duct by epithelial hyperplasia (see Chapter 12). [85,86]. Diagnosis is by biomicroscopic recognition of pathological signs, such as ductal orifice metaplasia (white shafts of keratin in the orifices), reduced expressibility of meibomian gland secretions, increased turbidity and viscosity of the expressed secretions, and dropout of glandular acini [27]. Photographic techniques to grade the extent of meibomian gland acinar loss have been reported [87]. Meibomian gland acinar dropout in chronic blepharitis has been imaged using an infrared video camera and hand-held transilluminating light source [88].

H.Evaluation of Conjunctival Mucin Production

The stratified epithelia and goblet cells in the conjunctiva produce mucins. In eyes with aqueous tear deficiency, the epithelium undergoes pathological changes, termed squamous metaplasia, and goblet cell density decreases. A deficiency of mucin in the tear film results and the tear film becomes unstable. Squamous metaplasia can occur in a variety of other dry eye conditions in addition to aqueous tear deficiency, including vitamin A deficiency (xerophthalmia), Stevens-Johnson syndrome, and ocular cicatricial pemphigoid [89,90].

Superficial cells may be obtained from the bulbar conjunctiva by application of a cytology membrane against the conjunctival surface (impression cytology), allowing quantitative measurement of goblet cells and a qualitative assessment of the epithelial morphology in various conjunctival diseases. Adequate samples of conjunctival cells may also be collected with a brush [90]. The extent and severity of squamous metaplasia are graded by loss of goblet cells,

enlargement and increased cytoplasmic/nuclear ratio of superficial epithelial cells, and keratinization [14,91,92]. Squamous metaplasia of the bulbar conjunctiva, mucous aggregates adherent to the bulbar conjunctiva, and inflammatory cell infiltration of the inferior tarsal conjunctiva occur in a significantly greater percentage of patients with Sjögren’s syndrome LKC than in other forms of dry eye [93]. Expression of specific mucin moieties (e.g., MUC4 and MUC5AC) can be assessed on impression cytology membranes with immunostaining techniques [94].

I.Ocular Ferning Test

The ocular ferning test is based on crystalization of a drop of tear fluid on a glass slide as it dries at room temperature. After crystallization, the ferning patterns are examined microscopically and classified as one of four types depending on their density and branching frequency [95]. Type I has uniform structures, whereas type IV shows no ferning. An increase in either temperature or humidity decreases the ferning phenomenon [96].

Dry eye patients displayed types III and IV ferning patterns more frequently than normal control subjects [95]. The ferning test had a sensitivity of 90% for diagnosis of primary Sjögren’s syndrome LKC, and 80% for identifying secondary Sjögren’s syndrome LKC [97,98], and is reported to have sensitivity and specificity similar to other commonly used diagnostic tests for Sjögren’s syndrome [99]. The test has been used as evidence of ocular surface dryness in several clinical trials [100–102].

J.Measurement of Tear Film Stability

An unstable tear film is the hallmark of dry eye and of dysfunction within the lacrimal functional unit [14]. Tear film stability can be assessed by a number of invasive and noninvasive techniques.

Tear film stability measured by the tear breakup time (TBUT) test may be the most important and practical test for diagnosing dry eye. It is performed by placing fluorescein in the lower conjunctival sac using a fluorescein-impregnated strip wetted with nonpreserved saline solution, asking the patient to blink, and measuring the interval between a complete blink and the first randomly appearing dry spot or discontinuity in the precorneal tear film. The test should be performed without topical anesthesia and without lid holding, because they reduce the tear breakup time [103]. Sensitivity is increased by viewing the corneal surface with a yellow filter. Three repetitions are recommended.

A mechanism to explain tear breakup proposes that after each blink, the precorneal tear film may thin secondary to evaporation and retract toward the fornices [104]. Meanwhile, the superficial lipid would diffuse through the

aqueous layer to the mucin surface, converting it to a hydrophobic surface, followed by retraction of the aqueous tear film from the contaminated area, forming a dry spot. However, some researchers believe that the aqueous layer in the tear film is too thick (6–9 m), and the attraction between mucin and lipid molecules too weak, to explain the proposed migration of lipid molecules [105]. Thus, a definitive mechanism for tear breakup remains to be elucidated.

An alternative method for measuring tear film stability reflects a regular pattern off the corneal surface and measures the time for it to distort or break up following a blink [106]. Because no instillation of fluorescein is required, this test is known as the noninvasive breakup time (NIBUT). Noninvasive techniques to evaluate tear film stability minimize effects of fluorescein and the reflex tearing caused by instilled fluorescein, confounding factors that may destabilize the tear film [107,108]. The fluorescein-added and the noninvasive techniques share the disadvantage that any local alteration of the corneal surface will cause a persistent breakup of the tear film in the area of alteration.

A xeroscope is used to measure noninvasive breakup time [107]. It consists of a hemispherical bowl mounted on a binocular slit lamp biomicroscope. The bowl has a white grid inscribed on its inner matte black surface and is uniformly illuminated by a ring fluorescent tube attached to the rim. The reflection of the grid off the cornea is viewed through the slit lamp and videotaped. Noninvasive breakup time can also be measured with a keratometer [109,110], which showed better reproducibility and lower variability than seen for fluorescein tear breakup time measurements [110]. Xeroscope grid distortion (Fig. 7) is greater in patients with aqueous tear deficiency than in those with meibomian gland disease [7].

The Keeler Tearscope is designed to provide a 360° specular reflection of white light off the tear film, permiting visualization of the tear film against this white background [111]. It can measure noninvasive breakup time, and also evaluate the tear lipid layer [112,113]. Attachments such as a xeroscope-like grid insert, a Placido disc, and blue and yellow filters for fluorescein observation provide additional functions [114].

Placido-based computerized videokeratoscopy instruments have also been used to evaluate tear film stability [115]. In one study, 4 images/s of the reflected ring were captured during 15 s after a complete blink. The tear film requires approximately 3–10 s (the tear film buildup time) to reach its most regular state [115]. This technique allows quantitative measurement of tear film dynamics but has not been used routinely for clinical diagnosis.

K.Clinical Assessment of Tear Film Stability

The original description of fluorescein tear breakup time found a wide variation in normal subjects (3–132 s, average 30 s) [116]. Although there is no consensus

Figure 7 Xeroscope images. (A) Normal patient showing uniform grid. (B) Patient with lacrimal keratoconjunctivitis, showing distortions of the grid indicated by arrows.

on a normal tear breakup time, a value less than 10 s is considered abnormal by many [116–118], and was sufficiently specific to screen patients for tear film instability [108].

Several factors influence tear breakup time. Lid holding and instillation of a local anesthetic reduced breakup time, but no correlation of breakup time with gender or age was found [117]. Other studies reported that women had shorter breakup times [108], and that tear breakup times correlated inversely with between palpebral fissure width [118]. Fluorescein instilled on the ocular surface shortened the noninvasive breakup time during the first 2 min after instillation [119].

One study found that that fluorescein tear breakup time was reliable and reproducible in normal subjects [116], but another noted variability in measurements performed on the same eye on successive days and questioned the reproducibility of the test [120]. Noninvasive breakup time measurement with a Mengher-Tongue xeroscope in normal individuals showed excellent repeatability in the same (normal) subjects on different days [110]. Noninvasive breakup time of dry eye patients, for whom diagnostic criteria were not defined, averaged 12.0 s (range 1–20 s), whereas normal eyes averaged 41 s (range 4–214 s) [107]. Another study using the same technique found that 53% of normal patients had noninvasive breakup time values greater than 30 s, whereas all patients with dry eyes had noninvasive breakup times less than 20 s [121].

Rapid fluorescein tear breakup time has previously been observed in different types of dry eye, including keratoconjunctivitis sicca, mucin deficiency, and meibomian gland disease [108,116,122,123]. In a controlled study, patients with aqueous tear deficiency or with meibomian gland disease exhibited a significantly faster fluorescein tear breakup time than normal subjects [7]. The tear breakup pattern for tear lipid deficiency tends to be linear on the inferior and central cornea compared with a more random circular breakup pattern over areas of punctuate epitheliopathy for aqueous tear deficiency (Fig. 8).

During the noninvasive tear breakup test, distortions of the xeroscope grid were apparent immediately after a blink for a significantly greater percentage of subjects with aqueous tear deficiency, particularly that associated with Sjögren’s syndrome, than for those with meibomian gland disease [7]. None of the eyes in the meibomian gland disease group showed this type of grid abnormality. This finding suggests that the xeroscope evaluates a different phenomenon than the fluorescein tear breakup technique and may be useful for differentiating aqueous tear deficiency from meibomian gland disease.

In summary, wide variability is evident in the tear breakup time of normal subjects, but an arbitrary cutoff time of 10 s for both fluoresceinadded and noninvasive techniques, if consistently obtained, appears to provide sufficient specificity to screen patients for evidence of tear film instability [124].

Figure 8 Patterns of tear breakup. (A, B). Tear breakup in meibomian gland disease. (C, D). Tear breakup in aqueous tear deficiency with corneal epitheliopathy.

L.Noninvasive Evaluation of Tear Film Regularity

Computerized videokeratoscopy (CVK) provides a quantitative measure of tear film regularity. This procedure uses computerized algorithms to evaluate Placido rings reflected off the surface of the cornea. About 12 different indices can be quantitated by the Klyce software package of the Tomey TMS videokeratoscope [125]. Among them are the surface regularity index (SRI), which measures local fluctuations in power in the central 10 rings, the surface asymmetry index (SAI), which measures the difference in corneal powers at every ring 180° apart over the entire corneal surface, the irregular astigmatism index (IAI), which reports an area-compensated average summation of inter-ring power variations along every meridian for the entire corneal surface, and the potential visual acuity index (PVA), which estimates the best corrected acuity that can be obtained through the viewing surface (Fig. 9).

The surface regularity index increased with contact lens warpage [126] and with increasing age [127]. The greatest increases were seen in patients with LKC (Fig. 10) [13,128–130], where the surface regularity index correlates with conventional dry eye tests such as corneal fluorescein dye staining [13,128]. Artificial tears transiently decrease the surface regularity index [126,131] and improve visual function [129,132]. Significantly increased videokeratoscopic indices indicating irregular corneal topography likely explain the frequent visual complaints of dry eye patients [132]. Consistent with this, the severity of blurred vision reported by a cohort of 90 patients with dry eye correlated significantly with the surface regularity and potential visual acuity index scores, but not with Snellen visual acuity [133]. However, another study reported that the surface regularity index did correlate with Snellen visual acuity and subjective measures of visual function, such as contrast sensitivity [134]. Experimental tear film removal [135] and a sustained pause in blinking [136] also increased the surface regularity index score. It appears that lubrication and hydration of regions of corneal desiccation can improve topographical irregularities detected by computerized videokeratoscopy [137].

M.Evaluation of the Lipid Layer

Several instruments have been developed to evaluate the tear lipid layer by detecting the fringe patterns generated by interference of white light reflected from, or transmitted through, the upper and lower interfaces of a thin film (the tear film). Interference colors depend on the thickness and refractive index of the layer, and on the angle of incident light [138]. Gray indicates a thin lipid layer (90–120 nm), brown indicates a thicker lipid layer (135–150 nm), and blue indicates the thickest lipid layer (165–180 nm) [139–141].

The interference pattern created by the lipid surface of the tear film can also be captured by confocal microscopy, then viewed on a video monitor and recorded. Confocal images may be evaluated for five properties: debris, pattern

variability, linearity, dry spots, and lipid thickness [142]. Lipid thickness has been estimated by an arbitrary increase in dark area immediately before and after manual meibomian gland expression. Patients with seborrheic meibomian gland dysfunction had a thicker lipid layer, greater pattern variability, and more debris than patients with obstructive meibomian gland dysfunction [142].

Lipid interference microscopy is performed using a white light source refracted by a half-mirror and focused by a lens onto the tear surface. The specular images are observed in a 2-mm-diameter zone of the central cornea, then videotaped and scored using five different grades: grade 1, somewhat gray color, uniform distribution; grade 2, gray color, nonuniform distribution; grade 3, few colors, nonuniform distribution; grade 4, many colors, nonuniform distribution; grade 5, corneal surface partially exposed [143]. For normal eyes, lipid layer interference is primarily grade 1 [138], whereas grades 3 and above are regarded as indicators of dry eye [143]. The interference pattern correlated strongly with tear function parameters such as the fluorescein staining score, tear breakup time, and the cotton thread test [143]. A thick lipid layer (grade 4) was more frequently observed in patients with aqueous tear deficiency than in patients with meibomian gland disease [144]. In a series of 114 eyes of diabetic patients, the tear lipid layer was less uniform than the tear film of the nondiabetic group, and the lipid interference grade indicated epitheliopathy [145]. Lipid interference patterns have been used to measure of corneal surface smoothness after phototheraupetic keratectomy [146].

Specular microscopy has been used for tear film evaluation by removing the cone lens from the tip of an S-III specular microscope (Konan Camera, Hyogo, Japan) and photographing the noncontact reflection. The color photomicrographs are classified in four grades depending on the intensity of the interference color of the lipid layer, from no interference color (grade 1) to high intensity (grade 4). A second parameter, termed “oil droplet” (oil droplets appearing to float over the tear film), was also evaluated. The dominant color in grades 2 and 3 was red and in grade 4 it was blue. In a study of 52 primary Sjögren’s syndrome patients, the grade of interference color was closely related to the intensity of ocular surface dye staining [147]. The oil droplet pattern appeared in eyes that also showed intense corneal staining with fluorescein and rose bengal [147].

N.Diagnostic Dye Staining

The simplest and most practical method of assessing the severity of LKC uses diagnostic dyes, such as fluorescein, rose bengal, and lissamine green. Fluorescein stains tissues by penetrating their intercellular spaces—an intact epithelium prevents its permeation into the stroma [148]. Fluorescein staining is more easily observed in the cornea than in the conjunctiva and is very well tolerated by patients.

Fluorescein strips should be wetted with a standardized volume of nonpreserved saline and the corneal staining observed after 2 min through a yellow filter