Approach Considerations
Dry eye disease (DED), or keratoconjunctivitis sicca (KCS), is a clinical diagnosis, made by combining information obtained from the history and from the physical examination, and performing one or more diagnostic tests to lend objectivity to the diagnosis. No single test is sufficiently specific to permit an absolute diagnosis of dry eye disease.
Studies that may be used in the workup include symptom questionnaires, impression cytology to monitor the progression of ocular surface changes, measurement of tear breakup time (TBUT), the Schirmer test, and quantification of tear components through analysis of tear proteins or tear-film osmolarity. [32] Serology for circulating autoantibodies may be indicated.
Sjögren syndrome
All cases of SS are characterized by a progressive infiltration of the lacrimal and salivary glands by lymphocytes, predominantly B cells and CD4+ lymphocytes, which leads to disorganization of the normal gland architecture and consequent loss of function. At this time, the most comprehensive criteria for a diagnosis of SS include the following:
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Abnormally low Schirmer test result
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Objective evidence of low salivary flow
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Biopsy-proven lymphocytic infiltration of the labial salivary glands
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Dysfunction of the immune system, as manifested by the presence of serum autoantibodies (eg, antinuclear antibody [ANA], rheumatoid factor [RF], and anti-Ro [SS-A] and anti-La [SS-B] antibodies)
A novel test called Sjo is available from IMMCO Laboratories through Bausch & Lomb. In addition to traditional ANA, RF, Ro, and La autoantibodies, it is used to evaluate for proprietary early markers of SS. These early antibodies may enable the clinician to identify SS up to 4 years earlier than the traditional antibody panel. [33]
Symptom Questionnaires
Ocular symptoms are difficult to standardize. Symptom questionnaires can be used to help establish a diagnosis of dry eye disease, validate medical necessity for further intervention, and to assess the effects of treatments or to grade disease severity. Among the most commonly used and validated include the following [34] :
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OSDI (Ocular Surface Disease Index) is the most established instrument in studies.
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Dry Eye Questionnaire (DEQ-5) is attractive due to its short length and discriminative ability.
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SANDE (Symptom Assessment in Dry Eye) should be considered for repeated comfort assessment.
There also are questionnaires developed specifically for contact lens wearers such as:
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Contact Lens Dry Eyes Questionaire (CLDEQ)
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8-item Contact Lens Dry Eye Questionnaire (CLDEQ-8)
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Contact Lens Impact on Quality of Life (CLIQ)
Tear Breakup Time
Tear breakup time (TBUT) is the most frequently used measurement to assess for tear film stability. It is determined by measuring the interval between instillation of topical fluorescein 0.5% and appearance of the first dry spots on the cornea. Measure it prior to instillation of any anesthetic eye drops. A fluorescein strip is moistened with saline and applied to the inferior cul-de-sac. After several blinks, the tear film is examined using a broad-beam of slit lamp with a blue filter for the appearance of the first dry spots on the cornea. Three consecutive measurements are taken, and the median value is recorded as TBUT. A TBUT of less than 10 seconds is considered abnormal, indicative of tear instability. If a patient blinks before the tear film breaks up, even with training, then the time is recorded as TBUT. The lower median TBUT between two eyes should be used in making clinical diagnosis. Besides subjective observation techniques, several devices can measure the TBUT objectively, including the Oculus Keratograph 5M. [34]
Other tests to assess tear film stability
Other tests to assess tear film stability include the following:
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Thermography measures the cooling of the ocuar surface as the result of evaporation. Studies have found that the area of cooling colocalizes with the area with tear break up, and in fact precedes the thinning and breakup of the tears. [35]
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Tear evaporation rate is an indicator for tear film stability and can be measured using a variety of techniques such as measuring the vapor pressure gradient, and the velocity of relative humidity increases within a goggle placed over the eye. However, the measurement is affected by environmental factors such as ambient temperature, humidity, and skin evaporation around the eye.
Epithelial Staining
Rose bengal, lissamine green, and fluorescein staining are used to evaluate epitheliopathy associated with ocular surface damage. Rose bengal stains any cells (devitalized or alive) that are not adequately protected by mucin. On the other hand, lissamine green stains only devitalized cells with damaged cell membranes. Both lissanine green and rose bengal are useful in asssessing conjunctival abnormalities. Fluorescein pools in epithelial erosions and stains exposed basement membrane due to a disruption in intercellular junctions or epithelial cell loss; generally, it stains the cornea more than the conjunctiva.
Among the 3 stains, flourescein and lissamine green are well tolerated. Rose bengal stings on instillation and also induces reflex tearing, and is thus less well tolerated. Furthermore, in vitro studies have shown that rose bengal stains suppress healthy corneal epithlial cell viabilitiy. As a result, lissanine green has largely replaced the use of rose bengal in the workup for ocular surface disease. [34] Lastly, mixture of these dyes (eg, 2% flourescein with 1% lissamine green) has been proposed to allow simultaneous staining of both the cornea and conjunctiva, but is not commercially available. [36]
Early or mild cases of dry eye disease are detected more easily with rose bengal or lissamine than with fluorescein staining, and the conjunctiva usually is stained more intensely than the cornea. Interpalpebral staining of the nasal or inferior paracentral cornea is seen in dry eye disease. A linear pattern of inferior conjunctiva and corneal staining by rose bengal or lissamine is characteristic of meibomian gland dysfunction (MGD).
Van Bijsterveld developed a scoring system for rose bengal/lissamine green staining that evaluates the intensity of staining on a scale of 0 to 3 in three areas: (1) nasal conjunctiva, (2) temporal conjunctiva, and (3) cornea. With this system, the maximum possible score is 9, and a score of 3.5 or higher is considered positive for dry eye disease.
Schirmer Test
The Schirmer test is used to test aqueous tear production. Traditionally, the Basic secretion test is performed by instilling a topical anesthetic and then placing a thin strip of filter paper in the inferior cul-de-sac. The corners of a soft tissue paper may be used to wick all liquid from the inferior fornix by capillary attraction without any wiping or direct irritation before the paper is placed. The patients’ eyes are then closed for 5 minutes, and the amount of wetting of the paper strip is measured. Less than 5 mm of wetting is abnormal; 5 to 10 mm is equivocal.
The Schirmer I test, which measures both basic and reflex tearing, consists of the same test without the use of a topical anesthetic agent. Less than 10 mm of wetting after 5 minutes is diagnostic of ATD. The test is relatively specific, but it is poorly sensitive.
The Schirmer II test, which measures reflex tearing, may be done if the initial Schirmer test yields abnormal results. It is essentially similar to the basic secretion test, but with the addition of nasal mucosal irritation induced with a cotton tip applicator. Wetting of less than 15 mm after 5 minutes is consistent with abnormalities of reflex secretion.
Absence of nasal lacrimal reflex tearing, presence of serum autoantibodies, and severe ocular surface disease demonstrated by rose bengal or fluorescein staining argues strongly in favor of a diagnosis of SS-associated dry eye disease.
Other tests to assess tear production
Other tests to assess tear production include the following:
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Meniscometry (measurement of tear meniscus radius, height, and cross-sectional area) is used to help diagnose ATD. A rotatable projection system with a target comprising black and white stripes is projected onto the lower central tear film meniscus. Images are recorded and then transferred to a computer for calculation of the radius of curvature. Several commercially available imaging devices can provide serial quantitative measurements.
Tests to Quantify Tear Composition
Tear film osmolarity has a central role in the homeostais of the tear film. Tear film hyperosmolarity is a critical component in the pathology of DED. (See Pathophysiology). Tear osmolarity is the single best marker of DED disease severity from normal to severe DED. Osmolarity increases with disease severity and various cutoff values have been studied. In general, a positive result for DED is defined to be greater than or equal to 308 mOsm/L in either eye or an interocular difference of >8 mOsm/L. [34]
Measurement of tear-film osmolarity may be performed to assess patients suspected of having dry eye disease, an application probably first considered and promoted by Gilbard et al. [37] Tear-film osmolarity has been shown to be elevated in patients with dry eyes. It is a very sensitive test for identifying a dry eye but lacks some specificity in meibomitis, herpes simplex keratitis, and bacterial conjunctivitis. Many clinicians consider tear film osmolarity to be the objective clinical foundation for dry eye disease evaluation, staging, and ongoing monitoring of therapeutic response.
In a multicenter study of 314 consecutive participants aged 18 to 82 years that compared bilateral tear osmolarity assessment, TBUT measurement, corneal staining, conjunctival staining, Schirmer testing, and meibomian gland grading, Lemp et al concluded that assessment of tear osmolarity had superior diagnostic performance and was the best single metric for diagnosing and classifying dry eye disease. [38] This test was more sensitive and specific than the others, and increasing dry eye disease severity was correlated with higher intereye differences in osmolarity.
The tear ferning test (TFT) can also be used to help diagnose the quality of tears (electrolyte concentration), dry eye disease, and hyperosmolarity. A drop of tear fluid is collected from the lower meniscus and placed onto a microscope slide and allowed to dry by evaporation. Different forms of branching crystallization patterns can be observed and classified. This test permits the separation of healthy eyes from dry eyes based on ferning patterns.
Additional tests may be performed to quantify each individual tear component.
Lipid component
Lipids may be tested for by collecting meibum, either by squeezing the eyelid margin to encourage expression from the meibomian glands or by using sterile curettes to suck meibum from individual gland orifices. Analysis may be accomplished by means of either high pressure liquid chromatography (HPLC) or gas chromatography with mass spectroscopy (GC-MS).
Meibomian gland morphology and density and dropout may be analyzed with meibography and/or meiboscopy to help diagnose meibomian gland dysfunction. Meiboscopy is the visualization of the meibomian gland via transillumination of the eyelid; meibography implies photographic image documentation. Meibomian gland morphology can be photographically documented by several commercially available devices, including the Oculus Keratograph 5M and the Tear Science LipiView. Dynamic Meibomian Imaging (DMI) from the LipiView device provides a distinct picture of the entire everted inferior tarsal plate, allowing both the clinician and the patient to assess the extent of meibomian gland dysfunction and its characteristic meibomian gland dropout. [39]
Meibomian gland expression of inspissated glands is another useful diagnostic and therapeutic in-office procedure.
Meibomian gland dysfunction may also be diagnosed using meibometry. Lipid on the lower central lid margin is blotted onto a plastic tape, and the amount taken up is read by optical densitometry. This provides an indirect measure of the steady state level of the meibomian lipid.
Aqueous component
The aqueous/protein component may be tested for by measuring tear lysozyme, tear lactoferrin, epidermal growth factor (EGF), aquaporin 5, lipocalin, and immunoglobulin A (IgA) concentrations with enzyme-linked immunosorbent assay (ELISA) techniques, as well as tear-film osmolarity.
Lysozyme accounts for approximately 20-40% of total tear protein. The main disadvantage of tear lysosome testing is its lack of specificity in cases of meibomitis, herpes simplex keratitis, and bacterial conjunctivitis. Lactoferrin has antibacterial and antioxidant functions. Lactoferrin analysis is commercially available through colorimetric solid-phase and ELISA techniques. This study offers good correlation with other tests.
Mucin component
Mucins may be analyzed by using impression cytology or brush cytology techniques, which obtain epithelial and goblet cells that can then be tested for mucin messenger RNA (mRNA) expression. Immunofluorescence, flow cytometry, ELISA, or immunoblotting techniques may also be used.
When the mucin layer of the tear is decreased, as with xerophthalmia or ocular cicatricial pemphigoid, squamous metaplasia and the following cytologic characteristics occur:
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Loss of goblet cells
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Enlargement of superficial epithelial cells and an increase in their cytoplasm-to-nucleus ratio
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Keratinization
Impression cytology is highly sensitive, but it does require proper staining and expert microscopic evaluation of samples. New in-office devices that measure lipid layer thickness have emerged, although the application of these products is under further investigation.
Matrix metalloproteinase 9
The constitutive production of MMP-9 for epithelial maintenance may be up-regulated in dry eye disease, contact lens use, or anterior basement membrane dystrophy (ABMD). MMP-9 on the ocular surface can now be measured at the point of service in any clinical setting with a noninvasive 22-minute technician-driven test. No special equipment is required.
InflammaDry (Quidel) is a rapid in-office test for diagnosing dry eye disease. The test, which takes less than 2 minutes to procure and 20 minutes to incubate, uses ocular surface samples to detect the inflammatory marker matrix metalloproteinase-9. MMP-9 has been shown to be consistently elevated in the tears of patients with dry eye disease. [40]
Other Tests
The tear stability analysis system (TSAS) is a noninvasive and objective test that is used to help diagnose tear-film instability.
The tear function index (TFI; Liverpool modification) is used to evaluate the tear dynamics of production and drainage, and helps to detect dry eye. The test involves the use of prepared filter paper strips that contain fluorescein, and it has been designed to allow direct measurement of the TFI through the use of these strips.
Central corneal thickness is reduced in patients with dry eye disease, possibly as a consequence of the hypertonicity of the tear film in these patients. Corneal thickness has been shown to increase after treatment with artificial tears, and this may be a useful diagnostic and follow-up criterion for dry eye disease.
Visual acuity and corneal topography and keratometry readings have been shown to improve after the use of artificial tears.
The tear turnover rate, defined as the percentage by which the fluorescein concentration in tears decreases per minute after instillation, is also reduced in patients with symptomatic dry eye disease. It is determined by means of fluorophotometry.
Histologic Findings
Lacrimal gland or minor (salivary) gland biopsy may be performed to aid in diagnosing SS. Conjunctival biopsy also may be performed.
Pathologic examination of the lacrimal gland in patients with dry eye disease reveals age-related changes, including lobular and diffuse fibrosis and atrophy, as well as periductal fibrosis. An underlying autoimmune mechanism represented by round-cell infiltration may be present. No circulating autoantibodies are found in patients who do not have SS with dry eye disease.
Histopathologically, dry eye disease is characterized by squamous metaplasia with loss of goblet cells, cellular enlargement, and an increase in the cytoplasm-to-nucleus ratio of the superficial conjunctival epithelial cells. The lacrimal gland and the conjunctiva are also heavily infiltrated by CD4+ T cells and B cells. In meibomian gland dysfunction, loss of glandular architecture, dilation of the ductules, ductal occlusion, and hyperkeratinization of the ductal epithelium are seen.
Staging
Severity
For classification of dry eye disease based on severity, the Delphi Panel Report was adopted and modified as a third component of the DEWS (see the Table below). [41]
Table. Dry Eye Severity Levels (Open Table in a new window)
Variable |
Dry Eye Severity Level |
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1 |
2 |
3 |
4 (must have signs and symptoms) |
|
Discomfort (severity and frequency) |
Mild, episodic; occurs under environmental stress |
Moderate, episodic or chronic; occurs with or without stress |
Severe, frequent, or constant; occurs without stress |
Severe or disabling, constant |
Visual symptoms |
None or episodic mild fatigue |
Annoying or activity-limiting, episodic |
Annoying, chronic, or constant; activity-limiting |
Constant and possibly disabling |
Conjunctival injection |
None to mild |
None to mild |
+/– |
+/++ |
Conjunctival staining |
None to mild |
Variable |
Moderate to marked |
Marked |
Corneal staining (severity and location) |
None to mild |
Variable |
Marked central |
Severe punctate erosions |
Corneal and tear signs |
None to mild |
Mild debris, decreased meniscus |
Filamentary keratitis, mucus clumping, increased tear debris |
Filamentary keratitis, mucus clumping, increased tear debris, ulceration |
Lid and meibomian glands |
MGD variably present |
MGD variably present |
MGD frequent |
Trichiasis, keratinization, symblepharon |
Tear breakup time |
Variable |
≤ 10 s |
≤ 5 s |
Immediate |
Schirmer score |
Variable |
≤ 10 mm/5 min |
≤ 5 mm/5 min |
≤ 2 mm/5 min |
MGD=meibomian gland dysfunction. |
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Eye tear system anatomy: a. tear gland / lacrimal gland, b. superior lacrimal punctum, c. superior lacrimal canal, d. tear sac / lacrimal sac, e. inferior lacrimal punctum, f. inferior lacrimal canal, g. nasolacrimal canal.
Tables
Variable |
Dry Eye Severity Level |
|||
1 |
2 |
3 |
4 (must have signs and symptoms) |
|
Discomfort (severity and frequency) |
Mild, episodic; occurs under environmental stress |
Moderate, episodic or chronic; occurs with or without stress |
Severe, frequent, or constant; occurs without stress |
Severe or disabling, constant |
Visual symptoms |
None or episodic mild fatigue |
Annoying or activity-limiting, episodic |
Annoying, chronic, or constant; activity-limiting |
Constant and possibly disabling |
Conjunctival injection |
None to mild |
None to mild |
+/– |
+/++ |
Conjunctival staining |
None to mild |
Variable |
Moderate to marked |
Marked |
Corneal staining (severity and location) |
None to mild |
Variable |
Marked central |
Severe punctate erosions |
Corneal and tear signs |
None to mild |
Mild debris, decreased meniscus |
Filamentary keratitis, mucus clumping, increased tear debris |
Filamentary keratitis, mucus clumping, increased tear debris, ulceration |
Lid and meibomian glands |
MGD variably present |
MGD variably present |
MGD frequent |
Trichiasis, keratinization, symblepharon |
Tear breakup time |
Variable |
≤ 10 s |
≤ 5 s |
Immediate |
Schirmer score |
Variable |
≤ 10 mm/5 min |
≤ 5 mm/5 min |
≤ 2 mm/5 min |
MGD=meibomian gland dysfunction. |
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