Continuing Education Activity

Dry eyes affect a significant number of people, but treatment remains unsatisfactory. Dry eyes, also known as dry eye disease (DED), dry eye syndrome, and keratoconjunctivitis sicca (KCS), are among the most common reasons for a visit to an eye doctor. The cause of this condition is multifactorial, in which ocular, anatomical and systemic factors play crucial roles. It is vital to thoroughly assess patients with signs and symptoms because prompt treatment can significantly improve long-term quality of life, provide relief from dry eyes, and improve outcomes. This activity reviews the evaluation and management of dry eyes and highlights the role of the interprofessional team in caring for affected patients.

Objectives:

• Identify the etiology of dry eye syndrome.
• Describe the presentation, diagnosis, signs, and symptoms of a patient with dry eye syndrome.
• Outline the treatment and management options available for dry eye syndrome.
• Explain interprofessional team strategies for improving care coordination and communication to advance the treatment of dry eyes and improve outcomes.

Introduction

Dry eyes, also known as dry eye disease (DED), dry eye syndrome, and keratoconjunctivitis sicca (KCS), are among the most common reasons for a visit to an eye doctor. The definition of a 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."[1]

The tear film is approximately 2 to 5 µm thick over the cornea and is composed of three main components.[2][3][4] These components (lipid, aqueous, and mucin) are often described as layers, although this may be an oversimplification of the tear film milieu.[5] 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.[6]

Etiology

Numerous potential etiologies may contribute to the development of DED, and many cases may be multifactorial.[7] These include local ocular factors, systemic diseases, sociodemographic factors, environmental conditions, and iatrogenic causes such as medications or surgeries.[8] A list of some of these potential etiologies has been compiled below.

Potential Causes and/or Factors Associated with DED

• Systemic medications such as antihistamines, antihypertensives, anxiolytics/benzodiazepines, diuretics, systemic hormones, non-steroidal anti-inflammatory drugs, systemic or inhaled corticosteroids, anticholinergic medications, isotretinoin (causes meibomian gland atrophy), and antidepressants.[9]
• Topical medications include glaucoma drops or preservative toxicity from eye drops containing preservatives.[10][11]
• Skin diseases on or around the eyelids, such as rosacea or eczema.[12]
• Meibomian gland dysfunction is a common co-morbidity with thickening and erythema of the eyelids and inadequate or altered secretions of meibomian glands.[13] 
• Ophthalmic surgery, including refractive surgery, cataract surgery, keratoplasty, and lid surgery.[14]
• Chemical or thermal burns that scar the conjunctiva.[15]
• Ocular allergies.[16]
• Computer or device usage as this may lead to decreased blinking when looking at the screen.[17]
• Excess or insufficient dosages of vitamins, particularly vitamin A deficiency, can lead to xerophthalmia and the appearance of Bitot spots on the conjunctiva in severe cases.[18]
• Decreased sensation in the cornea from long-term contact lens wear, herpes virus infections, or other causes of a neurotrophic cornea.[19]
• Graft-versus-host disease.[20]
• Systemic diseases, which include Sjogren syndrome and other autoimmune or connective tissue disorders such as rheumatoid arthritis and lupus, and thyroid disease.[21]
• Environmental factors include exposure to irritants like chemical fumes, cigarette smoke, pollution, or low humidity.[22]

Epidemiology

DED is more common in women than men (due to female hormonal effects on the lacrimal and Meibomian glands and ocular surface) and has an increased prevalence with age.[23] The prevalence of DED varies depending on the diagnostic criteria employed and has ranged from approximately 5 to 50% in population-based studies, which has been shown to be as high as 70 % in visual terminal users.[23][24]  In general, it is more common in Asian populations when compared to whites, although geographic, climatic, and environmental variations may also be significant factors.[23][25] Evaporative dry eye is considered the most common subtype of DED. There may be discordance between dry eye signs and symptoms, with signs being more prevalent and variable than symptoms.[23]

Pathophysiology

DED has traditionally been classified into two categories: aqueous deficient and evaporative.[1][26] These two categories, however, are not mutually exclusive, and numerous patients have a combination of these mechanisms of DED. Aqueous tear deficiency is characterized by inadequate tear production with predominant causes consisting of Sjogren Syndrome (primary or secondary); diseases, inflammation, and/or dysfunction of the lacrimal gland; obstruction of the lacrimal gland; and systemic drugs (i.e., decongestants, antihistamines, diuretics, beta-blockers, etc.) Evaporative dry eye is characterized by increased tear film evaporation and a deficiency in the lipid portion of the tear film. In this case, the quantity of tears produced is normal; however, the quality of tears causes excessive evaporation. This alteration 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, drop out 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, deficiency in vitamin A, contact lens use, and environmental factors (low humidity, high airflow).  

A hallmark of DED is hyperosmolarity of the tear film, which may damage the ocular surface directly or indirectly by inciting inflammation.[27] The normal osmolarity of the tear film is usually less than 300 mOsm/L, which has been reported to be as high as 360 mOsm/L in patients with DED.[28] Hyperosmolarity of the tear film leads to a cascade of signaling events that releases inflammatory mediators (i.e., tumor necrosis factor, interleukin 1 and 6, etc.) and leads to damage to the ocular surface which may further decrease tear film stability, leading to self-perpetuation of the disease in a "vicious circle."[29]  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.[30] 

History and Physical

DED may lead to a number of symptoms.[28] These may range from mild to severe:

• Stinging, burning, or a feeling of pressure in the eyes. 
• A sandy, gritty, or foreign body sensation.
• Epiphora, or tearing, is a symptom that is often counterintuitive. This is due to dryness leading to pain or irritation that results in intermittent excess tearing or epiphora.
• Pain is a broad term, and sharp and dull pain can be described as localized to some part of the eye, behind the eye, or even around the orbit.
• Redness is a common complaint and is often made worse by the rebound effect of vasoconstrictors found in many over-the-counter eye drops designed to reduce redness. Vasoconstrictors may decrease redness for the short term by constricting the vessels of the episclera but can have a rebound effect and increased redness after the drops wear off in a relatively short time period. 
• Blurry vision, particularly intermittent blurry vision, is a common complaint and may also be described as glare or haloes around lights at night.
• Vision fluctuation and difficulties in reading.
• A sensation of heavy eyelids or difficulty opening the eyes. 
• Excessive blinking.
• Eyelid twitching.
• Dryness is a common problem for contact lens wearers, and irritation may make contact lenses uncomfortable or even impossible to wear.
• Tired eyes. Closing the eyes may provide relief to some individuals with dry eyes.
• Inability to cry in severe DED.

Evaluation

There is no single 'gold standard' sign or symptom for the diagnosis of DED. Evaluation of both symptoms and signs of DED is recommended as signs may be present without symptoms, and vice-versa. 

Symptoms

A verbal history allows the non-scripted elicitation of dry eye symptoms. In addition, many questionnaires have been developed to screen for symptoms of DED. 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.[31]

Tear Stability

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 cutoff of fewer than ten seconds for the appearance of a patch in the tear film is often considered consistent with DED. Alternatively, a non-invasive tear breakup 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 assess for the appearance of discontinuity of the lipid layer after a blink.   

Tear Volume 

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.[32] 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 cutoff used) of wetting after 5 minutes of diagnostic of aqueous deficiency. Alternatively, a topical anesthetic can be administered. Then residual fluid blotted from the inferior fornix prior to performing testing to measure basic secretion with less than 5 to 10 mm of wetting is 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 cutoff 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 of fluorescein is instilled into the tear film with optimal viewing 1 to 3 minutes later. Greater than five spots of staining are considered a positive result with various grading scales such as the Oxford grading scale used as well.[33][34]

Lissamine green staining.  Lissamine allows the assessment of conjunctival and lid margin damage and, to a lesser extent, corneal damage. Greater than nine spots is a positive result.[33]  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.[35]

Conjunctival redness. Conjunctival redness, or hyperemia, is not specific to DED 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 characteristics of DED. Osmolarity values typically increase with disease severity. Various cutoff values have been reported, with 308 mOsm/L used as a threshold to diagnose mild/moderate disease, while 316 mOsm/L has been used as a cutoff for more severe disease.[31] Studies have shown that high levels of osmolarity can lead to pro-inflammatory effects on the ocular surface, with the secretion of inflammatory cytokines and metalloproteinases that can cause chronic epithelium dysfunction and induce apoptosis.[36]

Matrix Metalloproteinases. These proteases are found in the tears of individuals with dry eyes. Matrix metalloproteinase-9 (MMP-9) levels can be tested using a point-of-care test.[37]    

Eyelid Evaluation

Blepharitis. Evaluation of the eyelids is a crucial part of the evaluation to determine any factors contributing to DED. The evaluation includes assessment for anterior blepharitis and Demodex blepharitis, which are frequent comorbidities of DED.[38]

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.'[39] Lid wiper epitheliopathy, or staining of the lid wiper with fluorescein or lissamine green, may be seen more commonly in individuals with DED, presumably due to increased friction between the lid and ocular surface.

Meibomian gland evaluation. The evaluation of the 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.[31]  Expressibility is assessed by applying digital pressure along the eyelid margin with a clear meibum easily expressed from the normal eyelid. In meibomian gland dysfunction, the meibum is turbid or viscous and not easily expressed.  

Eyelid blink and closure. Incomplete blinking and nocturnal lagophthalmos can result in DED. 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

Numerous systemic diseases may cause DED, particularly primary Sjogren syndrome and secondary Sjogren syndrome caused by other autoimmune 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 DED. 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 a salivary gland biopsy by an oral surgeon.

Treatment / Management

Treatment of dry eye syndrome is performed in a step-wise approach that may vary depending on the severity of the disease.[40] 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).[28] 

Further treatment options include serum eye drops, oral or topical secretagogues, therapeutic contact lenses, amniotic membrane grafting, surgical punctal occlusion, and tarsorrhaphy. 

Differential Diagnosis

Many conditions may evoke symptoms similar to those caused by DED. Some conditions may also be associated with or lead to DED, such as allergic conjunctivitis, cicatricial conjunctivitis, filamentary keratitis, and neurotrophic keratitis. Identifying the underlying primary condition in these cases is key to reducing the progression of the disease and worsening of dry eye.

Differential diagnosis includes:

• Conjunctivitis (allergic, viral, bacterial, parasitic/chlamydial)
• Anterior blepharitis
• Demodex blepharitis
• Cicatricial conjunctivitis (Stevens-Johnson Syndrome, mucous membrane pemphigoid)
• Bullous Keratopathy
• Contact lens-related keratoconjunctivitis
• Eyelid malposition (entropion, ectropion) or abnormality (trichiasis) leading to ocular surface disease
• Keratitis (interstitial, filamentary, contact lens-related, neurotrophic)

Prognosis

There are minimal published data describing the natural history of treated and untreated DED.[23] DED is often considered 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 the regeneration of corneal nerves or reduction of ocular inflammation.[41]

Complications

Complications from DED range from mild to severe. Mild to moderate DED causes symptoms detailed above, including ocular irritation and/or visual disturbances. More severe diseases can result in corneal complications, including infectious keratitis, ulceration, and scarring, which may cause subsequent loss of vision.[42][43] While causation has not been established, several non-ocular associations exist with DED, including depression, sleep and mood disorders, dyslipidemia, and migraine headaches.[44][45]

Deterrence and Patient Education

Patients should be educated regarding environmental or behavioral modifications that can be performed to reduce DED. This includes education regarding the environment. For example, factors such as fans, air conditioners, or heating vents may worsen DED. Blinking awareness training or taking intermittent breaks may reduce the dry eye effects of staring at digital devices. Artificial tears should be promoted, while contact lens use can preferably be limited. Patients may also be educated regarding dietary factors that may influence DED, including supplementation with essential fatty acids.

Enhancing Healthcare Team Outcomes

The primary care provider, ophthalmic nurse, and pharmacist should educate the patient on the 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 the patient's primary care providers or rheumatologists to investigate possible underlying systemic diseases 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 treat the ocular manifestations adequately.

The interprofessional team approach with all clinicians, nursing staff, and pharmacists communicating openly and sharing information is the optimal approach to addressing patients with dry eyes syndrome. [Level 5]