Normal Physiology

The stratified tear film is composed of mucin, aqueous, and lipid components. The mucin layer consists of high-molecular-weight glycoproteins closely adherent to an inherently hydrophobic surface epithelium and its glycocalyx. Mucin provides a smooth, hydrophilic surface permitting even distribution of the overlying aqueous layer. Its primary source is conjunctival goblet cells with a small contribution from surface epithelial cells. Comprising the largest volume of the tear film, the aqueous is secreted by the main lacrimal gland, the accessory glands of Krause and Wolfring, and, minimally, a transudate of the conjunctival vessels and cornea. Consisting primarily of water, it also contains electrolytes (sodium [Na], potassium [K], chloride [Cl]) and proteins, including epidermal growth factor, immunoglobulins (IgA, IgG, IgM), lactoferrin, lysozyme, and other cytokines. These components likely play both a protective and a homeostatic role for the ocular surface. Last, meibomian glands (MGs) secrete a lipid layer, containing chiefly sterol esters and wax monoesters. Although only 0.1-µm thick, the lipid layer serves to stabilize the tear film by increasing surface tension and retarding evaporation.

The tear layer maintains a smooth surface for optical clarity, lubricates to facilitate eyelid blink, and offers protection against ocular infection. Average tear flow is about 1.2-µm/minute. Blinking serves to periodically distribute tears evenly over the ocular surface and encourages both secretion and mechanical drainage of tears through the lacrimal drainage system. Regulation likely involves both neuronal and hormonal pathways. Direct innervation of the lacrimal gland, MGs, and goblet cells has been demonstrated, with M3 class cholinergic receptors predominating in the lacrimal gland. Although estrogen has little effect on tear secretion, it may have a supportive role on the ocular surface. Androgens appear to have a positive effect on the secretion of both aqueous and lipid tears.

Pathophysiology

Reduced aqueous tear flow and increased evaporation of the aqueous component of tears leads to hyperosmolarity. Tear hyperosmolarity damages the ocular surface epithelium and sets off a cascade of inflammatory pathways that leads to apoptotic cell death, loss of goblet cells, and deficient mucus production, with resultant tear film instability. Tear film instability, in turn, leads to increased evaporation. Implicated cytokines include mitogen-activated protein (MAP) kinases, nuclear factor-κB (NF-κB), interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), and matrix metalloproteinases (MMP-9, in particular). In the early stages of DED, inflammation and mechanical irritation stimulates reflex secretion from the lacrimal gland and increased blink rate. Over time, damage to the ocular surface leads to reduction in corneal sensation and impaired reflex tearing. In advanced cases, chronic conjunctival damage can lead to metaplasia and keratinization.

Diagnosis and Classification

The 2017 report for the International Dry Eye Workshop (DEWS II) was a 2-year effort with 12 subcommittees made up of 150 experts from 23 countries. The DEWS II report updated the definition of dry eye as follows: “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 etiological roles.” The new definition emphasizes the multifactorial nature of DED, where loss of homeostasis of the tear film is the central pathophysiological concept. It also recognizes the role of neurosensory abnormalities in the development of DED. This definition continues to incorporate concepts introduced in the first DEWS report that DED results in ocular discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface. This definition encompasses all the clinical entities associated with systemic disease, as well as idiopathic DED.

A classification system algorithm for dry eye is depicted in Fig. 4.23.1 .The effect of the environment on an individual’s risk of developing dry eye also is considered. Low blink rate, wide lid aperture, aging, low androgen levels, high estrogen levels, and systemic drugs affect the so-called milieu interieur. Low relative humidity, air conditioning, air travel, high wind velocity, and other occupational environmental factors, such as video display terminal use affect the so-called milieu exterieur.

Dry eye disease classification.

(With permission from Lemp MA. The 1998 Castroviejo Lecture. New strategies in the treatment of dry-eye states. Cornea 1999;18:625–32.)

Aqueous Tear-Deficient Dry Eye

Sjögren described KCS in 1933. Consequently, defective lacrimal tear secretion is subdivided into non-Sjögren’s tear deficiency (NSTD) and Sjögren’s syndrome tear deficiency (SSTD). NSTD has no association with systemic autoimmune disease, which is a cardinal feature of SSTD.

Evaporative Dry Eye Disease

Excessive evaporation that occurs in specific periocular disorders can cause dry eye disease with or without concurrent aqueous tear deficiency. Evaporation leads to both loss of tear volume and a disproportionate loss of water, resulting in tear hyperosmolarity. Environmental conditions such as high altitude, dryness, or extreme heat accelerate evaporative tear loss even in normal eyes. Causes of evaporative DED can be intrinsic (disease affecting lid structures or dynamics) or extrinsic.

Meibomian Gland Disease and Blepharitis

Meibomian gland dysfunction (MGD) leads to both decreased secretion and abnormal composition of the tear film lipid layer. The abnormal composition leads to MG blockage and reduced effectiveness in the tear film. The resulting ocular surface and eyelid inflammation perpetuates a cycle of inflammation, scarring, hyperkeratosis, stenosis, and further MGD.

Often associated, bacterial colonization by normal lid commensals ( Staphylococcus aureus , Propionibacterium acnes , and coagulase-negative staphylococci) acts directly by altering secreted lipids and indirectly by causing inflammation. Esters and lipases produced by these commensals act on secreted lipids in the tear film, producing soaps that manifest as “meibomian foam.” An association also is seen with dermatological conditions, such as seborrheic dermatitis, atopic dermatitis, and acne rosacea, a disorder resulting in vascular dilation, telangiectasias, and plugging of sebaceous glands of both facial and eyelid skin. Secondary MGD can occur with use of 13- cis retinoic acid (isotretinoin) for treatment of acne, ingestion of polychlorinated biphenyls in contaminated cooking oil, and with cicatricial changes in conditions, such as chemical/thermal burns, trachoma, pemphigoid, erythema multiforme/Stevens–Johnson syndrome, acne rosacea, vernal keratoconjunctivitis, and atopic keratoconjunctivitis. In simple MGD, the MG orifices remain anterior to the mucocutaneous junction, whereas in cicatricial MGD, MG orifices are drawn posteriorly onto the lid and tarsal mucosa.

Exposure

Excessive exposure of the ocular surface leads to increased evaporative loss of tears; thus, any disorder that results in increased ocular exposure can cause evaporative DED. Psychological, psychiatric, mechanical, neurological, or traumatic impairment of eyelid function may result in impaired or reduced blinking, lagophthalmos, or an increased palpebral fissure width, resulting in an evaporative dry eye. Evaporative DED can be seen in thyroid eye disease secondary to proptosis or lid retraction.

Mucin Deficiency

Local conjunctival damage from cicatrizing disease or surgical trauma results not only in aqueous tear deficiency but also in depopulation of mucin-producing goblet cells and creation of anatomical abnormalities of the conjunctiva leading to improper tear distribution. Although uncommon in incidence, trachoma, pemphigoid, erythema multiforme/Stevens–Johnson syndrome, and chemical and thermal burns can result in severe DED characteristically resistant to aqueous tear replacement therapy.

Extrinsic Causes

Vitamin A deficiency can result in extensive goblet cell loss and dysfunction, leading to an unstable tear film and severe DED (xerophthalmia). Preservatives in many eyedrops (especially benzalkonium chloride) can lead to ocular surface toxicity and a dry-eye state that may be reversible if eyedrops are switched to nonpreserved formulations. Contact lens wear is commonly associated with DED symptoms. Pre-lens tear film thinning time and pre-lens lipid layer thickness is reduced in contact lens wearers with DED symptoms, and may lead to higher evaporative loss. Ocular allergies can cause a variety of corneal and conjunctival irregularities with decrease in tear film stability and consequent DED.

Non-Sjögren’s Tear Deficiency

NSTD can occur from primary lacrimal gland deficiencies, secondary lacrimal gland deficiencies, obstruction of lacrimal gland ducts, or reflex hyposecretion. Primary lacrimal gland deficiencies include age-related DED, congenital alacrima, and familial dysautonomia (Riley–Day syndrome). The most common form of NSTD is age-related DED, which is associated with ductal and interacinar fibrosis and obstruction within the lacrimal gland, possibly as a result of low-grade chronic inflammation. Congenital alacrima is a rare cause of DED in youth, resulting from primarily absent or hypoplastic lacrimal glands. Familial dysautonomia is an autosomal recessive multisystem disorder, in which generalized pain insensitivity accompanies absence of both emotional and reflex tearing. Defective sympathetic and parasympathetic innervation of the lacrimal gland and defective sensory innervation of the ocular surface occur.

Secondary lacrimal gland deficiency from infiltration and damage to the lacrimal gland in benign lymphoepithelial lesion of Godwin (“Mikulicz’s disease”), lymphoma, sarcoidosis, hemochromatosis, amyloidosis, human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), and graft-versus-host disease all can result in DED. Surgical or radiation-induced destruction or denervation of lacrimal tissue can result in secondary lacrimal deficiency. Secondary obstruction of the lacrimal gland ducts can occur with trachoma, ocular cicatricial pemphigoid, mucous membrane pemphigoid, erythema multiforme/Stevens–Johnson syndrome, chemical burns, and thermal burns.

Reflex hyposecretion of tears can be conceptually divided into reflex sensory block (damage to the afferent arm) and reflex motor block (damage to the efferent, or secretomotor arm). Reflex sensory block occurs with any reduction in ocular surface sensation and leads to decreased reflex-induced lacrimal secretion and decreased blink rate, which increases tear evaporation. Causes of decreased ocular surface sensation leading to dry eye include topical anesthetic use, contact lens wear, diabetes mellitus, aging, and neurotrophic keratitis.

As shown by studies utilizing topical anesthesia, interruption of the afferent stimulus of tear production, or sensory loss (denervation), results in decreased tear secretion and reduced blink rate. Damage to afferent sensory fibers occurs after incisional corneal surgery (penetrating or anterior lamellar keratoplasty, radial keratotomy, and limbal cataract incision) and after damage to the first division of the trigeminal ganglion from trauma, tumor, and herpes simplex or zoster, resulting in reduced tear production. Laser-assisted in situ keratomileusis (LASIK) and photorefractive keratectomy resulting in decreased corneal sensation and blink rate are recognized as precipitating causes of dry eye. Systemic medications are a common source for the inhibition of efferent lacrimal gland stimulation through anticholinergic activity or decreased secretion through systemic dehydration ( Table 4.23.1 ). Although DED has been reported in association with menopause, estrogen supplementation has not been shown to have a beneficial effect. Alterations in other hormones, especially androgens, which also are reduced during menopause, have been implicated.

Sjögren’s Syndrome Tear Deficiency

Sjögren’s syndrome is a clinical condition of aqueous tear deficiency combined with dry mouth. The syndrome is classified as primary (patients without a defined connective tissue disease) or secondary (patients who have a confirmed connective tissue disease). Primary SSTD refers to aqueous tear deficiency combined with symptoms of dry mouth, presence of autoantibodies to Ro(SSA) or La(SSB) antigens, decreased salivary secretion, and presence of lymphocytic foci on minor salivary gland biopsy. Secondary SSTD is associated with rheumatoid arthritis, systemic lupus erythematosus, polyarteritis nodosa, Wegener’s granulomatosis, systemic sclerosis, primary biliary cirrhosis, and mixed connective tissue disease. Both subtypes of SSTD feature progressive lymphocytic infiltration of the lacrimal and salivary glands and can be associated with severe and painful ocular and oral discomfort. The pathogenesis of the tear deficit in SSTD is infiltration of the lacrimal gland by B and CD4 lymphocytes (with some CD8 lymphocytes) and by plasma cells, with subsequent fibrosis.

Revised American-European consensus diagnostic and classification criteria for Sjögren’s syndrome were published in 2002. One point is given for at least one positive response or positive result in each of the following categories:

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  Ocular symptoms —daily dry eye symptoms for more than 3 months, ocular irritation, use of artificial tears more than three times per day.

  
  
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  Oral symptoms —daily dry mouth symptoms for more than 3 months, presence of swollen salivary glands, frequent drinking of liquids to aid in swallowing.

  
  
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  Ocular signs —Schirmer’s test I (without anesthetic) ≤5 mm in 5 minutes, Rose Bengal score ≥4 according to the van Bijsterveld scoring system.

  
  
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  Histopathology —biopsy of minor salivary gland showing inflammation with lymphocytic foci.

  
  
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  Oral signs —reduced salivary flow ≤1.5 mL in 5 minutes, parotid sialography showing salivary duct dilation without obstruction, salivary scintigraphy showing signs of decreased saliva production.

  
  
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  Autoantibodies —presence of anti-Ro(SSA) antibody, presence of anti-La(SSB) antibody.

For a diagnosis of primary Sjögren’s syndrome, either four of the six categories (including either histopathology or autoantibodies) or three of the four objective categories (ocular signs, histopathology, oral signs, and autoantibodies) must be met. For diagnosis of secondary Sjögren’s syndrome, in patients with a defined connective tissue disease, the presence of one symptom (ocular or oral) plus two of the three objective categories (ocular signs, histopathology, and oral signs) must be met.