Dry eye diagnosis and management
Dry eye disease (DED) is one of the most prevalent ophthalmic disorders, which is influenced by geographic location, climatic conditions, life style of the people, and ranges from 5% to 35% .   It may have an adverse impact on the quality of life and on the results of corneal, cataract, and refractive surgical procedures. Due to a wide variety of presentations, multi-factorial and elusive etiology, it is often challenging to treat.
Recent studies have given insights into inflammation and hyperosmolarity in etiology of dry eye , which go hand in hand in a vicious cycle . The conventional approach to the treatment of dry eye is providing lubricating eye drops or tear substitutes. However, we now have a variety of treatments available in the market making it difficult which to choose for which patient; with the newer treatment approach being to target the underlying cause rather than symptomatic relief alone.
In light of the above knowledge, this article focuses on simple clinical examination techniques and newer diagnostic modalities used for differential diagnosis of DED which includes Aqueous-Deficiency Dry Eye(ADDE) and Evaporative Dry Eye (EDE) and highlights the various molecules which help in supplementation of the insufficient components of tear film and maintain homeostasis.
After a dry eye suspect is identified, a complete medical history including drug history should be taken and the patient can fill out the OSDI (Ocular Surface Disease Index) questionnaire and then potentially undergo the following tests.
- Evaluation of Tear secretion: In practice the most clinically used test is the Basic Secretion Test(BST): After instillation of topical anesthetic, filter paper marked 0-30 mm is placed at the lateral 1/3rd of lower fornix of both eyes for 5 mins with wetting of less than 3 mm indicative of ADDE and results of3-10 mm being equivocal. Commonly this is interpreted in the following manner: 0-3 mm severe dry eye, 3-5 mm moderate dry eye and 5-10 mm mild dry eye (of note: this is the test most colloquially referred to as the "Schirmer test") . Schirmer Test (ST)- 1 is similar to BST without instilling topical anesthetic (measures both reflex and basal tear secretion);<5 mm of wetting is consisting with ADDE. ST- 2 after instilling topical anesthetic a nasal irritant of a cotton tipped applicator is placed in the nose. < 15 mm at 5 minutes is a positive test (this measures reflex tear secretion)
- TEAR BREAK UP TIME: One drop of fluorescein is placed in the lower fornix and patient is made to blink multiple times and then asked to stop blinking . The stained cornea is examined under the slit lamp in cobalt blue filter. "APPEARANCE OF 1ST DRY SPOT ON CORNEA IN LESS THAN 10 SEC" is indicative of EDE .
- OCULAR SURFACE PUNCTATE STAINING : Of Cornea with fluorescein sodium and conjunctiva with lissamine green . Appearance of > 5 CORNEAL SPOTS >9 CONJUNCIVAL SPOTS & LID MARGIN (2mm length & 25% width) seen under cobal blue light is indicative of dry eye.
- TEAR FILM ORIENTED DIAGNOSIS(TFOR), FLUORESCEIN BREAK UP PATTERN : TFOD is the method used for the differential diagnosis of DE, which includes aqueous-deficiency DE (ADDE), decreased wettability DE (DWDE), and increased evaporation DE (IEDE), through the dynamics of tear film (TF) and breakup patterns (BUPs) after the eye is opened. BUPs and/or each diagnosed DE subtype are/is able to distinguish the insufficient components of the ocular surface that are responsible for each BUP in a layer-by-layer fashion. Aqueous fluid, membrane-associated mucins (especially MUC16), and the lipid layer and/or secretory mucins must be insufficient in ADDE, DWDE, and IEDE, respectively, and this allows for a layer-by-layer treatment to be proposed for each BUP via the supplementation of the insufficient components, using the topical therapy currently available.
Newer Diagnostic Modalities
- QUANTIFY HYPEROSMOLARITY AND IDENTIFY INFLAMMATORY MARKERS IN DRY EYE.
- HAND HELD DEVICES LIKE I-PEN® AND TEAR LAB OSMOMETER : Diagnosing dry eye is challenging as the patient symptoms often don’t match clinical signs. Hence objective diagnostic method is essential. Osmolarity testing has been declared the “gold standard” of objective dry eye diagnosis.
- INFLAMMADRY: InflammaDry is a rapid, in-office test that detects elevated levels of MMP-9, an inflammatory marker which is consistently elevated in the tears of patients with DED.
- LIPID LAYER INTERFEROMETRY - Measures lipid layer thickness and accurately diagnoses and monitors lipid-deficient EDE.
- MEIBOGRAPHY: Specialized imaging study developed exclusively for the purpose of directly visualizing the morphology of Meibomian gland, they play a significant role in tear production by contributing lipids to the superficial tear film and hence dysfunction of the Meibomian glands results EDE.
After carrying out these test the root cause of dry eye can be identified (ADDE/ EDE, ASSOCIATED WITH/WITHOUT SIGNIFICANT INFLAMMATION AND HYPEROSMOLARITY) and then the choice of treatment can be made.
- AQUEOUS DEFICIENCY : When the root cause of dry eye is insufficient tear production aim of treatment is tear replacement and reversing the hyperosmolar state with osmoregulators. The following are the lubricants of choice:
- MUCIN DEFICIENCY : Mucin is thought to contribute to stabilization of tear film because of its ability to promote water retention on the ocular surface for long periods by binding to large number of water molecules. Secretagogues increase mucin secretion from goblet cells on the conjunctiva . Can be used in both ADDE and IEDE.
- Rebamipide 2% : Rebamipide is a novel quinolinone derivative earlier used for gastric ulcer therapy. However, this was later studied and found that Rebamipide increases the secretion of both membrane-associated and secreted-type mucins through mucin production in the conjunctival goblet cells, and in the corneal epithelial cells.
- Diquafosol tetrasodium: A P2Y2 Receptor agonist that stimulates fluid and mucin secretion on ocular surface.
- LIPID LAYER DEFICIENT-EVAPORATIVE DRY EYE: PG:Propylene glycol 0.2-1% , PEG: Polyethylene glycol 0.2-1% , HP GUAR: Hydroxypropyl Guar; When in contact with tear film increase in viscosity forming a protective layer preventing evaporation of tears.
- OSMOPROTECTANTS: They suppress the production and activity of MMP induced hyperosmolarity in human corneal epithelial cells and protect the cells under extreme osmotic stress by balancing the osmotic pressure without disturbing cell metabolism. Osmoprotective agents used are:
- Trehalose  : It is a natural alpha linked disaccharide which provides protection from oxidative & osmotic stress and apoptosis induced cell death.
- L-carnnitine , GlycerolL ,Erythritol : Their osmoprotectant action is directly proportional to the amount of time they are retained in the cell .L-carnnitine is retained longer hence more effective. These work best when used in combination.
- ANTI-INFLAMMATORY AGENTS: Severe aqueous deficiency results in increase of inflammatory cytokines which worsen the ocular surface damage and cause tear film instability .Mainly useful for aqueous deficiency dry eye with Sjogren syndrome or autoimmune diseases. Topical steroids may be used sparingly for flares of inflammatory dry eyes. Long terms anti-inflammatory options include cyclosporine drops (RESTASIS® (cyclosporine) Ophthalmic Emulsion 0.05% or CEQUA™ (cyclosporine) Ophthalmic Solution 0.09%) and Xiidra (lifitegrast). The cyclosporine drops are used to increase tear production and restore the ocular surface. These medications can take up to 3-6 months to reach full efficacy. Lifitegrast decreases inflammation by inhibiting inflammatory cell binding.
- The epidemiology of dry eye disease: Report of the Epidemiology Subcommittee of the International Dry Eye Workshop (2007). Ocul Surf 2007;5:93-107.
- McCarty CA, Bansal AK, Livingston PM, Stanislavsky YL, Taylor HR. The epidemiology of dry eye in Melbourne, Australia. Ophthalmology 1998;105:1114-9. [PUBMED]
- Lin PY, Tsai SY, Cheng CY, Liu JH, Chou P, Hsu WM, et al. Prevalence of dry eye among an elderly Chinese population in Taiwan: The Shihpai eye study. Ophthalmology 2003;110:1096-101.
- Jacobi C, Jacobi A, Kruse FE, Cursiefen C. Tear film osmolarity measurements in dry eye disease using electrical impedance technology. Cornea. 2011;30(12):1289‐1292. doi:10.1097/ICO.0b013e31821de383
- Wolffsohn JS, Arita R, Chalmers R, et al. TFOS DEWS II Diagnostic Methodology report. Ocul Surf. 2017;15(3):539‐574. doi:10.1016/j.jtos.2017.05.001
- Norihiko Yokoi; Georgi As Georgiev
- J. Necas , L. Bartosikova1 , P. Brauner2 , J. Kolar2 . Veterinarni Medicina, 53, 2008 (8): 397–411
- American Journal of Ophthalmology.2010 apr 1; 149(4):594-601.
- Lesley J, Hascall VC, Tammi M, Hyman R. Hyaluronan binding by cell surface CD44. J Biol Chem. 2000;275(35):26967‐26975. doi:10.1074/jbc.M002527200
- Tomoyuki Kashima, Clin Ophthalmol. 2014; 8: 1003–1010
- Deng R, Su Z, Hua X, Zhang Z, Li DQ, Pflugfelder SC. Osmoprotectants suppress the production and activity of matrix metalloproteinases induced by hyperosmolarity in primary human corneal epithelial cells. Mol Vis. 2014;20:1243‐1252. Published 2014 Sep 12.
- Br J Ophthalmol 2001; 885;610-612
- Int Ophthalmol. 2018; 38(2): 875-895;