Dry Eye Epidemiology in Practice
Understand who gets dry eye, and why, to help you better diagnose and manage these patients. 
By Michelle Hessen, OD 

Release Date: January 15, 2020
Expiration Date: January 15, 2023
Estimated Time to Complete Activity: 2 hours

Jointly provided by Postgraduate Institute for Medicine (PIM) and Review Education Group

Educational Objectives: After completing this activity, the participant should be better able to:

  • Discuss the epidemiology of dry eye.
  • Describe the clinically relevant definition of dry eye.  
  • Identify dry eye patients in their practice.  
  • Recognize the long-term prognosis of dry eye as a diagnosis.   

Target Audience: This activity is intended for optometrists engaged in the care of patients with secondary glaucomas.

Accreditation Statement: In support of improving patient care, this activity has been planned and implemented by the Postgraduate Institute for Medicine and Review Education Group. Postgraduate Institute for Medicine is jointly accredited by the Accreditation Council for Continuing Medical Education, the Accreditation Council for Pharmacy Education, and the American Nurses Credentialing Center, to provide continuing education for the healthcare team. Postgraduate Institute for Medicine is accredited by COPE to provide continuing education to optometrists.

Faculty/Editorial Board: Michelle Hessen, OD.

Credit Statement: This course is COPE approved for 2 hours of CE credit. Course ID is 66103-AS. Check with your local state licensing board to see if this counts toward your CE requirement for relicensure.

Disclosure Statements: 
Dr. Hessen has nothing to disclose. 

Managers and Editorial Staff: The PIM planners and managers have nothing to disclose. The Review Education Group planners, managers and editorial staff have nothing to disclose.

Keratoconjunctivitis sicca, referred to as dry eye disease (DED), is a growing public health concern affecting as many as 17% of women and 11.1% of men in the United States.1 This is likely an underestimation, considering the number of self-treating patients and mild/periodic cases with intermittent symptoms. 

The Tear Film and Ocular Surface Society’s Dry Eye Workshop II (DEWS II) defined DED as a “multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiologic roles.”2 This definition adds “a loss of homeostasis” as a disease characterization, which is the “unifying characteristic describing the fundamental process in the development of dry eye disease.”2 An additional change in definition is the generalization of ocular symptoms. DEWS I includes discomfort and visual disturbance, while the new definition describes DED as “accompanied by ocular symptoms.”2 This change encompasses all symptoms that are now used to describe dry eye. Both DEWS I and DEWS II definitions state that DED is a multifactorial disease. 

DEWS II also recognized three subgroups based on etiopathogenesis: aqueous deficient, evaporative and mixed, as the lines between aqueous deficient and evaporative have become less distinct.

Fig. 1. Fluorescein tear break-up time assessment.
Fig. 1. Fluorescein tear break-up time assessment. Click image to enlarge.

Dry Eye By the Numbers
DED prevalence varies considerably due to different definitions and study parameters, something DEWS II aims to improve. A population-based study of DED in Melbourne, Australia, reported that of the 926 participants aged 40 to 97 years, 16.3% had a low Schirmer test (≤8mm) and 10.8% had a high rose bengal score (≥4mm).3 The prevalence of self-reported dry eye in 3,722 participants of the Beaver Dam (Wisconsin) Eye Study varied from 8.4% of subjects younger than 60 to 19.0% of those older than 80, with an overall prevalence of 14.4%.1 

Influencing factors remain constant despite diagnostic criteria used, and include sex, age and geographic location.4 Prevalence increases linearly with age, and females are more affected according to the report.4 Prevalence appears higher in Asian than in Caucasian populations, though studies have not been conducted in all major geographic regions. Peri- and postmenopausal females seem to be particularly at a higher risk. In addition, hormonal studies demonstrate that sex hormones influence ocular surface conditions through their effects on aqueous tear secretion, meibomian gland function and conjunctival goblet cell density.5,6 

Thus, an altered hormonal state (e.g., following menopause) may be an underlying cause of dry eye. Diabetes and other systemic conditions, such as connective tissue diseases, Sjögren’s syndrome (SS) and thyroid disease have also been associated with DED prevalence. 

Several other external factors are also known to precipitate and exacerbate dry eye, including long-term contact lens wear, refractive laser surgery, smoking and extended visual tasks such as computer use, television watching and prolonged reading.7-9 Worsening of dry eye may also be attributed to low relative humidity conditions that are common in office environments, air-conditioned cars, airplane cabins and extreme hot or cold weather.10 

Dry eye may be caused by systemic medications such as antihistamines, antidepressants, anticholinergics, isotretinoin, anxiolytics, diuretics and beta-blockers.4,11 Frequent instillation (more than four to six times daily) of preserved eye drops, particularly with benzalkonium chloride (e.g., for glaucoma), may also contribute to DED because of their well-established ocular surface toxicity.2 Another important etiology is neuropathic pain due to a lesion or disease in the somatosensory system, in which ocular pain symptoms of dry eye disproportionally outweigh clinical signs, possibly with no ocular surface staining. 

Irrespective of the presence of any identifiable underlying local or systemic inflammatory disorder, DED seems to be invariably associated with chronic inflammation of the ocular surface, although it is not known whether the local inflammation is causative or simply occurs as a consequence of ocular dryness. One of the major challenges in the area of dry eye, a multifactorial condition, is proper assessment.

Diagnostic Testing
There is a notoriously poor correlation between dry eye symptoms and signs. The DEWS II Diagnostic Methodology report asserts that the first step in a dry eye workup should include gathering a comprehensive patient history via one of the available patient questionnaires.12 Those listed below all help clinicians quantify a patient’s experience of their condition in a systematic fashion and provide early signals to pursue: 

  • Ocular Surface Disease Index
  • Dry Eye Questionnaire
  • Impact of Dry Eye on Everyday Living
  • Visual Function Questionnaire
  • Dry Eye-related Quality-of-life Score
  • Computer Vision Symptom Scale 

Because routine diagnostic testing of the ocular surface is often variable, the diagnosis of DED should be based on a combination of symptoms and objective, repeatable diagnostic clinical tests—any one of them alone may miss a number of patients with the disease.

Eyelid and tear film evaluation. Slit lamp examination begins with the evaluation of the eyelid positioning relative to the globe as well as evaluation of the meibomian glands. Meibomian gland dysfunction (MGD) is often diagnosed through clinical exam of the lid margin to assess the degree of inspissation and telangiectasia, as well as the assessment of meibomian gland expressibility and meibum quality. Commercially available meibography imaging systems can help to assess meibomian gland atrophy.

It is also important to evaluate the blink cycle: are the spontaneous blinks complete and at an appropriate rate? The tear film lipid layer is formed in the upstroke of each blink, when lipid from the lower meibomian reservoir spreads upward over the aqueous subphase of the preocular tear film.13 Blink rates vary considerably in normal adults, which likely reflects individual variation and influence of environmental conditions. Blink rates can be influenced by mental state, attention, activity, exposure of the ocular surface and environmental conditions. In controlled environments (about 22°℃C with humidity of 40%), the blink rate in normal adults ranges between 15 and 20 blinks per minute.14-16 Blink rate increases in dry eye, where it is thought to be compensatory. Blink rate falls during a number of common tasks requiring visual concentration, such as visual display use, reading and driving, and the increased evaporative loss may act as a trigger for DED.14 

Fig. 2. Corneal punctate epithelial erosions viewed with sodium fluorescein and cobalt blue filter.
Fig. 2. Corneal punctate epithelial erosions viewed with sodium fluorescein and cobalt blue filter. Click image to enlarge.

The tear meniscus is a strip of fluid lying at the junction of the lid margin and the globe formed by surface tension forces as the lid margin separates from one another in the upstroke of a blink.17 The volume of the menisci is directly related to the total volume of the tear fluid and indirectly to the lacrimal secretory rate.18,19 For this reason the height and radius of curvature of the tear menisci are reduced in aqueous-deficient DED and their measurement in the lower meniscus is used in dry eye diagnosis.20-24 

Anterior segment optical coherence tomography as well as some other ocular surface imaging systems that deliver interferometry, provide a noninvasive measure of the tear volume by quantifying the meniscus height. In clinical practice, a tear meniscus below 0.2mm is regarded as pathological. A foamy tear meniscus is an indicator of altered lipid layer in patients with MGD.

Tear film stability. Assessed as fluorescein tear break-up time (TBUT), this is determined by instilling fluorescein dye from a strip moistened with sterile non-preserved saline in the inferior cul-de-sac then evaluating stability of the precorneal tear film. TBUT is a test to determine the homeostasis of the tear film. It is subjective and may be influenced by fluorescein volume at the slit lamp with a cobalt blue filter (Figure 1). Values below 10 seconds are definitively pathological. TBUT may be best measured noninvasively, as fluorescein can reduce the stability of the tear film, compromising the accuracy of the measurements. 

Noninvasive topography-based imaging systems, such as the keratograph (Oculus), CA-800 (Topcon) and the HD analyzer (Visiometrics) also provide an automated measurement of TBUT using the distortion of the mires reflected from the precorneal tear layer.25 Recurrent tear break-up in the same area may be an indication of localized anterior basement membrane abnormalities.

Ocular surface staining. Vital dye staining has been the mainstay of clinical diagnosis and a significant component of DED severity grading. The two most commonly used dyes in clinical practice are sodium fluorescein for highlighting corneal defects and lissamine green for conjunctival staining (Figures 2 and 3). It is recommended to wait one to three minutes to assess fluorescein staining after instillation of the dye.26 

Corneal punctate staining is actually a small area of pooled dye in a space where a cell is missing; hence, the term punctate epithelial erosion.27 However, several studies show that even under normal conditions, some corneal epithelial cells actually take up the dye and are stained.28,29 Researchers suggest that corneal epithelial cells that are in the process of sloughing (those with damaged cell membranes or an altered glycocalx) can take up fluorescein dye.27 Both cellular uptake and intercellular dye diffusion may occur with damage or stress to the corneal epithelium. 

Diffuse corneal and conjunctival staining is commonly seen in viral keratoconjunctivitis and medicamentosa.30,31 Staining of the inferior cornea and bulbar conjunctiva is typically observed in patients with staphylococcal blepharitis, MGD, lagophthalmos and exposure, whereas staining of the superior bulbar conjunctiva is typically seen in superior limbic keratoconjunctivitis.30,31 A pattern of exposure-zone (interpalpebral) corneal and bulbar conjunctival staining is typically seen with aqueous tear deficiency.30,31 

Fig. 3. Conjunctival staining with lissamine green.
Fig. 3. Conjunctival staining with lissamine green. Click image to enlarge.

Lissamine green penetrates membrane-damaged conjunctival cells to stain the nucleus.27 Lissamine staining of the conjunctiva should be assessed one to four minutes after instilling the dye using a drop from a strip inside the far lower temporal lid in upgaze with the lower eyelid pulled slightly temporally to avoid damage to the conjunctival or lid wiper tissue.12,32,33 Lissamine green stains epithelial cells only if the cell membrane is damaged. Corneal and conjunctival staining are informative markers of disease severity in severe DED; however, staining of the ocular surface in mild-moderate DED shows poor correlation with disease severity.34

Tear film osmolarity. This test uses a micro-electrode to measure the number of charged particles in a tear sample (~0.2µl); the electrode is designed to reduce potential reflex tearing as it avoids direct contact with the ocular surface and collects the tear fluid by passive capillary reaction.35 The accuracy differs by only 2mOsm/L in both normal and dry eye patients.35 The instant result also minimizes the level of tear evaporation.35,36 

Tear osmolarity threshold values vary from 305mOsm/L to 316mOsm/L.36,37 One study reported that using tear osmolarity threshold of 305mOsm/L gave a 98.4% positive predictive value.37 Other studies suggest using a threshold of 316mOsm/L to 317mOsm/L provides a sensitivity that varied from 59% to 81%, specificity from 78% to 94%, a positive predictive value of 85% and a negative predictive value of 74%.35,38,39 Tear osmolarity can be influenced by, and correlated with, disease severity.35,38

Currently, the 316mOsm/L threshold is believed to better discriminate between mild and moderate/severe DED, while 308mOsm/L is now considered the accepted threshold.36 One study found 308mOsm/L was most sensitive for discriminating between normal eyes and those presenting with early stages of DED; it correctly diagnosed severe dry eye and normal tear film 90.7% and 81.3% of the time, respectively.38 

Reliability studies determined diagnostic performance and revealed a sensitivity of 81% and a specificity of 80% of the threshold value of 308mOsm/L.40 Another study reported the coefficient of reproducibility was 39mOsml/L and the coefficient of repeatability was 33mOsm/L.41 Researchers show that a variation of 35mOsml/L in consecutive tear osmolarity readings in an individual and three consecutive readings are required with the osmometer to obtain a reliable measure of tear osmolarity.42  

Tear osmolarity variability can also be diagnostic of dry eye; variability between the two eyes in normal, mild or moderate DED patients and severe dry eye patients was 6.9±5.9mOsm/L, 11.7±10.9mOsm/L and 26.5±22.7mOsm/L, respectively.38 Variability also increases with the severity of dry eye both in inter-eye measurements as well as repeat measurements in the same eye. In contrast to patients with normal tear film, tear osmolarity has good repeatability with no significant difference in osmolarity values when using up to four readings taken one to 15 minutes apart.37,43 

Matrix metalloproteinase (MMP-9) testing. This commercially available point-of-care test can also be used as an aid in the diagnosis of dry eye. MMP-9 is an effector molecule that participates in the inflammatory DED cycle by disrupting the epithelial layers by cleaving tight junctions.44 Researchers report that conjunctival expression of MMP-9 was significantly higher in subjects with SS DED and MGD than in a control group; furthermore, the expression was significantly higher in the SS DED than the MGD group.45 The qualitative nature of this test may be used to assess change in the disease state. Although the test does not differentiate dry eye from other inflammatory ocular surface diseases, it can be helpful in the management as it marks the presence of inflammation despite lack of staining.46

Schirmer testing. This measures the secretions of the lacrimal gland by using calibrated filter paper strips placed in the conjunctival sac of the temporal third of the lower eyelid with the patient’s eyes closed for a five-minute period of time. Schirmer I testing is performed without anesthesia, whereas the Jones basal secretion test is performed after instillation of a topical anesthetic. In theory, the latter measures only the basal secretion, without reflex tearing. A value of 10mm or less is considered abnormal.47,48

Treatment Approaches for Dry Eye

Managing dry eye can be frustrating at times, but with new treatment options you can help the patient overcome the signs and symptoms of their condition. Patient education is crucial for successful treatment, as proper explanation of possible causative factors helps the patient understand the condition and aids in setting realistic expectations. Therapy recommendations are related to the severity of both the signs and symptoms. 

Clinicians should discuss lifestyle and environmental modifications, regardless of disease severity. Humidifiers, smoking cessation, essential fatty acid supplementation and the use of non-preserved ocular lubricants and lid hygiene may all be beneficial. For MGD management, in-office eyelid procedures such as Lipiflow (Johnson & Johnson Vision), iLux (Alcon) or intense pulsed light may be options. Punctal occlusion can help to increase tear volume. Therapeutic contact lenses (soft bandage contact lenses and scleral lenses) are often helpful in managing DED. Dehydrated and cryopreserved amniotic membranes are also available for the treatment of severe ocular surface disease. One study showed sustained improvement for four months in DED subjects who wore Prokera Slim (Bio-tissue) for approximately five days.50 The authors also reported reduced corneal and conjunctival staining and improved visual acuity.

Anti-inflammatories
Because inflammation has a significant role in the etiopathogenesis of dry eye, promoting ocular surface disruption and symptoms of irritation, a number of anti-inflammatory and immunomodulating agents are available:

Corticosteroids. Through several mechanisms of action, these topical agents help reduce ocular inflammation. In the context of DED therapy, topical steroids are used for a short course to avoid possible unwanted side effects such as raised intraocular pressure and cataract formation.51 Randomized controlled clinical studies show that unpreserved corticosteroid eye drops, instilled for two to four weeks, improve the symptoms and clinical signs of moderate to severe DED.51,52 After two weeks of treatment, symptoms regressed moderately (43%) or completely (57%), while corneal fluorescein staining reduced significantly. Patient discomfort and clinical signs remained reduced for several weeks after therapy ceased.51,52 

Similarly, a retrospective review of 31 patients treated with preservative-free 0.01% topical dexamethasone showed a significant subjective improvement in symptoms in 84% of the subjects with chronic ocular surface irritation and/or tearing, refractory to various preserved topical steroids, including 0.2% loteprednol, 0.1% fluorometholone and 1% prednisolone.53

Cycylosporine A. This is a mainstay medication for DED. As an immunosuppressant, it inhibits the calcineurin–phosphatase pathway by complex formation with cyclophilin, reducing the transcription of T-cell–activating cytokines such as interleukin-2.54 When used to treat DED, it can improve OSDI scores, TBUT, Schirmer I scores, corneal fluorescein staining and goblet cell density.55 

Lifitegrast. This pharmaceutical agent blocks the binding of the surface proteins lymphocyte function-associated antigen-1 and intercellular adhesion molecule-1, thereby reducing inflammation in DED.56 One study shows lifitegrast ophthalmic solution 5.0% reduced corneal fluorescein and conjunctival lissamine staining and improved symptoms of ocular discomfort and eye dryness compared with placebo when administered twice daily.56

Tetracycline derivatives. Oral tetracycline derivatives uniquely possess antibacterial as well as anti-inflammatory properties. Doxycycline inhibits c-Jun N-terminal kinase and extracellular signal-related kinase mitogen-activated protein kinase signaling in epithelial cells of the ocular surface exposed to hyperosmolar stress, downregulating the expression of CXCL8 and proinflammatory cytokines IL-1βand TNF.57 Doxycycline inhibits MMP-9 activity and supports ocular surface integrity.58,59 Additionally, studies demonstrate that minocycline inhibits expression of cell-associated proinflammatory molecules, including major histocompatibility complex class II.60 Doxycycline can be effective in patients with ocular rosacea by reducing irritation symptoms, improving tear film stability, and decreasing the severity of ocular surface disease.61-63 In addition, doxycycline is useful in the treatment of corneal erosions.64,65

Azithromycin
This is a broad-spectrum macrolide antibiotic, used both topically and orally, with anti-inflammatory properties. Azithromycin can block the activation of NF-kB, leading to decreased inflammatory cytokine levels such as interleukin-6 and interleukin-8.66 It also suppresses the production of proinflammatory mediators by inhibiting cultured human corneal epithelial cells.67 Topical azithromycin is FDA approved for the treatment of bacterial conjunctivitis; however, it may be used as off-label therapy for clinical control or relief of symptoms and signs of MGD, as well as improvement in lipid behaviors of meibomian gland secretion.68 

Two studies compare the efficacy of doxycycline and azithromycin for the management of MGD.69,70 A five-day oral azithromycin regimen was compared with one month of doxycycline 200mg in one study.69 Although both treatments significantly improved clinical scores and symptoms, azithromycin was more effective in improving clinical signs. In the second study, both topical 1% azithromycin for four weeks and twice daily 100mg oral doxycycline for two months significantly decreased the clinical signs of MGD. Oral doxycycline treatment was slightly less effective in improving foreign body sensation and the signs of plugging and secretion than topical azithromycin.70

Autologous Serum 
Serum contains several anti-inflammatory factors that have the capability to inhibit soluble mediators of the ocular surface inflammatory cascade of DED. These include inhibitors of inflammatory cytokines and MMP inhibitors.71-73 Clinical trials show autologous serum drops can improve ocular irritation symptoms and conjunctival and corneal dye staining in SS DED.74-76

Dry Eye Forecast
A five-year natural history study was performed on patients with mild-moderate DED to explore the hypothesis that dry eye is a progressive condition that has substantive and measurable impacts not only on the ocular surface, but on quality of life and visual functioning.49 Patients were using artificial tears as needed. A striking disease burden is observed with regard to blurred vision, productivity and visits to eye care practitioners in mild to moderate DED patients compared with normal subjects of similar ages and genders.49 

With the evolution of anti-inflammatory based therapies for dry eye, it is a reasonable expectation that ocular surface disruption can be controlled and patient symptoms may be substantially minimized, thus reducing the impact of this condition on their quality of life. It is important nonetheless to educate DED patients on potential increased risks of dry eye associated with refractive surgery, multifocal cataract surgery and other anterior segment surgical procedures. Comanaging with other medical professionals is essential for successful treatment in cases with underlying systemic conditions. Clinicians must help patients understand the chronicity of DED and the goals of management to lay the groundwork for realistic expectations. 

Dr. Hessen is an assistant professor at the Wilmer Eye Institute’s Ocular Surface Diseases and Dry Eye Clinic at Johns Hopkins School of Medicine, where she specializes in ocular surface disease.

 

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