European Journal of Medical Sciences Eur J Med Sci Dec; 1(4): Tear Film Osmolarity in Diagnosis of Dry Eye Syndrome

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1 Review Article Tear Film Osmolarity in Diagnosis of Dry Eye Syndrome H.Murat Sagdikˡ, Sinan Caliskan², Mehmet Tetikogluˡ, Serdar Aktasˡ, Fatma Ucar³, Fatih Ozcuraˡ 1 Department of Ophthalmology, Dumlupinar University School of Medicine, Kütahya, Turkey 2 Department of Ophthalmology, Diskapi Yildirim Beyazit Training and Research Hospital, Ankara, Turkey 3 Department of Clinical Biochemistry, Diskapi Yildirim Beyazit Training and Research Hospital, Ankara, Turkey Abstract Dry eye disease (DED) is a multifactorial disease which is characterized by the symptoms including burning, dryness, itching, pain, foreign body sensation and watering eyes. As causative mechanisms, the tear hyperosmolarity and tear film instability may initiate the dry eye. Increased tear osmolarity and ocular surface inflammation have a key role in the pathogenesis of DED. Tear osmolarity has been an exciting issue as in the diagnosis and management of DED. Herein, we discussed the role of tear osmolarity in the diagnosis procedures of DED. Keywords: Dry Eye Syndrome, Tear Film Osmolarity Corresponding Author: H. Murat SAGDIK. Department of Ophthalmology, Dumlupinar University School of Medicine, Kütahya, Turkey Introduction Dry eye is a multifactorial disease mainly related to altered tears and ocular surface. Although, the prevalence of dry eye disease (DED) varies with the selected population, applied dry eye criteria and geographic location, it is estimated about 5% to 30%(1). Dry eye causes symptoms including burning, dryness, itching, pain, foreign body sensation and watering eyes. Although the mechanism of the DED not fully understood, tears film instability and inflammation construct the core mechanism. Ocular inflammation is a secondary consequence which leads to epithelial damage(2). The tear composition can be compromised secondary to decreased lacrimal tears secretion or increased tears evaporation. Classification of the DED can be grouped as etiopathology, causative mechanism, severity of disease and dry eye symptoms(3). The etiopathogenic classification of dry eye disease includes two major categories: aqueous teardeficient dry eye and evaporative dry eye. As causative mechanisms, the tear hyperosmolarity and tear film instability may initiate the dry eye and alter the course of DED. 117

2 Role of Osmolarity in Etiopathogenesis of Dry eye Normal tear osmolarity is roughly 295 mosmol/l which is isotonic with blood(1). Lacrimal gland failure and/or excessive evaporation from tears film leads to reduced aqueous tear flow and increased tear osmolarity. It s considered that tear hyperosmolarity is the main actor which cause ocular surface inflammation, damage, and symptoms, and the initiation of compensatory events in dry eye(4). Increased osmolarity with sodium or sucrose, induce activation of epithelial signaling molecule cascade, production of proinflammatory mediators and matrix metalloproteinases (MMPs) by conjunctival and corneal epithelial cells (5, 6). Local apoptotic cell death, decreased conjunctival goblet cell is also associated with a tear hyperosmolarity (7-9). As a first compensatory mechanism response to ocular surface damage, reflex tears secretion and blink rate increases which controlled by trigeminal reflex activity. Diagnosis of Dry Eye Dry eye diagnostic tests used to discriminate dry eye and its subsets, monitoring of therapy and identify poor candidates for the ocular procedure. Although, various diagnostic techniques have been described for the diagnosis of dry eye, five main groups of dry eye diagnostic test will be discussed below. a) Symptom Questionnaires Several symptom questionnaires have been developed for use in dry eye diagnosis. The questionnaires most commonly used are The Ocular Surface Disease Index (OSDI), McMonnies Dry Eye Index and Dry Eye Questionnaire (DEQ)(10).Although the symptom questionnaire able to distinguish dry eye and non-dry eye groups, there is no always correlation between dry eye tests and symptoms (11, 12). The questionnaires may allow for rapid and efficient collection of relevant information by utilizing trained auxiliary staff but their length and composition and the time taken to administer and interpreting may not be practical in general clinical use (4, 13). The Dry Eye Workshop (DEWS) reports suggest the structured questionnaire for screening patients with potential dry eye disease. a) Grading Ocular Surface Staining Ocular surface staining is an invasive procedure to assess ocular surface damage by instilling a dye such as sodium fluorescein, Rose Bengal, or lissamine green. Currently, fluorescein and lissamine green dyes are mostly used in clinical practice. Fluorescein dye is an orange dye, seems green when excited by blue light. When there is a epithelial cell-to-cell junction s damage, it stains cornea, conjunctiva epithelia and may shows different pattern according to underlying causes (14). Advantages of fluorescein are well tolerated, cause minimal irritation, stain both cornea and conjunctiva epithelium. After instillation of fluorescein does not allow optimal observation of the ocular surface immediately, but improves some seconds or minutes later after diluted by the tears and blinking (14). The Rose Bengal dye has been used for many years in the diagnosis of dry eye (15). It s believed that Rose Bengal stains degenerated or dead cells and mucous strands, however, Feenstra et al. postulated that it also stain vital which loss the normal mucin layer and protective function of the preocular tear film (16). The main disadvantages of Rose Bengal is a great discomfort due to Rose Bengal toxicity which induces a loss of vitality, even cellular death and light exposure exacerbate cell toxicity (17). Lissamin green has been used as a substitute for Rose Bengal because of the less toxic structure. Both of them shows similar staining properties 118

3 (18). To standardize subjective ocular staining reading, there are several grading systems, comprising the van Bijsterveld system, the Oxford Scheme, and the National Eye Institute/Industry Workshop guidelines. However, there are no published studies that show one is superior to another (19). c) Tear Film Stability Tear film stability can be assessed with invasive tear break-up time (TBUT) and noninvasive break-up time (NIBUT). Currently, TBUT is the most commonly used test to asses tears film quality(20). TBUT is defined as the interval between the last complete blink and the appearance of a random break or disruption in the tear film after application of a standard volume of fluorescein. Although 1mL of 2% fluorescein solution improve the repeatability of TBUT measurement, excessive fluorescein volume, over the average tear volume of 6 to 7 ml may increase TBUT artificially(21). The cutoff time recommended for the diagnosis of DED was 5 seconds and < 10 seconds suggest unstable tear film(4, 22). d) Tear Flow the Schirmer Test The Schirmer tear test has been used to indirectly measure the volume of tears(23). The Schirmer I test measure reflex and basal tear production without prior installation of an anesthetic drops. A variation of the Schirmer I with instillation of a topical anesthetic measures basal tear production(10). The Schirmer II test with nasal stimulation with a cotton tip applicator only measure reflex secretion of tears. Recently, the Schirmer type 1 performed without anesthesia have a cut-off of < 5 mm/5 min for tear deficiency and a value greater 10 mm/5 min is accepted as normal (23, 24). Although repeatability of The Schirmer I test improved in advanced dry eye disease, it has a wide variation between subjects and visits (25, 26). e) Tear Osmolarity The tear film maintain a vital hemostatic function for epithelium and anterior stroma by delivering or excreting the nutrients and metabolic products(27). There is a dynamic equilibrium in the production, evaporation, absorption and drainage of the tear film. Any disequilibrium leads to alteration of the tear film structure and composition, eventually leading to tear film hyperosmolarity(28). Both osmolality and osmolarity terms used to describe the amount of osmotically active particles; however, there is a small differences between the two terms(29). Osmolality is defined as the total number of dissolved solute particles in one kilogram of solution and osmolarity as the number of osmoles per litre of solution. Osmolarity is temperature dependent by way of the solution of volume changes with temperature. If a solute is dissolved in a solvent, it shows some chemical properties which is known as colligative properties including: increase in osmotic pressure, increase boiling point, decrease in vapor pressure and decrease in freezing point properties(30, 31). These are all directly related to osmolarity and could be used as a basis for the measurement of osmolality. The most common method for measuring osmotic pressure in the clinic was the freezing point depression(32). I. Freezing point depression osmometer The osmometers such as Clifton nanoliter osmometer (Clifton Technical Physics of Hartford, NY), Advanced Tear Osmometer (Advanced Instruments, Inc, Norwood, MA) and the Otago Osmometer (Otago Osmometers, Ltd, Dunedin, New Zealand) used to measure tear osmolarity with the freezing point depression 119

4 methods(33, 34). The temperature of the freezing point is directly proportional to the total number of dissolved particles in the tear sample. Thus, the osmolarity can be calculated from the depression in the freezing point of the tear sample(35). The methods require significant expertise, takes considerable time, potential errors due to evaporation of test sample and temperature rate changes could not be controlled reliably(33, 35). II. Vapor pressure osmometer The measurement of osmolarity with vapor pressure depression depends on the principle that the vapor pressure of a solution is lower than that of the pure solvent at the same temperature and pressure. Vapor pressure depression is proportional to the number of dissolved particles in the solution (35, 36). Recently, vapor pressure osmometers, such as the Wescor (Wescor, Inc, Logan, UT) have been used in the clinical settings. It requires relatively a larger sample volume 2 µl and needs saturating a cellulose acetate disc to collect the tears (37, 38). Both freezing point depression and vapor pressure techniques needs to the tear collection and transferred for measurement, both collection ( reflex tears secretion) and transfer (evaporation) may cause unreliable measurements (39). III. Electrical impedance Electrical impedance is not a colligative property of the solution. Measurement of tears osmolarity using electrical conductivity or impedance is a newly developed technique that measures only charged particles and depends on conductivity is dependent on the number of particles (35, 40). The OcuSense TearLab osmometer (OcuSense Inc., San Diego, CA, USA) uses a temperaturecorrected impedance measurement and provides instant assessment of tear osmolarity(38). It uses the disposable a non-sterile and disposable osmolarity test card. The card system contain a microchip which has a microfluidic channel to collect the tears and a gold electrode embedded in the polycarbonate plate to enable measurement of the impedance of the sample(38). The TearLab require 50 nl tear sample for the measurement (41). Although the system have advantages such as, portable, require a small volume sample, eliminated risk of evaporation during transfer, real time measurement of both eyes, the possible disadvantages of the TearLab are the reasonably difficult standardization, avoiding the induction of reflex tearing(40, 42). The electrical conductivity is dependent on the number of charged particles, it could be argued that unappreciated, uncharged particle limits the conductivity technique for measuring osmolarity. The recommended diagnostic cut-off of 316 mosm/l has been well validated (4, 43). In a recent study, the devices utilizing the electrical impedance and the freezing point depression technique was compared, and found a slight difference with the devices utilizing the electrical impedance producing lower values, but a good correlation with each other(35). Eperjesi et al. found noise value as 33 mosms/l with repeated OcuSense TearLab osmometer tear osmolarity readings over time which means only increases or decreases of more than 33 mosms/l can be classed as clinically relevant for healthy subjects(38). With an aspect that all types of dry eyes eventually leads to increase in tear osmolarity, the measurement of tear osmolarity may be seems the best diagnostic test for dry eye. Khanal et postulated that tear hyperosmolarity has the potential to be a gold standard for dry eye diagnosis, tear osmolarity is ineffective in differentiating between aqueous deficient dry eye and evaporative dry eye(44). Although, recent studies reports that tear osmolarity is the best marker, correlates with dry eye severity (45-120

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