Dry eye disease

INTRODUCTION — Dry eye disease (DED) is a multifactorial disease of the ocular surface with loss of homeostasis of the tear film and ocular symptoms. DED is also known as keratoconjunctivitis sicca, dry eye syndrome, and dysfunctional tear syndrome.

The epidemiology, pathophysiology, clinical presentation, diagnosis, and treatment options for DED will be reviewed here. Various conditions associated with DED are discussed separately. (See "Diagnosis and classification of Sjögren's disease" and "Allergic conjunctivitis: Clinical manifestations and diagnosis" and "Blepharitis" and "The red eye: Evaluation and management".)

EPIDEMIOLOGY

Prevalence — In epidemiologic studies performed globally, the prevalence of DED ranges from 5 to 50 percent, with persons living in Asia (principally China, Tibet, Korea) having a higher prevalence [1].The wide range in prevalence is due to different definitions of DED being used, as well as variation in study populations.

Based on data from the 2017 National Health and Wellness Survey, 6.8 percent of the United States adult population has been diagnosed with DED, with an increasing prevalence with older age and greater prevalence in women than men [2]. In a 2022 meta-analysis of three United States studies, the prevalence ranged from 5.3 to 14.5 percent with an estimated pooled prevalence of 8.1 percent [2].

Risk factors — Risk factors for DED include [3-7]:

●Nonmodifiable

•Older age

•Female sex

•Hormonal changes (primarily due to decreased androgens)

•Systemic diseases (eg, diabetes mellitus, Parkinson disease, Sjögren's disease)

•Ophthalmic surgery (especially corneal refractive surgery)

•Decreased corneal sensation (possible causes include herpes zoster ophthalmicus, diabetic neuropathy, local trauma, ocular surgery, other)

●Potentially modifiable

•Contact lens wear

•Smoking, or exposure to second-hand smoke

•Systemic medications (antihistamines, anticholinergics, estrogens, isotretinoin, selective serotonin receptor antagonists, amiodarone, nicotinic acid)

•Ocular medications (especially those containing preservatives)

•Nutritional deficiencies (eg, vitamin A deficiency)

•Low-humidity environments, exposure to dust, allergens, air pollution

•Excessive use of digital screens (which results in decreased blinking)

PATHOPHYSIOLOGY — DED is a multifactorial disease of the ocular surface with loss of homeostasis of the tear film resulting in ocular discomfort, visual disturbance, and potential damage to the ocular surface. Tear film instability and hyperosmolarity, ocular surface inflammation, and neurosensory abnormalities play etiologic roles [8]. Symptoms in DED result from activation of sensory nerves of the ocular surface, either due to tear hyperosmolarity, the presence of inflammatory mediators, or hypersensitivity of the sensory nerves [9,10]. (See 'Symptoms' below.)

Tear film homeostasis — The tear film of the eye consists of aqueous, mucous, and lipid components. A healthy tear film relies on a synergistic interaction of the lacrimal glands, eyelids, and ocular surface, which together comprise the lacrimal functional unit (figure 1) [11]. In a normally functioning eye, the mucous layer allows even spreading of the tear film to form a membrane, and the lipid layer provides a barrier to minimize evaporation of tears [12]. Abnormalities of the lipid layer are associated with a higher rate of tear film evaporation [13]. Dysfunction of any component in the lacrimal functional unit can lead to DED.

DED has been classified into two general mechanisms, the first being aqueous deficient DED due to decreased tear production and the other being evaporative DED due to abnormal meibomian gland function (the meibomian glands are sebaceous glands of the eyelid margin that produce the outer lipid layer of the tear film). It is now believed that both mechanisms are present in most patients, although one may be predominant [8].

Decreased tear production — Impaired lacrimal tear production can be caused by any form of lacrimal gland destruction or dysfunction. The reduced volume of aqueous fluid leads to hyperosmolarity of the tear film which incites inflammation of the ocular surface cells [14].

Deficiency of aqueous tear production can be subclassified into two main subtypes:

●Sjögren's disease – Sjögren's disease is a chronic autoimmune inflammatory disorder characterized by diminished lacrimal and salivary gland function with resultant dryness of the eyes and mouth. DED related to Sjögren's disease is reviewed separately. (See "Diagnosis and classification of Sjögren's disease" and "Clinical manifestations of Sjögren's disease: Exocrine gland disease", section on 'Dry eye'.)

●Dry eye syndrome not due to Sjögren's disease – This disease refers to patients with aqueous tear-deficient DED involving lacrimal dysfunction without associated systemic findings.

Causes include:

•Age-related DED (most common cause) due to lacrimal ductal obstruction over time and glandular atrophy, leading to decreased lacrimal gland function [15].

•Lacrimal gland obstruction due to conjunctival scarring conditions such as trachoma, pemphigoid, vitamin deficiency, post-viral syndromes, and ocular burns [16]. (See "Trachoma".)

•Lacrimal gland infiltration due to sarcoidosis, lymphoma, graft versus host disease, or episcleritis.

•Contact lens use, which is associated with reduced corneal sensitivity and subsequent reduced reflex sensory tear secretion [17]. (See "Complications of contact lenses" and "Episcleritis".)

•Diabetes mellitus [18], usually primarily ascribed to neurotrophic changes (loss of sensation and alterations to autonomic function).

•Certain systemic medications.

Increased evaporative loss — Excessive water loss from the ocular surface leads to tear film instability and a cycle of tear hyperosmolarity and lacrimal functional unit inflammation.

Causes include:

●Meibomian gland dysfunction, also known as posterior blepharitis, in which the accessory lacrimal glands responsible for the lipid component of the tear film are dysfunctional [16]. (See "Blepharitis".)

●Structural abnormalities of eyelid position or decreased blink function also increase evaporation of the tear film by increasing the area or the time of tear film exposure [16,19].

●Ocular surface irritation due to topical medicated or preserved eye drop use, chronic contact lens wear, or ocular allergy syndromes [16,19].

SYMPTOMS

Common symptoms — Most patients will present with symptoms of chronic eye irritation associated with mild to moderate discomfort [20]. However, there is considerable variability in patient-reported symptoms and clinically-measurable signs over time, as well as a recognized lack of correlation between these symptoms and signs [19,21-23].

DED, particularly when severe, can have a significant impact on visual acuity, daily activities, social and physical functioning, and workplace productivity [24-27]. For example, patients may describe impaired functional vision, especially in reading, when using screens or computers, or when driving.

Eye complaints are usually bilateral but may be asymmetric, and include:

●Dryness

●Red eyes

●General eye irritation

●Gritty sensation

●Burning sensation

●Foreign body sensation

●Paradoxical excessive tearing

●Light sensitivity

●Blurred vision

Exacerbating causes include windy conditions, cold weather, low-humidity environment, extended time spent looking at screens, and time of day.

The blurred vision associated with DED tends to be quite variable. Since the tear film is the first layer encountered by light rays as they enter the eye, an irregular tear film can degrade the quality of the image that is received by the retina. The visual impairment associated with DED is usually temporary and often improves with treatment of the condition [28,29]. Rarely, in severe DED conditions, permanent damage to visual acuity can occur from corneal scarring or ulceration.

Questionnaires — Due to the variability of findings on clinical evaluation of DED, some clinicians base their assessment of DED on the results of validated questionnaires [30]. These can also be used for monitoring DED and can be useful for standardizing the identification and classification of DED [31].

Some of the more widely available questionnaires that are used specifically for the evaluation of DED symptoms include:

●Ocular Surface Disease Index (OSDI) – Twelve-item questionnaire that is the most widely used and is validated in patients with DED [32]. The OSDI can be useful clinically, particularly in patients with more severe symptoms, to monitor the response to therapy and variability in symptoms over time.

●Dry Eye Questionnaire (DEQ-5) – Five-item questionnaire reduced from the Dry Eye Questionnaire and validated to determine DED symptom severity [33].

●Impact of Dry Eye on Everyday Life (IDEEL) – Fifty-seven questions in three modules validated in patients with DED [34].

●Salisbury Eye Evaluation Questionnaire (SEE) – Six-item questionnaire used in self-reported, population-based prevalence surveys to determine visual impairment among older adult subjects [35].

DIAGNOSIS — DED is based on characteristic patient symptoms, supporting findings on the physical examination, and testing. However, symptoms and findings can vary considerably in intensity over time and under different environmental conditions.

Initial primary care evaluation

History — The goals of the history should be to assess the severity and nature of the symptoms and to assess for other conditions that may be contributory.

We ask about the following [36]:

●Ocular symptoms, and their impact on daily activities and function. (See 'Common symptoms' above.)

●Conditions that place patients at higher risk of more severe DED: Sjögren's disease, collagen vascular disease, Graves disease, chronic systemic graft-versus-host disease, diabetes mellitus, Parkinson disease.

●Potentially modifiable risk factors: (See 'Risk factors' above.)

•Ocular and systemic medications

•A history of bariatric surgery or malnutrition (related to vitamin A deficiency)

•Contact lens use

•Smoking, or exposure to second-hand smoke

•Exposure to dust, allergens, air pollution, or low humidity environments

●Symptoms associated with Sjögren's disease: If ocular complaints are accompanied by mouth dryness and other systemic complaints (eg, joint pain, rashes), an assessment for Sjögren's disease should be performed. DED related to Sjögren's disease is reviewed separately. (See "Diagnosis and classification of Sjögren's disease" and "Clinical manifestations of Sjögren's disease: Exocrine gland disease", section on 'Dry eye'.)

Physical examination — Features of the examination include the following [36]:

●Conjunctival injection, usually symmetric in both eyes (picture 1).

●Breakdown of ocular surface, and corneal scarring. Early or subtle findings are difficult to identify without slit lamp examination (picture 2A-B).

●Excessive reflex tearing from irritation due to dryness.

●Reduced blink rate or excessive blink rate. Normal blink rate varies by environment and activity but is generally in the range of 5 to 26 blinks per minute [37].

●Visual impairment, with visual acuity assessed in each eye separately. This should include evaluation as to whether acuity improves with increased blink rate or use of lubricating eye drops.

●Evaluation for the presence of contributory conditions:

•Examination of the patient's facial and eyelid skin to evaluate for rosacea or atopic dermatitis, which are associated with ocular surface inflammation.

•Blepharitis/meibomian gland dysfunction: Posterior blepharitis can result in increased tear film evaporative loss. Patients with blepharitis often have erythematous or irritated eyelid edges (picture 3A-B). (See "Blepharitis".)

•Malposition of the eyelids (inward or outward turning, also called entropion and ectropion, respectively) (picture 4 and picture 5) can disturb the tear film.

Ophthalmologic evaluation — A presumptive diagnosis can be made by a primary care provider, and mild disease can be treated empirically. However, for more severe cases, evaluation by an ophthalmologist may be required to guide treatment in cases that have not responded to initial empiric therapy. The ophthalmologist can perform a thorough slit lamp examination along with other testing to assess the status of the patient's lacrimal functional unit to determine the severity of DED and possible etiologies. Evaluation includes:

●Extent and pattern of conjunctival injection.

●Eyelid health – Any eyelid or punctal malpositions are noted as they can lead to DED and often can be surgically repaired. Careful evaluation for meibomian gland dysfunction (posterior blepharitis) is performed.

●Ocular surface staining – Fluorescein is used to stain for areas of discontinuity in the epithelial surface of the cornea (picture 6). Lissamine green and rose bengal are used to stain areas of devitalized epithelium in the cornea and conjunctiva.

●Tear break-up time – Measured with fluorescein stain in the eye to determine tear film stability. The patient is instructed not to blink and the tear film is observed through the slit lamp. If the smooth, stained green tear film layer begins to develop blue gaps in less than 10 seconds, the patient's tear film is considered abnormal.

●Schirmer test – Assessed by quantifying the number of tears produced by each eye. Small strips of filter paper are placed in the lower eyelids of each eye, either with or without prior instillation of anesthetic eye drops. Results are measured in millimeters of tears collected over a five-minute time period. This test is often used in the clinical setting but provides extremely variable results [21].

●Corneal sensation – Objectively measured with a variety of techniques to provide information about ocular surface and possibly systemic associations of DED.

●Tear hyperosmolarity [38,39].

●Ocular surface inflammation (eg, matrix metalloproteinase-9 as a marker of ocular surface inflammation) [40,41].

●Tear film measurements – In-office imaging instruments can be used to more objectively measure the ocular surface and the tear film, including tear meniscus height, tear film stability, blink dynamics, and meibography of the eyelids.

DIFFERENTIAL DIAGNOSIS — DED can present in a similar fashion to other conditions. Treatment of incorrectly diagnosed conditions (eg, ocular allergies or infections) may worsen DED symptoms. In general, the primary care provider can exclude conditions in the differential diagnosis: (See "The red eye: Evaluation and management".)

●Viral conjunctivitis – DED can be confused with "pink eye." A careful patient history to elicit course of recent and abrupt onset of symptoms, any recent illnesses or sick contacts, and presence of lymphadenopathy can help to distinguish the diagnosis. (See "Conjunctivitis".)

●Other microbial infections – Some ocular infections can begin with an indolent course of symptoms similar to DED. Referral to an ophthalmologist should be considered for any patients at high risk for ocular infections (eg, contact lens wearer, history of diabetes mellitus), particularly those with signs of an infectious process on physical examination (eg, unilateral conjunctival injection, purulent drainage).

●Ocular allergies – Allergic conjunctivitis can also coexist with DED. Symptoms of itching will often be the primary complaint. The allergen should be promptly identified and avoided. (See "Allergic conjunctivitis: Clinical manifestations and diagnosis".)

INITIAL MANAGEMENT

Patients who require early ophthalmologic evaluation — Patients with severe pain, associated visual loss, abnormal blinking, or inability to close their eyes completely should be seen initially by an ophthalmologist [42].

General measures in all patients — DED is aimed at improving symptoms by increasing or supplementing tear production, slowing tear evaporation, reducing tear resorption, or reducing ocular surface inflammation. Initial treatment includes addressing modifiable risk factors and conditions, tear supplementation, environmental adjustment, and use of warm compresses. Treatment is typically not curative and patients should be aware of the need for continued management. Patients who do not obtain adequate relief from initial treatment should be referred to an eye specialist.

Address modifiable risk factors or associated conditions — Certain conditions, medications, and practices can contribute to DED, and should be addressed if possible. These include:

●Systemic or ocular medications that can contribute to dryness (see 'Risk factors' above)

●Contact lens use

●Contributory conditions such as posterior blepharitis or malposition of the eyelids (see "Blepharitis", section on 'Management')

●Smoking

Eye lubricants — Eye lubricants generally include cellulose to maintain viscosity, a spreading agent such as polyethylene glycol or polyvinyl alcohol to prevent evaporation, and a preservative to prevent contamination. Available without a prescription, eye lubricants come in liquid, gel, and ointment forms and provide symptomatic relief [6,43,44].

Preservative-free forms of these supplements are often recommended as some individuals with DED will have inflammatory reactions to the preservatives particularly if used more than four times daily [45]. However, these are often expensive, single-use formulations. Further, there may be an increased potential risk of infection [46].

●Drops – A reasonable starting dose is one drop in each eye, four times per day. Patients often begin to notice improvement within a few days of initiating treatment but may take up to three to four weeks to note a significant change in their symptoms. Some patients may benefit from viewing an online video (eg, YouTube) for a demonstration of eyedrop administration methods.

If individuals remain symptomatic, the frequency can be increased to as frequently as every hour. However, if used more often than four to six times per day, a preservative-free formulation is strongly recommended to minimize the potential for toxicity [47]. (See "Toxic conjunctivitis".)

●Gels and ointments – Higher-viscosity eye lubricant gels and ointments are also commercially available and can be used if patients feel that the liquid eye drops are not providing enough symptomatic relief. Patients should be warned that the gels, and especially ointments, can blur vision temporarily and are often best used at bedtime.

Randomized trials of efficacy are mostly limited due to sample size, lack of an adequate control group, lack of clear diagnostic criteria, and nonstandardized outcomes [48-50]. As laser-assisted in situ keratomileusis (LASIK) is a refractive procedure that causes dry eyes, in part due to decreased postoperative corneal sensation, LASIK serves as a model for assessing treatment of DED. Eye lubricants given to postoperative LASIK patients appear to improve DED symptoms compared with placebo [51]. Issues related to DED and LASIK are discussed separately. (See "Laser refractive surgery".)

Environmental strategies — Environmental coping strategies address the importance of environmental causes that could be contributing to or even causing DED symptoms.

●Encourage frequent blinking, especially during visually attentive tasks such as reading or computer use.

●Minimize exposure to air conditioning or heating.

●Use humidifiers in the bedroom, office, or any space where the patient spends a significant amount of time.

●Avoid second-hand smoke, dust, or other allergens.

Physical barriers around the eyes or "moisture chambers" are recommended to protect the humidity of the local environment around the eyes. Moisture chambers can be purchased and fitted to current glasses in select optical shops by trained opticians (picture 7A-B).

Follow-up — Response to therapy can be monitored subjectively or with standardized questionnaires (see 'Questionnaires' above). Chronic treatment is usually needed unless a specific inciting factor can be eliminated.

We typically recommend that patients return in four to six weeks for re-evaluation. Patients who have not had adequate relief from initial treatments are referred to an ophthalmologist.

PERSISTENT SYMPTOMS — Patients with persistent symptoms can be referred to an ophthalmologist for further treatment. Several options are available, but there are no predictive algorithms for knowing which treatments will work best for which patients, and so a series of medication trials is common, partially guided by medication cost and insurance coverage.

Topical cyclosporine — Topical cyclosporine is a safe and well-tolerated immunosuppressive agent, although it is not clear that it leads to a clinically important benefit in the treatment of DED [52-55]. The multiple randomized trials of topical cyclosporine indicating its efficacy vary greatly by dose of cyclosporine, the comparator control used (ie, active comparator or no treatment), and the endpoint reported; thus, the degree of benefit afforded by use of this agent remains uncertain.

Although not universally beneficial, there appears to be a subset of patients who do respond favorably to this treatment, but there are no good predictive models available to guide clinical decision making. In the author's anecdotal experience, patients with a systemic condition associated with inflammation, including graft-versus-host disease, tend to have the highest likelihood of response to cyclosporine drops [56].

In such patients, a 0.05% emulsion, a 0.09% solution, and a 0.1% solution of cyclosporine are available for treatment of DED. It may take up to six weeks or longer of treatment to achieve noticeable improvement of dryness. In some patients, cyclosporine can result in long-term resolution of DED symptoms, as shown in one case series describing eight such patients, five of whom represented about 4 percent of all cyclosporine-treated patients with chronic DED in one clinical practice [57].

Serum cyclosporine concentrations have been undetectable or negligible with topical use, and no systemic toxicity has been reported. Cyclosporine can cause an occasional, temporary (usually less than 10 minute) burning sensation in the eye [43].

As patients may have other concurrent problems such as infection leading to eye irritation, they should have a complete ophthalmologic examination prior to receiving cyclosporine.

Topical lifitegrast — A topical eye drop formulation, lifitegrast 5%, an integrin antagonist, is used twice a day and has side effects of eye irritation or discomfort and an associated bad taste in approximately 25 percent of users [58]. In randomized trials, lifitegrast improved DED signs and symptoms in patients with mild to moderate and moderate to severe symptoms [58-62].

The prescription and monitoring of response to this agent should be done by an ophthalmologist.

Intranasal varenicline — A preservative-free nasal spray formulation of varenicline, a nicotinic acetylcholine receptor agonist, has been approved by the US Food and Drug Administration (FDA) for the treatment of dry eyes. The suspected mechanism of action is by activating the trigeminal parasympathetic pathway to stimulate natural tear production. In a trial conducted among adults with DED, varenicline use resulted in an increase in tear production, as measured by Schirmer test, after four weeks of twice-daily dosing compared with placebo (vehicle) [63]. The most common reported adverse events were sneezing, cough, and throat irritation.

Perfluorohexyloctane — Perfluorohexyloctane eye drops are available as a tear substitute (FDA approved in the United States in 2023). They have been found to help improve both the signs and symptoms of dry eye disease [64].

Other — Although several other treatments are available for DED, although they are not in common use and should only be used as an adjunctive treatment by eye specialists.

●Topical glucocorticoids – Low-dose topical glucocorticoid eye drops can help to relieve symptoms and signs of DED [65,66] and are useful on a short-term basis. As these drops can have significant side effects with continued use, including cataracts and glaucoma, glucocorticoid eye drops should be used with caution and only be prescribed by an ophthalmologist for this indication.

●Punctal occlusion – Either temporary punctal plugs or permanent cauterization of the puncta can be performed in an attempt to reduce the rate of tear drainage from the ocular surface and thereby possibly improve the signs and symptoms of DED [67].

●Autologous serum tears – The serum of a patient's blood can be formulated into eye drops. Autologous serum tears may improve DED symptoms [68,69], but there is not strong evidence for long-term or significant benefit over eye lubricants [70]. Access to these eye drops and cost are barriers to its use.

●Scleral contact lenses – In patients with severe DED, large-diameter contact lenses can be used to help retain a tear reservoir over the ocular surface [71]. These types of contact lenses require a specialized fitting by an experienced contact lens practitioner.

●Tear stimulation – Systemic pilocarpine (a cholinergic agonist) has been found to improve DED symptoms in patients, most commonly those with Sjögren's disease, but is associated with systemic side effects in a significant portion of patients [72]. Diquafosol [73-75] and rebamipide [76-78] eye drops have also shown promise in improving DED.

●Acupuncture – Small studies have shown some improvement in DED signs and symptoms following acupuncture therapy [79,80]. Acupuncture is discussed in detail separately. (See "Overview of the clinical uses of acupuncture".)

●Surgery – Eyelid abnormalities should be surgically corrected to realign and maintain normal lid architecture. Surgery can also be performed on structurally normal eyelids to reduce the ocular surface area and thus reduce tear evaporation. In appropriate candidates, minor salivary gland transplantation can be a promising surgical treatment for severe DED [81].

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Dry eye (The Basics)").

SUMMARY AND RECOMMENDATIONS

●Pathophysiology – DED is a multifactorial disease of the tears and ocular surface that can result in ocular discomfort and visual impairment. DED is generally due to both decreased tear production and/or excessive evaporative loss. (See 'Pathophysiology' above.)

●Clinical manifestations – Most patients present with symptoms of chronic eye irritation such as eye dryness, red eyes, and burning. However, there is considerable variability in patient-reported symptoms over time. (See 'Common symptoms' above.)

●Diagnosis – The diagnosis is based on patient symptoms, supportive findings on examination, and testing. Common findings include conjunctival injection and reduced blink rate. (See 'Diagnosis' above.)

●Indications for initial referral – Referral to an ophthalmologist is appropriate for patients with severe pain or associated visual loss, or those with abnormal blinking or inability to close their eyes completely. (See 'Patients who require early ophthalmologic evaluation' above.)

●Initial treatment – We suggest initial treatment with eye lubricants and environmental strategies for all patients with dry eye disease (Grade 2C). Key environmental strategies include frequent blinking and minimizing exposure to air conditioning or heating. (See 'General measures in all patients' above.)

●Further treatment – Other treatment options require referral to an ophthalmologist and include topical cyclosporine, topical medications, scleral contact lenses, punctal occlusion, surgery, and other treatments. (See 'Persistent symptoms' above.)