Dry eyes, also known as dry eye disease, dry eye syndrome, and keratoconjunctivitis sicca (KCS) is one of the most common reasons for a visit to an eye doctor. The definition of dry eye according to the Tear Film and Ocular Surface Society Dry Eye Workshop II is: "Dry eye is 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".
The tear film is approximately 2 to 5 µm thick over the cornea and is composed of three main components. These components (lipid, aqueous, and mucin) are often described as layers, although this may be an oversimplification of the tear film milieu. The most superficial layer, the lipid layer, is produced by the meibomian glands of the eyelids and functions to reduce the evaporation of tears. The middle aqueous layer is the thickest component of the tear film and is produced by the lacrimal glands, located in the orbits, and the accessory lacrimal glands (glands of Krause and Wolfring) in the conjunctiva. The basal layer is composed of mucins, or glycoproteins, and is predominantly produced by conjunctival goblet cells. Mucins enhance the spread of the tear film over the corneal epithelium through the regulation of surface tension. 
Numerous potential etiologies may contribute to the development of dry eye disease and many cases may be multifactorial. These include local ocular factors, systemic diseases, and iatrogenic causes such as medications or surgeries. A list of some of these potential etiologies has been compiled below.
Potential causes and/or factor associated with dry eye disease include:
Dry eye disease is more common in women than men and has an increased prevalence with age. The prevalence of dry eye disease varies depending on the diagnostic criteria employed and has ranged from approximately 5 to 50% in population-based studies. In general, it is more common in Asian populations when compared to Caucasians although geographic, climatic, and environmental variations may also be significant factors. Evaporative dry eye is considered the most common subtype of dry eye disease. There may be discordance between dry eye signs and symptoms with signs being more prevalent and variable than symptoms.
Dry eye disease has traditionally been classified into two categories: aqueous deficient and evaporative. However, these categories are not mutually exclusive and many patients have a combination of these mechanisms of dry eye disease. Aqueous tear deficiency is characterized by inadequate tear production with predominant causes consisting of Sjogren Syndrome (primary or secondary), diseases of the lacrimal gland such as obstruction, or systemic drugs affecting tear production. Evaporative dry eye is characterized by increased tear film evaporation and is most frequently caused by meibomian gland dysfunction. Meibomian glands line the eyelid margins and secrete oils that become the lipid layer of the tear film and reduce the evaporation of tears. Meibomian gland dysfunction may be caused by inadequate secretion due to atrophy, dropout of the glands, or obstruction of the gland orifices. Other major causes of increased tear evaporation include poor blinking (low rate, incomplete lid closure), disorders of the lid aperture, and environmental factors (low humidity, high airflow).
A hallmark of dry eye disease is hyperosmolarity of the tear film which may damage the ocular surface directly or indirectly by inciting inflammation. Hyperosmolarity of the tear film leads to a cascade of signaling events that releases inflammatory mediators and leads to damage of the ocular surface which may further decrease tear film stability, leading to self-perpetuation of the disease in a 'vicious circle'. Apart from hyperosmolarity, other factors may initiate this pathologic cycle including ocular surface inflammation caused by conditions such as allergic eye disease, topical preservative toxicity, or xerophthalmia.
Dry eye disease may lead to any of the following symptoms:
There is no single 'gold standard' sign or symptoms for the diagnosis of dry eye disease. Evaluation of both symptoms and signs of dry eye disease is recommended as signs may be present without symptoms, and vice-versa.
A verbal history allows the non-scripted elicitation of dry eye symptoms. In addition, many questionnaires have been developed to screen for symptoms of dry eye disease. The use of a validated questionnaire allows accurate quantification of symptoms as a screening tool as well as monitoring for progression and response to treatments. Several questionnaires exist such as the Ocular Surface Disease Index (OSDI), Dry Eye Questionnaire (DEQ-5), and Symptoms Analysis in Dry Eye (SANDE), and others, which may be useful in assessing dry eye symptoms. Many questionnaires also include questions about subjective visual function or disturbances that may be attributable to dry eye.
Tear Film Break-up Time (TBUT). This is the interval of time between a complete blink and the first break in the tear film. This is most often performed in the clinic using a slit lamp microscope after instilling sodium fluorescein stain to enhance the visibility of the tear film. A cut-off of fewer than ten seconds is often considered consistent with dry eye disease. Alternatively, a non-invasive tear break up time can be measured without fluorescein using instrumentation that evaluates the reflections of patterns or rings from the tear film or the use of interferometry to evaluate for the appearance of discontinuity of the lipid layer after a blink.
Tear meniscus assessment. Assessment of the tear meniscus is performed at the slit-lamp by judging the inferior tear film meniscus height. This technique is simple to perform but is subject to poor intervisit repeatability. Instrumentation has been developed for more objective measurement of the tear film meniscus but is not currently widely available in most clinics.
Schirmer test. A Schirmer paper strip is folded at the notch with the shorter end hooked over the lateral lid margin to avoid irritation of the cornea while the patient rests with closed eyes. The Schirmer I test is performed without topical anesthetic to measure basic and reflex tearing with less than 5 to 10mm (depending on cut-off used) of wetting after 5 minutes diagnostic of aqueous deficiency. Alternatively, a topical anesthetic can be administered and then residual fluid blotted from the inferior fornix prior to performing testing to measure basic secretion with less than 5 to 10mm of wetting considered diagnostic for aqueous deficiency.
Phenol red test. Similar to Schirmer testing, a cotton thread dyed with phenol red is hooked over the temporal eyelid into the sulcus for 15 seconds while the patient rests with closed eyes. When wet, the thread turns red with cut-off values ranging from less than 10 to 20mm used clinically.
Ocular Surface Assessment
Fluorescein staining. Fluorescein staining allows the assessment of corneal damage. A minimal volume if fluorescein is instilled into the tear film with optimal viewing 1 to 3 minutes later. Greater than 5 spots of staining is considered a positive result with various grading scales such as the Oxford grading scale used as well.
Lissamine green staining. Lissamine allows the assessment of conjunctival and lid margin damage, and to a lesser extent, corneal damage. Greater than 9 spots is a positive result. Lid wiper epitheliopathy, or staining of the lid margin, can be performed with a positive result as 2 mm or more staining in length and/or greater than 25% in sagittal width.
Conjunctival redness. Conjunctival redness, or hyperemia, is not specific to dry eye disease as this may result from any stimulus that results in conjunctivitis, including infective, allergic, chemical, or mechanical etiologies. Grading is generally determined subjectively by slit-lamp examination although some devices with automated grading or digital photography can also be used.
Tear Film Assays
Tear film Osmolarity. Elevated osmolarity and increased variability of osmolarity of the tears are characteristic of dry eye disease. Osmolarity values typically increase with disease severity. Various cutoff values have been reported with 308mOsm/L used as a threshold to diagnose mild/moderate disease while 316 mOsm/L has been used as a cutoff for more severe disease.
Matrix Metalloproteinases. These proteases are found in the tears of individuals with dry eye. Matrix metalloproteinase-9 (MMP-9) levels can be tested using a point-of-care test.
Blepharitis. Evaluation of the eyelids is a crucial part of the evaluation to determine any factors contributing to dry eye disease. The evaluation includes assessment for anterior blepharitis and Demodex blepharitis which are frequent comorbidities of dry eye disease
Lid wiper epitheliopathy. The portion of conjunctiva along the lid margin that contacts the ocular surface to spread tears has been termed the 'lid wiper'. Lid wiper epitheliopathy, or staining of the lid wiper with fluorescein or lissamine green, may be seen more commonly in individuals with dry eye disease, presumably due to increased friction between the lid and ocular surface.
Meibomian gland evaluation. The evaluation of meibomian gland structure can be performed with meibography. While the outline of meibomian glands can be seen at the slit lamp or with a penlight by transilluminating the everted eyelid, enhanced visualization is obtained using infrared imaging systems to perform meibography. Inspection of the meibomian gland orifices along the eyelid margin can be performed to detect external obstructions of orifices. Meibomian gland function can be assessed by evaluating meibum quantity, quality, and expressibility. Expressibility is assessed by applying digital pressure along the eyelid margin with clear meibum easily expressed from the normal eyelid. In meibomian gland dysfunction, meibum is turbid or viscous, and not easily expressed.
Eyelid blink and closure. Incomplete blinking and nocturnal lagophthalmos can result in dry eye disease. Assessment of the blink can be performed with or without a microscope or video recording equipment. Lagophthalmos can be estimated by having the patient gently close their eyes and assessing for incomplete closure.
Evaluation for systemic disease
Many systemic diseases may cause dry eye disease, particularly primary Sjogren syndrome and secondary Sjogren syndrome caused by other conditions such as rheumatoid arthritis, lupus, progressive systemic sclerosis, and dermatomyositis. Other systemic abnormalities such as Parkinson's disease, androgen deficiency, thyroid disease, and diabetes have also been associated with dry eye disease. Evaluation for systemic disease causing secondary dry eye may be warranted if an underlying condition is suspected. A review of systems is indicated to screen for underlying systemic diseases. Sjogren syndrome may also involve the salivary glands leading to dry mouth and predisposing to periodontal disease and other mucous membranes may be affected such as vaginal, gastric, and respiratory mucosae. Laboratory testing for Sjogren syndrome (antibodies to Ro/SS-A or La/SS-B), rheumatoid factor, and antinuclear antibodies. Referral to a rheumatologist may be indicated and some cases of Sjogren syndrome may require salivary gland biopsy by an oral surgeon.
Treatment of dry eye syndrome is performed in a step-wise approach that may vary depending on the severity of the disease. Initial approaches include education about the condition, modification of the environment (eliminating direct high airflow/fans, reduced screen time, humidifier), identification and elimination of offending topical and systemic agents, topical ocular lubricants, and lid hygiene (warm compresses and lid scrubs), oral essential fatty acids.
The next step of treatment options includes preservative-free ocular lubricants, reversible punctal occlusion (punctal plugs), night-time ointment or moisture goggles, device-assisted heating and/or expression of the meibomian glands, intense pulsed light therapy, topical anti-inflammatory medications (corticosteroids, cyclosporine, lifitegrast), and oral antibiotics (macrolide or tetracycline).
Further treatment options include serum eye drops, oral or topical secretagogues, therapeutic contact lenses, amniotic membrane grafting, surgical punctal occlusion, and tarsorrhaphy.
Many conditions may evoke symptoms similar to those caused by dry eye disease. Some conditions may also be associated with or lead to dry eye disease, such as allergic conjunctivitis, cicatricial conjunctivitis, filamentary keratitis, and neurotrophic keratitis. Identification of the underlying primary condition in these cases is key to reducing the progression of the disease and worsening of dry eye.
Differential diagnosis includes:
There are minimal published data describing the natural history of treated and untreated dry eye disease. Dry eye disease is often considered to be chronic with periods of exacerbation due to intermittent contributing factors. Post-surgical dry eye (such as following cataract surgery or refractive surgery) often improves with time, possibly related to regeneration of corneal nerves or reduction of ocular inflammation.
Complications from dry eye disease range from mild to severe. Mild to moderate dry eye disease causes symptoms detailed above including ocular irritation and/or visual disturbances. More severe disease can result in corneal complications including infectious keratitis, ulceration, and scarring which may cause subsequent loss of vision. While causation has not been established, there are several non-ocular associations with dry eye disease including depression, sleep and mood disorders, dyslipidemia, and migraine headaches.
Patients should be educated regarding environmental or behavioral modifications that can be performed to reduce dry eye disease. This includes education regarding the environment. For example, factors such as fans, air conditioners, or heating vents may worsen dry eye disease and furniture or beds can be moved away from the direct path of the air. The use of digital devices is a more recently recognized cause of reduced blinking and subsequent evaporative dry eye disease. Blinking awareness training or taking intermittent breaks may reduce dry eye effects of staring at digital devices. Patients may also be educated regarding dietary factors that may influence dry eye disease including supplementation with essential fatty acids.
The role of the primary care provider, ophthalmic nurse, and pharmacist should be to educate the patient on prevention and basic treatments of dry eyes by limiting screen time, blinking often, using artificial tears, and keeping the home environment cool and moist. Eye care providers should work with patients' primary care providers or rheumatologists to investigate possible underlying systemic disease in cases where an underlying systemic disease is suspected. In cases of primary or secondary Sjogren syndrome, treatment of the underlying disorder is often needed to adequately treat the ocular manifestations.
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