Dry Eye Syndrome
Dry Eye Syndrome is a pervasive issue in society. With appropriate evaluation and treatment, people can be quite comfortable.
Dry eye syndrome is one of the most common problems affecting the general population and can cause problems that range in severity from mildly irritating to debilitating. Dry eye syndrome is a general term that describes the state of the front of the eye in response to a breakdown in the natural layer of tears that coats the front of the eye, called the tear film. Normally, this layer of tears is a stable, homogenous layer that not only provides the cornea and conjunctiva a healthy buffer from damage were it constantly exposed to the air, but this interface between the tear film and the air is also responsible for a significant amount of the focusing power of the eye. When the tear film becomes unhealthy, it breaks down in different places on the cornea and conjunctiva, leading not only to symptoms of irritation, but also to unstable and intermittently changing vision.
While there are numerous different symptoms one can experience, prominent amongst these symptoms is tearing; naturally, a patient may wonder why their eye can be “dry” despite producing plenty of tears. This is because the unhealthy tear film and the irritation that comes from it stimulates the brain to produce a wave or reflex of tears to help counteract the irritation. However, this reflex tearing is simply insufficient to correct the overall problem. For this reason, dry eye syndrome could more appropriately be termed “Tear Film Dysfunction.” Other symptoms of dry eye syndrome or tear film dysfunction include:
- Sandy or gritty feeling
- Scratchy or foreign-body sensation
- Frequent blinking
- Mattering or caking of the eyelashes (usually worse upon waking)
- Blurry or fluctuating vision (made worse when reading, computer, watching television, driving, or playing video games)
- Eye pain and/or headache
- Heavey eye lids
- Eye fatigue
Dry eye is a common ocular condition and a major reason for visits to ophthalmologists. Its prevalence varies widely among epidemiological studies depending on how the disease is defined and diagnosed, and which population is surveyed. It is estimated to be 7.4%–33.7%. 
Moreover, the definition of dry eye is still under continual revision, and the lack of a single diagnostic tool challenges ophthalmologists worldwide. The 2007 Report of International Dry Eye Workshop recommended to combine subjective symptoms with objective clinical tests to confirm dry eye diagnosis.
- Decreased hormones associated with aging
- Pregnancy and associated hormonal changes
- Thyroid eye conditions
- Eyelid inflammation (blepharitis)
- Medication/supplement use including, but not limited to: psychiatric medicines, OTC cold medicines, anti-histamines, beta-blockers, pain relievers, sleeping pills, diuretics, hormonal replacement, and oral contraceptives
- Sjogren's syndrome (dry mucus membranes throughout body)
- Other autoimmune disorders including Lupus and/or Rheumatoid Arthritis
- Chemical exposures / injuries to the eyes
- Eye surgery
- Infrequent blinking, associated with staring at computer or video screens (which is becoming a more frequent contributor), and Parkinson's
- Environmental (dusty, windy, hot/dry)
- Contact lens use
- Neurologic conditions including: stroke, Bell's palsy, Parkinson's, trigeminal nerve dysfunction
- Exposure keratitis, in which the eyelids do not close completely during sleep (i.e. lagophthalmos)
- Post refractive surgery (LASIK or PRK)- while typically transient can become a chronic issue in some
- Inflammatory eye conditions, including Herpes virus infections and uveitis / iritis
- Vitamin A deficiency (rare in US except in certain diseases such as Crohn's)
Sometimes there are obvious signs of dry eye syndrome / tear film dysfunction that you, acquaintances or even your primary care doctor may notice that may prompt you to seek treatment. However, if you have any symptoms indicative of this but there don’t seem to be obvious signs of it, that doesn’t mean you don’t suffer from it. In fact, most people with dry eye syndrome / tear film dysfunction have signs of it which are not even obvious on a general, screening eye exam. For this reason, if dry eye syndrome / tear film dysfunction is suspected by you or your primary care doctor, a thorough, targeted evaluation for dry eye syndrome by your eye MD doctor is frequently necessary to uncover the diagnosis. Depending on your particular constellation of signs, symptoms, history and comorbidities, your doctor may order tests ranging from Shirmer tear test to blood tests to check for systemic disease.
An individual with dry eye syndrome / tear film dysfunction may, in fact, have more than one cause acting simultaneously to produce the symptoms. This is actually the case for many persons who suffer from dry eye syndrome. For this reason, many persons who undergo casual evaluations and/or treatment attempts of dry eye syndrome without investigating for and treating all the possible causes can end up becoming frustrated, have persistent symptoms that can worsen, and may jump from doctor to doctor to seek relief.
Diagnostic testing for dry eye disease
History and Physical
A thorough history is essential in the workup of dry eye symptoms due to the frequent lack of correlation between symptoms and exam findings. Examination should include evaluation of the face and eyelids, blinking patterns, eyelid margins, eyelashes, conjunctiva, cornea, and tear film.
Corneal hyperesthesia and/or reduced sensation may be present in severe and chronic dry eye disease . Sensory denervation may cause dry eye by reducing the afferent signaling of tear production, reducing the blink rate, and by altering trigeminal nerve influences on ocular epithelial health. Decreased corneal sensation can also result from chronic dry eye.
Corneal sensation can be measured using a cotton tip applicator or more precisely with a Cochet-Bonnet esthesiometer.
Tear break up time (TBUT)
TBUT is an indication of tear film stability. The proper method of TBUT testing is using a fluorescein-impregnated strip wet with non-preserved saline solution (benzalkonium chloride can increase tear break up speed). The dye is distributed by blinking, and the patient is then asked to stare straight ahead without blinking. The tear film is observed under the cobalt blue light of a slit lamp, and the time between the last blink and the appearance of the first dry spot or hole in the tear film is measured and equal to the TBUT.
TBUT has been shown to be decreased in keratoconjunctivitis sicca, mucin deficiency, and meibomian gland disease. Normal subjects show variability in TBUT, although 10 seconds is the typical cutoff between normal and abnormal results and has been found to be relatively specific in screening patients for tear film instability .
Ocular surface staining
Fluorescein dye is the most commonly used stain in ophthalmology. Areas in which the corneal or conjunctival surface epithelial cells are loose or desquamated will stain with fluorescein. Fluorescein dye should be instilled as described above. The degree of staining can be graded using various scales .
Rose Bengal is more sensitive for conjunctival staining, but also more difficult to visualize and less well tolerated compared to fluorescein. Rose Bengal stains devitalized epithelial cells that lack a healthy mucin coating. It is applied using a dye-impregnated paper strip.
Interpretation of staining is based on intensity and location using a grading scale described by van Bijsterveld . The nasal and temporal conjunctiva and the cornea are graded on a scale of 0-3 with a maximum possible score of 9.
In aqueous tear deficiency, the interpalpebral conjunctiva is the most common location for Rose Bengal staining. The severity of staining has been shown to correlate with the degree of aqueous deficiency, tear film instability, and reduced mucin production by conjunctival goblet and epithelial cells .
Lissamine green has similar staining characteristics but is much better tolerated than Rose Bengal. Lissamine green is also available in dye-impregnated paper strips.
The Schirmer test is performed by placing a paper test strip in the lateral third of the lower eyelid after drying the inferior fornix and then measuring the length of the moistened portion of the strip after 5 minutes.
The Schirmer I test is performed without anesthesia and, thus, measures basic and reflex tearing. The Schirmer II test also lacks anesthesia but is done following nasal stimulation; it measures reflex tearing only and has has been shown to be reduced more in Sjögren’s syndrome compared to non-Sjögren’s dry eye.
“Schirmer with anesthesia” or the basic secretion test is also commonly performed and measures basal tear secretion.
The Schirmer test is often criticized for its variability and poor reproducibility. It is most useful in the diagnosis of patients with severe aqueous deficiency, but is relatively insensitive for patients with mild dry eye .
Delayed tear clearance
Following fluorescein placement, the persistence of fluorescein in the tear film at various time points can be determined. This may be more important to rule out nasolacrimal duct issues as a cause of tearing or epiphora.
Tear meniscus height (meniscometry)
The tear meniscus height can be used to estimate tear volume. A tear meniscus height less than 0.25 mm is suggestive of dry eye.
Stressed epithelial cells on the ocular surface can produce matrix metalloproteinases (MMP). MMP-9 has been shown to be elevated in the tears of patient with dry eye disease, and levels correlate with examination findings in patients with moderate to severe dry eye. The normal range of MMP-9 levels in human tears is 3 to 40 ng/mL. MMP-9 levels can be elevated in other inflammatory conditions, such as graft-versus-host disease, Stevens-Johnson syndrome, and following corneal surgery.
InflammaDry (Rapid Pathogen Screening Inc, Sarasota, FL) is a single use, noninvasive, disposable test that detects MMP-9 levels of 40 ng/mL or higher.
The InflammaDry test is performed prior to instillation of anesthetic eye drops by dabbing the sample collector at multiple sites along the palpebral conjunctiva. The lid can be released every 2 to 3 dabs to allow blinking. This should be repeated 6 to 8 times, after which the sampling fleece should rest against the conjunctiva for at least 5 seconds or until it is saturated with tears (indicated by a pink or glistening appearance). The sample collector is then snapped onto the test cassette and dipped into the buffer solution for activation. After 10 minutes, the test is read. One blue line and one red line indicate a positive test result, and the intensity of the red line is related to MMP-9 concentration. One blue line only indicates a negative test result.
The InflammaDry test was shown to have a sensitivity of 85% and specificity of 94% . In another study by Sambursky et al , the test was found to have a total positive and negative agreement of 81% (127/157) and 98% (78/80), respectively, with clinical assessment when OSDI was included in the definition of mild dry eye. When OSDI was excluded, the InflammaDry demonstrated a positive and negative agreement with clinical assessment of 86% (126/146) and 97% (88/91), respectively. Studies have also demonstrated that elevated MMP-9 levels correlate most with other dry eye tests in advanced disease and is likely a late sign that is rarely present in mild cases .
Patients with dry eye disease have been found to have elevated tear film osmolarity (TFO) . Tear hyperosmolarity can induce tear film instability by modifying the interaction between tear film lipids and proteins, damaging the epithelial cell membranes, triggering inflammation, and stimulating corneal nerves 
Tear osmolarity can be determined easily in the office using the point of care TearLab Osmolarity System (TearLab, San Diego, CA), which measures the osmolarity of a 50-nL tear sample. Normal values are considered to be 296±9.8 mOsm/L. Greater than 308 mOsm/L is considered to indicate at least mild dry eye and has been demonstrated to serve as an early indicator of ocular surface instability .
The test is performed by placing the tip of the handheld device at the lateral tear meniscus and then docking the sampler into the reader. The device contains a gold-plated microchip that measures electrical impedance in the sample and displays the osmolarity measurement within seconds.
TFO testing is indicated for use in conjunction with other signs and symptoms. Combination of TFO with at least one other dry eye test will enhance the sensitivity and specificity . Schargus et al, however, did not find a significant correlation between TFO and MMP-9 levels or with any other clinical dry eye test.
Tear film interferometry
Interferometry of the lipid layer of the tear film is a noninvasive method of grading tear film quality and estimating the thickness of the lipid layer, which have been shown to be abnormal in evaporative dry eye that is secondary to meibomian gland dysfunction. The LipiView interferometer (TearScience Inc, Morrisville, NC) is a commercially available tool that can measure lipid layer thickness.
Traditionally, Sjögren’s syndrome has been diagnosed using the detection of SS-A (anti-Ro) and SS-B (anti-La) autoantibodies in serum. Recently, additional autoantibodies were identified as diagnostic of Sjogrens syndrome. These include autoantibodies to salivary gland protein 1 (SP-1), carbonic anhydrase 6 (CA6), and parotid secretory protein (PSP). SP-1, CA6, and PSP were found in 45% of patients who met clinical criteria for Sjögren’s syndrome but tested negative for anti-Ro and anti-La. The novel autoantibodies may be present earlier in the disease course. In a study of patients with xerostomia and xerophthalmia for less than two years, 76% had autoantibodies to SP-1 or CA6 compared to 31% who had anti-Ro or anti-La antibodies .
Currently in clinical practice, SP-1, CA-6, and PSP autoantibody levels can be determined using a commercially available blood test called Sjö (Bausch & Lomb), which also includes SS-A, SS-B, antinuclear antibody (ANA), and rheumatoid factor (RF) levels in its panel.
The test can be administered in the office using a simple finger stick with a lancet. Once a large drop of blood appears, the five dotted circles on the test card are filled. The sample is then allowed to air dry for 30 minutes, after which it can be sealed in a plastic envelope with a dessicating package. The sample along with the patient information is then mailed in. Test results are typically available within one week.
Depending on the causes, there are numerous treatments for dry eye syndrome / tear film dysfunction, but the more common treatment modalities include:
- Artificial tears (preferably ones without a redness-reliever component in them)
- Longer acting agents such as artificial tear gel and ointments and LACRISERT® (hydroxypropyl cellulose ophthalmic insert)
- Tear conserving interventions such as punctal plugs or nighttime masks/goggles
- Warm compresses
- Eyelash and eyelid scrubs
- Prescription medicines such as Restasis (cyclosporine 0.05%)(increase tear-production) or Xiidra (lifitegrast 5%) (mechanism unknown-however is a small molecule integrin antagonist)
- Topical ophthalmic steroids are helpful in controlling the inflammatory aspect of the disease in short bursts.
- Oral flaxseed oil or fish oil supplements 2000mg/day has also been found to be useful in alleviating symptoms and decreasing the frequency of topical agents anecdotally. However, the DREAM (Dry Eye Assessment and Management Study) Research Group concluded that patients with dry eye who received 3,000 mg of fish-derived n-3 fatty acids for 12 months had no significantly better outcomes than patients who received an olive oil placebo.
- Autologous serum tears, compounded artificial tears with mixed with the patient's serum, can be particularly helpful in recalcitrant cases.
Prognosis / Follow up
Most people with dry eye syndrome who keep up with their regimen as prescribed by their eye doctor are able to have their symptoms controlled, allowing them to function either symptom-free or with minimal difficulty. Because of the nature of the causes of dry eye syndrome, most people do not get “cured” of their problem, but with regular maintenance can function as though they are cured. However, even the patient who is well-controlled on maintenance therapy can have break-through episodes and require a visit to their eye doctor, in addition to regularly scheduled visits.
Visit EyeSmart from the American Academy of Ophthalmology for a patient-friendly explanation of dry eye.
- Boyd K, Pagan-Duran B. Dry Eye. American Academy of Ophthalmology. EyeSmart® Eye health. https://www.aao.org/eye-health/diseases/dry-eye-list. Accessed March 08, 2019.
- Alshamrani AA, Almousa AS, Almulhim AA, Alafaleq AA, Alosaimi MB, Alqahtani AM, Almulhem AM, Alshamrani MA, Alhallafi AH, Alqahtani IZ, Alshehri AA. Prevalence and risk factors of dry eye symptoms in a Saudi Arabian population. Middle East Afr J Ophthalmol 2017;24:67-73 
- The epidemiology of dry eye disease: report of the Epidemiology Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf. 2007;5(2):93-107.
- Nichols KK, Nichols JJ, Mitchell GL. The lack of association between signs and symptoms in patients with dry eye disease. Cornea. 2004;23:762-770.
- De Paiva CS, Pfugfelder SC. Corneal epitheliopathy of dry eye induces hyperesthesia to mechanical air jet stimulation. Am J Ophthalmol. 2004;137(1):109-115.
- Methodologies to diagnose and monitor dry eye disease: report of the Diagnostic Methodology Subcommitte of the International Dry Eye WorkShop (2007). Ocul Surf. 2007;5:108-152.
- Van Bijsterveld OP. Diagnostic tests in the Sicca syndrome. Arch Ophthalmol. 1969;82:10-14
- Krachmer. (2013). Cornea, 3rd Edition. Elsevier.
- Sambursky R, O’Brien TP. MMP-9 and the perioperative management of LASIK surgery. Curr Opin Ophthalmol. 2011;22:294–303.
- Sambursky R, Davitt IWF, Latkany R, et al. Sensitivity and specificity of a point-of-care matrix metalloproteinase 9 immunoassay for diagnosing inflammation related to dry eye. JAMA Ophthalmol. 2013;131:24–28.
- Sambursky R, Davitt WF, Friedberg M, et al. Prospective, Multicenter, Clinical Evaluation of Point-of-Care Matrix Metalloproteinase-9 Test for Confirming Dry Eye Disease. Cornea 2014;33:812–818.
- Schargus M, Ivanova S, Kakkassery V, et al. Correlation of Tear Film Osmolarity and 2 Different MMP-9 Tests With Common Dry Eye Tests in a Cohort of Non–Dry Eye Patients. Cornea 2015;34:739–744.
- Chotikavanich S, de Paiva CS, Li de Q, et al. Production and activity of matrixmetalloproteinase-9 on the ocular surface increase in dysfunctional tear syndrome. Invest Ophthalmol Vis Sci. 2009;50:3203–3209.
- Versura P, Profazio V, Campos EC. Performance of tear osmolarity compared to previous diagnostic tests for dry eye diseases. Curr Eye Res. 2010;35:553–564.
- Lemp MA, Bron AJ, Baudouin C, et al. Tear osmolarity in the diagnosis and management of dry eye disease. Am J Ophthalmol. 2011;151:792– 798.e1.
- The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf. 2007;5:75–92.
- Baudouin C. The pathology of dry eye. Surv Ophthalmol. 2001;45(suppl 2): S211–S220.
- Schargus M, Ivanova S, Kakkassery V, et al. Correlation of Tear Film Osmolarity and 2 Different MMP-9 Tests With Common Dry Eye Tests in a Cohort of Non–Dry Eye Patients. Cornea 2015;34:739–744.
- Sullivan BD, Crews LA, Sonmez B, et al. Clinical utility of objective tests for dry eye disease: variability over time and implications for clinical trials and disease management. Cornea. 2012;31:1000–1008.
- Szalai E, Berta A, Szekanecz Z, et al. Evaluation of tear osmolarity in non-Sjogren and Sjogren syndrome dry eye patients with the TearLab system. Cornea. 2012;31:867–871.
- Baudouin C, Aragona P, Messmer EM, et al. Role of hyperosmolarity in the pathogenesis and management of dry eye disease: proceedings of the OCEAN group meeting. Ocul Surf. 2013;11:246–258.
- Shen L, Suresh L, Lindemann M, et al. Novel autoantibodies in Sjögren’s syndrome. Clin Immunol. 2012;145:251-255.
- The Dry Eye Assessment and Management Study Research Group. n−3 Fatty Acid Supplementation for the Treatment of Dry Eye Disease. N Engl J Med 2018; 378:1681-1690 DOI: 10.1056/NEJMoa1709691