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. Tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles [1]. 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 epidemiological studies performed globally, the prevalence of dry eye disease (DED) ranges from 5 to 50 percent [2].

Based on data from the National Health and Wellness Survey, 6.8 percent of the United States adult population (approximately 16.4 million people) have been diagnosed with DED [3]. The prevalence increased with age (2.7 percent in those 18 to 34 years old versus 18.6 percent in those ≥75 years old) and was higher in women than men (8.8 versus 4.5 percent). Prevalence was not affected by education or location of residence. A 2022 meta-analysis of three United States studies estimated a pooled prevalence of dry eye of 8.1 percent [4].

Risk factors — Risk factors for DED include [5-9]:

●Advanced age

●Female sex

●Hormonal changes (primarily due to decreased androgens)

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

●Contact lens wear

●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)

●Decreased corneal sensation

●Ophthalmic surgery (especially corneal refractive surgery)

●Low-humidity environments

Studies of the global burden of DED report that persons living in Asia (principally China, Tibet, Korea) have a higher prevalence [2].

CLINICAL SIGNIFICANCE — Dry eye disease (DED), particularly when severe, can have a significant impact on visual acuity, daily activities, social and physical functioning, and workplace productivity [10-12].

In addition, patients with DED incur direct medical costs through frequent visits to health care professionals as well as pharmacologic and nonpharmacologic therapies. Indirect costs include decreased productivity and time lost from work [13].

PATHOPHYSIOLOGY — Dry eye disease (DED) has a complex and multifactorial etiology. 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) [14]. Dysfunction of any component in the lacrimal functional unit can lead to DED.

Historically, DED has been classified into two general groups: decreased tear production (resulting in aqueous deficient DED) and abnormal meibomian gland physiology (resulting in evaporative DED). However, it is now believed that both mechanisms are present in most patients, although one may be predominant [1]. For all patients, tear film hyperosmolarity and subsequent ocular surface inflammation lead to the variety of symptoms and signs associated with DED.

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 [15,16]. (See 'Symptoms' below.)

CAUSES

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 and subsequently the ocular surface, which incites inflammation of the ocular surface cells [17].

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

●Sjögren's syndrome – Sjögren's syndrome is a chronic autoimmune inflammatory disorder characterized by diminished lacrimal and salivary gland function with resultant dryness of the eyes and mouth. The onset of Sjögren's syndrome is rare after age 65 years [18]. DED related to Sjögren's syndrome 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 syndrome – This syndrome refers to patients with aqueous tear-deficient DED involving lacrimal dysfunction without associated systemic findings. The most common form is age-related DED in which it is believed that there is lacrimal ductal obstruction over time, leading to decreased lacrimal gland function [19]. Lacrimal gland obstruction can also be due to conjunctival scarring conditions such as trachoma, pemphigoid, vitamin deficiency, post-viral syndromes, and ocular burns [20]. (See "Trachoma".)

This syndrome can also be caused by lacrimal gland infiltration due to sarcoidosis, lymphoma, graft versus host disease, and episcleritis. Other causes include contact lens use, which is associated with reduced corneal sensitivity and subsequent reduced reflex sensory tear secretion [21], and diabetes mellitus [22]. (See "Complications of contact lenses" and "Episcleritis".)

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. Increased tear evaporation is most commonly caused by 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 [20]. In a normally functioning eye, the nature of the mucin allows even spreading of the tear film to form a membrane, and the lipid layer provides a barrier to minimize evaporation of tears [23]. Abnormalities of the lipid layer are associated with a higher rate of tear film evaporation [24].

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 [20,25]. Lastly, topical medicated or preserved eye drop use, chronic contact lens wear, and ocular allergy syndromes can cause ocular surface irritation and increased tear film evaporation [20,25].

SYMPTOMS — Most patients will present with symptoms of chronic eye irritation associated with mild to moderate discomfort [26]. 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 [25,27-29].

Common eye complaints include:

●Dryness

●Red eyes

●General irritation

●Gritty sensation

●Burning sensation

●Foreign body sensation

●Paradoxical excessive tearing

●Light sensitivity

●Blurred vision

Inciting or exacerbating causes include medications, 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 [30,31]. Rarely, in severe DED conditions, permanent damage to visual acuity can occur from corneal scarring or ulceration.

If ocular complaints are accompanied by mouth dryness and other systemic complaints, an evaluation for Sjögren's syndrome should be performed. (See "Diagnosis and classification of Sjögren’s disease".)

Questionnaires — Due to the variability of findings on clinical evaluation of dry eye disease (DED), some clinicians base their assessment of DED on the results of validated questionnaires [32]. These can also be used for monitoring DED and can be useful for standardizing the identification and classification of DED [33].

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 validated in patients with DED [34]. 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 [35].

●Impact of Dry Eye on Everyday Life (IDEEL) – Fifty-seven questions in three modules validated in patients with DED [36].

●Salisbury Eye Evaluation Questionnaire (SEE) – Six-item questionnaire used in self-reported, population-based prevalence surveys to determine visual impairment among older adult subjects [37].

DIAGNOSIS — The diagnosis of dry eye disease (DED) is based on characteristic patient symptoms and supporting findings on the physical examination, both of which can vary considerably in intensity over time and under different environmental conditions. Potential supportive findings on physical examination include:

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

●Breakdown of ocular surface, and corneal scarring (picture 2A-B).

●Excessive reflex tearing from irritation due to dryness, which can paradoxically be a sign of DED.

●Blepharitis, often visible as erythematous or irritated eyelid edges (picture 3A-B).

●Malposition of the eyelids (inward or outward turning, also called entropion and ectropion, respectively) (picture 4 and picture 5).

●Reduced blink rate. Normal blink rate varies by environment and activity but is generally in the range of 5 to 26 blinks per minute [38].

●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.

Differential diagnosis and coexisting conditions — Other conditions that can cause similar symptoms to DED include:

●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).

Coexisting disorders include:

●Blepharitis/Meibomian gland dysfunction – Posterior blepharitis often coexists with DED and may require specific treatments, including warm compresses and patient education on eyelid hygiene. (See "Blepharitis".)

●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 TREATMENT — Treatment for dry eye disease (DED) is aimed at improving symptoms by increasing or supplementing tear production, slowing tear evaporation, reducing tear resorption, or reducing ocular surface inflammation. In addition to symptomatic relief, treatment with artificial tears may improve visual acuity and prevent against ocular damage [8,39,40].

First line treatments — The first line of treatment in patients complaining of DED are:

●Tear supplementation

●Environmental coping strategies

●Amelioration of eyelid abnormalities including blepharitis (see "Blepharitis")

●Application of warm compresses (to soften secretions in obstructed meibomian gland excretory ducts)

●Discontinuation of systemic or ocular medications that can contribute to dryness, if possible (see 'Risk factors' above)

Patients who do not obtain adequate relief from tear supplementation or environmental adjustment should be referred to an ophthalmologist.

Artificial tears — Artificial tears 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, artificial tears come in liquid, gel, and ointment forms. Preservative-free forms of these supplements are often recommended as some individuals with DED will have inflammatory reactions to the preservatives [41]. However, these are often expensive, single-use formulations.

In February of 2023, the Centers for Disease Control and Prevention (CDC) recommended discontinuation of use of over-the-counter EzriCare Artificial Tears due to an outbreak of extensively drug-resistant Pseudomonas aeruginosa associated with that product [42].

●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. If used more often than four to six times per day, a preservative-free formulation is preferable to minimize the potential for toxicity [43].

●Gels and ointments – Higher-viscosity artificial tear gels and ointments are also commercially available and can be used if patients feel that the 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.

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.

Randomized trials of efficacy are mostly limited due to sample size, lack of an adequate control group, lack of clear diagnostic criteria, and non-standardized outcomes [44-47]. 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. Artificial tears given to postoperative LASIK patients appear to improve DED symptoms compared with placebo [48]. 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. One important strategy includes frequent blinking, especially during visually attentive tasks such as reading or computer use. The patient should also be urged to minimize exposure to air conditioning or heating. Humidifiers are useful in the bedroom, office, or any space where the patient spends a significant amount of time.

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 6A-B).

Indications for referral — In most patients, first-line treatment can be initiated by the primary care provider. However, initial referral to an ophthalmologist is appropriate for patients with neuropathy (including diabetic neuropathy), as they may have reduced sensation and be unaware of severe dryness, which may cause visual disturbance or ocular surface damage if not treated. We also suggest initial referral to an ophthalmologist if the diagnosis is in question or if the patient has severe pain or associated visual loss, or abnormal blinking or inability to close their eyes completely [49]. (See 'Ophthalmology evaluation and treatment' below.)

OPHTHALMOLOGY EVALUATION AND TREATMENT

Evaluation — The ophthalmologist will 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 dry eye disease (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 7). 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 [27].

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

●Tear hyperosmolarity [50,51].

●Ocular surface inflammation (eg, matrix metalloproteinase 9 as a marker of ocular surface inflammation) [52,53].

●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.

Treatment — The choice of topical treatments is usually 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 [54,55]. 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 and a 0.09% 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 burning sensation in the eye. Another important limiting factor is high cost [39].

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

Topical lifitegrast — A topical eye drop formulation, lifitegrast 5.0%, 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.

Other — Although several other treatments are available for DED, 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 [64,65] 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 [66].

●Autologous serum tears – The serum of a patient's blood can be formulated into eye drops. Autologous serum tears may improve DED symptoms [67,68], but there is not strong evidence for long-term or significant benefit over artificial tears [69]. Access to these eye drops and cost are barriers to its use.

●Tear stimulation – Systemic pilocarpine (a cholinergic agonist) has been found to improve DED symptoms in patients, most commonly those with Sjögren's syndrome, but is associated with systemic side effects in a significant portion of patients [70]. Other tear stimulation agents, including those for topical use, are being explored as potential treatments for DED [71].

●Omega-3 fatty acids – Trials of oral omega-3 fatty acids for DED have shown mixed results, with a large multicenter clinical trial showing no additional benefit of omega-3 fatty acid supplementation over placebo in the improvement of DED signs and symptoms [72-76].

●Oral antioxidants – Small randomized trials have shown some efficacy of oral antioxidants in the treatment of DED [77,78]. As an example, in a blinded, placebo-controlled cross-over trial of 24 DED patients, those randomly assigned an antioxidant combination (vitamins E, B2, C, zinc and selenium) compared with placebo had improved tear break-up times, Schirmer scores, and clinical symptoms, including burning, itching, and redness [77].

●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 [79]. These types of contact lenses require a specialized fitting by an experienced contact lens practitioner.

●Acupuncture – Small studies have shown some improvement in DED signs and symptoms following acupuncture therapy [80,81]. Acupuncture is discussed in detail separately.

●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.

●Investigational – Diquafosol [82-84] and rebamipide [85-87] eye drops have also shown promise in improving DED.

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 – Dry eye disease (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 'Clinical significance' above.)

●Diagnosis – The diagnosis is based primarily on patient symptoms and supportive findings of DED from examination. Common findings include conjunctival injection and reduced blink rate. Some patients may have paradoxical excess reflex tearing. (See 'Diagnosis' above.)

●Initial treatment – We suggest initial treatment with artificial tears for all patients with dry eye disease (Grade 2C). This is particularly important in patients who have reduced ocular sensation, such as those with neuropathy (including diabetic neuropathy), who may be unaware of severe dryness, which may cause visual disturbance or ocular surface damage if not treated. In addition to symptomatic relief, artificial tears may improve visual acuity and prevent against ocular damage.

When appropriate, environmental strategies should also be undertaken, including discussing the importance of frequent blinking and minimizing exposure to air conditioning or heating. (See 'Initial treatment' above.)

●Indications for referral – Referral to an ophthalmologist is appropriate for patients with neuropathy (including diabetic neuropathy), those in whom the diagnosis is in question, patients with severe pain or associated visual loss, or those with abnormal blinking or inability to close their eyes completely. (See 'Indications for referral' above.)

●Further treatment – Other treatment options include topical cyclosporine, other topical medications, oral medications, scleral contact lenses, punctal occlusion, and surgery. (See 'Treatment' above.)