Dry Eye Disease (Keratoconjunctivitis Sicca)

Although dry eye disease may result purely from aqueous tear deficiency or be purely evaporative, it usually is of mixed etiology. 

Patients with ADDE may be further differentiated into those with dry eye disease associated with Sjögren syndrome (SS) and those with dry eye disease not associated with SS (non-SS KCS). It is estimated that 10% of patients with ADDE have Sjogren syndrome. Patients are considered to have SS-associated dry eye disease if they have concomitant xerostomia or connective tissue disease (CTD). SS-associated dry eye disease itself is subclassified as either primary SS or secondary SS. Patients with primary SS meet the diagnostic criteria for Sjögren syndrome but do not meet diagnostic criteria for other CTD. Patients with secondary SS have Sjögren-type symptoms that develop in the setting of a diagnosed CTD, most commonly rheumatoid arthritis, systemic lupus erythematosus, psoriatic arthritis, and systemic sclerosis (scleroderma). Patients with SS-related dry eye disease often have more visual difficulty but also have less severe ocular discmofort compared with patients with non-SS KCS.[15]  The diagnosis of SS in patients with dry eye patients often is delayed or remains undiagnosed in many patients. 

Dry eye disease most frequently is found in women, specifically those who are postmenopausal, are pregnant, are taking oral contraceptives, or are on hormone replacement therapy (especially estrogen-only pills). The common denominator is a decrease in androgens, from either reduced ovarian function (in postmenopausal women) or increased levels of the sex hormone–binding globulin (in women who are pregnant or are taking birth control pills).

Meibomian gland dysfunction is a key component of evaporative dry eye disease, with a growing awareness among clinicians of the key role played by surface lipids. In Lemp et al’s cohort of 224 subjects with dry eye disease, 86% demonstrated signs of meibomian gland dysfunction based on an objective, composite, disease severity scale. The proportion of subjects exhibiting signs of evaporative dry eye resulting from meibomian gland dysfunction far outweighs that of subjects with pure aqueous deficiency dry eye in that general clinic-based patient cohort.[16]

Dry eye disease essentially is a clinical diagnosis made by combining information obtained from the history and physical examination by performing one or more tests to lend some objectivity to the diagnosis. No single test is sufficiently specific to permit an absolute diagnosis of dry eye disease, and the entire clinical context is needed to make an appropriate treatment recommendation. 

Early detection and aggressive treatment of dry eye disease may help prevent corneal ulcers and scarring, as well as improve quality of life metrics. Treatment depends on the level of severity and may include medications, eye protection devices, and surgical interventions. The frequency of follow-up care depends on the severity of the signs and symptoms. Environment-related issues that may exacerbate dry eye disease should be discussed; alternatives may be needed.

The tear film covers the normal ocular surface that protects the cornea. The previous model of a 3-layer model of lipid, aqueous, and mucin layer now has been replaced with a 2-phase model of the tear film as described below[17] :

• A superficial thin lipid layer (42nm) - This layer is produced by the meibomian glands and the sebaceous gland of Zeis, and its principal function is to retard tear evaporation and to assist in uniform tear spreading ^[18]
• A mucoaqueous layer (3 µm) - This layer has 2 components - the aqueous component and the mucin component. The aqeous component is secreted by the main lacrimal gland (reflex tearing) and accessory lacrimal glands of Krause and Wolfring (basic tearing). The mucin component is secreted by conjunctival goblet cells and associates itself with ocular surface via its loose attachments to the glycocalyx of the microplicae of the epithelium. The hydrophilic quality of the secreted mucin and membrane-spanning mucins, which are expressed by conjunctival and corneal epithelium cells, also help spread the tear film across the ocular surface. The mucoaqueous layer primarily serves a lubricating function, and ensures an even and spontaneous distribution of the tear film across the ocular surface. It also provides an antimicrobial defense and transmits oxygen to the avascular corneal epithelium. 

The lipid layer acts as a surfactant, constitutes an aqueous barrier, retards evaporation of the underlying aqueous layer, and provides a smooth optical surface. It may also act as a barrier against foreign particles, and it may possess some antimicrobial properties.

Because the meibomian glands are holocrine in nature, the secretions contain both polar lipids (aqueous-lipid interface) and nonpolar lipids (air-tear interface), as well as proteinaceous material. All of these are held together by ionic bonds, hydrogen bonds, and van der Waals forces. The secretions are subject to neuronal (parasympathetic, sympathetic, and sensory sources), hormonal (androgen and estrogen receptors), and vascular regulation. Evaporative loss is predominantly due to meibomian gland dysfunction (MGD).

The aqueous component of the mucoaqueous layer includes about 60 different proteins, electrolytes, and water from the lacrimal gland, conjunctiva, and meibomian gland. Lysozyme, the most abundant (20-40% of total protein) and most alkaline of the tear proteins, is a glycolytic enzyme capable of breaking down bacterial cell walls. Lactoferrin has antibacterial and antioxidant functions, and epidermal growth factor (EGF) helps maintain the normal ocular surface and promote corneal wound healing. Other components include albumin, transferrin, immunoglobulin A (IgA), immunoglobulin M (IgM), and immunoglobulin G (IgG).

The secretion of the lacrimal gland is controlled by a neural reflex arc, with afferent nerves (trigeminal sensory fibers) in the cornea and the conjunctiva passing to the pons (superior salivary nucleus), from which efferent fibers pass in the nervus intermedius to the pterygopalatine ganglion and postganglionic sympathetic and parasympathetic nerves terminating in the lacrimal glands.

The glycocalyx of the corneal epithelium contains the transmembrane mucins (glycosylated glycoproteins present in the glycocalyx) MUC1, MUC4, and MUC16. These membrane mucins interact with soluble, secreted, gel-forming mucins produced by the goblet cells (MUC5AC) and also with others, such as MUC2. The lacrimal gland also secretes MUC7 into the tear film.

These soluble mucins move about freely in the tear film, a process facilitated by blinking and electrostatic repulsion from the negatively charged transmembrane mucins. Soluble mucins also function as cleanup proteins by picking up dirt, debris, and pathogens, holding fluids because of their hydrophilic nature, and harboring defense molecules produced by the lacrimal gland.

Transmembrane mucins prevent pathogen adherence and entrance. They also provide a smooth lubricating surface, allowing lid epithelia to glide over corneal epithelia with minimal friction during blinking and other eye movements. It has been suggested that the mucins are mixed throughout the aqueous layer of tears owing to their hydrophilic nature and, being soluble, move freely within this layer.

Tear hyperosmolarity and instabiliy are the principal components of the primary drivers of dry eye disease.[2]  The 2 major types of DED, aqueous deficient dry eyes (ADDE) and evaporative dry eyes (EDE), can both be related to tear hyperosmolarity and instability. 

• In EDE, tear film lipid deficiency from meibomian gland dysfunction results in excessive evaporation of the tear film. This leads to tear hyperosmolarity in the presence of normal lacrimal function. 
• In ADDE, reduced tear secretion from the lacrimal glands due to lacrimal gland damage (for exmaple, in Sjögren disease) leads to the hyperosmolarity of the tear film despite a normal evaporation rate of the tear film. 

Both EDE and ADDE often co-exist and contribute to the mixed type of dry eye disease. Tear hyperosmolarity, which is present in both EDE and ADDE, eventually enters into a vicious cycle that leads to chronic inflammation, loss of conjunctival goblet cells, ocular surface damage, and self-perpetuating disease.[19]  

Proinflammatory Activity

Various proinflammatory cytokines that may cause cellular destruction, including interleukin (IL)–1, IL-6, IL-8, TGF-β, tumor necrosis factor alpha (TNF-α), and chemokine ligand 5 (CCL5 or RANTES), are altered in patients with dry eye disease. IL-1β and TNF-α, which are present in the tears of patients with dry eye disease, cause the release of opioids that bind to opioid receptors on neural membranes and inhibit neurotransmitter release through production of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB).

IL-2 also binds to the delta opioid receptor and inhibits cAMP production and neuronal function. This loss of neuronal function diminishes normal neuronal tone, leading to sensory isolation of the lacrimal gland and eventual atrophy.

Proinflammatory neurotransmitters, such as substance P and calcitonin gene–related peptide (CGRP), are released, and these substances recruit and activate local lymphocytes. Studies suggest that dry eye severity is directly correlated with nerve growth factor (NGF) levels and inversely correlated with CGRP and neuropeptide Y (NPY) tear levels.

NGF tear levels point to a direct relation with conjunctival hyperemia and fluorescein staining results, suggesting that tear levels of NGF are more closely connected to corneal epithelial damage, perhaps as a reflection of attempted compensatory repair responses, and that the decreased tear levels of NPY and CGRP in dry eye disease are linked to impaired lacrimal function.[20] In one study, elevated NGF tear levels were decreased by giving 0.1% prednisolone.[21]

Substance P also acts via the nuclear factor of activated T cells (NF-AT) and through the NF-κB signaling pathway. This leads to expression of intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), adhesion molecules that promote lymphocyte homing and chemotaxis to sites of inflammation.

Inflammatory cytokines, in addition to inhibiting neural function, also may convert androgens into estrogens, resulting in meibomian gland dysfunction. An increased rate of apoptosis also is seen in conjunctival and lacrimal acinar cells, perhaps owing to the cytokine cascade. Elevated levels of tissue-degrading enzymes called matrix metalloproteinases (MMPs) also are present in the epithelial cells.

Mucin deficiency

Mucin-synthesizing genes representing both transmembrane mucins and goblet cell–secreted soluble mucins have been isolated and designated MUC1 through MUC17. Their roles in hydration and stabilization of the tear film are being investigated in patients with KCS. Particularly significant is MUC5AC, which is expressed by stratified squamous cells of the conjunctiva and whose product is the predominant component of the mucous layer of tears. A defect in this and other mucin genes may be a factor in the development of dry eye disease.

Besides dry eye disease, other conditions may eventually lead to loss of goblet cells, including ocular cicatricial pemphigoid, Stevens-Johnson syndrome, and vitamin A deficiency. These conditions may lead to drying and eventual keratinization of the ocular epithelium. Both classes of mucins are decreased in these diseases, and, on a molecular level, mucin gene expression, translation, and posttranslational processing are altered.

Mucin deficiency leads to poor wetting of the corneal surface with subsequent desiccation and epithelial damage, even in the presence of adequate aqueous tear production.

Reduced tear protein production

Normal production of tear proteins, such as lysozyme, lactoferrin, lipocalin, and phospholipase A2, is decreased in dry eye disease.

Lipocalins, previously known as tear-specific prealbumin, are inducible lipid-binding proteins produced by the lacrimal glands and are present in the mucous layer. They lower the surface tension of normal tears, which provides stability to the tear film and also explains the increase in surface tension seen in dry eye disease characterized by lacrimal gland deficiency. Lipocalin deficiency can lead to precipitation in the tear film, forming the characteristic mucous strands seen in patients with dry eye symptoms.

Sex Hormone Deficiency

Androgens are believed to be trophic for the lacrimal and meibomian glands. They exert potent anti-inflammatory activity via production of transforming growth factor–beta (TGF-β), suppressing lymphocytic infiltration.

Both androgen and estrogen receptors are located in the lacrimal and meibomian glands. At menopause, a decrease in circulating sex hormones occurs, possibly affecting the functional and secretory aspect of the lacrimal gland. Initial interest in this area centered on evaluating estrogen or progesterone deficiency, and was done to explain the link between dry eye disease and menopause whereas subsequent research has tended to focus more on androgens (specifically, testosterone) or metabolites of androgens.[22, 23]  A 2017 randomized, controlled trial of 46 androgen-deficient patients showed that those treated with androgen replacement had statistically significant improvements in tear breakup time, corneal staining, Schirmer scores, and Ocular Surface Disease Index (OSDI) scores at 4 weeks compared with those receiving placebo.[24]

In meibomian gland dysfunction, androgen deficiency results in loss of the lipid layer—specifically, loss of triglycerides, cholesterol, monounsaturated essential fatty acids such as oleic acid, and polar lipids, including phosphatidylethanolamine and sphingomyelin. Loss of polar lipids, which are present at the aqueous-tear interface, exacerbates evaporative tear loss, and loss of unsaturated fatty acids raises the melting point of meibomian gland secretions, or meibum, leading to thicker, more viscous secretions that obstruct ductules and cause stagnation of secretions.

Patients on antiandrogenic therapy for prostate disease also have increased viscosity of meibum, decreased tear breakup time (TBUT), and increased tear film debris, all of which indicate a deficient or abnormal tear film.

SS-Associated Dry Eye Disease (Primary or Secondary)

SS-associated dry eye disease leads to a chronic inflammatory state, with the production of autoantibodies, including antinuclear antibody (ANA), rheumatoid factor (RF), fodrin (a cytoskeletal protein), the muscarinic M3 receptor, or SS-specific antibodies (eg, anti-RO [SS-A] and anti-LA [SS-B]); inflammatory cytokine release; and focal lymphocytic infiltration of the lacrimal and salivary gland, with glandular degeneration and induction of  apoptosis in the conjunctiva and lacrimal glands. The lymphocytic infiltrates consist mainly of CD4+ T cells but also B cells.

This results in dysfunction of the lacrimal gland with reduced tear production, as well as loss of response to nerve stimulation and less reflex tearing. Active T-lymphocytic infiltrate in the conjunctiva has also been reported in non-SS dry eye disease.

The International Dry Eye WorkShop II (DEWS II) classifies dry eye disease as the following 2 major subtypes:

• Aqueous deficient dry eye (ADDE)
• Evaporative dry eye (EDE)

Etiology: Aqueous Deficient Dry Eye (ADDE)

Causes of deficient aqueous production can further be classified as related or unrelated to SS.

Non-Sjögren syndrome

Primary lacrimal gland deficiencies that may impair aqueous production include the following:

• Idiopathic
• Age-related dry eye
• Congenital alacrima (eg, Riley-Day syndrome)
• Familial dysautonomia

Secondary lacrimal gland deficiencies that may impair aqueous production include the following:

• Lacrimal gland infiltration
• Sarcoidosis
• Lymphoma
• AIDS
• Amyloidosis
• Hemochromatosis
• Lacrimal gland infectious diseases
• HIV diffuse infiltrative lymphadenopathy syndrome
• Trachoma
• Systemic vitamin A deficiency (xerophthalmia) – Malnutrition, fat-free diets, intestinal malabsorption from inflammatory bowel disease, bowel resection, or chronic alcoholism
• Lacrimal gland ablation
• Lacrimal gland denervation
• IgG-4 disease with ocular involvement

Lacrimal obstructive diseases that may impair aqueous production include the following:

• Trachoma
• Ocular cicatricial pemphigoid
• Stevens-Johnson syndrome/toxic epidermal necrolysis
• Chemical and thermal burns
• Endocrine imbalance
• Post-irradiation fibrosis
• Ocular graft-versus-host disease 

Medications that may impair aqueous production include the following:

• Antihistamines
• Beta blockers
• Phenothiazines
• Atropine
• Oral contraceptives
• Anxiolytics
• Antiparkinsonian agents
• Diuretics
• Anticholinergics
• Antiarrhythmics
• Topical preservatives in eye drops (eg, benzalkonium chloride [BAK], thimerosal)
• Topical anesthetics
• Isotretinoin

The following conditions may lead to reflex hyposecretion:

• Neurotrophic keratitis – Cranial nerve (CN) V/ganglion section/injection/compression
• Corneal surgery - Limbal incision (eg, extracapsular cataract extraction), keratoplasty, and refractive surgery
• Infective - Herpes simplex keratitis and herpes zoster ophthalmicus
• Topical agents - Topical anesthesia
• Systemic medications – Beta blockers and atropine-like drugs
• Chronic contact lens wear
• Diabetes
• Aging
• Trichloroethylene toxicity
• CN VII damage

Sjögren syndrome

Primary SS has no associated CTD.

Secondary SS may be associated with any of the following CTDs:

• Rheumatoid arthritis
• Systemic lupus erythematosus
• Progressive systemic sclerosis (scleroderma)
• Psoriatic arthritis
• Primary biliary cirrhosis
• Interstitial nephritis
• Polymyositis
• Dermatomyositis
• Granulomatosis with polyangiitis (formerly Wegener granulomatosis)
• Polyarteritis nodosa
• Hashimoto thyroiditis
• Lymphocytic interstitial pneumonitis
• Idiopathic thrombocytopenic purpura
• Hypergammaglobulinemia
• Waldenstrom macroglobulinemia

Etiology: Evaporative Dry Eye (EDE)

Intrinsic causes

Meibomian gland disease may involve a reduced number of functioning glands, as in congenital deficiency or acquired meibomian gland dysfunction, or complete gland replacement, as in distichiasis, lymphedema-distichiasis syndrome, or metaplasia. Meibomian gland dysfunction may be divided into 3 subtypes, as follows:

• Hypersecretory - Meibomian seborrhea
• Hyposecretory - Isotretinoin therapy 
• Obstructive - This may be simple, primary, or secondary to local disease (eg, anterior blepharitis), systemic disease (eg, acne rosacea, seborrheic dermatitis, atopy, ichthyosis, or psoriasis), syndromes (eg, anhidrotic ectodermal dysplasia, ectrodactyly syndrome, or Turner syndrome), or systemic toxicity (eg, 13- cis retinoic acid or polychlorinated biphenyls); or it may be cicatricial, primary or secondary to local disease (eg, chemical burns, trachoma, pemphigoid, erythema multiforme, acne rosacea, vernal keratoconjunctivitis [VKC], or atopic keratoconjunctivitis [AKC])

Evaporative loss may result from a low blink rate caused by the following:

• Physiologic phenomenon, such as may occur during performance of tasks that require concentration (eg, working at a computer or a microscope)
• Extrapyramidal disorder, such as Parkinson disease (decreasing dopaminergic neuron pool)

Evaporative loss may result from the following disorders of eyelid aperture and eyelid-globe congruity:

• Exposure (eg, craniosynostosis, proptosis, exophthalmos, lagaophthalmos, and high myopia)
• Lid palsy
• Eyelid malposition (eg, ectropion, entropion, floppy eyelid syndrome)
• Lid margin abnormality (eg, lid margin coloboma)

In addition, the actions of drugs such as isotretinoin may lead to evaporative loss.

Extrinsic causes

Vitamin A deficiency may cause dry eye as a consequence of the following:

• Development disorder of goblet cells
• Lacrimal acinar damage

Other extrinsic causes of dry eye are as follows:

• Topical drugs and preservatives that cause surface epithelial cell damage
• Contact lens wear
• Ocular surface disease (eg, atopic keratoconjunctivitis, chronic anterior blepharitis, chronic conjunctivitis, ocular cicatricial pemphigoid, Stevens-Johnson syndrome)

Dry eye disease is very common in the United States, affecting a significant percentage of the population, especially those older than 50 years. Prevalence estimates range from 10-30%. An estimated 3.23 million women and 1.68 million men aged 50 years and older are affected.[25, 26] The prevalence of dry eye disease also is increasing among young adults aged 18-34 years, mostly owing to increased use of soft contact lenses and frequent smartphone and computer usage.[27]

Dry eye disease is one of the most common reasons for a patient to seek eye care.[28] Furthermore, its widespread prevalence has created a significant socioeconomic burden on the United States healthcare system. Lost productivity through missed work days, the rising cost of treatment, and the social and emotional stressors encountered by patients with dry eye disease are notable.[29]

As a consequence of the demographic pressure created by an aging population, meibomian gland dysfunction is expected to increase in prevalence and thus to impose a growing burden on ophthalmologic practices.[30] Development of thoughtful, effective strategies that involve the underlying mechanism of meibomian gland dysfunction is critical to the effective, patient-satisfying functioning of every ophthalmologist’s practice.

The reported frequency of dry eye in other countries closely parallels that in the United States.

Dry eye is more common in women.[25] Dry eye disease associated with SS is believed to affect 1-2% of the population, and 90% of those affected are women. Data on race and ethnicity in dry eye disease are limited, but the frequency and the clinical diagnosis of dry eye appear to be greater in the Hispanic and Asian populations than in whites.

The prognosis of dry eye disease varies depending on the severity of the condition. Most patients have mild-to-moderate cases that can be treated symptomatically with lubricants, often providing adequate relief of symptoms. More severe cases may require surgical management such as punctal occlusion or correcting eyelid malposition. In general, the prognosis for visual acuity in patients with dry eye disease is good. Patients with SS or prolonged untreated dry eye represent a subgroup with a worse prognosis, requiring a longer course of treatment.

Dry eye may be complicated by sterile or infectious corneal ulceration, particularly in patients with SS. Ulcers are typically circular central or paracentral corneal lesions that are smaller than 3 mm in diameter. Occasionally, corneal perforation may occur. In rare cases, sterile or infectious corneal ulceration in dry eye disease can cause blindness. This risk is markedly increased with contact lens use, particularly with overnight wear.

Punctate epithelial defects (PEDs) may be present. Significant punctate epitheliopathy can lead to corneal erosions, both sterile and infectious corneal ulceration, corneal neovascularization, corneal scarring, corneal thinning, and even corneal perforation.`

A wide variety of educational materials is available for patients with dry eye disease, particularly online. For patients with SS, regular dental examinations are important because dry mouth or xerostomia, a component of SS, significantly increases the risk for dental problems. Women should receive regular checkups from their gynecologists.

Patients with SS can obtain up-to-date information from the Sjögren’s Syndrome Foundation, 6707 Democracy Boulevard, Suite 325, Bethesda, MD 20817; (301) 530-4420 or (800) 475-6473; fax, (301) 530-4415.

For patient education information, see the Eye and Vision Center, as well as Dry Eye Syndrome, Pink Eye, How to Instill Your Eyedrops, and Sjögren’s Syndrome. Other resources include the National Eye Insitute Fact page about dry eyes and the Sjögren Foundation. See also the following topics:

• Atopic Keratoconjunctivitis
• Epidemic Keratoconjunctivitis
• Superior Limbic Keratoconjunctivitis
• Acute Hemorrhagic Conjunctivitis
• Allergic Conjunctivitis
• Bacterial Conjunctivitis
• Emergent Treatment of Acute Conjunctivitis
• Giant Papillary Conjunctivitis
• Neonatal Conjunctivitis
• Viral Conjunctivitis

Depending on the severity of dry eye disease (DED), or keratoconjunctivitis sicca (KCS), the following are the most common patient complaints:

• Foreign-body, burning, gritty, or itching sensation. 
• Redness
• Mucoid discharge
• Ocular irritation
• Ocular dryness
• Excessive tearing (secondary to reflex secretion)
• Photophobia
• Itching
• Fluctuating or blurry vision that may improve with blinking 

These symptoms often are exacerbated in smoky or dry environments, by indoor heating, by fans, or by excessive reading or computer use. Often, the symptoms worsen as the day goes on.

These symptoms are quantified objectively in the Ocular Surface Disease Index (OSDI) questionnaire, which lists 12 symptoms and grades each on a scale of 1 to 4.

Patients with meibomian gland dysfunction (MGD) may complain of redness of the eyelids and conjunctiva, but in these patients, the symptoms are often worse upon awakening in the morning.

Paradoxically, some patients with dry eye disease complain of too much tearing. When evidence of dry eye disease exists, this symptom often is explained by excessive reflex tearing due to severe corneal surface disease from the dryness. Epiphora also may accompany conjunctivochalasis, which demands consideration of surgical intervention.

The patient’s medical history may be significant for coexisting connective tissue disease (CTD), rheumatoid arthritis (RA), or thyroid abnormalities. A thorough review of systems should be obtained, focusing specifically on dry mouth, arthritis, cutaneous changes, malaise, weight loss, and lymphadenopathy. Within the veteran population, a study found an increased incidence of dry eye disease in both men and women that was also strongly connected to cases of posttraumatic stress disorder and depression.[31]

Dry eye disease (DED), or keratoconjunctivitis sicca (KCS), is a clinical diagnosis, made by combining information obtained from the history and from the physical examination, and performing one or more diagnostic tests to lend objectivity to the diagnosis. No single test is sufficiently specific to permit an absolute diagnosis of dry eye disease. 

Studies that may be used in the workup include symptom questionnaires, impression cytology to monitor the progression of ocular surface changes, measurement of tear breakup time (TBUT), the Schirmer test, and quantification of tear components through analysis of tear proteins or tear-film osmolarity.[32] Serology for circulating autoantibodies may be indicated.

Sjögren syndrome

All cases of SS are characterized by a progressive infiltration of the lacrimal and salivary glands by lymphocytes, predominantly B cells and CD4+ lymphocytes, which leads to disorganization of the normal gland architecture and consequent loss of function. At this time, the most comprehensive criteria for a diagnosis of SS include the following:

• Abnormally low Schirmer test result
• Objective evidence of low salivary flow
• Biopsy-proven lymphocytic infiltration of the labial salivary glands
• Dysfunction of the immune system, as manifested by the presence of serum autoantibodies (eg, antinuclear antibody [ANA], rheumatoid factor [RF], and anti-Ro [SS-A] and anti-La [SS-B] antibodies)

A novel test called Sjo is available from IMMCO Laboratories through Bausch & Lomb. In addition to traditional ANA, RF, Ro, and La autoantibodies, it is used to evaluate for proprietary early markers of SS. These early antibodies may enable the clinician to identify SS up to 4 years earlier than the traditional antibody panel.[33]

Ocular symptoms are difficult to standardize. Symptom questionnaires can be used to help establish a diagnosis of dry eye disease, validate medical necessity for further intervention, and to assess the effects of treatments or to grade disease severity. Among the most commonly used and validated include the following[34] :

• OSDI (Ocular Surface Disease Index) is the most established instrument in studies. 
• Dry Eye Questionnaire (DEQ-5) is attractive due to its short length and discriminative ability. 
• SANDE (Symptom Assessment in Dry Eye) should be considered for repeated comfort assessment.

There also are questionnaires developed specifically for contact lens wearers such as:

• Contact Lens Dry Eyes Questionaire (CLDEQ)
• 8-item Contact Lens Dry Eye Questionnaire (CLDEQ-8)
• Contact Lens Impact on Quality of Life (CLIQ)

Tear breakup time (TBUT) is the most frequently used measurement to assess for tear film stability. It is determined by measuring the interval between instillation of topical fluorescein 0.5% and appearance of the first dry spots on the cornea. Measure it prior to instillation of any anesthetic eye drops. A fluorescein strip is moistened with saline and applied to the inferior cul-de-sac. After several blinks, the tear film is examined using a broad-beam of slit lamp with a blue filter for the appearance of the first dry spots on the cornea. Three consecutive measurements are taken, and the median value is recorded as TBUT. A TBUT of less than 10 seconds is considered abnormal, indicative of tear instability. If a patient blinks before the tear film breaks up, even with training, then the time is recorded as TBUT. The lower median TBUT between two eyes should be used in making clinical diagnosis. Besides subjective observation techniques, several devices can measure the TBUT objectively, including the Oculus Keratograph 5M.[34]

Other tests to assess tear film stability

Other tests to assess tear film stability include the following:

• Thermography measures the cooling of the ocuar surface as the result of evaporation. Studies have found that the area of cooling colocalizes with the area with tear break up, and in fact precedes the thinning and breakup of the tears. ^[35]
• Tear evaporation rate is an indicator for tear film stability and can be measured using a variety of techniques such as measuring the vapor pressure gradient, and the velocity of relative humidity increases within a goggle placed over the eye. However, the measurement is affected by environmental factors such as ambient temperature, humidity, and skin evaporation around the eye. 

Rose bengal, lissamine green, and fluorescein staining are used to evaluate epitheliopathy associated with ocular surface damage. Rose bengal stains any cells (devitalized or alive) that are not adequately protected by mucin. On the other hand, lissamine green stains only devitalized cells with damaged cell membranes. Both lissanine green and rose bengal are useful in asssessing conjunctival abnormalities. Fluorescein pools in epithelial erosions and stains exposed basement membrane due to a disruption in intercellular junctions or epithelial cell loss; generally, it stains the cornea more than the conjunctiva. 

Among the 3 stains, flourescein and lissamine green are well tolerated. Rose bengal stings on instillation and also induces reflex tearing, and is thus less well tolerated. Furthermore, in vitro studies have shown that rose bengal stains suppress healthy corneal epithlial cell viabilitiy. As a result, lissanine green has largely replaced the use of rose bengal in the workup for ocular surface disease.[34]  Lastly, mixture of these dyes (eg, 2% flourescein with 1% lissamine green) has been proposed to allow simultaneous staining of both the cornea and conjunctiva, but is not commercially available.[36]  

Early or mild cases of dry eye disease are detected more easily with rose bengal or lissamine than with fluorescein staining, and the conjunctiva usually is stained more intensely than the cornea. Interpalpebral staining of the nasal or inferior paracentral cornea is seen in dry eye disease. A linear pattern of inferior conjunctiva and corneal staining by rose bengal or lissamine is characteristic of meibomian gland dysfunction (MGD).

Van Bijsterveld developed a scoring system for rose bengal/lissamine green staining that evaluates the intensity of staining on a scale of 0 to 3 in three areas: (1) nasal conjunctiva, (2) temporal conjunctiva, and (3) cornea. With this system, the maximum possible score is 9, and a score of 3.5 or higher is considered positive for dry eye disease. 

The Schirmer test is used to test aqueous tear production. Traditionally, the Basic secretion test is performed by instilling a topical anesthetic and then placing a thin strip of filter paper in the inferior cul-de-sac. The corners of a soft tissue paper may be used to wick all liquid from the inferior fornix by capillary attraction without any wiping or direct irritation before the paper is placed. The patients’ eyes are then closed for 5 minutes, and the amount of wetting of the paper strip is measured. Less than 5 mm of wetting is abnormal; 5 to 10 mm is equivocal.

The Schirmer I test, which measures both basic and reflex tearing, consists of the same test without the use of a topical anesthetic agent. Less than 10 mm of wetting after 5 minutes is diagnostic of ATD. The test is relatively specific, but it is poorly sensitive.

The Schirmer II test, which measures reflex tearing, may be done if the initial Schirmer test yields abnormal results. It is essentially similar to the basic secretion test, but with the addition of nasal mucosal irritation induced with a cotton tip applicator. Wetting of less than 15 mm after 5 minutes is consistent with abnormalities of reflex secretion.

Absence of nasal lacrimal reflex tearing, presence of serum autoantibodies, and severe ocular surface disease demonstrated by rose bengal or fluorescein staining argues strongly in favor of a diagnosis of SS-associated dry eye disease.

Other tests to assess tear production 

Other tests to assess tear production include the following:

• Meniscometry (measurement of tear meniscus radius, height, and cross-sectional area) is used to help diagnose ATD. A rotatable projection system with a target comprising black and white stripes is projected onto the lower central tear film meniscus. Images are recorded and then transferred to a computer for calculation of the radius of curvature. Several commercially available imaging devices can provide serial quantitative measurements.

Tear film osmolarity has a central role in the homeostais of the tear film. Tear film hyperosmolarity is a critical component in the pathology of DED. (See Pathophysiology). Tear osmolarity is the single best marker of DED disease severity from normal to severe DED. Osmolarity increases with disease severity and various cutoff values have been studied. In general, a positive result for DED is defined to be greater than or equal to 308 mOsm/L in either eye or an interocular difference of >8 mOsm/L.[34]  

Measurement of tear-film osmolarity may be performed to assess patients suspected of having dry eye disease, an application probably first considered and promoted by Gilbard et al.[37]  Tear-film osmolarity has been shown to be elevated in patients with dry eyes. It is a very sensitive test for identifying a dry eye but lacks some specificity in meibomitis, herpes simplex keratitis, and bacterial conjunctivitis. Many clinicians consider tear film osmolarity to be the objective clinical foundation for dry eye disease evaluation, staging, and ongoing monitoring of therapeutic response.

In a multicenter study of 314 consecutive participants aged 18 to 82 years that compared bilateral tear osmolarity assessment, TBUT measurement, corneal staining, conjunctival staining, Schirmer testing, and meibomian gland grading, Lemp et al concluded that assessment of tear osmolarity had superior diagnostic performance and was the best single metric for diagnosing and classifying dry eye disease.[38]  This test was more sensitive and specific than the others, and increasing dry eye disease severity was correlated with higher intereye differences in osmolarity.

The tear ferning test (TFT) can also be used to help diagnose the quality of tears (electrolyte concentration), dry eye disease, and hyperosmolarity. A drop of tear fluid is collected from the lower meniscus and placed onto a microscope slide and allowed to dry by evaporation. Different forms of branching crystallization patterns can be observed and classified. This test permits the separation of healthy eyes from dry eyes based on ferning patterns.

Additional tests may be performed to quantify each individual tear component.

Lipid component

Lipids may be tested for by collecting meibum, either by squeezing the eyelid margin to encourage expression from the meibomian glands or by using sterile curettes to suck meibum from individual gland orifices. Analysis may be accomplished by means of either high pressure liquid chromatography (HPLC) or gas chromatography with mass spectroscopy (GC-MS).

Meibomian gland morphology and density and dropout may be analyzed with meibography and/or meiboscopy to help diagnose meibomian gland dysfunction. Meiboscopy is the visualization of the meibomian gland via transillumination of the eyelid; meibography implies photographic image documentation. Meibomian gland morphology can be photographically documented by several commercially available devices, including the Oculus Keratograph 5M and the Tear Science LipiView. Dynamic Meibomian Imaging (DMI) from the LipiView device provides a distinct picture of the entire everted inferior tarsal plate, allowing both the clinician and the patient to assess the extent of meibomian gland dysfunction and its characteristic meibomian gland dropout.[39]

Meibomian gland expression of inspissated glands is another useful diagnostic and therapeutic in-office procedure.

Meibomian gland dysfunction may also be diagnosed using meibometry. Lipid on the lower central lid margin is blotted onto a plastic tape, and the amount taken up is read by optical densitometry. This provides an indirect measure of the steady state level of the meibomian lipid.

Aqueous component

The aqueous/protein component may be tested for by measuring tear lysozyme, tear lactoferrin, epidermal growth factor (EGF), aquaporin 5, lipocalin, and immunoglobulin A (IgA) concentrations with enzyme-linked immunosorbent assay (ELISA) techniques, as well as tear-film osmolarity.

Lysozyme accounts for approximately 20-40% of total tear protein. The main disadvantage of tear lysosome testing is its lack of specificity in cases of meibomitis, herpes simplex keratitis, and bacterial conjunctivitis. Lactoferrin has antibacterial and antioxidant functions. Lactoferrin analysis is commercially available through colorimetric solid-phase and ELISA techniques. This study offers good correlation with other tests.

Mucin component

Mucins may be analyzed by using impression cytology or brush cytology techniques, which obtain epithelial and goblet cells that can then be tested for mucin messenger RNA (mRNA) expression. Immunofluorescence, flow cytometry, ELISA, or immunoblotting techniques may also be used.

When the mucin layer of the tear is decreased, as with xerophthalmia or ocular cicatricial pemphigoid, squamous metaplasia and the following cytologic characteristics occur:

• Loss of goblet cells
• Enlargement of superficial epithelial cells and an increase in their cytoplasm-to-nucleus ratio
• Keratinization

Impression cytology is highly sensitive, but it does require proper staining and expert microscopic evaluation of samples. New in-office devices that measure lipid layer thickness have emerged, although the application of these products is under further investigation.

Matrix metalloproteinase 9

The constitutive production of MMP-9 for epithelial maintenance may be up-regulated in dry eye disease, contact lens use, or anterior basement membrane dystrophy (ABMD). MMP-9 on the ocular surface can now be measured at the point of service in any clinical setting with a noninvasive 22-minute technician-driven test. No special equipment is required.

InflammaDry (Quidel) is a rapid in-office test for diagnosing dry eye disease. The test, which takes less than 2 minutes to procure and 20 minutes to incubate, uses ocular surface samples to detect the inflammatory marker matrix metalloproteinase-9. MMP-9 has been shown to be consistently elevated in the tears of patients with dry eye disease.[40]

The tear stability analysis system (TSAS) is a noninvasive and objective test that is used to help diagnose tear-film instability.

The tear function index (TFI; Liverpool modification) is used to evaluate the tear dynamics of production and drainage, and helps to detect dry eye. The test involves the use of prepared filter paper strips that contain fluorescein, and it has been designed to allow direct measurement of the TFI through the use of these strips.

Central corneal thickness is reduced in patients with dry eye disease, possibly as a consequence of the hypertonicity of the tear film in these patients. Corneal thickness has been shown to increase after treatment with artificial tears, and this may be a useful diagnostic and follow-up criterion for dry eye disease.

Visual acuity and corneal topography and keratometry readings have been shown to improve after the use of artificial tears.

The tear turnover rate, defined as the percentage by which the fluorescein concentration in tears decreases per minute after instillation, is also reduced in patients with symptomatic dry eye disease. It is determined by means of fluorophotometry.

Lacrimal gland or minor (salivary) gland biopsy may be performed to aid in diagnosing SS. Conjunctival biopsy also may be performed.

Pathologic examination of the lacrimal gland in patients with dry eye disease reveals age-related changes, including lobular and diffuse fibrosis and atrophy, as well as periductal fibrosis. An underlying autoimmune mechanism represented by round-cell infiltration may be present. No circulating autoantibodies are found in patients who do not have SS with dry eye disease.

Histopathologically, dry eye disease is characterized by squamous metaplasia with loss of goblet cells, cellular enlargement, and an increase in the cytoplasm-to-nucleus ratio of the superficial conjunctival epithelial cells. The lacrimal gland and the conjunctiva are also heavily infiltrated by CD4+ T cells and B cells. In meibomian gland dysfunction, loss of glandular architecture, dilation of the ductules, ductal occlusion, and hyperkeratinization of the ductal epithelium are seen.

Severity

For classification of dry eye disease based on severity, the Delphi Panel Report was adopted and modified as a third component of the DEWS (see the Table below).[41]

Table. Dry Eye Severity Levels (Open Table in a new window)

Early detection and aggressive treatment of dry eye disease (DED), or keratoconjunctivitis sicca (KCS), may help prevent corneal ulcers and scarring. The frequency of follow-up care depends on the severity of the signs and symptoms.

Although supplemental lubrication is the mainstay of treatment for mild and moderate aqueous-deficient dry eye disease, any concomitant lid disease also must be treated. The use of topical cyclosporine has been shown to enhance the production of the aqueous component of the tear layer, as well as increase goblet cell density and decrease inflammatory tear cytokines. The use of oral omega-3 fatty acids has beneficial anti-inflammatory properties that aid in the production of tears. Numerous preparations of omega-3 fatty acids are available for point-of-service sales and provide pharmaceutical-grade, mercury-free sources of essential fatty acids known to improve ocular surface function.[42, 43]

Other forms of treatment include the use of plugs that block the puncta. Temporary punctal occlusion may be accomplished with collagen (dissolvable) or silicone (permanent) plugs; newer cross-linked collagen punctal plugs have a longer duration of action before dissolving, with labeling from 3-6 months postimplantation. If plugs are ineffective, electrocauterization of the inferior puncta may be performed in patients with severe dry eye disease, documented Schirmer tear test deficiency, and patent upper lid puncta. In some cases, other surgical options may be considered.

Environment-related issues that may exacerbate dry eye disease should be discussed; alternatives may be needed.

Treatment of very severe dry eye disease or dry eye disease associated with a connective tissue disorder (CTD), including Sjögren syndrome (SS), should be coordinated with an internist or a rheumatologist, as well as relevant dental and gynecologic consultants.

DEWS II treatment recommendations

The Management and Therapy Subcommittee of the Tear Film and Ocular Surface Society's Dry Eye Workshop II (TFOS DEWS II) have proposed an updated (2017) algorithm to approach the treatment of dry eye. The algorithm, adapted here from the published report,[44] is presented in a stepwise approach, beginning with low-risk, highly available interventions and progressing for cases of treatment failure or severe dry eye.

Step 1 is as follows:

• Educate the patient regarding the condition, management, and prognosis
• Modify the patient’s local environment
• Educate the patient on dietary modifications (including oral essential fatty acid supplementation)
• Identify any potentially etiologic systemic/topical medications and consider modification or elimination of offending agents
• Apply ocular lubricants (lipid-containing supplements in patients with MGD)
• Institute proper lid hygiene and apply warm compresses

Step 2 (used if the above options are inadequate) is as follows:

• Use of nonpreserved ocular lubricants to minimize preservative-induced toxicity
• Tea tree oil therapy to treat demodicosis, if present
• Tear conservation therapy (punctal occlusion, moisture chamber spectacles/goggles)
• Overnight treatments (eg, ointment or moisture chamber devices)
• In-office, physical heating and expression of the meibomian glands (including device-assisted therapies [eg, LipiFlow])
• In-office intense pulsed light therapy to treat MGD
• Prescription drug therapy (topical antibiotic with or without steroid applied to lid margins for anterior blepharitis, limited-duration topical corticosteroid, topical secretagogues, topical nonglucocorticoid immunomodulators (eg, cyclosporine), topical LFA-1 antagonists (eg, lifitegrast), oral macrolide or tetracycline antibiotics

Step 3 (used if the above options are inadequate) is as follows:

• Oral secretagogue therapy
• Application of autologous/allogeneic serum eye drops
• Therapeutic contact lenses (soft bandage lenses, rigid scleral lenses)

Step 4 (used if the above options are inadequate) is as follows:

• Longer-duration topical corticosteroid therapy
• Amniotic membrane grafting
• Surgical punctal occlusion
• Other surgical options (eg, salivary gland transplantation, tarsorrhaphy)

Agents that have been used to treat dry eye disease include the following:

• Artificial tear substitutes
• Gels, emulsions and ointments
• Anti-inflammatory agents - Topical cyclosporine, ^{[5, 6]} topical corticosteroids
• Topical or systemic omega-3 fatty acids: Omega-3 fatty acids inhibit the synthesis of lipid mediators and block the production of interleukin (IL)–1 and tumor necrosis factor alpha (TNF-α)
• Topical or systemic tetracyclines: Decrease MMP, collagenase, and phospholipase A2 activity and inhibit bacterial lipase with a resultant decrease in pro-inflammatory free fatty acids
• Systemic immunosuppressants
• Lymphocyte function-associated antigen 1 (LFA-1) antagonists (eg, lifitegrast) 
• Selective nicotinic acetylcholine receptor agonists (eg, varenicline) 
• Tear evaporation prevention (perfluorohexyloctane)
• Secretagogues - Diquafosol (approved in Japan ^{[9, 10]}  but not in the United States)
• Autologous or umbilical cord serum

Lubricating supplements are the medications most commonly used to treat dry eye disease. If these agents are to be used more frequently than every 3 hours, preservative-free formulations are the treatment of choice. If a patient has SS, the use of systemic immunosuppressants should be considered.

Prescribe artificial tears, preferably preservative-free artificial tears, and a lubricating ointment. Mild dry eye disease can be treated with drops up to 4 times a day; more severe cases call for more aggressive treatment, such as drops 10-12 times a day. Thick artificial tear drops or gels also can be used in more severe cases, although these agents tend to blur the vision. Tear ointments can be used during the day, but they are generally reserved for bedtime use because of the poor vision after placement.

Cyclosporine

Cyclosporine is a neurokinin (NK)–1 and NK-2 receptor inhibitor that can down-regulate these signaling molecules. It improves goblet cell counts and reduces the numbers of inflammatory cells and cytokines in the conjunctiva. Another novel addition to the therapeutic armamentarium for dry eye disease is lifitegrast, which commonly is used in conjunction with cyclosporine to treat both aqueous tear deficiency and evaporative dry eye disease. 

The clinical trials that led to FDA approval of topical cyclosporine 0.05% emulsion for the treatment of moderate to severe dry eye disease demonstrated statistically significant tear production increases in treated patients compared to tear-only controls. In addition, these trials demonstrated that topical cyclosporine emulsion produced no detectable serum levels, reduced concomitant artificial tear use, reduced ocular surface goblet cell density and T-cell expression based on conjunctival biopsy analysis, and reduced inflammatory tear cytokine production based on tear analysis.

A randomized, double-masked, vehicle-controlled clinical study evaluated the efficacy and safety of 2 different concentrations of cyclosporine (1% and 0.05%) in aqueous solution compared with vehicle. At Day 21, noted as early in the trial, statistically significant improvement in 4 symptoms and 3 ocular signs were observed when cyclosporine 1% was administered, and equivalent improvement in 3 symptoms and 3 ocular signs was observed when cyclosporine 0.5% was used.[45]

Lifitegrast

Lifitegrast  is a small-molecule integrin antagonist that reduces ocular surface inflammation and T-cell activation by blocking the interaction of lymphocyte function-associated antigen 1 (LFA-1) with intracellular adhesion molecule 1 (ICAM-1). It is safe and effective and is FDA-approved for the treatment of dry eye disease.[7, 8, 46]

The first LFA-1 antagonist, lifitegrast ophthalmic (Xiidra), was approved by the FDA in July 2016 for treatment of the signs and symptoms of dry eye disease. Lifitegrast binds to the integrin lymphocyte function-associated antigen-1 (LFA-1), a cell surface protein bound on leukocytes, and blocks the interactions of LFA-1 with its cognate ligand intercellular adhesion molecule-1 (ICAM-1). ICAM-1 may be overexpressed in corneal and conjunctival tissues in dry eye disease; LFA-1/ICAM-1 interaction can contribute to the formation of an immunologic synapse, resulting in T-cell activation and migration to target tissues.

Approval of lifitegrast was based on four phase 3 trials (n >2500), OPUS-1, OPUS-2, OPUS-3, and one long-term (1-year) phase 3 safety study (SONATA).[7, 8, 46, 47, 48] Lifitegrast improved inferior corneal staining score (ICSS) in the OPUS-1 and OPUS-3 studies.[47, 48] Ocular safety and tolerability were similar to those of placebo.[7]

Loteprednol

Loteprednol etabonate is an analog of prednisolone acetate. After ocular administration, it is converted to inactive metabolites rapidly by the cellular esterases and therefore has relatively less risk for systemic side effects. Given its high anti-inflammatory efficacy and improved safety profile, loteprednol of a variety of concentrations has been used in reducing post-operative ocular inflammations and treating seasonal allergic conjunctivitis. Studies have also found that loteprednol etabonate 0.5% provided short-term rapid relief for dry eye signs and symptoms in patients with mild-to-moderate DED who are about to start cyclosporine therapy.[49]

The FDA has now also approved a formuation of loteprednol etabonate specifically for short-term relief of DED symptoms up to 2 weeks. Loteprednol 0.25% ophthalmic suspension (eyesuvis) uses nanoparticle technology to enhance the ocular delivery of the medication.[50]  In a report of four randomized, vehicle-controlled and double-masked studies, loteprednol 0.25% was found to have good safety profile and was well-tolerated. It is associated with low incidences of significant IOP elevation (0.6% in the medication group vs 0.2% in the control group). The most common adverse event is instillation site pain.[51]

Varenicline Nasal Spray

Varenicline is a selective nicotinic acetylcholine receptor agonist. Oral varenicline form has been used commonly as a medication that help in smoking cessation with established safety profile. The nasal spray form is administered in the nasal cavity and reacts with the nicotinic acetylcholine receptors present on the trigeminal nerve in the nasal cavity and stimulates the lacrimal functional units that produce tears. In the ONSET-2 study, a phase 3 randomized study, statistically significantly higher percentages of participants who received twice-daily varenicline nasal spray of 0.6mg/mL or 1.2mg/mL achieved a 10-mm improvement in Schirmer's test relative to the control group. The medication was also relatively well tolerated in the study, with the most common ocular and non-ocular adverse effects being conjunctival hyperemia and transient sneezing, respectively. Other common adverse effects reported included instillation site irritation (nasal), cough, and throat irritation.[52] This varenicline nasal spray received FDA approval in October 2021 as a treatment for signs and symptoms of DED. It is the only nasal spray approved for treatment for DED and may serve as an important tool in patients with DED who do not achieve adequate relief with frequent administration of artificial tears. 

Perfluorohexyloctane ophthalmic

Perfluorohexyloctane ophthalmic (Miebo) is a semifluorinated alkane that forms a monolayer at the tear film air-liquid interface, which can be expected to reduce evaporation. It is indicated for treatment of signs and symptoms of dry eye disease.  

Approval is based on the MOJAVE and GOBI randomized clinical trials (n >1200) in patients who had a history of dry eye disease and signs of meibomian gland dysfunction. Participants received perfluorohexyloctane 4 times daily for 2 months or a placebo solution of hypotonic saline 0.6%. Those who received perfluorohexyloctane experienced statistically significant reductions in eye dryness and on total corneal fluorescein staining.[63, 64]  

Other Pharmacological Treatments

In a 2012 study, diquafosol and sodium hyaluronate showed similar efficacy in improving fluorescein staining scores of dry eye patients and diquafosol was superior in improving rose bengal staining scores. There was no significant difference between groups in adverse event rates.[53]

In-Office Procedures

Several in-office procedures are available for the treatment of dry eye disease, including the following:

• Vectored thermal pulsation (LipiFlow)
• Meibomian gland probing (Maskin probe or hyfrecator probe)
• Meibomian gland liquefaction and expression (MiBo ThermoFlo, TearCare System)
• Intense pulsed light therapy
• Intranasal tear neurostimulator (TrueTear)
• Lid-margin scrubbing (BlephEx)

Intranasal Tear Neurostimulator

Intranasal tear neurostimulation is a novel approach to the treatment of dry eyes.[54] The use of neurostimulation was first introduced for the treatment of dry eye disease by Kossler et al in 2015.[55] Intranasal tear neurostimulation works via an external, nonimplantable device to stimulate the nasal mucosa and activate the nasolacrimal reflex to increase tear production and improve tear film homeostasis. Stimulation of the nasal mucosa activates the afferent branch of the nasolacrimal reflex, whereby the anterior ethmoidal nerve relays a signal to the superior salivary nucleus in the pons. The efferent branch is then activated as the parasympathetic nerves of CN VII travel to the pterygopalatine ganglion and exit via the inferior orbital fissure as the zygomaticotemporal nerve, which innervates several components of the lacrimal functional unit. Activation of the main and accessory lacrimal glands, as well as conjunctival goblet cells and meibomian glands by the stimulated zygomaticotemporal nerve, results in increased tear production and enhances tear film homeostasis.

Several clinical trials have been conducted on the use of intranasal tear neurostimulation for the treatment of dry eye disease. This treatment modality has been shown to be safe with consistent use over 3 to 6 months and improves dry eye symptoms and tear production;  may also improve corneal and conjunctival staining.[56, 57] The device for tear neurostimulation has been shown to be superior to sham treatment.[58]

The TrueTear intranasal tear neurostimulator is FDA-approved for the treatment of dry eye disease. The current recommendation is to use the stimulator for 1 to 3 minutes 2 to 4 times daily and not to exceed 10 applications in a 24-hour period. The device is generally well tolerated, with the most common adverse effects including epistaxis and, occasionally, pain.

Eye Protection

Specially made glasses known as moisture chamber spectacles, which wrap around the eyes to retain moisture and protect against irritants, may be helpful in some cases of dry eye disease.

Contact lenses may also be helpful; these are available in the following types:

• Silicone rubber lenses
• Gas permeable scleral-bearing hard contact lenses with or without fenestration
• Highly oxygen-permeable lenses (overnight wear)
• Cryopreserved sutureless amniotic membrane is available as a 5- to 10-day contact lens ^[59]

Punctal plugs often are employed in the treatment of dry eye disease. Available types include the following:

• Absorbable plugs - These plugs are made of collagen or polymers and either dissolve by themselves or may be removed by saline irrigation; occlusion duration ranges from 7-180 days
• Nonabsorbable plugs - These plugs are made of silicone; two main categories of silicone plugs are available for dry eye, capped punctal plugs and intracanalicular plugs
• Thermoplastic plugs (eg, SmartPLUG; Medennium, Irvine, CA) – These plugs are made of a thermosensitive, hydrophobic acrylic polymer that changes from a rigid solid to a soft, cohesive gel when its temperature changes from room temperature to body temperature
• Hydrogel plugs (eg Oasis Form Fit; Sigma Pharmaceuticals, Monticello, IA)

A study by Mataftsi et al found that punctal plugs offer an effective and safe treatment for children with persistent symptoms and should be considered.[60]

In a study of punctal occlusion surgery using a high heat-energy–releasing cautery device to treat severe dry eye disease and recurrent punctal plug extrusion, Ohba et al concluded that the device was associated with a low recanalization rate and demonstrated improvements in ocular surface wetness and visual acuity.[61]

In patients with dry eyes, close the puncta. If plugs are not available or are repeatedly lost, cautery or hyfrecation is indicated for permanent closure, beginning with the lower puncta and proceeding to the upper if necessary.

Surgical treatment of dry eye disease is reserved for very severe cases in which ulceration or impending perforation of the sterile corneal ulcer occurs.

Surgical options include the following:

• Sealing of the perforation or descemetocele with corneal cyanoacrylate tissue adhesive
• Corneal or corneoscleral patching for an impending or frank perforation
• Lateral tarsorrhaphy - Temporary tarsorrhaphy (50%) is indicated in patients with dry eye disease secondary to exposure keratitis after facial nerve paralysis and after trigeminal nerve lesions that give rise to dry eye disease secondary to loss of corneal sensation
• Conjunctival flap
• Conjunctivoplasty excision of symptomatic conjunctivochalasis
• Surgical cautery occlusion of the lacrimal drainage system ^[62]
• Mucous membrane grafting
• Salivary gland duct transposition
• Amniotic membrane transplantation or amniotic membrane contact lens therapy
• Prosthetic replacement of the ocular surface ecosystem (PROSE) lens therapy

The goals of pharmacotherapy are to reduce morbidity and to prevent complications. For treatment of dry eye disease (DED), or keratoconjunctivitis sicca (KCS), artificial tears are administered with and without preservatives, depending on severity. Doxycycline 100 mg once daily or twice daily may be given for meibomian gland dysfunction (MGD), if indicated, followed by a supervised decrease in dosage to as low as 20 mg PO QD. Topical cyclosporine 0.05% ophthalmic emulsion is effective FDA-approved treatment for dry eye disease.

Lifitegrast ophthalmic solution is the first prescription specifically approved for dry eye disease by the FDA. It is a lymphocyte function-associated antigen-1 (LFA-1) antagonist.

In addition to the list below, autologous serum eye drops are unpreserved, are nonantigenic by nature, and contain growth factors, fibronectin, immunoglobulins, and vitamins at concentrations similar to or higher than those in natural or artificial tears. Serum eye drops are used for severe dry eye disease with punctate epithelial defects and corneal damage to promote reepithelialization. They can be used successfully in patients who are refractory to other forms of treatment.

Class Summary

Lubricants act as humectants in the eye. The ideal artificial lubricant should be preservative-free; contain potassium, bicarbonate, and other electrolytes; and have a polymeric system to increase its retention time. Lubricating drops are used to reduce morbidity and to prevent complications. Lubricating ointments prevent complications from dry eyes. Ocular inserts reduce symptoms resulting from moderate to severe dry eye disease.

Artificial tears (Advanced Eye Relief, Bion Tears, Hypo Tears, Murine Tears, Tears Naturale II)

Artificial tears are used to increase lubrication of the eye.

Hydroxypropyl cellulose (Lacrisert)

Hydroxypropyl cellulose acts to stabilize and thicken precorneal tear film and to prolong tear breakup time (TBUT). It is applied as a once- or twice-daily insert into the inferior cul de sac, thereby reducing the ongoing need for continuous application of supplementary topical artificial tears.

Carboxymethylcellulose (GenTeal, Lubricating Plus Eye Drops, Refresh Celluvisc, Refresh Optive, Theratears, Ultra Fresh)

These substances serve as lubricants and emollients.

Class Summary

Intercellular adhesion molecule-1 (ICAM-1) may be overexpressed in corneal and conjunctival tissues in dry eye disease. The integrin lymphocyte function-associated antigen-1 (LFA-1) interacts with ICAM-1 to contribute to the formation of an immunological synapse, resulting in T-cell activation and migration to target tissues. In vitro studies demonstrated that lifitegrast may inhibit T-cell adhesion to ICAM-1 in a human T-cell line and may inhibit secretion of inflammatory cytokines in human peripheral blood mononuclear cells.

Lifitegrast ophthalmic (Xiidra)

Lifitegrast binds to the integrin lymphocyte function-associated antigen-1 (LFA-1), a cell surface protein bound on leukocytes, and blocks the interactions of LFA-1 with its cognate ligand ICAM-1. It is indicated for treatment of the signs and symptoms of dry eye disease in adults.

Class Summary

Mucolytic agents such as topical 10% N-acetylcysteine lower mucous viscosity by digesting mucoproteins. They are used when mucous discharge or plaques are present.

Acetylcysteine

Mucolytic agents lower mucous viscosity by digesting mucoproteins. They are used when mucous discharge or plaques are present.

Class Summary

Empiric antimicrobial therapy must be comprehensive, covering all likely pathogens in the context of the clinical setting. Oral tetracycline analogues, such as doxycycline and minocycline, have been shown to be effective against meibomian gland dysfunction. They exert the following 4 types of effects:

- Antibacterial effects, resulting from a reduction in the bacterial load on the eyelid; despite considerable antimicrobial resistance in common ocular surface flora and pathogens, long-term tetracycline analogue therapy has not been shown to promote infectious complications by resistant organisms

- Antiangiogenic effects

- Anti-inflammatory effects, resulting from a decrease in activity of collagenase, phospholipase A2, and several matrix metalloproteinases (MMPs), as well as from a decrease in the production of interleukin (IL)-1 and tumor necrosis factor alpha (TNF-α)

- Inhibition of lipase production, which decreases production of diglycerides and free fatty acid (FFA) in meibomian secretions (FFA can destabilize the tear film and can cause inflammation) 

- Doxycycline and minocycline are preferred over tetracycline because they are more lipophilic and achieve a higher target tissue concentration, while having a more tolerable systemic side effect profile.

- Azithromycin is an additional antibacterial agent with anti-inflammatory effects that may be beneficial for treating dry eye disease. This drug, in low doses, inhibits the NFκB pathway with a resultant decrease in MMP activity and decreased levels of IL-8, RANTES, IL-1β, and TNF-α. However, it should be used with caution, as macrolide antibiotics may have notable systemic side effects.

Doxycycline (Acticlate, Adoxa, Doryx, Doxy 100, Solodyn, Targadox, Vibramycin)

Doxycycline inhibits protein synthesis and thus bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria.

Minocycline (Minocin, Solodyn)

Minocycline treats infections caused by susceptible gram-negative and gram-positive organisms, in addition to infections caused by susceptible Chlamydia, Rickettsia, and Mycoplasma.

Class Summary

Systemic immunosuppressants are indicated when dry eye disease is accompanied by a CTD with significant systemic complications.

Cyclosporine ophthalmic (Restasis, Cequa, Vevye)

Cyclosporine may act as a partial immunomodulator. The exact mechanism of action is not known, although it inhibits T-cell function and inhibits calcineurin. Cyclosporine emulsion has never been shown to place patients at risk of any ocular or systemic infections.

Class Summary

Corticosteroids have anti-inflammatory properties with diverse mechanisms of action and cause profound and varied metabolic effects. They modify immune response to diverse stimuli. Inflammation is the key component of the pathogenesis of dry eye disease. Topical corticosteroids can be used to reduce the inflammation.

Loteprednol etabonate (Lotemax, Alrex, Inveltys, Eysuvis)

Loteprednol etabonate decreases inflammation by numerous mechanisms, including suppressing migration of polymorphonuclear leukocytes (PMNs), reducing production of inflammatory mediators at the nuclear mRNA level, and reversing increased capillary permeability. It is a topical ester steroid available in 0.2%, 0.25%, 0.5%, and 1% drops that is associated with a decreased risk of glaucoma and cataractogenesis.

Fluorometholone (Flarex, FML, FML Forte)

Fluorometholone inhibits edema, fibrin deposition, capillary dilation, phagocytic migration, capillary proliferation, collagen deposition, and scar formation. It decreases inflammation and corneal neovascularization, suppresses migration of PMNs, and reverses capillary permeability. It is believed to act by inducing phospholipase A2 inhibitory proteins. Used topically, fluorometholone can elevate intraocular pressure (though more slowly than dexamethasone phosphate does) and cause steroid-response glaucoma.

Class Summary

Certain dietary supplements may have beneficial effects.

Omega-3 fatty acids (Lovaza)

Omega-3 fatty acids may have anti-inflammatory effects and may inhibit leukocyte function. Numerous preparations are available for point-of-service sales and provide pharmaceutical-grade, mercury-free sources of essential fatty acids known to improve ocular surface function.

Class Summary

Cholinergic agonist activity activates the trigeminal parasympathetic pathway resulting in increased production of basal tear film.

Varenicline intranasal (Tyrvaya)

Varenicline nasal spray is a water-soluble agonist for nicotinic cholinergic receptor. It increases lacrimal unit production of tear film by stimulating trigeminal nerve within the nasal cavity. It is currently approved for the treatment of signs and symptoms of DED.