5. • Dry eye disease (DED), also known as dry eye syndrome (DES) or ker-atoconjunctivitis
• It is characterized by ocular irritation and visual disturbance resulting from alterations
of the tear film and ocular surface.
• The effects of DED can vary from minor inconvenience to rare sight-threatening
• Although the diagnosis of DED traditionally has focused on inadequate secretion or
aqueous tear deficiency, the tear film is a complex and delicately balanced unit
dependent on the normal function of several distinct components.
6. • Current treatment is heavily weighted toward supplementation, stimulation,
preservation of aqueous tears, or treatment of ocular surface inflammation, which
is satisfactory for many patients.
• DED, however, often involves multiple deficiency states, which, when disregarded,
can result in treatment failure and frustration for both the patient and the
physician. Currently, a large unmet need still exists for better treatment options
for patients with DED.
8. • Estimating the prevalence of DED is complicated by the absence of consensus on
a single reliable diagnostic test.
• Several population-based epidemiological studies have utilized questionnaires to
assess prevalence of dry eye symptoms.
• American and Australian studies have revealed a prevalence of 5%–16%, whereas
Asian studies have revealed a higher prevalence of approximately 27%–33%.
10. NORMAL PHYSIOLOGY
• The stratified tear film is composed of mucin, aqueous, and lipid com-ponents.
• 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
• 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
• Consisting primarily of water, it also contains electrolytes (sodium [Na], potassium [K], chloride [Cl])
and proteins, including epidermal growth factor, immu-noglobulins (IgA, IgG, IgM), lactoferrin,
lysozyme, and other cytokines.
• These components likely play both a protective and a homeostatic role for the ocular surface.
11. • Last, meibomian glands (MGs) secrete a lipid layer, containing chiefly sterol esters and wax
• 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.
• Reduced aqueous tear flow and increased evaporation of the aqueous component of tears leads to
• 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 metal-loproteinases (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 meta-plasia and keratinization.
15. 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
• 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
16. • 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/StevensJohnson
syndrome, acne rosacea, vernal keratoconjunctivitis, and atopic
• In simple MGD, the MG orifices remain anterior to the mucocutaneous junction.
• In cicatricial MGD, MG orifices are drawn posteriorly onto the lid and tarsal
19. 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
• 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
20. • 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:
1. Ocular symptoms—daily dry eye symptoms for more than 3 months, ocular irritation, use of artificial tears more than three times per day.
2. Oral symptoms—daily dry mouth symptoms for more than 3 months, presence of swollen salivary glands, frequent drinking of liquids to aid in
3. Ocular signs—Schirmer’s test I (without anesthetic) ≤5 mm in 5 minutes, Rose Bengal score ≥4 according to the van Bijsterveld scoring system.
4. Histopathology—biopsy of minor salivary gland showing inflammation with lymphocytic foci.
5. 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.
6. 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.
21. 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
• 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
22. • Secendery 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/StevensJohnson syndrome, chemical burns, and thermal burns.
23. • 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
• 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.
24. • 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
photorefractivekeratectomy 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
• 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.
• Excessive exposure of the ocular surface leads to increased evaporative loss of
tears; thus, any disorder that results in increased ocular exposure can cause
• 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
26. 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/StevensJohnson syndrome, and chemical and thermal burns can
result in severe DED characteristically resistant to aqueous tear replacement
27. 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.
30. • Regardless of the cause, most forms of DED share similar symptoms, interpalpebral surface damage, tear instability,
and tear hyperosmolarity. Typical complaints include burning, itching, foreign body sensation, stinging, dryness,
photophobia, ocular fatigue, and redness.
• Although symptoms usually are nonspecific, careful attention to details will help refine the diagnosis.
• Patients commonly describe a diurnal pattern of aqueous tear deficiency with progression of symptoms over the
day and decompensation in particular environmental conditions, such as low humidity in airline cabins, climate
control, and the use of video display terminals.
• Conversely, nighttime exposure, floppy eyelid syndrome, and inflammatory conditions often present with worst
discomfort upon awakening.
• MGD creates an unstable tear film resulting in intermittent visual blurring and a gritty or sandy sensation. DED in
diabetes and other corneal neuropathies may exhibit little or no discomfort and create high risk for keratolysis.
31. • Common signs of DED include conjunctival injection, decreased tear meniscus, photophobia, increased tear debris,
and loss of corneal sheen found more commonly in the exposed interpalpebral fissure.
• Paradoxical epiphora in DED is usually a result of reflex tearing. Greater risk for external infections exists
secondary to decreased tear turnover and desiccation of the surface epithelium. Instability of the surface epithelium
and disordered mucin production may lead to painful and recurrent filamentary keratitis.
• Although keratinization may occur uncommonly in chronic DED, vitamin A deficiency also should be suspected.
Patients who have SSTD tend to have more severe symptoms and more serious findings compared with NSTD
• Sterile ulceration of the cornea in SSTD can be peripheral or paracentral; both thinning and perforation of these
ulcers can occurs.
• Acute lacrimal enlargement may be seen in SSTD but should be differentiated from benign lymphoepithelial lesion
of Godwin (Mikulicz’s disease), which results from infiltration of the gland without surface findings.
32. • Patient (age 73 years) with
rheumatoid arthritis and
37. DIAGNOSTIC DYE EVALUATION
• Fluorescein is a large molecule unable to traverse normal corneal epithelial tight
junctions. In advanced DED, these junctions are disrupted, allowing characteristic
diffuse subepithelial or punctate staining.
• Rose Bengal stain, a derivative of fluorescein, in a 1% solution or impregnated
strips, stains devitalized epithelial cells.
• Alternatively, lissamine green stains for cell death or degeneration, as well as cell-
to-cell junction disruption, but does not irritate the eye.
38. TEAR FILM STABILITY
• Tear film instability may be a result of either tear deficiency or evaporative DED.
• In the tear break-up time (TBUT) test, described by Norn and revised by Lemp and
Holly, fluorescein dye is instilled and the time interval is measured between a
complete blink to the first appearance of a dry spot in the precorneal tear film.
TBUTs shorter than 10 seconds indicate tear film instability.
39. MEASUREMENT OF TEAR PRODUCTION
• The most common means of measuring tear production has been Schirmer’s test, the
details of which were first published in 1903.
• Jones later advocated the use of topical anesthesia combined with a Schirmer’s test
strip for 5 minutes to reduce the stimulating effect of the filter paper strip—the
“basal” tear secretion test.
• Inconsistencies in its application limit repeatability in DED, but it still enjoys
widespread use. With these caveats in mind, the following general guidelines are
recommended (when topical anesthesia is used): a 5-minute test that results in less
than 5 mm of wetting confirms the clinical diagnosis of DED, and a result of 6–10
mm of wetting suggests DED.
40. • Hamano et al. developed the phenol red thread test to obviate the disadvantages
of Schirmer’s test by eliminating the need for anesthesia. Three millimeters of a
fine dye-impregnated 75-mm cotton thread is placed under the lateral one fifth
of the inferior palpebral lid margin for15 seconds; alkalinity changes its color to
bright orange from tear contact.
• Asian populations show a lessened wet-length response with diminishing racial
differences with advancing age.
41. • Hyperosmolarity is a common endpoint for all DED. Its measurement can be a sensitive and specific
• Its use had previously been limited to specialized research centers because of the need for expensive
equipment, but commercially available devices may now make this test more widely used in the
• Researchers also have sampled tears or ocular surface cells looking for inflammatory biomarkers, such
as IL-1, IL-17, MMP-9, interferon-γ(IFN-γ) and human leukocyte antigen–antigen D–related (HLA-DR).
• A qualitative commercial test currently is available to sample ocular surface tears for MMP-9 in the
• Other rarely performed tests for reduced tear function include fluorophotometry for decreased protein
content, lysozyme levels, ocular ferning, impression cytology, and lactoferrin assays.
• Noninvasive imaging of the tear film using meniscometry, lipid layer interferometry, high-speed
videography, optical coherence tomography, and confocal microscopy has been advocated as well.
42. OTHER TESTS
• Corneal sensation may be qualitatively assessed with a cotton wisp, but quantification requires an
instrument, such as the Cochet–Bonnet aesthesiometer.
• The tear clearance test measures tear turnover with serial tear collection after instillation of a
standardized volume of dye.
• Serological tests, traditionally including antinuclear, anti-Ro, and anti-La antibodies, should be
performed in patients suspected of having autoimmune DED.
• A recently launched commercial diagnostic test combines traditional biomarkers with novel,
proprietary biomarkers to create a more accurate diagnostic test for patients suspected of having
• A definitive diagnosis of Sjögren’s syndrome requires minor salivary or, rarely, lacrimal gland biopsy.
• Neither clinical presentation nor individual ancillary tests alone are sufficient for an accurate diagnosis
44. • Significant advances have been made in treating the many facets of DED,
but it remains a disorder of long-term maintenance rather than permanent cure.
• Current therapy focuses on restoring a normal ocular surface through tear
supplementation as well as inhibition of aberrant inflammation seen in
• Since the tear film is a highly integrated unit, addressing each component is
central to the successful treatment of DED.
45. AQUEOUS TEAR DEFICIENCY
• As the first line of treatment, artificial tears increase available tears and, through
dilution, reduce tear hyperosmolarity.
• Commercial artificial tears differ in electrolyte composition, thickening agents
(methylcellulose, hydroxypropyl methylcellulose, polyvinyl alcohol), physiological
buffering, tonicity, and preservative system.
• Individual patient preferences involve such disparate concerns as cost, comfort,
visual blurring, and ease of use.
46. • Preserved tears (i.e., benzalkonium chloride) can be toxic in moderate or severe
DED, are poorly tolerated, and harmful.
• For patients with significant DED, single-dose, nonpreserved tear preparations are
the mainstay of therapy with bottled tear products a reasonable alternative
when preserved with relatively nontoxic compounds. These less toxic
preservatives include polyquaternium-1, sodium chlorite, and sodium perborate.
47. • Some artificial tear preparations are formulated to be hypo-osmotic, with the goal of
balancing the hyperosmolarity of the tear film in DED.
• Artificial tear ointments are effective for longer-lasting control of symptoms,
especially during sleep, but visual blurring limits their daytime usefulness.
• In addition, some ointments contain lanolin and parabens, which can be poorly
tolerated by patients with severe DED.
• Autologous serum tears contain trophic factors and other proteins useful in ocular
surface maintenance. These can be useful as a preservative-free, biological tear
substitute, but their preparation is labor intensive.
48. • Punctal occlusion retards tear drainage, thereby increasing tear volume on the ocular surface and lowering tear
• Occlusion may be achieved irreversibly by cauterization or semi-permanently with the use of nonabsorbable plugs.
• Occlusion with collagen plugs provides temporary relief (3 days to 6 months) and may identify those at risk for
epiphora prior to permanent occlusion.
• Secretagogues, agents that stimulate lacrimal gland secretion, require functional glandular tissue.
• Oral pilocarpine (Salagen) and cevimeline (Evoxac) are M3 cholinergic agonists approved for use in dry mouth that
also stimulate tear secretion. Their effect tends to be greater in oral dryness rather than ocular dryness.
• Systemic cholinergic side effects, such as sweating reduce patients’ acceptance.
• Various nutritional supplements are also touted for DED but without clear confirmation of their efficacy.
49. EVAPORATIVE DRY EYE DISEASE
• Primary treatment of MGD involves improving the quality and quantity of native
• Lid hygiene, in the form of warm compresses and lid massage, is effective in
improving MG secretion.
• Several techniques, including the Lipiflow System, have been developed to help
with expression of meibomian glands.
• Lid scrubs with dilute detergents decrease the seborrheic or bacterial load,
thereby breaking the proinflammatory cycle of MGD.
50. • Systemic tetracyclines have been shown to decrease local inflammation and
improve MG function after several weeks.
• The antibacterial effect also contributes to a decrease in meibomian lipid
breakdown products in the tear film.
• Topical erythromycin or azithromycin applied to the eyelid margins are
alternatives for patients who are unable to tolerate tetracycline derivatives.
• A number of lipid-like tear substitutes have become commercially available, which
have been used with some success.
51. • Correction of eyelid abnormalities that increase exposure of the ocular surface, such as lower lid
ptosis and lagophthalmos, can stabilize a decompensated ocular surface.
• In severe cases, a partial or complete tarsorrhaphy or a conjunctival flap may be necessary to
prevent decompensation of the cornea.
• The use of humidifiers, moisture chambers, glasses, or goggles increases periocular humidity
and decreases surface evaporative pressure.
• New high-Dk (oxygen permeability), high-water-content contact lenses and new polymer
lenses, accompanied by proper tear supplementation and hygiene, are effective in treating
patients with DED with poor corneal wetting.
• In patients with severe DED, scleral contact lenses can promote lubrication and slow evaporation
of tears from the ocular surface.
52. OCULAR SURFACE INFLAMMATION
• A common endpoint of all treatments of DED is not only prevention of ocular surface
inflammation and its consequential cellular changes but also restoration of the ocular
• DED-induced ocular surface inflammation disrupts the epithelial and mucin layers,
further exacerbating tear film breakdown.
• Suppression of inflammation creates a supportive environment for reversal of DED-
induced cellular changes.
• Topical cyclosporine A has been shown to increase tear production in a subset of
patients through inhibition of lacrimal gland inflammation and suppression of DED-
induced ocular surface inflammation.
53. • Lifitegrast 0.05% is the drug most recently (July 11, 2016) approved by the U.S.
Food and Drug Administration to address DED and is the only therapy approved
to treat both the signs and symptoms of DED.
• Lifitegrast is a topical anti-inflammatory drug that blocks the binding of
intercellular adhesion molecule-1 (ICAM-1) to lymphocyte function associated
antigen-1 (LFA-1) on the T-cell surface.
• Lifitegrast decreases inflammation by inhibiting T-cell recruitment and activation.
54. • Judicious use of low-dose topical corticosteroids has been shown to reduce
inflammation and allow normal reparative mechanisms to restore the natural
equilibrium of the ocular surface.
• Use of topical corticosteroids in DED currently is limited because of concerns
about adverse events with chronic use, such as glaucoma and cataract.
• Control of these reactive epithelial changes restores normal cell morphology, cell-
to-cell interactions, and critical mucin production and clearly has a role in the
global treatment of all forms of DED.
55. • Essential fatty acids cannot be synthesized by humans and must be consumed in the diet. The
typical Western diet contains a ratio of omega-6 to omega-3 fatty acids of approximately 25 : 1.
• Omega-6 fatty acids are precursors to arachidonic acid and proinflammatory molecules,
including prostaglandin E2 and leukotriene B4.
• Omega-3 fatty acids inhibit synthesis of these inflammatory mediators and decrease production
of IL-1 and TNF-α. Supplementing the diet with omega-3 fatty acids has been shown to
decrease both signs and symptoms of DED.
• Omega-3 fatty acids include eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and
alpha-linolenic acid (ALA). EPA and DHA are believed to be primarily responsible for the
beneficial health effects of omega-3 fatty acids.
56. • Fish oil contains high levels of EPA and DHA, and flaxseed oil contains high levels of
• Although ALA is converted by the body into EPA and DHA, this process is not efficient;
much higher quantities of flaxseed oil must therefore be consumed to achieve
equivalent EPA and DHA levels from smaller quantities of fish oil.
• A number of drugs (mostly topical and a few systemic) are currently being evaluated
in clinical trials aimed at providing new treatment options for patients with DED.
• Success with this research should provide patients with many more treatment options
in the future and has the potential to improve quality of life for patients suffering from