The Pathophysiology, Diagnosis, and Treatment of Dry Eye Disease
Background: Dry eye disease (DED) is common; its prevalence around the world varies from 5% to 34%. Its putative pathogenetic mechanisms include hyperosmolarity of the tear film and inflammation of the ocular surface and lacrimal gland. Dry eye is clinically subdivided into two subtypes: one with decreased tear secretion (aqueous-deficient DED), and one with increased tear evaporation (hyperevaporative DED).
Methods: This review is based on pertinent publications retrieved by a selective PubMed search and on the authors’ own clinical and scientific experience.
Results: The diagnostic evaluation of dry eye disease should include a detailed patient history, thorough split-lamp examination, and additional tests as indicated. Few randomized controlled therapeutic trials for dry eye have been published to date. Artificial tears of various kinds are recommended if the symptoms are mild. Lid hygiene is helpful in the treatment of hyperevaporative dry eye, while collagen or silicon plugs can be used for partial occlusion of the efferent lacrimal ducts to treat severe hyposecretory dry eye. The benefit of long-term topical anti-inflammatory treatment of moderate or severe dry eye disease with corticosteroids or cyclosporine A eye drops has been documented in clinical trials on a high evidence level. Orally administered tetraycycline derivatives and omega-3 or omega-6 fatty acids are also used.
Conclusion: The treatment of dry eye has evolved from tear substitution alone to a rationally based therapeutic algorithm. Current research focuses on pathophysiology, new diagnostic techniques, and novel therapies including secretagogues, topical androgens, and new anti-inflammatory drugs.
Dry eye disease is defined as a “multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface. It is accompanied by increased osmolarity of the tear film and subacute inflammation of the ocular surface” (1).
The ocular surface (cornea, conjunctiva, accessory lacrimal glands), meibomian glands (specific sebaceous glands of the eyelid margin, which produce the outer lipid film of the tear film), the main lacrimal gland, and the innervation between them form a functional unit. Any or all of these structures may be affected in dry eye disease (2). Recent studies have shown that dry eye is an inflammatory disease that has many features in common with autoimmune disease (2, 3, e1). Stress to the ocular surface (environmental factors, infection, endogenous stress, antigens, genetic factors) is postulated as the pathogenetic triggering mechanism. Proinflammatory cytokines, chemokines, and matrix metalloproteinases lead to the expansion of autoreactive T helper cells which infiltrate the ocular surface and lacrimal gland (2, 3). The result is a vicious circle of damage to the ocular surface and inflammation.
Classification into “dry eye with reduced tear production (aqueous-deficient)” and “dry eye with increased evaporation of the tear film (hyperevaporative)” has proved useful on practical grounds.
Around 10% of patients with dry eye have a solely aqueous-deficient disorder. Hyperevaporative disorders, mostly caused by dysfunction of the meibomian glands, and mixed hyperevaporative/aqueous-deficient forms account for more than 80% of cases (4, e2, e3). Based on this new insight, novel diagnostic procedures and therapeutic approaches have evolved.
After reading this article, the reader should:
- Have learned that dry eye disease is not a minor complaint but a disease that has much in common with autoimmune diseases.
- Understand that the modern diagnostic procedure for dry eye disease requires, in addition to careful history taking and examination, specific tests to distinguish it from other diseases of the ocular surface such as allergies and infections.
- Be able to implement a sophisticated therapeutic regimen in which anti-inflammatory therapy plays an important role.
Around the world, between 5% and 34% of people suffer from dry eye (5, 6, e4–e7); prevalence increases significantly with age. The large differences in prevalence figures are due to variations in study populations, geographical differences and differences in method, and, until the middle of 2007, variations in the definition of the disease. No current prevalence figures exist for Germany. A study dating from 1977 showed that 11.7% of the German population—about 9 million people in all—suffered from symptoms of dry eye (7).
Dry eye impairs functional vision, especially in reading, at the computer, or when driving (9, 10, e10, e11). Reading speed is significantly reduced and correlates with disease severity (9). Tests in a driving simulator have shown significantly reduced reaction time (10). Reduced quality of life in everyday activities and leisure pursuits is reported by 60% of patients—comparable to the decrease in quality of life reported for angina pectoris—while 38% of patients complain of reduced efficiency at work (11, 12, e12).
Dry eye disease is significantly associated with anxiety disorders and depression (11, 13, e13). One large population-based cross-sectional study found manifest depression in 13.7% of patients with dry eye disease, compared with 8.6% of the control group.
Annual treatment costs per patient with dry eye in the USA are US$ 783 (taking account of the fact that patients themselves pay for a large proportion of the artificial tears required). The cost to the health care system is US$ 3.84 million a year (14).
The subjective symptoms in dry eye disease are often nonspecific. They include (1):
- Foreign body sensation
More or less pronounced conjunctival redness and damage to the ocular surface with punctate epithelial erosions (superficial punctate keratitis) are typical in dry eye; temporal conjunctival folds parallel to the lid margin are indicative. The lower tear meniscus is reduced. In addition, there are often signs of meibomian gland dysfunction with thickened eyelid margins and telangiectasia. The meibomian gland orifices are obstructed with a cloudy, granular or solid secretion that can only be expressed by exerting considerable pressure on the lower lid (15). If the meibomian gland dysfunction is associated with inflammation, blepharitis (inflammation of the lid margin) or meibomitis (inflammation of the meibomian glands) is present.
In late stages or in severe forms of the disease, conjunctival scarring or corneal complications can occur. In addition to filamentary keratitis, persistent epithelial defects, ulceration, and even corneal perforation can complicate the course. Severe complications of dry eye disease are rare and are observed in the context of primary or secondary Sjögren's syndrome, graft-versus-host disease, ichthyosis, Stevens–Johnson syndrome, and xerophthalmia (e14–e21). They can result in loss of vision or even functional blindness.
A classification of dry eye based on the severity of symptoms and clinical signs has been established (1) (Table 1).
Unfortunately subjective and objective clinical findings do not always correlate (16, 17). There are patients in considerable discomfort who have no significant clinical signs, and also those with severe dry eye and vision-threatening ocular complications who suffer from only mild symptoms.
Diagnostic tests are necessary in order to distinguish between dry eye, infections and allergies, which can present very similar clinically, but require different treatment. If an incorrect clinical diagnosis is made and antiallergic drugs or epitheliotoxic antibiotics are prescribed, dry eye may worsen. The diagnostic tests allow patients to be classified into one of two treatment-based subgroups, “aqueous-deficient” or “hyperevaporative.” Diagnostic guidelines were published in 2007 by the Dry Eye Workshop (1). The suggested sequence of dry eye tests is presented in Box 2.
A comprehensive history is essential, including (e22):
- Time, place, and diurnal variation of symptoms, workplace stress (e.g., VDU work; dry, dusty air; air conditioning)
- Systemic diseases (especially collagen vascular disease, Graves' disease, diabetes mellitus, infections such as hepatitis C and HIV)
- Medication history.
Questionnaires are available for standardized history taking in suspected dry eye disease (e.g., Ocular Surface Disease Index [OSDI] or the Impact of Dry Eye on Everyday Life [IDEEL] questionnaire) (e23, e24).
Examination of the eyelids
Blinking is important to distribute the tear fluid over the ocular surface, and supports secretion from the meibomian glands. The normal blink rate while speaking is extremely variable at 15.5 ± 13.7 blinks/minute. During reading and computer work, the blink rate is significantly reduced, to 5.3 ± 4.5 blinks/minute (e25, e26), which promotes evaporation of tear fluid. A reduced interval between blinks, from about 6 seconds to 2.6 seconds, and incomplete blinking, are typical of patients with dry eye (19).
Lid congruity and lid closure
Lid incongruity (e.g., ectropion, entropion) or insufficient lid closure (e.g., facial nerve palsy) can disturb the integrity of the tear film on the ocular surface and must be surgically corrected.
Detailed examination of the eyelid margin will yield information about its inflammation or any dysfunction of the meibomian glands with associated hyperevaporative disorder. Eyelashes, eyelid margin, and meibomian gland orifices are examined using the slit lamp. Noncontact infrared meibography allows the meibomian glands to be visualized directly (20) (Figure 1a and 1b).
Examination of the conjunctiva
Temporal lid-parallel conjunctival folds (LIPCOFs) in straight gaze are a result of increased friction between the lids and the conjunctiva. They are regarded as an important indicator of dry eye, with a sensitivity of 84.9% and a specificity of up to 90% (21). They can be simply, quickly, and noninvasively identified using the slit lamp. LIPCOFs are classified according to Höh et al. into three grades (22) (Box 3) (Figure 2).
Examination of the ocular surface
The surface of the eye is examined using the slit lamp and vital stains. The usual dyes in clinical practice are fluorescein and lissamine green. Fluorescein stains both the precorneal tear film and epithelial erosions in the conjunctiva and cornea. Lissamine green highlights superficially damaged cells with a defective mucin layer (e27) (Figure 3).
With all dyes, the intensity of staining and the dye distribution pattern are assessed semiquantitatively. Staining in the area of the palpebral fissure is suggestive of dry eye.
Several indices are available for the assessment of staining, such as the van Bijsterveld Index (Figure 4), the Oxford Grading Scale, and the CLEK scheme (1).
Examination of the tear film
Tear film meniscus
The height of the tear film meniscus observed during slit lamp examination can provide clues about the presence of hyposecretory dry eye. The tear film can be objectively measured using optical coherence tomography (e28). Tear meniscus height was 0.2 ± 0.09 mm in patients with dry eye versus 0.5 ± 0.02 mm in patients with healthy eyes (e29). In clinical practice, a tear meniscus below 0.2 mm is regarded as pathological. A foamy tear film is an indicator of an altered lipid layer in patients with meibomian gland dysfunction.
Tear film break-up time
The tear film break-up time (TFBUT) describes the stability of the tear film. It is determined after instillation of unpreserved fluorescein drops without topical anesthesia using a slit lamp with a cobalt blue filter. After a complete blink, the time to the first break-up of the tear film is measured. The normal range lies between 20 and 30 seconds. Values below 10 seconds are definitely pathological (23) (Figure 5a). Tear film break-up time can be assessed noninvasively, without fluorescein, by using videokeratography (Figure 5b).
Tear secretion tests
The Schirmer test measures the secretions of the lacrimal gland. In the Schirmer I test, calibrated filter paper strips (35 × 5 mm) are placed in the conjunctival sac of the temporal third of the lower eyelid and, with the patient's eyes closed, wetting of the strip is measured after 5 minutes (Figure 6). There are large inter- and intraindividual differences, which make the evaluation difficult. However, both the variation range and the absolute values are reduced in aqueous-deficient dry eye, probably because of the reduced reflex tear secretion (1). Values of 5 or less are certainly pathological (1).
The Jones basal secretion test is performed like the Schirmer I test, but after topical anesthesia. Test results are about 40% lower than in Schirmer I (23) and are also subject to marked inter- and intraindividual fluctuations. In theory, this test measures only the basal secretion, without reflex tears.
Other additional investigations
Tear film osmolarity/MMP-9 test
Measuring tear film osmolarity is regarded as an important further test in the diagnosis of dry eye. A portable osmometer suitable for tear film analysis in routine clinical practice is currently under evaluation in clinical trials (e30, e31). A quick test to determine matrix metalloproteinase-9 (MMP-9) in the tear film of patients with dry eye disease is also being currently evaluated in clinical trials (e32). Because of the paucity of data, however, and partially conflicting results, neither of these techniques is yet part of the standard diagnostic repertoire.
Differentiating between aqueous-deficient and hyperevaporative dry eye
Indicators of tear deficiency include a reduced tear meniscus, LIPCOFs, and a low Schirmer I test result. Patients with hyperevaporative dry eye usually show pathological changes to the lid margins, obstructed meibomian gland orifices, and thickened meibomian gland secretion. Tear film break-up time is reduced. Ocular surface damage and elevated tear film osmolarity can occur with both forms.
Diagnosing Sjögren's syndrome
Patients with xerostomia in addition to dry eye must be investigated for the possible presence of Sjögren's syndrome (SS).
The revised criteria of the European–American Consensus Group for the diagnosis of Sjögren's syndrome are summerized in Box 4 (24). If four of the six criteria are fulfilled, a diagnosis of Sjögren's syndrome can be made (24).
If SSA/SSB diagnostic testing is negative, a positive ANA (antinuclear antibody) test or positive rheumatoid factors may be indicative (25).
Treatment of dry eye disease
Patient education is important and includes the facts that dry eye is a chronic disease, that treatment is long-term and may be slow to take effect. Treatment for dry eye disease involves a step ladder approach corresponding to disease severity and must take into account associated meibomian gland dysfunction, (subclinical) inflammation of the ocular surface, and/or associated systemic disease (16).
The avoidance of aggravating factors such as cigarette smoke, dry heating air, air conditioning, and others is a fundamental part of treatment.
Artificial tears are the mainstay of therapy for all severity grades of dry eye. Although artificial tears are regarded as standard, no large, randomized, controlled studies have been carried out to evaluate the many different kinds of artificial tears available in the market. The licensing of artificial tears, most of which are marketed as CE products, is not based on their clinical effectiveness. Small randomized studies have shown that artificial tears
- Increase tear film stability
- Reduce ocular surface stress
- Improve contrast sensitivity and the optical quality of the surface
- Are able to increase quality of life (e33–e38).
A large number of preparations based on polyvinyl alcohol, povidone, hydroxypropyl guar, cellulose derivatives, and hyaluronic acid are available. Depending on the severity of disease, a whole range of substances from low-viscosity preparations to high-viscosity gels (carbomeres) and ointments can be used (16). As a matter of principle, for ocular surface disorders, products should be recommended that do not contain benzalkonium chloride (an epitheliotoxin) as a preservative (26). For meibomian gland dysfunction, artificial tears containing lipids such as triglycerides, phospholipids, and castor oil are available. In small randomized, controlled trials these led to improved meibomian gland function and increased tear film stability (27, e39–e41).
Eyedrops made from the patient’s own serum (autologous serum eyedrops) are used in a concentration of 20% to 100%. They contain a multitude of epitheliotropic growth factors and anti-inflammatory substances. Autologous serum eyedrops are used particularly in severe cases of dry eye. Their production is regulated by the German Medicines Act and Transfusion Law (28). A randomized, controlled study in patients with severe dry eye disease showed a significant improvement in tear film stability and subjective symptoms but no reduction in surface staining with autologous serum eyedrops compared to preservative-free artificial tears (29).
Even with only moderately severe dry eye, there is an (often subclinical) inflammatory reaction of the ocular surface and the lacrimal gland (2, 3). To break the vicious circle of surface damage and inflammation, anti-inflammatory treatment is required in patients with moderate to severe dry eye disease.
Randomized, controlled clinical studies have shown that unpreserved corticosteroid eyedrops, instilled over a period of 2 to 4 weeks, improve the symptoms and clinical signs of moderate to severe dry eye disease (30, 31). After 2 weeks of treatment, symptoms regressed moderately (43%) or completely (57%). Corneal fluorescein staining reduced significantly. Patient discomfort and clinical signs remained reduced for several weeks after therapy ceased (30, 31). A few patients developed complications with long-term therapy (raised intraocular pressure, cataract), and for this reason corticosteroid eyedrops are recommended only for short-term use (30). A cycle of treatment is also useful for testing patients’ response for long-term anti-inflammatory treatment with cyclosporine A.
Topical cyclosporine A
Cyclosporine A is an immunosuppressant that inhibits the calcineurin–phosphatase pathway by complex formation with cyclophilin, and thus reduces the transcription of T-cell-activating cytokines such as interleukin-2 (IL-2) (e42). Topical application of cyclosporine A leads to increased production of tear fluid, possibly via local release of parasympathetic neurotransmitters (e43). In randomized, controlled clinical trials, treatment with 0.05% eyedrops 2 ×/day led to improvement in keratopathy, increased Schirmer test values, reduced symptoms (blurry vision, ocular dryness, foreign body sensation, and epiphora), and a reduction in the use of artificial tears (32, e44, e45). This clinical improvement was associated with a reduction in inflammatory cells and inflammatory markers on the ocular surface (e46, e47) and an increase in the number of goblet cells in the conjunctiva (e45). Cyclosporine A eyedrops 0.05% are commercially available as a long-term therapeutic agent in the USA. In Germany, cyclosporine A can be prescribed as extemporaneous product from dispensing pharmacies.
Tacrolimus 0.03% eyedrops 1 to 2 ×/day have been successfully used in pilot studies and in small uncontrolled interventional case series in patients with severe dry eye disease. They appear to be as effective as cyclosporine A and are used in patients who cannot tolerate cyclosporine A (e48, e49). Tacrolimus/pimecrolimus skin ointment has been reported as successfully used on the eyelids 1 to 2 ×/day in treatment-resistant blepharokeratoconjunctivitis (e50).
Tetracyclines are bacteriostatic antibiotics with anti-inflammatory effect. They reduce the synthesis and activity of matrix metalloproteinases, the production of interleukin-1 (IL-1) and tumor necrosis factor, collagenase activity, and B-cell activation (e51, e52). Tetracycline analogs have been successfully used in small controlled studies to treat meibomian gland dysfunction and rosacea (33, e53). Dosages varied between 40 and 400 mg/day for doxycycline and between 50 and 100 mg/day for minocycline. Even at low doses, improvements were seen in tear film stability, tear production, and symptoms (33). Because of the significantly higher rate of adverse effects (primarily gastrointestinal and skin problems) at higher dosages, a low dosage for 6 to 12 weeks is recommended (16, 33).
Azithromycin, in addition to its well-known antibiotic effect, also has anti-inflammatory capacities (34). Azithromycin 1% has been successfully used in several small evidence-level-2/3 studies to treat blepharitis and meibomian gland dysfunction (35, e54). In addition to improved meibomian gland function and symptoms, a reduction in bacterial colonization of the eyelid margins and normalization of the meibomian gland secretion lipid profile were found (35, e54).
Omega fatty acids
Omega-3 and omega-6 are essential fatty acids for ocular surface homeostasis. They have to be absorbed from food. Omega-3 fatty acids, especially, work by blocking proinflammatory eicosanoids and reducing cytokines through anti-inflammatory activity (36). In a randomized, controlled clinical study systemic linoleic acid and gamma-linolenic acid given to 26 patients with dry eye disease reduced ocular surface inflammation, surface staining, and symptoms (36). Very recently, omega-3 fatty acid eyedrops have become available, and are currently under investigation.
The melting point of meibomian lipids is between 28 and 32°C. In patients with meibomian gland dysfunction, the melting point rises to 35°C (e55). The amount of lipid released depends on the temperature of the eyelid. Consistent eyelid hygiene is the basic treatment for meibomian gland dysfunction (37).
Hot compresses, eye lid warming masks or goggles, infrared heaters, and eyelid massage have been investigated in evidence-level-2/3 clinical studies. They led to clinical improvement in eyelid margin morphology with a reduction in blocked meibomian gland excretory ducts, and an increase in tear film stability and lipid layer thickness of the tear film (e56–e59). The effect of a 12-minute one-time automated thermodynamic treatment was compared with conventional eyelid hygiene 2×/day in a randomized clinical observer-masked study. After 1 and 3 months, a significant improvement in symptoms was seen compared to the conventional treatment. The improvement in expressibility of the meibomian secretion was similar for both treatments (e60).
Temporary occlusion of the tear ducts by small collagen or silicone plugs (punctal plugs) is effective in patients with severe aqueous-deficient dry eye disease (38, e61, e62). In a retrospective study, punctal plugs led to an improvement in subjective symptoms in 73.9% of patients, with a significant reduction in surface staining (38). The most frequent ‘complication' is loss of the plug (38, 39). In one prospective observation cohort study, 84.2% of plugs were retained at the end of 3 months, 69.5% after a year, and 55.8% at the end of 2 years (39). Since delayed tear drainage leads to the persistence of toxic and inflammatory factors on the ocular surface, concomitant anti-inflammatory treatment is indicated (e63). Rarely, the plug migrates into the nasolacrimal duct, resulting in inflammation or pyogenic granuloma, conjunctival epithelial erosion, or epiphora (38, 39). Because of the paucity of data, a Cochrane Review dating from 2010 recommended that large, randomized, controlled studies should be carried out to evaluate punctal plugs (40).
For severe ocular surface disorders in dry eye disease, bandage contact lenses and scleral lenses are available (e64). Surgical options such as tarsorrhaphy, amniotic membrane transplantation, and keratoplasty are used in cases of persistent corneal ulceration and perforation (16). Salivary glands have occasionally been transplanted to replace lacrimal glands, but in the long term this led to corneal edema and excessive lacrimation (e65).
To summarize, dry eye is a common disease, the differential diagnosis of which requires
- Careful history taking
- Detailed examination
- A series of diagnostic tests.
Studies show that tear deficiency alone is rarer than hyperevaporative dry eye. Artificial tears, regular eyelid hygiene, and punctal plugs together with anti-inflammatory treatment constitute the established approach to treatment. For patients with only minor symptoms, e.g., when working at a VDU, the primary care physician can try treatment with artificial tears. Patients with persistent moderate to severe clinical symptoms should be referred to an ophthalmologist for diagnosis and treatment.
Conflict of interest statement
Professor Messmer has received consultancy fees, fees for the preparation of scientific continuing education events, reimbursement of conference attendance fees and of travel and accommodation costs, and fees for carrying out clinical trials, from the following firms: Alcon Pharma, Bitop, Bausch & Lomb/Dr. Mann Pharma, Croma Pharma, Oculus Optikgeräte, Pharm-Allergan, Santen, Thea Pharma, and Ursapharm.
Manuscript received on 2 May 2014, revised version accepted on
27 August 2014.
Translated from the original German by Kersti Wagstaff, MA.
Prof. Dr. med. Elisabeth M. Messmer
Augenklinik der Ludwig-Maximilians-Universität
Mathildenstr. 8, 80336 München, Germany
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