Dry Eye Disease (Keratoconjunctivitis Sicca) Workup

Updated: Dec 12, 2019
  • Author: C Stephen Foster, MD, FACS, FACR, FAAO, FARVO; Chief Editor: Andrew A Dahl, MD, FACS  more...
  • Print

Approach Considerations

Dry eye disease (DED), or keratoconjunctivitis sicca (KCS), is essentially 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. Symptom questionnaires can be used to help establish a diagnosis of dry eye disease and to assess the effects of treatments or to grade disease severity. At least 14 questionnaires are available in PubMed. Among the most commonly used and validated include the following:

  • OSDI (Ocular Surface Disease Index)
  • SPEED (System for Patient Evaluation of Eye Dryness)
  • VAS (Visual Analog Scale)
  • McMonnies Questionnaire
  • SANDE (Symptom Assessment in Dry Eye)

Studies that may be used in the workup include 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. [29] Serology for circulating autoantibodies (see below) may be indicated.

Sjögren syndrome

Sjögren syndrome (SS) is characterized by the combination of aqueous tear deficiency (ATD) and dry mouth (xerostomia). Patients with this syndrome may be classified into 3 subsets, as follows:

  • Patients who have systemic immune dysfunction but no defined connective tissue disease (CTD) – These patients have primary SS
  • Patients who lack evidence of systemic immune dysfunction and have no defined CTD
  • Patients who have a defined CTD, most commonly rheumatoid arthritis (RA) – These patients have secondary SS; dry eye disease is common in patients with RA, including those without SS [30] ; thus, dry eye disease should always be taken into consideration regardless of RA activity, because the severity of dry eye disease is independent of RA activity

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:

  • Abnormally low Schirmer test result
  • Objective evidence of low salivary flow
  • Biopsy-proven lymphocytic infiltration of the labial salivary glands
  • 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 additional 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. [31]


Tear Breakup Time

Tear breakup time (TBUT) 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 time is averaged to obtain the TBUT. A TBUT of less than 10 seconds is considered abnormal, indicative of tear instability. Several devices can measure the TBUT objectively, including the Oculus Keratograph 5M.


Epithelial Staining

Rose bengal, lissamine green, and fluorescein staining are used to evaluate epitheliopathy. Rose bengal and lissamine green stain not only dead and devitalized cells but also healthy cells that are protected inadequately by a mucin coating. Fluorescein pools in epithelial erosions and stains exposed basement membrane; generally, it stains the cornea more than the conjunctiva.

Early or mild cases of dry eye disease are detected more easily with rose bengal or lissamine than with fluorescein staining, and the conjunctiva is usually 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 0-3 in 3 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. Rose bengal also possesses antiviral activity. [32]

Lissamine green staining combines the advantages of fluorescein and rose bengal staining. Like rose bengal, it stains healthy epithelial cells that are not protected by a mucin layer, and like fluorescein, it stains degenerating or dead cells. Lissamine green avoids the pain, discomfort, and corneal toxicity that are associated with rose bengal, but is somewhat less sensitive and more transient and thus may be more difficult to appreciate on slit-lamp examination.


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 in the paper strip is measured. Less than 5 mm of wetting is abnormal; 5-10 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.

Frankly, the authors prefer a modification of the Schirmer I test, aiming to measure basal tear secretion by minimizing reflex tearing through the application of topical anesthetic (proparacaine), followed by removal of that drug and resident tears through the capillary attraction of all liquid from the inferior fornix via 2 corners, in sequence, of a tissue paper very gently placed over the inferior tarsal conjunctiva. The patient's eyes are then closed for 5 minutes and the amount of wetting measured.


Tests to Quantify Tear Components

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. [33]

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.

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. [34] 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 subjects aged 18-82 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. [35] This test was more sensitive and specific than the others, and increasing dry eye disease severity was correlated with higher intereye differences in osmolarity.

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:

  • Loss of goblet cells
  • Enlargement of superficial epithelial cells and an increase in their cytoplasm-to-nucleus ratio
  • 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. [36]


Other Tests

The tear stability analysis system (TSAS) is a noninvasive and objective test that is used to help diagnose tear-film instability.

Tear evaporation is tested by means of evaporimetry.

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.

The tear ferning test (TFT) can 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.

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.

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 may also 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.