Dry eye disease Results from localized immune-mediated inflammation that ultimately affects the entire ocular surface/lacrimal gland/neural feedback functional unit. The main and accessory lacrimal glands: Susceptible to inflammation due to decreased neural or androgen support. Activation of lymphocytes leads to T-cell-mediated inflammation, cytokine production, the presence of cytokines in tears, and acinar cell apoptosis. The ocular surface: Cytokines in tears trigger inflammation (T-cell and epithelial cell activation, leukocyte recruitment) on the ocular surface, disrupt epithelial cell function, interfere with mucin production. Irritation can also trigger chemically mediated inflammation leading to activation of trafficking lymphocytes (T cells). The neural feedback loop: Sensory activity on the ocular surface is disrupted by pro-inflammatory cytokines and compromised epithelial cells, impacting afferent signaling. Sensory input to the lacrimal glands is decreased by disruption of the neuronal loop and by the direct inhibitory effect of inflammatory cytokines in the glands on secretomotor nerve endings. Dysfunction in any one element can lead to dysfunction in all elements, with subsequent development of chronic inflammation and dry eye disease. Inadequate tear production, altered tear composition, or secretion of inflammatory substances into tears can result in ocular surface inflammation. Stern et al, Cornea. 1998;17:584; Nelson et al, Adv Ther. 2000:17:84.
To understand dry eye disease as a disorder of the tear film, we need to appreciate the components of tears and their functions in the normal, healthy tear film. Normal, healthy tears contain, in addition to water, a complex mixture of proteins, mucins, and electrolytes. The most abundant proteins have antimicrobial functions: lysozyme and lactoferrin. Immunoglobulins, such as IgA, IgG, and IgM, also have protective functions. Cells are constantly sloughed off and lost from the most superficial layer of ocular epithelia. Growth factors are very small proteins that regulate the process for replacement of epithelial cells and are necessary for wound healing. Many growth factors are present in tears, including epidermal growth factor (EGF), as shown here. Mucins are critical for the viscosity of the tear film. The soluble mucin (mucin 5AC) is secreted by conjunctival goblet cells, whereas membrane-bound mucins originate from the epithelial cells they are bound to. The electrolyte concentrations in healthy tears are maintained in the proper ranges to ensure correct osmolarity, which is important for many aspects of epithelial and nerve cell function. Reference Stern ME, Beuerman RW, Pflugfelder SP. The normal tear film and ocular surface. In: Pflugfelder SP, Beuerman RW, Stern ME, eds. Dry Eye and Ocular Surface Disorders . New York, NY: Marcel Dekker; 2004:41-62.
Now let’s look at the abnormal composition of tears that are characteristic of chronic dry eye. The concentrations of many tear proteins, including those with antimicrobial functions, are reduced. Growth factor concentrations are reduced as well. The soluble mucin 5AC is greatly reduced in concentration because of the profound loss of goblet cells from the conjunctival epithelium that is typical of chronic dry eye. This impacts the viscosity of the tear film. Proteases, which are normally latent and inactivated in healthy tears, become activated. They can degrade the extracellular matrix and the tight junctions between adjacent cells of the corneal epithelium. Activated proteases are also responsible for cleavage of many cytokines into an activated pro-inflammatory form. The concentration of electrolytes increases, meaning that the osmolarity of the tear film is increased in chronic dry eye. References Solomon A, Dursun D, Liu Z, Xie Y, Macri A, Pflugfelder SC. Pro- and anti-inflammatory forms of interleukin-1 in the tear fluid and conjunctiva of patients with dry-eye disease. Invest Ophthalmol Vis Sci. 2001;42:2283-2292. Zhao H, Jumblatt JE, Wood TO, Jumblatt MM. Quantification of MUC5AC protein in human tears. Cornea. 2001;20:873-877. Ogasawara K, Mitsubayashi K, Tsuru T, Karube I. Electrical conductivity of tear fluid in healthy persons and keratoconjunctivitis sicca patients measured by a flexible conductimetric sensor. Graefes Arch Clin Exp Ophthalmol. 1996;234:542-546.
The prevalence of dry eye increases with age, particularly for women age 50 or older, and among postmenopausal women using hormone replacement therapy. This association with postmenopausal status is consistent with the known role of androgens in stimulation of the lacrimal and meibomian glands, which help maintain a normal tear film. Androgen levels naturally decline after menopause. Ocular comorbidities such as graft-versus-host disease, xerophthalmia, cicatricial pemphigoid, atopic keratoconjunctivitis, and ocular rosacea are also associated with increased risk of dry eye disease. Smokers are also at risk, perhaps due to repeated irritation of the ocular surface by smoke. Patients who feel the need to use artificial tears 3 or more times per day should always be evaluated further for dry eye disease. References Schaumberg DA, Sullivan DA, Buring JE, Dana MR. Prevalence of dry eye syndrome among US women. Am J Ophthalmol. 2003;136:318-326. Schaumberg DA, Buring JE, Sullivan DA, Dana MR. Hormone replacement therapy and dry eye syndrome. JAMA. 2001;286:2114-2119. Lemp MA. Report of the National Eye Institute/industry workshop on clinical trials in dry eyes. CLAO J. 1995;21:221-232. Multi-Sponsor Surveys, Inc. The 2005 Gallup Study of Dry Eye Sufferers; Princeton, NJ: 2004.
The Schirmer test (minus anesthesia) measures reflex tear secretion “ Schirmer I” With anesthesia (“Schirmer II”), eliminates stimulated tearing Stimulated tearing can occur because of introduction of the filter paper strip Measures so-called “basal” tearing A filter paper strip is introduced to the lower lid of the eye. Dry eye is indicated if less than 10 mm of the strip becomes wet with tears after 5 minutes of exposure. Lemp, CLAO J. 1995;21:221-232.
What Is Restasis ™ ? Emulsion of cyclosporine 0.05% for human ocular use Unique emulsion technology allows a low concentration of cyclosporine to be effective Cyclosporine is an immunomodulator with anti-inflammatory effects Low concentrations of cyclosporine are effective Specifically targets an underlying pathology of dry eye disease, immune-mediated inflammation, by inhibiting T-cell activation
What is Dry Eye Disease?Disease of ocular surface caused bydisturbances of natural function andprotection of external eye leading to anunstable tear film when eye is open
Prevalence of Dry Eye DiseaseAverage age of a dry eye patient is 54; most are women.Dry Eye Syndrome affects 75% of people over age 65.Common reason for ophthalmologist visits.
Normal tearing depends on a neuronal feedback loop Secretomotor Nerve ImpulsesLacrimal Glands Tears Support and Maintain Ocular Surface Ocular Surface Neural Stimulation
Inflammation disrupt normal neuronalLacrimal Glands: control of tearing.• Neurogenic Interrupted Secretomotor Inflammation Nerve Impulses• T-cell Activation• Cytokine Secretion into Tears Tears Inflame Ocular Surface Cytokines Disrupt Neural Arc
A complex mixture of proteins, mucin, and electrolytes Antimicrobial proteins: Lysozyme, lactofer rin Growth factors & suppressor s of inflammation: EGF, IL-1RA Soluble mucin 5AC secreted by goblet cells for viscosity Electrolytes for proper osmolarity
Decrease in many proteins Decreased growth factor concentrations Altered cytokine balance promotes inflammation Soluble mucin -5AC g reatly decreased Due to goblet cell loss Impacts viscosity of tear film Pr oteases activated Increased electrolytes
AQUEOUS TEAR DEFICIENCY: also known as KCS seen in 1.congenital alacramia 2.paralytic hyposecretion 3.1˚& 2˚ sjogrens disease 4.Riley day syndrome 5.Idiopathic• MUCIN DEFICIENCY: occurs when goblet cells damaged 1.hypovitaminosis A 2.trachoma 3.chemical burns & radiations 4.ocular pemphigoid, SJS
LIPID DEFICIENCY:Rare phenomenaCongenital anhydrotic ectodermal dysplasia with absence of meibomian glandsChronic blepharitis and chronic meibomitisIMPAIRED EYELID FUNCTION:.Bells palsy .Lagophthalmus.Exposure keratitis .ectropion.Dellen.Sympblepheron
EPITHELIOPATHIES:Alteration in cor neal epithelium
Medications T hat MayContributeto Dr y Eye DiseaseSystemic Antihyper tensives • Topical Antiandr ogens – Preservatives in Anticholiner gics Tears Antidepr essants Antiar rhythmic Dr ugs Par kinson’s Disease Agents Antihistamines
SYMPTOMSIr ritationFor eign body sensationItchingNon specific ocular discomfor tChr onicall y sor e eyes not responding to variety of dr ops instilled
SIGNSString y mucus and par ticulate matter in tear filmLustureless ocular surfaceConjunctival xer osisCor neal changes - punctate epithelial er osions and filaments
Patient Types with HighIncidence of Dr y EyeDisease Women aged 50 or older Women using postmenopausal hor mone replacement therapy T hose with ocular comorbidities Contact lens wearer s Smoker s 1 Schaumberg et al. Am J Ophthalmol. 2003; 2 Schaumberg et al. JAMA. 2001; 3 Lemp. CLAO J. 1995; 4 Multi-Sponsor Surveys, Inc. The 2005 Gallup Study of Dry Eye Sufferers. 2005.
DRY EYESYNDROMES XEROSIS(XEROPHTHALMIA) Dry lustureless condition of conjunctiva due to deficiency of mucin LOCAL OCULAR GENERAL DISEASE AFFECTIONa) Trachoma , burns, Deficiency of vitamin A pemphigoid, diphtheriaCicatricial degeneration Occurrence of bitots of conjunctival spots epitheliumb) Ectropion or proptosis
KERATOCONJUNCTIVITIS SICCA: deficiency of aqueous component of tear s i.e lacrimal tear s primar y secondar ykcs & xer ostomia kcs & rheumatoid ar thritis Pathologically focal accumulation & infiltr ation with l ymphocytes & plasma cells Tear lysozyme r atio of 0.1 -> KCS
DIAGNOSIS1.TEAR FILM BREAK UP TIME(BUT): interval between complete blink & appearance of first randomly distributed dry spot on corneaAfter instilling drops of fluorescein dye, examintion under SLE is carried out with cobalt blue light NORMAL – 15 -35 SECONDS <10 SECS- UNSTABLE TEAR FILMBUT- an indicator of adequacy of mucin component
Schirmer Test: 5 * 35 mm strip of w hatman 41 filter paper folded 5mm fr m one end kept in lower for nix at jn of lateral 1/3 rd & medial 2/3 rd NORMAL >15mm MILD TO MODERATE KCS 5-10 mm
ROSE BENGALSTAININGUseful for detecting even mild cases
4. Restasis ™ Ophthalmic emulsion of cyclosporine 0.05%. Prescription therapy for dry eye disease. Restasis™ is FDA approved to increase tear production in patients whose tear production may be reduced by inflammation of the eye associated with keratoconjunctivitis sicca.
5.PRESERVATION OF EXISTING TEARS BY REDUCING DECREASING EVAPORATION DRAINAGE: 1. Room temperature 1.Collagen implants 2. Moist chambers 2.Electrocauterisation 3. Protective glasses 3.Cyanoacrylate tissue adhesives 4.Argon laser & surgical occlusions.