Clinical Science J. DANIEL NELSON, MD,
EDITOR
An Examination of the Relationship Between Ocular Surface Tear Osmolarity Compartments and Epitheliopathy CHARLES W. MCMONNIES, DSC ABSTRACT A 2014 PubMed search for tear hyperosmolarity and corneal stain yielded 2960 results. Selections from those providing evidence of variations in osmolarity were used to refine the compartmentalization model of tear osmolarity over the ocular surface. This new model includes the low point of freshly produced isotonic tears in the upper conjunctival sac, with osmolarity increasing successively in the upper meniscus, the upper area of exposed ocular surface, the lower area of over-exposed ocular surface, the lower meniscus, and the lower conjunctival sac. Compartmentalization is used to explain epitheliopathy over the ocular surface as resulting from variable degrees of exposure to hyperosmolarity-induced insult and/or frictionrelated mechanical damage. Also recognized is the role of localized increases in osmolarity, which appear likely to occur in the black lines and tear breakup areas of the exposed ocular surface. Variables such as the influence of ambient conditions of air humidity, temperature and movement have been considered, as well as rates of complete and incomplete blinks and associated potential for over-exposure of the inferior area of the normally exposed ocular surface. The exacerbating contribution from contact lens wear has been included. Friction-related damage may
Accepted for publication July 2014. From the School of Optometry and Vision Science, University of New South Wales, Kensington, Australia. Research funding in relation to this review: None. The author has no proprietary or financial interest in any product or concept dicussed in this article. Single-copy reprint requests to Charles W. McMonnies, DSc (address below). Corresponding author: Adjunct Professor Charles W. McMonnies, DSc, 77 Cliff Avenue, Northbridge, Sydney, New South Wales, 2000. Tel: 61 2 9958 3046. Fax: 61 2 9958 3012. Mobile: 0409 038 799. E-mail address: [email protected] © 2015 Elsevier Inc. All rights reserved. The Ocular Surface ISSN: 15420124. McMonnies CW. An examination of the relationship between ocular surface tear osmolarity compartments and epitheliopathy. 2015;13(2):110-117.
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be the primary basis for lid wiper epitheliopathy, but tear hyperosmolarity could have an important contributory role. Subcompartmental consideration of variation in osmolarity may improve understanding of different presentations of epitheliopathy. KEY WORDS blinking, compartment, dry eye, epitheliopathy, evaporation, exposure, ocular surface, osmolarity
I. INTRODUCTION ears are necessary for the health of the ocular surface, maintaining the non-keratinized surface essential for corneal transparency as well as the lubrication required for movement of lid on globe.1 The mucosae of the ocular surface (the visible bulbar conjunctiva and the cornea) are exposed directly to the ambient air and are therefore at risk of desiccation through water loss2 and associated increased tear osmolarity. Any quantitative or qualitative inadequacy of the tear lipid layer increases water loss.3 People with reduced blink frequency or incomplete blinks have longer interblink intervals and greater tear evaporation due to increased exposure of the ocular surface.4 Exposure to adverse ambient conditions, such as low humidity and/or increased air temperature and/or air movement, also increases evaporation.5 The performance of tasks that reduce the overall blink rate and/or produce incomplete blinks are likely to greatly increase evaporation.4 Studies of evaporation rates that use goggles do not address the influence of ambient conditions.5,6 Moreover, the goggles may interfere with blinking frequency and completeness, altering interblink intervals and evaporation rates. Evaporation rates from ocular surfaces under ambient conditions may be four to five times faster than the average of the values found when goggles are worn.7 Prior to evaporation, the lacrimal secretion is generally considered to be isotonic with blood.8 The osmolarity of human serum is 290 mOsm/I, equivalent to a 0.9% NaCl aqueous solution.9 A meta-analysis of published data taken from 16 studies indicated a mean value for “normal eye”
T
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TEAR OSMOLARITY AND EPITHELIOPATHY / McMonnies OUTLINE I. II. III. IV. V.
Introduction Mechanisms for Tear Volume Reduction Influences of Contact Lenses Compartmental Variations in Osmolarity Influence of Tear Quality and Quantity on Lid Wiper Tissue VI. Over-exposure Stain Location VII. Conclusions
lower meniscus tear osmolarity of 302þ/8 mOsm/I.10 The mean value for 11 studies of tear osmolarity in keratoconjunctivitis sicca was 326þ/22 mOsm/I.10 The TearLab osmometer (San Diego, CA, USA) method of assessing osmolarity, which assesses lower meniscus samples, using a cutoff of 312 mOsms/l, achieved 73% sensitivity and 92% specificity.11 As with other measures of dry eye disease (DED), there may be overlapping of the distributions for hyperosmolarity findings between normals and DED subjects. However, tear film osmolarity was found to be the single best marker of disease severity across normals and mild/moderate and severe categories of DED.12 In the open eye, the tears are distributed in three compartments: the conjunctival sac, the preocular tear film, and the tear menisci.3 It has been suggested that in the open eye, tear osmolarity is not uniformly distributed between the tear compartments, but differs between the conjunctival sac (the preocular tear film and the fornical compartment behind the lids and in the fornix), the preocular tear film; and the tear menisci.2 Consequently, measurement or specification of tear osmolarity would require identification of the tear compartment in which measurements are taken. Osmolarity has been found to vary only diurnally in normals, but not during normal assessment hours.13,14 However, it can vary significantly during normal assessment hours in eyes with DED, and this may contribute to variations in findings among DED subjects.14 Exposure to different conditions (e.g., during sustained reading and/or major variations in air movement or humidity) before or during assessment might also contribute to variations in osmolarity. The location of tear sampling in the lower meniscus may be important.15 For example, the increased staining of Marx’s line nasally (further discussed below)15 suggests that there might be a corresponding increase in osmolarity in the nasal portions of the menisci. This review examines the evidence for compartmental variations in osmolarity and associated potential for ocular surface and lid wiper epitheliopathy. (Lid wiper refers to a localized portion of the marginal conjunctiva of the upper eyelid that has a rubbing effect on the ocular surface during blinking.) In particular, the significance of considering the upper and lower menisci, the upper and lower areas of exposed ocular surface, and the upper and lower conjunctival sacs as separate compartments is discussed.
II. MECHANISMS FOR TEAR VOLUME REDUCTION Apart from evaporation, tears can be lost by tangential flow and drainage into the lacrimal sacs and by movement into the epithelium of the cornea or conjunctiva.7 However, under conditions of hyperosmotic tears, transfer of water from the epithelium into tears appears more likely.5 It is possible for tears to be transferred into a hydrophilic contact lens, but the primary routes of exit are by evaporation and tangential flow.5 A blink mechanism is necessary for effective tear drainage, although the puncta close during blinking.16 Tear exit occurs even when the lids do not meet during a blink.16 The puncta actually come into full contact after one-third to one-half of the full downward excursion of the upper lid.17 Lid closure during blinks has both vertical and lateral-tomedial components.18 The tears are not only swept vertically down the cornea during a blink, but also pushed medially toward the sites of drainage at the medial canthi.18 A driver of fluid from the meniscus into the nasolacrimal drainage system was proposed under the name of the “lacrimal pump.”17,19 This mechanism assumes that contraction of the orbicularis muscle during the blink compresses the lacrimal sac.19 The negative pressure produced by the subsequent expansion of the lacrimal sac is transmitted to the tear menisci at the start of the interblink interval (and relaxation of the orbicularis muscle), resulting in drainage.17 The central parts of the lid margins, described as the occlusal surfaces,20 do not touch in spontaneous blinks due to their misalignment, with the top lid overhanging the bottom lid.21 The keratinized portions of the upper and lower lid margins do not make complete contact during deliberate blinking.22 Even with forced blinks, when greater contact occurs between the lids, an over-blink can still be observed.21 Depending on how easily the lid stretches, lid tightness and compressive loading on the ocular surface may increase during the initial down-phase of a blink, as the lid must stretch over increasing corneal sag height. Tightness and compressive loading likely reaches a peak as the lid moves over the maximum sag height at the corneal apex. As the blink moves down beyond this position, the corneal sag height or vault is reduced, and lid tightness as well as its compressive loading of the ocular surface may diminish accordingly. Perhaps the lids have not fully recovered from their stretching over the corneal apex when they complete their downward excursion. Residual upper lid stretch or looseness may contribute to the degree to which they over-blink or overhang the lower lid at the completion of the down phase of a complete blink. When passive closure is sustained, giving the upper lid time to regain normal length (compared to a blink), the overhang of the top lid lessens or even disappears, allowing the two menisci to fuse. However, lid overhang does not seem to help menisci fusion during a spontaneous blink. Differences in lid anatomy among racial groups may affect blink functions. For example, compared to Caucasians, Asian (Korean) lids have more subcutaneous and suborbicularis fat, with a pretarsal fat component being present.23 The upper lid crease is also a feature of
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TEAR OSMOLARITY AND EPITHELIOPATHY / McMonnies distinction.23 There are three morphological types of Asian upper eyelid: the single lid with no lid crease and puffiness; the lid with a low-seated nasally tapered inside-fold type of crease; and the double eyelid with lid crease parallel to the lid margin.23 These features may be associated with more or less upper lid overhang or other differences in Asian compared to Caucasian lids, possibly associated with differences in blink-related tear function. Tears are drawn into the canaliculi during the relaxation phase of blinking, and the superior punctum route alone is sufficient to handle tear drainage.16 The exception is when an increase in lacrimation rate is sufficient to challenge the capacity of the superior route. Nevertheless, in healthy subjects in the supine position, 60% of tear outflow was found to occur through the inferior canaliculus.24 For an initial thickness of 3 mm, and for a thinning rate of 20 mm/min, the tear film would thin to zero thickness (tear breakup) in only 9 seconds, a value that is comparable with measured tear film breakup times.25 It has been calculated that reported evaporation rates were only about 20-25% of the calculated thinning rates.7 This finding suggests that other mechanisms for loss of tear volumeeinto the epithelium (and/or a hydrogel contact lens) and/or tangential flow and loss by drainage into the canaliculi7e could account for most of the tear loss. However, when the lipid layer is removed, evaporation increases about four-fold.26 Tear film instability and evaporation also depend on the strength of healing flow from the neighboring region outside the breakup area, which is determined by the surface tension at the tear film surface and by the repulsive thin-film disjoining pressure.27 As noted above, evaporation rates may be greatly increased by adverse ambient conditions,27 low blink rate, and/or incomplete blinks.4 The rate of tear loss by evaporation also increases with the area of exposed ocular surface during primary gaze, which varies with the width of the palpebral aperture and the distance between the inner and outer canthi.3 Both exposure and over-exposure of the ocular surface due to evaporation could be expected to be much higher in certain patients, for example, in those with wider lid apertures, which are associated with proptosis3 or exophthalmos, such as that which occurs in axial myopia, especially in association with posterior staphyloma. The overall area of exposure is greater in upgaze than in downgaze. During downgaze, the upper lid is lowered, while the lower lid is relatively stationary.3 Rapid evaporation and tear thinning over the exposed ocular surface due to lipid layer dysfunction promotes tear and localized increases in osmolarity.19 Obstructed meibomian glands and/or increased viscosity of meibum are the underlying causes of lipid layer dysfunction.28 Evaporation of the tear film may give rise to considerable increases in the local osmolarity of the exposed tear between blinks.7,11 It is likely that the osmolarity of the exposed tear film always exceeds that of the menisci, especially in DED.3 However, with lid wiper-driven flow from the exposed surface of 112
hyperosmolar tears into the lower meniscus, osmolarity becomes elevated, albeit more modestly. III. INFLUENCES OF CONTACT LENSES Soft contact lenses were shown to dehydrate during wear, with associated reduced noninvasive tear film breakup times for the lens front surface, especially in patients who reported symptoms of discomfort and dryness.29 Use of daily wear soft contact lenses was associated with tear osmolarity increases after contact lens wear, from a mean of 284þ/ 10mOsm/l before wear to a mean of 314þ/84mOsm/l after wear.30 This increase is just above the cutoff for keratoconjunctivitis sicca and helps explain symptoms of dryness. Increased tear osmolarity was also found in normal wearers of extended-wear soft contact lenses.31 Reduced corneal touch sensitivity was found in wearers of both rigid and soft lenses after only 12 hours of wear.32 The loss in corneal sensitivity that developed progressively over 20 weeks of soft lens wear was to a level similar to that found in rigid lens wearers after 12 hours.33 To the extent that soft and scleral contact lenses shield the cornea from its normal exposure to ambient conditions, the lenses produce a form of contact lens-induced corneal hypoalgesia.34 Contact lens-related decreases in corneal innervation with a resultant reduced tear secretion rate are likely to be one of the causes of associated increases in osmolarity.35 Reduced tear flow rates and associated delayed exit result in longer exposure to evaporation and increased osmolarity. Compared to controls, incomplete blinking was found to be associated with a significant decrease in the hydration of the over-exposed lower half of nonrotating soft contact lenses.36 Consistent staining of the over-exposed inferior cornea was observed in an incomplete blinking group.36 This group also appeared to have a higher prevalence of adverse symptoms and to more frequently develop contact lens surface deposits.36 A higher proportion of incomplete blinks was apparent in both healthy subjects and soft contact lens wearers, who were found to have fluorescein staining in the area over-exposed by incomplete blinks.37 The association between degree of incomplete blinking and the grade of fluorescein staining was stronger in soft lens wearers.37 Loss of tears from the post-lens space into the lens (perhaps in response to those lost by evaporation from the lens front surface) may help explain the increased exposure staining in some soft lens wearers. Both healthy subjects and soft lens wearers showed 22% incomplete blinks.37 However, soft lens wearers who performed blink efficiency exercises for 2 weeks displayed an increased frequency of complete blinks over their pre-training performance, compared with controls, who did not attempt to improve their blink efficiency.38 Successful contact lens wear can be enhanced if patients are encouraged to improve blink functions.4 For example, contact lens wearers who normally have efficient blink habits but who use computers or similar digital devices for long periods are at risk for reduced blink function and
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TEAR OSMOLARITY AND EPITHELIOPATHY / McMonnies associated symptoms of dryness.4,34 People with symptoms of DED who do not wear contact lenses and who have a tendency to blink less frequently or less completely may also benefit from performing exercises to improve blink efficiency.4 The best time to perform blink exercises might be immediately after instillation of lubricant tear replacement drops, as this may enhance delivery of the lubricant to the epithelial cells, increasing the potential therapeutic benefit of the drop.4 IV. COMPARTMENTAL VARIATIONS IN OSMOLARITY Because of the hydrophilic nature of the conjunctiva, the tear film forms menisci adjacent to the upper and lower eyelid margins, which ensures that one apex of each meniscus wets up to a contact line at the mucocutaneous junction.39 The other apex of each meniscus asymptotes to the black line region.39 The black line is a juncture between each meniscus and the central tear film on the ocular surface.39 In a tear film stained with fluorescein, black lines arise at this juncture immediately following a blink.40 The black lines are regions of very thin tear-film thickness,40 thus having much less fluorescence than the thin precorneal tear layer. Their blackness also contrasts with the strong fluorescence from normal menisci. Mathematical modelling of the spatial distribution of tear film osmolarity indicates increases in osmolarity with evaporation at the black lines.39 The highest increases in osmolarity predicted by modelling are amply sufficient to raise meniscus osmolarity into the regime diagnostically classified as DED.39 This finding may not apply as much to the upper meniscus because, in normal eyes, isotonic tears are delivered to the temporal upper fornix from a healthy lacrimal gland and into the superior conjunctival sac from normal functioning accessory lacrimal glands.8 Compared with the tear layer and menisci, which are exposed to air, the newly secreted lacrimal fluid appears likely to be the low point for osmolarity, given its lack of exposure to evaporation. Modelling shows that lacrimal gland aqueous deficiency also results in hyperosmolarity, but the increase in osmolarity is less than that resulting from evaporation.39 Consequently, any reduction in tear production and associated tear hyperosmolarity in newly secreted lacrimal fluid is likely to be greatly exacerbated by further increases in hyperosmolarity due to the influence of lipid layer dysfunction, contact lens wear, and exposure to adverse ambient conditions on the rate of evaporation. Hyperosmolarity in the precorneal tear film may transiently spike during tear instability, resulting in corneal inflammation and symptoms due to the triggering of sensory neurons.41 Hyperosmolarity may contribute to inflammatory processes at the ocular surface by causing epithelial damage, possibly inducing release of cytokines from epithelial cells.3 Hyperosmolarity may also involve autoimmune destruction of lacrimal gland and ducts and release of inflammatory mediators from the gland and conjunctiva into the tears.3 Pro-inflammatory mitogen-activated protein kinase was found experimentally to be activated by 600
mOsm/L of transient hyperosmolar stress.41 Measurements of hyperomolarity at this level have not been published. However, that such levels could be found in the precorneal tear film within an area of breakup is supported by the following reasoning. If, due to tear evaporation, the tear film thins by a factor of 3, for example, from 3 mm to 1 mm, then if no solute is lost, the tear osmolarity could increase by a corresponding factor (e.g., from 300 to 900 mOsm/L).7 Thus, osmolarity measured from the lower tear meniscus may not reflect the rapid spatial and temporal changes that occur over the exposed corneal and conjunctival surfaces during breakup within the interblink interval.41 In addition, Marx’s line stain is hypothesized to be a consequence of evaporation from the tear menisci after many iterations of the interblink interval, which results in an increase in osmolarity at the peripheral apices of each meniscus.2,42 Marx’s line stain is observed in subjects with apparently normal tear function.43 The gradient of Marx’s line staining, dissipating posteriorly,15 may be explained by a gradient of reducing osmolarity, starting from a maximum at the meniscus apex and anterior edge of Marx’s line. Of course, the location of the hyperosmolar apex of the meniscus would shift posteriorly with any reduction in meniscus volume. This explanation depends on higher osmolarity being due to the greater relative susceptibility to evaporation of the thin anterior meniscus apex. Increases in osmolarity in the deeper meniscus are likely to be proportionately less than the increases that occur at the apices of the meniscus. However, on the ocular surface, and despite being the thinnest region of the tear film with associated hyperosmolarity, the black line is not normally associated with staining analogous to Marx’s line stain.42 This may be because, for the normal meniscus volume for any individual, the position of the thinned apex, which is apparently responsible for the staining of Marx’s line, is more stable and usually just behind the mucocutaneous junction. On the other hand, the black line on the ocular surface is usually being frequently relocated by vertical saccades. That is, up- and downgaze eye movements allow the potential for black line hyperosmolarity-related tissue damage to be shared over a wide area of the ocular surface. This may not be the case during reading, watching television, or similar activity, when up and down eye movements are limited, maintaining a more stable location for the black line on the ocular surface. Stability of the location of the black line is likely to be associated with increased risk of hyperosmolarity-related epitheliopathy. Hyperosmolarity of the black line tears may then contribute to over-exposure epitheliopathy due to incomplete blinking. The tear film rapidly becomes stationary following a blink,44 with rapid black line formation. No gravityinduced drainage occurs between blinks even for upright body (head) positions.45 Evaporation from the exposed tear film during the interblink interval, and associated increased osmolarity, means that the lower meniscus is
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TEAR OSMOLARITY AND EPITHELIOPATHY / McMonnies likely to have higher osmolarity than the upper meniscus. This could be the result of supplementation of the lower meniscus with tears of higher osmolarity. These would be delivered from the exposed ocular surface and both black lines via the wiping action of the downward movement of the upper lid during a blink. Incomplete blinking over-exposes the normally exposed inferior ocular surface by approximately doubling the interblink interval,4 as well as doubling the opportunity for tear evaporation. Over-exposure challenges lipid layer function with associated potential for tear breakup, greater levels of evaporation, and increases in osmolarity. DED-induced tear hyperosmolarity is recognized as a major cause of ocular surface damage.46 For example, the tear film osmolarities observed in keratoconjunctivitis sicca are sufficient to cause the corneal epithelial changes seen in patients with this disease.46 Higher osmolarity in the tear layer over the band of inferior corneal surface can be explained by the association between incomplete blinking and exposure epitheliopathy and staining of only that part of the cornea.37 Over-exposure epitheliopathy contrasts with nonstaining of the upper cornea. This observation supports a division of the tear layer compartment into upper and lower zones of correspondingly exposed and over-exposed zone of higher osmolarity, with the highest osmolarity being present in the lower zones. Over-exposure stain is likely to be exacerbated by sequences of successive incomplete blinks. Even with complete blinks, tear film evaporation and increased osmolarity of exposed tears would cause the tears in the inferior meniscus to have higher osmolarity than those in the superior meniscus. However, it was found that tear fluid from the inferior conjunctival sac had even higher osmolarity than tear fluid of the inferior meniscus.47 Without upgaze to expose the inferior bulbar conjunctiva to the atmosphere,3 the tears in the inferior conjunctival sac appear to be relatively stagnant compared to those in the lower meniscus, which have ready access to the punctum. Fluorescein stain instilled into the inferior conjunctival sac takes several minutes to disperse over the ocular surface, providing evidence of deficiency of flow from the inferior conjunctival sac.48 However, with upgaze, the inferior bulbar conjunctival tear layer is exposed to evaporation and increased osmolarity. Evaporation is temperaturedependent, and lower conjunctival sac tears enclosed between palpebral and bulbar conjunctiva during primary or downgaze will warm and become susceptible to faster evaporation when exposed by upgaze. Warming would be greater for eyes with hyperemic conjunctivae, as is often the case in DED.49 For example, consistent with conjunctival hyperemia in dry eyes, the difference between limbal and corneal temperature is significantly greater in dry eyes than in normal eyes.50 With the rapid evaporation of the exposed warm tears on the inferior bulbar conjunctiva, osmolarity can increase significantly. Hyperosmotic tears would then be returned to the inferior conjunctival sac with a resumption of 114
primary gaze or downgaze, elevating the osmolarity of the conjunctival sac tear pool. Increased osmolarity in the inferior cul-de-sac and the lower meniscus would expose the inferior “lid wiper” to increased risk of hyperosmolarity-related damage. For example, increased upgaze is common for students, who assume a headdown posture to take notes, but frequently look up from that position to view the lecturer or a visual presentation. A much greater than normal time in upgaze would allow the inferior conjunctival sac tears to increase in osmolarity. Exposure of the upper lid wiper to over-exposed surface tear layer hyperosmolarity during a blink may also contribute to epitheliopathy. However, the most probable cause of lid wiper epitheliopathy is inadequate lubrication between the lid wiper and the ocular surfaces.51,52 A thicker hydrodynamic tear film appears to be the basis for normal lid wiper lubrication function.51,53 Boundary lubrication involves very thin films with increases in the friction coefficient and a concomitant increase in potential damage to ocular surfaces.52,53 Lubricin is an amphiphilic glycoprotein expressed by ocular surface epithelia. It functions as an effective friction-lowering boundary lubricant at the human corneaeyelid interface.54 Lubricin significantly reduces friction between the cornea and lid wiper.54 This effect is specific and cannot be duplicated by the application of hyaluronate or bovine serum albumin solutions.54 Lubricin deficiency may play a role in promoting corneal damage.54 Cultured cell studies have shown that a hyperosmolarity environment can induce blunting and loss of microplicae in rabbit epithelial cells.55 The blunting of the microplicae and associated increased surface area may increase friction between the ocular surface and lid wiper, especially in lubricant-deficient eyes. Friction-related damage also depends on the compressive force with which the lid wiper loads the ocular surface. Using measurements made with a pressure sensor attached to a rigid contact lens, the mean central upper eyelid static pressure on the ocular surface was estimated to be 8.0þ/3.4 mmHg (range 4.4 to 14.4 mmHg).56 Depending on the level of forces involved in blinking and associated variations in orbicularis muscle tonus, wide variations are likely in ocular surface compressive loading by the lid wiper and potential for frictional damage. It is possible that damage and loss of smoothness of the lid wiper increases the risk of damage to the ocular surface with boundary lubrication. It is also possible that damage and loss of smoothness of the ocular surface increases the risk of damage to the lid wiper, especially if lubrication is deficient. Similarly, damage and loss of smoothness of the lid wiper surface may increase the risk of damage to the ocular surface. For example, depending on the quality, quantity, and distribution of the lipid layer, ocular surface drying during an interblink period may significantly increase the frictional coefficient for the next blink, especially if areas of tear breakup have formed. Incomplete blinks appear to increase friction; they prolong the interblink interval for the
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TEAR OSMOLARITY AND EPITHELIOPATHY / McMonnies over-exposed area and may be associated with greater evaporation and tear breakup, resulting in increased osmolarity as well as risk of over-exposure epitheliopathy. V. INFLUENCE OF TEAR QUALITY AND QUANTITY ON LID WIPER TISSUE The dependence of lid-wiper epitheliopathy on ocular surface lubrication appears to also be a function of the distance the lid travels over the ocular surface. The distance is a function of blink frequency, blink completeness, and the depth of the palpebral aperture. The lower lid sometimes moves slightly downward during a blink, but its main movement is a horizontal translation nasally.44 The total lateral movement is synchronized with upper lid movement,44 but it does not involve the same kind of upper lid surface wiping function performed by the upper lid wiper. Unless another term is specified, lower lid “wiper” seems appropriate to specify the corresponding part of the lower lid. When between-lid “contact” is made, the lower lid carries the top lid nasally for the brief time of contact.44 The mean horizontal lower eyelid excursion over the ocular surface with eyelid closure or a gentle blink was 3.3 mm.57 This finding is consistent with a reported range of blink-related lower eyelid excursions of 2-5 mm.44 The mean horizontal lower eyelid excursion with eyelid closure was found to decrease with age by 0.015 mm per year.57 Decreases with age were closely correlated with age-related increases in eyelid laxity and were accompanied by a lower position of the lower lid against the globe in older than in younger patients.57 The vertical dimension of the palpebral aperture gives an indication of the potential for an upper eyelid excursion during a complete blink. For example, in a sample of young Chinese subjects, the mean palpebral aperture depth was 10þ/1.3 mm.58 In an Indian population, the mean vertical dimension of the palpebral aperture was 12.3þ/1.7 mm for men and 11.7þ/1.6 mm for women.59 Differences in morphological types of upper lids may contribute to these variations,23 although they may have been influenced by measurement criteria and technique. Palpebral aperture depth may be affected by contact lens wear. Fonn et al found depth to be 9.76þ/0.99 mm for rigid lens wearers in Canada.60 This finding is significantly lower than the 10.24þ/0.94 mm found in soft lens wearers and 10.10þ/1.11 mm in non-contact lens wearers (the latter two findings not being significantly different).60 However, it seems that the average blink-related excursion for the upper lid wiper and the associated potential for accumulating friction-related damage, is at least three times greater than the average 3.3 mm excursion of the lower lid. However, movement of the upper lid wiper over an area covered by a thinner exposed tear layer and areas of tear breakup also appears likely to have more potential for friction-related damage. By comparison, the lower lid “wiper” makes a relatively better lubricated sliding movement over an area of unexposed ocular surface. For example, DED symptoms in soft contact lens wearers were found to be strongly associated
with upper lid wiper epitheliopathy.51 Only 20% of symptomatic soft lens wearers were found to be free of upper lid wiper staining compared to 87% of asymptomatic soft lens wearers.51 Sequential staining of the upper lid wiper in non-contact lens wearers had been found in only 12%51 and 20%52 of asymptomatic subjects. VI. OVER-EXPOSURE STAIN LOCATION Upper lid forces on the cornea cause topographic changes close to the interblink upper lid margin positions during visual tasks involving downgaze.37 It was concluded that passive compressive upper eyelid forces are capable of altering corneal topography, especially when the eyes look down during a sustained reading task.37 Similarly, it was found that the compressive loading by the lid wiper region of the lid margin creates an indentation and adjacent peaks in the epithelial surface.56 These epithelial changes56 could explain the altered topography previously observed under similar conditions.37 The mean width of contact between the eyelids and the ocular surface was estimated to be 0.60þ/0.16 mm.56 This finding is consistent with the 0.3-1.5 mm width found for the central upper lid wiper.61 Downgaze during reading could result in relative stability for the hyperosmolar black line. Its position on the ocular surface would be at a level above its position during primary gaze. As a region of greater increase in osmolarity,2,39,42 the black line, as well as the lower meniscus, may contribute to epitheliopathy over a wide area of the over-exposed cornea, depending on eye position. Thus, epitheliopathy that is observed lower on the cornea may be more likely to develop during activities using predominantly primary gaze, e.g., driving or watching television. However, a band of exposure epitheliopathy over a higher area of the over-exposed cornea may be more likely to develop during activities involving downgaze, e.g., reading and other tasks requiring lowered directions of gaze. In this case, the higher position of the lower lid relative to the cornea provides protection for the most inferior part of the cornea, which does not stain. For the superior cornea wiped by an incomplete blink, a stable tear film can be deposited by the upper meniscus alone, without a contribution from the lower meniscus, even in DED subjects.62 Increased tear stability over the less exposed upper surface following incomplete blinks in DED subjects might be due to less stretching of an already fragile tear film.62 By comparison, a complete blink requires a greater tear volume in the upper meniscus to cover (replenish) a greater area of the ocular surface.62 Consequently, significantly greater areas of tear breakup were observed following a full blink in DED subjects but not in controls.62 Meniscus height is reduced in DED subjects, especially perhaps those with aqueous-production deficiency but even more so if evaporation rates are also higher than normal.62 Consequently, reduced meniscus heights in DED subjects appear to help explain the increased rate of tear breakup observed following a complete blink. Reduced meniscus heights may significantly reduce the opportunity for mixing of the two menisci with any complete blinks.
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Table 1.
Proposed scheme for tear distribution over the ocular surface by sub-compartmentalizing according to variable levels of osmolarity
1. Isotonic tears in the superior conjunctival sac feed into the superior meniscus. 2. Although formed from isotonic tears, the osmolarity of the upper tear meniscus may become elevated according to the extent to which it mixes with tears on the interpalperbral surface, which are exposed to evaporative ambient conditions during interblink intervals. 3. Osmolarity increases in the exposed interpalpebral tears due to evaporation. Evaporation could be exacerbated by lipid layer dysfunction and shorter tear breakup times, air movement, increased temperature, and contact lens wear, for example. Ultra-thin tears indicated by the superior and inferior black lines, which are seen to form in sodium fluorescein stained tears after a blink, may be sites of greater osmolarity. 4. However, the inferior exposed area is over-exposed by incomplete blinks and may develop greater osmolarity than the superior exposed area. Epithelial stain due to hyperosmotic insult in the inferior (over-exposed) area fits this model. 5. The inferior meniscus is primarily formed from hyperosmotic tears delivered from the exposed areas by the top lid during a blink and is presumably more hypertonic than the superior meniscus for this reason. 6. Even though the tears in the inferior conjunctival sac are exposed to evaporation only during upgaze, their relative stagnancy may contribute to their even higher osmolarity.
VII. CONCLUSIONS This review of the evidence provides considerable support for compartmental variations in tear osmolarity.3 Upper and lower conjunctival sacs, upper and lower menisci, and exposed and over-exposed ocular surface appear to be useful subcompartmental classifications with corresponding differences in osmolarity. For example, in normal eyes there appears to be the basis for a progressive increase in osmolarity from the isotonic freshly produced tears in the upper conjunctival sac, to the upper meniscus, the upper exposed ocular surface, the lower over-exposed ocular surface, the lower meniscus, with highest osmolarity in the lower conjunctival sac (Table 1). Subcompartmental differences may be exaggerated in DED, especially when hyperosmotic tears are delivered to the upper conjunctival sac. Specification of tear osmolarity for any eye should be qualified according to which compartment or subcompartment has been assessed. Friction-related damage appears to be the primary basis for upper lid wiper epitheliopathy, but tear hyperosmolarity in the exposed areas may also have a role. Positive correlation was observed between staining of the upper lid margin and tear osmolarity measured in the inferior meniscus.63 Blink-related excursions for the lower “lid wiper” are much less than for the upper lid wiper. As a consequence, it has less opportunity for friction-related damage, and any epitheliopathy observed may more likely be due to hyperosmotic insult. Subcompartmental consideration of variation in osmolarity may contribute to the understanding of different forms of epitheliopathy. REFERENCES 1. Bron AJ. Eyelid secretions and the prevention and production of disease. Eye 1988;2:164-71 2. Bron AJ, Yokoi N, Gaffney EA, et al. A solute gradient in the tear meniscus. I. A hypothesis to explain Marx’s line. Ocul Surf 2011;9:70-91 3. Bron AJ, Tiffany JM, Yokoi N, et al. Using osmolarity to diagnose dry eye: a compartmental hypothesis and review of our assumptions. Adv Exp Med Biol 2002;506(Pt B):1087-94
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4. McMonnies CW. Incomplete blinking: exposure keratopathy, lid wiper epitheliopathy, dry eye, refractive surgery, and dry contact lenses. Cont Lens Ant Eye 2007;30:37-51 5. Kimball SH, King-Smith PE, Nichols JJ. Evidence for the major contribution of evaporation to tear film thinning between blinks. Invest Ophthalmol Vis Sci 2010;51:6294-7 6. King-Smith PE, Fink BA, Nichols JJ, et al. The contribution of lipid layer movement to tear film thinning and breakup. Invest Ophthalmol Vis Sci 2009;50:2747-56 7. King-Smith PE, Nichols JJ, Nichols KK, et al. Contributions of evaporation and other mechanisms of tear film thinning and break-up. Optom Vis Sci 2008;85:623-30 8. Gilbard JP, Farris L, Santamaria II J. Osmolarity of tear microvolumes in keratoconjunctivitis sicca. Arch Ophthalmol 1978;96:677-81 9. Murube J, Paterson A, Murube E. Classification of artificial tears. 1: composition and properties. Adv Exp Med Biol 1998;438:693-704 10. Tomlinson A, Khanal S, Ramaesh K, et al. Tear film osmolarity: determination of a referent for dry eye diagnosis. Invest Ophthalmol Vis Sci 2006;47:4309-15 11. Lemp MA, Bron AJ, Baudouin C, et al. Tear osmolarity in the diagnosis and management of dry eye disease. Am J Ophthalmol 2011;151:792-8 12. Sullivan BD, Whitmer D, Nichols KK, et al. An objective approach to dry eye disease severity. Invest Ophthalmol Vis Sci 2010;51:6125-30 13. Niimi J, Tan B, Chang J, et al. Diurnal pattern of tear osmolarity and its relationship to corneal thickness and deswelling. Cornea 2013;32: 1305-10 14. Keech A, Senchyna M, Jones L. Impact of time between collection and collection method on human tear fluid osmolarity. Curr Eye Res 2013;38:428-36 15. Pult H, Korb DR, Blackie CA, et al. About vital staining of the eye and eyelids. 1. The anatomy, physiology, and pathology of the eyelid margins and the lacrimal puncta by E. Marx. Optom Vis Sci 2010;87:718-24 16. Lemp MA, Weiler HH. How do tears exit? Invest Ophthalmol Vis Sci 1983;24:619-22 17. Doane MG. Blinking and the mechanics of the lacrimal drainage system. Ophthalmology 1981;88:844-51 18. Oyster CW. The human eye; structure and function. Sunderland, MA, Sinauer Associates, 1999. p. 299 19. Gaffney EA, Tiffany JM, Yokoi N, et al. A mass and solute balance model for tear volume and osmolarity in the normal and the dry eye. Prog Ret Eye Res 2010;29:59-78
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TEAR OSMOLARITY AND EPITHELIOPATHY / McMonnies 20. McGowan DP, Lawrenson JG, Ruskell GL. Touch sensitivity of the eyelid margin and palpebral conjunctiva. Acta Ophthalmologica 1994;2:57-60 21. Pult H, Riede-Pult BH, Murphy PJ. A new perspective on spontaneous blinks. Ophthalmology 2013;120:1086-91 22. Korb DR, Blackie CA. Evidence suggesting that the keratinized portions of the upper and lower lid margins do not make complete contact during deliberate blinking. Cornea 2013;32:491-5 23. Jeong S, Lemke BN, Dortzback RK, et al. The Asian upper eyelid: An anatomical study with comparison to the Caucasian eyelid. Arch Ophthalmol 1999;117:907-12 24. Murgatroyd H, Craig JP, Sloan B. Determination of relative contribution of the superior and inferior canaliculi to the lacrimal drainage system in health using the drop test. Clin Exp Ophthalmol 2004;32:404-10 25. Mengher LS, Pandher KS, Bron AJ. Non-invasive tear film breakuptime: sensitivity and specificity. Acta Ophthalmologica 1986;64:441-4 26. Iwata S, Lemp MA, Holly FJ, Dohlman CH. Evaporation rate of water from the precorneal tear film and cornea in the rabbit. Invest Ophthalmol Vis Sci 1969;8:613-9 27. Peng C-C, Cerretani C, Braum RJ, Radke CJ. Evaporation driven instability of the precorneal tear film. Adv Colloid Interface Sci 2014;206: 250-64 28. Finis D, Hayajneh J, Konig C, et al. Evaluation of an automated thermodynamic treatment (LipiFlowÒ) system for meibomian gland dysfunction: a prospective, randomized observer-masked trial. Ocul Surf 2014;12:146-54 29. Fonn D, Situ P, Simpson T. Hydrogel lens dehydration and subjective discomfort and dryness ratings in symptomatic and asymptomatic contact lens wearers. Optom Vis Sci 1999;76:700-4 30. Iskeleli G, Karakoc Y, Aydn O, et al. Comparison of tear-film osmolarity in different type of contact lenses. Cont Lens Assoc Opthalmol J 2002;28:174-6 31. Farris RL. Tear analysis in contact lens wearers. Cont Lens Assoc Ophthalmol 1986;12:70-117 32. Millodot M. Effect of the length of wear of CLs on corneal sensitivity. Acta Ophthalmol (Copenh) 1976;54:721-30 33. Larke JR, Hirji NK. Some clinically observed phenomena in extended CL wear. Br J Ophthalmol 1979;63:475-7 34. McMonnies CW. Psychological and other mechanisms for end-of-day soft lens symptoms. Optom Vis Science 2013;90:e175-81 35. Gilbard JP, Gray KL, Rossi SR. A proposed mechanism for increased tear-film osmolarity in contact lens wearers. Am J Ophthalmol 1986;102:505-7 36. Collins MJ, Stahmer D, Pearson G. Clinical findings associated with incomplete blinking in soft lens wearers. Clin Exp Optom 1989;2:55-60 37. Collins MJ, Iskander DR, Saunders A, et al. Blinking patterns and corneal staining. Eye Cont Lens 2006;32:287-93 38. Collins M, Heron H, Larsen R, et al. Blinking patterns in soft contact lens wearers can be altered with training. Am J Optom Physiol Opt 1987;6:100-3 39. Zubkov VS, Breward CJW, Gaffney EA. Coupling fluid and solute dynamics within the ocular surface tear film: a modeling study of black line osmolarity. Bull Math Biol 2012;74:2062-93 40. McDonald JE, Brubaker S. Meniscus-induced thinning of tear films. Am J Ophthalmol 1971;72:139-46
41. Liu H, Begley C, Chen M, et al. A link between tear instability and hyperosmolarity in dry eye. Invest Ophthalmol Vis Sci 2009;50: 3671-9 42. Bron AJ, Yokoi N, Gaffney EA, et al. A solute gradient in the tear meniscus. II. Implications for lid margin disease, including meibomian gland dysfunction. Ocul Surf 2011;9:92-7 43. Norn M. Meibomian orifices and Marx’s line. Studied by triple vital staining. Acta Ophthalmol (Copenh) 1985;63:698-700 44. Doane MG. Dynamics of the human blink. Ber Dtsch Ophthalmol Ges 1980;77:13-7 45. Miller KL, Polse KA, Radke CJ. Black-line formation and the “perched” human tear film. Curr Eye Res 2002;25:155-62 46. Gilbard JP, Carter JB, Sang DN, et al. Morphologic effect of hyperosmolarity on rabbit corneal epitheilium. Ophthalmology 1984;91:1205-12 47. Benjamin WJ, Hill RM. Tonicity of human tear fluid sampled from the cul-de-sac. Br J Ophthalmol 1989;73:624-7 48. Sang NM, Maurice DM. Poor mixing of microdrops with the tear fluid reduces the accuracy of tear flow estimates by fluorophotometry. Curr Eye Res 1995;14:275-80 49. Management and therapy of dry eye disease: Report of the Management and Therapy Subcommittee of the International Dry Eye Workshop (2007). Ocul Surf 2007;5:163-78 50. Morgan PB, Tullo AB, Efron N. Infrared thermography of the tear film in dry eye. Eye 1995;9:615-8 51. Korb DR, Greiner JV, Herman JP, et al. Lid-wiper epitheliopathy and dry eye symptoms in contact lens wearers. CLAO J 2002;28:211-6 52. Korb DR, Herman JP, Griener JV, et al. Lid wiper epitheliopathy and dry eye symptoms. Eye Cont Lens 2005;31:2-8 53. Korb DR, Herman JP, Blackie CA, et al. Prevalence of lid wiper epitheliopathy in subjects with dry eye signs and symptoms. Cornea 2010;29: 377-83 54. Schmidt TA, Sullivan DA, Knop E, et al. Transcription, translation, and function of lubricin, a boundary lubricant, at the ocular surface. JAMA Ophthalmol 2013;131:766-76 55. Gilbard J. Tear film osmolarity and keratoconjunctivitis sicca. CLAO J 1985;11:243-50 56. Shaw AJ, Collins MJ, Davis BA, et al. Eyelid pressure and contact with the ocular surface. Invest Opthalmol Vis Sci 2010;51:1911-7 57. Shore JW. Changes in lower eyelid resting position, movement, and tone with age. Am J Opthalmol 1985;99:415-23 58. Cho P, Leung L, Lam A, et al. Tear break-up time: clinical procedures and their effects. Ophthalmic Physiol Opt 1998;18:319-24 59. Patil S, Kale SM, Math M, et al. Anthropometry of the eyelid and palpebral fissure in an Indian population. Aesthet Surg J 2011;31:290-4 60. Fonn D, Pritchard N, Garnett B, et al. Palpebral aperture sizes of rigid and soft contact lens wearers compared to nonwearers. Optom Vis Sci 1996;73:211-4 61. Knop E, Knop N, Zhivov A, et al. The lid wiper and muco-cutaneous junction anatomy of the human eyelid margins: an in vivo confocal and histological study. J Anat 2011;218:449-61 62. Harrison WW, Begley CG, Liu H, et al. Menisci and fullness of the blink in dry eye. Optom Vis Sci 2008;85:706-14 63. Golebiowsky B, Chim K, So J, et al. Lid margins: sensitivity, staining, Meibomian gland dysfunction, and symptoms. Optom Vis Sci 2012;89:1443-9
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EDITOR
An Examination of the Relationship Between Ocular Surface Tear Osmolarity Compartments and Epitheliopathy CHARLES W. MCMONNIES, DSC ABSTRACT A 2014 PubMed search for tear hyperosmolarity and corneal stain yielded 2960 results. Selections from those providing evidence of variations in osmolarity were used to refine the compartmentalization model of tear osmolarity over the ocular surface. This new model includes the low point of freshly produced isotonic tears in the upper conjunctival sac, with osmolarity increasing successively in the upper meniscus, the upper area of exposed ocular surface, the lower area of over-exposed ocular surface, the lower meniscus, and the lower conjunctival sac. Compartmentalization is used to explain epitheliopathy over the ocular surface as resulting from variable degrees of exposure to hyperosmolarity-induced insult and/or frictionrelated mechanical damage. Also recognized is the role of localized increases in osmolarity, which appear likely to occur in the black lines and tear breakup areas of the exposed ocular surface. Variables such as the influence of ambient conditions of air humidity, temperature and movement have been considered, as well as rates of complete and incomplete blinks and associated potential for over-exposure of the inferior area of the normally exposed ocular surface. The exacerbating contribution from contact lens wear has been included. Friction-related damage may
Accepted for publication July 2014. From the School of Optometry and Vision Science, University of New South Wales, Kensington, Australia. Research funding in relation to this review: None. The author has no proprietary or financial interest in any product or concept dicussed in this article. Single-copy reprint requests to Charles W. McMonnies, DSc (address below). Corresponding author: Adjunct Professor Charles W. McMonnies, DSc, 77 Cliff Avenue, Northbridge, Sydney, New South Wales, 2000. Tel: 61 2 9958 3046. Fax: 61 2 9958 3012. Mobile: 0409 038 799. E-mail address: [email protected] © 2015 Elsevier Inc. All rights reserved. The Ocular Surface ISSN: 15420124. McMonnies CW. An examination of the relationship between ocular surface tear osmolarity compartments and epitheliopathy. 2015;13(2):110-117.
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be the primary basis for lid wiper epitheliopathy, but tear hyperosmolarity could have an important contributory role. Subcompartmental consideration of variation in osmolarity may improve understanding of different presentations of epitheliopathy. KEY WORDS blinking, compartment, dry eye, epitheliopathy, evaporation, exposure, ocular surface, osmolarity
I. INTRODUCTION ears are necessary for the health of the ocular surface, maintaining the non-keratinized surface essential for corneal transparency as well as the lubrication required for movement of lid on globe.1 The mucosae of the ocular surface (the visible bulbar conjunctiva and the cornea) are exposed directly to the ambient air and are therefore at risk of desiccation through water loss2 and associated increased tear osmolarity. Any quantitative or qualitative inadequacy of the tear lipid layer increases water loss.3 People with reduced blink frequency or incomplete blinks have longer interblink intervals and greater tear evaporation due to increased exposure of the ocular surface.4 Exposure to adverse ambient conditions, such as low humidity and/or increased air temperature and/or air movement, also increases evaporation.5 The performance of tasks that reduce the overall blink rate and/or produce incomplete blinks are likely to greatly increase evaporation.4 Studies of evaporation rates that use goggles do not address the influence of ambient conditions.5,6 Moreover, the goggles may interfere with blinking frequency and completeness, altering interblink intervals and evaporation rates. Evaporation rates from ocular surfaces under ambient conditions may be four to five times faster than the average of the values found when goggles are worn.7 Prior to evaporation, the lacrimal secretion is generally considered to be isotonic with blood.8 The osmolarity of human serum is 290 mOsm/I, equivalent to a 0.9% NaCl aqueous solution.9 A meta-analysis of published data taken from 16 studies indicated a mean value for “normal eye”
T
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TEAR OSMOLARITY AND EPITHELIOPATHY / McMonnies OUTLINE I. II. III. IV. V.
Introduction Mechanisms for Tear Volume Reduction Influences of Contact Lenses Compartmental Variations in Osmolarity Influence of Tear Quality and Quantity on Lid Wiper Tissue VI. Over-exposure Stain Location VII. Conclusions
lower meniscus tear osmolarity of 302þ/8 mOsm/I.10 The mean value for 11 studies of tear osmolarity in keratoconjunctivitis sicca was 326þ/22 mOsm/I.10 The TearLab osmometer (San Diego, CA, USA) method of assessing osmolarity, which assesses lower meniscus samples, using a cutoff of 312 mOsms/l, achieved 73% sensitivity and 92% specificity.11 As with other measures of dry eye disease (DED), there may be overlapping of the distributions for hyperosmolarity findings between normals and DED subjects. However, tear film osmolarity was found to be the single best marker of disease severity across normals and mild/moderate and severe categories of DED.12 In the open eye, the tears are distributed in three compartments: the conjunctival sac, the preocular tear film, and the tear menisci.3 It has been suggested that in the open eye, tear osmolarity is not uniformly distributed between the tear compartments, but differs between the conjunctival sac (the preocular tear film and the fornical compartment behind the lids and in the fornix), the preocular tear film; and the tear menisci.2 Consequently, measurement or specification of tear osmolarity would require identification of the tear compartment in which measurements are taken. Osmolarity has been found to vary only diurnally in normals, but not during normal assessment hours.13,14 However, it can vary significantly during normal assessment hours in eyes with DED, and this may contribute to variations in findings among DED subjects.14 Exposure to different conditions (e.g., during sustained reading and/or major variations in air movement or humidity) before or during assessment might also contribute to variations in osmolarity. The location of tear sampling in the lower meniscus may be important.15 For example, the increased staining of Marx’s line nasally (further discussed below)15 suggests that there might be a corresponding increase in osmolarity in the nasal portions of the menisci. This review examines the evidence for compartmental variations in osmolarity and associated potential for ocular surface and lid wiper epitheliopathy. (Lid wiper refers to a localized portion of the marginal conjunctiva of the upper eyelid that has a rubbing effect on the ocular surface during blinking.) In particular, the significance of considering the upper and lower menisci, the upper and lower areas of exposed ocular surface, and the upper and lower conjunctival sacs as separate compartments is discussed.
II. MECHANISMS FOR TEAR VOLUME REDUCTION Apart from evaporation, tears can be lost by tangential flow and drainage into the lacrimal sacs and by movement into the epithelium of the cornea or conjunctiva.7 However, under conditions of hyperosmotic tears, transfer of water from the epithelium into tears appears more likely.5 It is possible for tears to be transferred into a hydrophilic contact lens, but the primary routes of exit are by evaporation and tangential flow.5 A blink mechanism is necessary for effective tear drainage, although the puncta close during blinking.16 Tear exit occurs even when the lids do not meet during a blink.16 The puncta actually come into full contact after one-third to one-half of the full downward excursion of the upper lid.17 Lid closure during blinks has both vertical and lateral-tomedial components.18 The tears are not only swept vertically down the cornea during a blink, but also pushed medially toward the sites of drainage at the medial canthi.18 A driver of fluid from the meniscus into the nasolacrimal drainage system was proposed under the name of the “lacrimal pump.”17,19 This mechanism assumes that contraction of the orbicularis muscle during the blink compresses the lacrimal sac.19 The negative pressure produced by the subsequent expansion of the lacrimal sac is transmitted to the tear menisci at the start of the interblink interval (and relaxation of the orbicularis muscle), resulting in drainage.17 The central parts of the lid margins, described as the occlusal surfaces,20 do not touch in spontaneous blinks due to their misalignment, with the top lid overhanging the bottom lid.21 The keratinized portions of the upper and lower lid margins do not make complete contact during deliberate blinking.22 Even with forced blinks, when greater contact occurs between the lids, an over-blink can still be observed.21 Depending on how easily the lid stretches, lid tightness and compressive loading on the ocular surface may increase during the initial down-phase of a blink, as the lid must stretch over increasing corneal sag height. Tightness and compressive loading likely reaches a peak as the lid moves over the maximum sag height at the corneal apex. As the blink moves down beyond this position, the corneal sag height or vault is reduced, and lid tightness as well as its compressive loading of the ocular surface may diminish accordingly. Perhaps the lids have not fully recovered from their stretching over the corneal apex when they complete their downward excursion. Residual upper lid stretch or looseness may contribute to the degree to which they over-blink or overhang the lower lid at the completion of the down phase of a complete blink. When passive closure is sustained, giving the upper lid time to regain normal length (compared to a blink), the overhang of the top lid lessens or even disappears, allowing the two menisci to fuse. However, lid overhang does not seem to help menisci fusion during a spontaneous blink. Differences in lid anatomy among racial groups may affect blink functions. For example, compared to Caucasians, Asian (Korean) lids have more subcutaneous and suborbicularis fat, with a pretarsal fat component being present.23 The upper lid crease is also a feature of
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TEAR OSMOLARITY AND EPITHELIOPATHY / McMonnies distinction.23 There are three morphological types of Asian upper eyelid: the single lid with no lid crease and puffiness; the lid with a low-seated nasally tapered inside-fold type of crease; and the double eyelid with lid crease parallel to the lid margin.23 These features may be associated with more or less upper lid overhang or other differences in Asian compared to Caucasian lids, possibly associated with differences in blink-related tear function. Tears are drawn into the canaliculi during the relaxation phase of blinking, and the superior punctum route alone is sufficient to handle tear drainage.16 The exception is when an increase in lacrimation rate is sufficient to challenge the capacity of the superior route. Nevertheless, in healthy subjects in the supine position, 60% of tear outflow was found to occur through the inferior canaliculus.24 For an initial thickness of 3 mm, and for a thinning rate of 20 mm/min, the tear film would thin to zero thickness (tear breakup) in only 9 seconds, a value that is comparable with measured tear film breakup times.25 It has been calculated that reported evaporation rates were only about 20-25% of the calculated thinning rates.7 This finding suggests that other mechanisms for loss of tear volumeeinto the epithelium (and/or a hydrogel contact lens) and/or tangential flow and loss by drainage into the canaliculi7e could account for most of the tear loss. However, when the lipid layer is removed, evaporation increases about four-fold.26 Tear film instability and evaporation also depend on the strength of healing flow from the neighboring region outside the breakup area, which is determined by the surface tension at the tear film surface and by the repulsive thin-film disjoining pressure.27 As noted above, evaporation rates may be greatly increased by adverse ambient conditions,27 low blink rate, and/or incomplete blinks.4 The rate of tear loss by evaporation also increases with the area of exposed ocular surface during primary gaze, which varies with the width of the palpebral aperture and the distance between the inner and outer canthi.3 Both exposure and over-exposure of the ocular surface due to evaporation could be expected to be much higher in certain patients, for example, in those with wider lid apertures, which are associated with proptosis3 or exophthalmos, such as that which occurs in axial myopia, especially in association with posterior staphyloma. The overall area of exposure is greater in upgaze than in downgaze. During downgaze, the upper lid is lowered, while the lower lid is relatively stationary.3 Rapid evaporation and tear thinning over the exposed ocular surface due to lipid layer dysfunction promotes tear and localized increases in osmolarity.19 Obstructed meibomian glands and/or increased viscosity of meibum are the underlying causes of lipid layer dysfunction.28 Evaporation of the tear film may give rise to considerable increases in the local osmolarity of the exposed tear between blinks.7,11 It is likely that the osmolarity of the exposed tear film always exceeds that of the menisci, especially in DED.3 However, with lid wiper-driven flow from the exposed surface of 112
hyperosmolar tears into the lower meniscus, osmolarity becomes elevated, albeit more modestly. III. INFLUENCES OF CONTACT LENSES Soft contact lenses were shown to dehydrate during wear, with associated reduced noninvasive tear film breakup times for the lens front surface, especially in patients who reported symptoms of discomfort and dryness.29 Use of daily wear soft contact lenses was associated with tear osmolarity increases after contact lens wear, from a mean of 284þ/ 10mOsm/l before wear to a mean of 314þ/84mOsm/l after wear.30 This increase is just above the cutoff for keratoconjunctivitis sicca and helps explain symptoms of dryness. Increased tear osmolarity was also found in normal wearers of extended-wear soft contact lenses.31 Reduced corneal touch sensitivity was found in wearers of both rigid and soft lenses after only 12 hours of wear.32 The loss in corneal sensitivity that developed progressively over 20 weeks of soft lens wear was to a level similar to that found in rigid lens wearers after 12 hours.33 To the extent that soft and scleral contact lenses shield the cornea from its normal exposure to ambient conditions, the lenses produce a form of contact lens-induced corneal hypoalgesia.34 Contact lens-related decreases in corneal innervation with a resultant reduced tear secretion rate are likely to be one of the causes of associated increases in osmolarity.35 Reduced tear flow rates and associated delayed exit result in longer exposure to evaporation and increased osmolarity. Compared to controls, incomplete blinking was found to be associated with a significant decrease in the hydration of the over-exposed lower half of nonrotating soft contact lenses.36 Consistent staining of the over-exposed inferior cornea was observed in an incomplete blinking group.36 This group also appeared to have a higher prevalence of adverse symptoms and to more frequently develop contact lens surface deposits.36 A higher proportion of incomplete blinks was apparent in both healthy subjects and soft contact lens wearers, who were found to have fluorescein staining in the area over-exposed by incomplete blinks.37 The association between degree of incomplete blinking and the grade of fluorescein staining was stronger in soft lens wearers.37 Loss of tears from the post-lens space into the lens (perhaps in response to those lost by evaporation from the lens front surface) may help explain the increased exposure staining in some soft lens wearers. Both healthy subjects and soft lens wearers showed 22% incomplete blinks.37 However, soft lens wearers who performed blink efficiency exercises for 2 weeks displayed an increased frequency of complete blinks over their pre-training performance, compared with controls, who did not attempt to improve their blink efficiency.38 Successful contact lens wear can be enhanced if patients are encouraged to improve blink functions.4 For example, contact lens wearers who normally have efficient blink habits but who use computers or similar digital devices for long periods are at risk for reduced blink function and
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TEAR OSMOLARITY AND EPITHELIOPATHY / McMonnies associated symptoms of dryness.4,34 People with symptoms of DED who do not wear contact lenses and who have a tendency to blink less frequently or less completely may also benefit from performing exercises to improve blink efficiency.4 The best time to perform blink exercises might be immediately after instillation of lubricant tear replacement drops, as this may enhance delivery of the lubricant to the epithelial cells, increasing the potential therapeutic benefit of the drop.4 IV. COMPARTMENTAL VARIATIONS IN OSMOLARITY Because of the hydrophilic nature of the conjunctiva, the tear film forms menisci adjacent to the upper and lower eyelid margins, which ensures that one apex of each meniscus wets up to a contact line at the mucocutaneous junction.39 The other apex of each meniscus asymptotes to the black line region.39 The black line is a juncture between each meniscus and the central tear film on the ocular surface.39 In a tear film stained with fluorescein, black lines arise at this juncture immediately following a blink.40 The black lines are regions of very thin tear-film thickness,40 thus having much less fluorescence than the thin precorneal tear layer. Their blackness also contrasts with the strong fluorescence from normal menisci. Mathematical modelling of the spatial distribution of tear film osmolarity indicates increases in osmolarity with evaporation at the black lines.39 The highest increases in osmolarity predicted by modelling are amply sufficient to raise meniscus osmolarity into the regime diagnostically classified as DED.39 This finding may not apply as much to the upper meniscus because, in normal eyes, isotonic tears are delivered to the temporal upper fornix from a healthy lacrimal gland and into the superior conjunctival sac from normal functioning accessory lacrimal glands.8 Compared with the tear layer and menisci, which are exposed to air, the newly secreted lacrimal fluid appears likely to be the low point for osmolarity, given its lack of exposure to evaporation. Modelling shows that lacrimal gland aqueous deficiency also results in hyperosmolarity, but the increase in osmolarity is less than that resulting from evaporation.39 Consequently, any reduction in tear production and associated tear hyperosmolarity in newly secreted lacrimal fluid is likely to be greatly exacerbated by further increases in hyperosmolarity due to the influence of lipid layer dysfunction, contact lens wear, and exposure to adverse ambient conditions on the rate of evaporation. Hyperosmolarity in the precorneal tear film may transiently spike during tear instability, resulting in corneal inflammation and symptoms due to the triggering of sensory neurons.41 Hyperosmolarity may contribute to inflammatory processes at the ocular surface by causing epithelial damage, possibly inducing release of cytokines from epithelial cells.3 Hyperosmolarity may also involve autoimmune destruction of lacrimal gland and ducts and release of inflammatory mediators from the gland and conjunctiva into the tears.3 Pro-inflammatory mitogen-activated protein kinase was found experimentally to be activated by 600
mOsm/L of transient hyperosmolar stress.41 Measurements of hyperomolarity at this level have not been published. However, that such levels could be found in the precorneal tear film within an area of breakup is supported by the following reasoning. If, due to tear evaporation, the tear film thins by a factor of 3, for example, from 3 mm to 1 mm, then if no solute is lost, the tear osmolarity could increase by a corresponding factor (e.g., from 300 to 900 mOsm/L).7 Thus, osmolarity measured from the lower tear meniscus may not reflect the rapid spatial and temporal changes that occur over the exposed corneal and conjunctival surfaces during breakup within the interblink interval.41 In addition, Marx’s line stain is hypothesized to be a consequence of evaporation from the tear menisci after many iterations of the interblink interval, which results in an increase in osmolarity at the peripheral apices of each meniscus.2,42 Marx’s line stain is observed in subjects with apparently normal tear function.43 The gradient of Marx’s line staining, dissipating posteriorly,15 may be explained by a gradient of reducing osmolarity, starting from a maximum at the meniscus apex and anterior edge of Marx’s line. Of course, the location of the hyperosmolar apex of the meniscus would shift posteriorly with any reduction in meniscus volume. This explanation depends on higher osmolarity being due to the greater relative susceptibility to evaporation of the thin anterior meniscus apex. Increases in osmolarity in the deeper meniscus are likely to be proportionately less than the increases that occur at the apices of the meniscus. However, on the ocular surface, and despite being the thinnest region of the tear film with associated hyperosmolarity, the black line is not normally associated with staining analogous to Marx’s line stain.42 This may be because, for the normal meniscus volume for any individual, the position of the thinned apex, which is apparently responsible for the staining of Marx’s line, is more stable and usually just behind the mucocutaneous junction. On the other hand, the black line on the ocular surface is usually being frequently relocated by vertical saccades. That is, up- and downgaze eye movements allow the potential for black line hyperosmolarity-related tissue damage to be shared over a wide area of the ocular surface. This may not be the case during reading, watching television, or similar activity, when up and down eye movements are limited, maintaining a more stable location for the black line on the ocular surface. Stability of the location of the black line is likely to be associated with increased risk of hyperosmolarity-related epitheliopathy. Hyperosmolarity of the black line tears may then contribute to over-exposure epitheliopathy due to incomplete blinking. The tear film rapidly becomes stationary following a blink,44 with rapid black line formation. No gravityinduced drainage occurs between blinks even for upright body (head) positions.45 Evaporation from the exposed tear film during the interblink interval, and associated increased osmolarity, means that the lower meniscus is
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TEAR OSMOLARITY AND EPITHELIOPATHY / McMonnies likely to have higher osmolarity than the upper meniscus. This could be the result of supplementation of the lower meniscus with tears of higher osmolarity. These would be delivered from the exposed ocular surface and both black lines via the wiping action of the downward movement of the upper lid during a blink. Incomplete blinking over-exposes the normally exposed inferior ocular surface by approximately doubling the interblink interval,4 as well as doubling the opportunity for tear evaporation. Over-exposure challenges lipid layer function with associated potential for tear breakup, greater levels of evaporation, and increases in osmolarity. DED-induced tear hyperosmolarity is recognized as a major cause of ocular surface damage.46 For example, the tear film osmolarities observed in keratoconjunctivitis sicca are sufficient to cause the corneal epithelial changes seen in patients with this disease.46 Higher osmolarity in the tear layer over the band of inferior corneal surface can be explained by the association between incomplete blinking and exposure epitheliopathy and staining of only that part of the cornea.37 Over-exposure epitheliopathy contrasts with nonstaining of the upper cornea. This observation supports a division of the tear layer compartment into upper and lower zones of correspondingly exposed and over-exposed zone of higher osmolarity, with the highest osmolarity being present in the lower zones. Over-exposure stain is likely to be exacerbated by sequences of successive incomplete blinks. Even with complete blinks, tear film evaporation and increased osmolarity of exposed tears would cause the tears in the inferior meniscus to have higher osmolarity than those in the superior meniscus. However, it was found that tear fluid from the inferior conjunctival sac had even higher osmolarity than tear fluid of the inferior meniscus.47 Without upgaze to expose the inferior bulbar conjunctiva to the atmosphere,3 the tears in the inferior conjunctival sac appear to be relatively stagnant compared to those in the lower meniscus, which have ready access to the punctum. Fluorescein stain instilled into the inferior conjunctival sac takes several minutes to disperse over the ocular surface, providing evidence of deficiency of flow from the inferior conjunctival sac.48 However, with upgaze, the inferior bulbar conjunctival tear layer is exposed to evaporation and increased osmolarity. Evaporation is temperaturedependent, and lower conjunctival sac tears enclosed between palpebral and bulbar conjunctiva during primary or downgaze will warm and become susceptible to faster evaporation when exposed by upgaze. Warming would be greater for eyes with hyperemic conjunctivae, as is often the case in DED.49 For example, consistent with conjunctival hyperemia in dry eyes, the difference between limbal and corneal temperature is significantly greater in dry eyes than in normal eyes.50 With the rapid evaporation of the exposed warm tears on the inferior bulbar conjunctiva, osmolarity can increase significantly. Hyperosmotic tears would then be returned to the inferior conjunctival sac with a resumption of 114
primary gaze or downgaze, elevating the osmolarity of the conjunctival sac tear pool. Increased osmolarity in the inferior cul-de-sac and the lower meniscus would expose the inferior “lid wiper” to increased risk of hyperosmolarity-related damage. For example, increased upgaze is common for students, who assume a headdown posture to take notes, but frequently look up from that position to view the lecturer or a visual presentation. A much greater than normal time in upgaze would allow the inferior conjunctival sac tears to increase in osmolarity. Exposure of the upper lid wiper to over-exposed surface tear layer hyperosmolarity during a blink may also contribute to epitheliopathy. However, the most probable cause of lid wiper epitheliopathy is inadequate lubrication between the lid wiper and the ocular surfaces.51,52 A thicker hydrodynamic tear film appears to be the basis for normal lid wiper lubrication function.51,53 Boundary lubrication involves very thin films with increases in the friction coefficient and a concomitant increase in potential damage to ocular surfaces.52,53 Lubricin is an amphiphilic glycoprotein expressed by ocular surface epithelia. It functions as an effective friction-lowering boundary lubricant at the human corneaeyelid interface.54 Lubricin significantly reduces friction between the cornea and lid wiper.54 This effect is specific and cannot be duplicated by the application of hyaluronate or bovine serum albumin solutions.54 Lubricin deficiency may play a role in promoting corneal damage.54 Cultured cell studies have shown that a hyperosmolarity environment can induce blunting and loss of microplicae in rabbit epithelial cells.55 The blunting of the microplicae and associated increased surface area may increase friction between the ocular surface and lid wiper, especially in lubricant-deficient eyes. Friction-related damage also depends on the compressive force with which the lid wiper loads the ocular surface. Using measurements made with a pressure sensor attached to a rigid contact lens, the mean central upper eyelid static pressure on the ocular surface was estimated to be 8.0þ/3.4 mmHg (range 4.4 to 14.4 mmHg).56 Depending on the level of forces involved in blinking and associated variations in orbicularis muscle tonus, wide variations are likely in ocular surface compressive loading by the lid wiper and potential for frictional damage. It is possible that damage and loss of smoothness of the lid wiper increases the risk of damage to the ocular surface with boundary lubrication. It is also possible that damage and loss of smoothness of the ocular surface increases the risk of damage to the lid wiper, especially if lubrication is deficient. Similarly, damage and loss of smoothness of the lid wiper surface may increase the risk of damage to the ocular surface. For example, depending on the quality, quantity, and distribution of the lipid layer, ocular surface drying during an interblink period may significantly increase the frictional coefficient for the next blink, especially if areas of tear breakup have formed. Incomplete blinks appear to increase friction; they prolong the interblink interval for the
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TEAR OSMOLARITY AND EPITHELIOPATHY / McMonnies over-exposed area and may be associated with greater evaporation and tear breakup, resulting in increased osmolarity as well as risk of over-exposure epitheliopathy. V. INFLUENCE OF TEAR QUALITY AND QUANTITY ON LID WIPER TISSUE The dependence of lid-wiper epitheliopathy on ocular surface lubrication appears to also be a function of the distance the lid travels over the ocular surface. The distance is a function of blink frequency, blink completeness, and the depth of the palpebral aperture. The lower lid sometimes moves slightly downward during a blink, but its main movement is a horizontal translation nasally.44 The total lateral movement is synchronized with upper lid movement,44 but it does not involve the same kind of upper lid surface wiping function performed by the upper lid wiper. Unless another term is specified, lower lid “wiper” seems appropriate to specify the corresponding part of the lower lid. When between-lid “contact” is made, the lower lid carries the top lid nasally for the brief time of contact.44 The mean horizontal lower eyelid excursion over the ocular surface with eyelid closure or a gentle blink was 3.3 mm.57 This finding is consistent with a reported range of blink-related lower eyelid excursions of 2-5 mm.44 The mean horizontal lower eyelid excursion with eyelid closure was found to decrease with age by 0.015 mm per year.57 Decreases with age were closely correlated with age-related increases in eyelid laxity and were accompanied by a lower position of the lower lid against the globe in older than in younger patients.57 The vertical dimension of the palpebral aperture gives an indication of the potential for an upper eyelid excursion during a complete blink. For example, in a sample of young Chinese subjects, the mean palpebral aperture depth was 10þ/1.3 mm.58 In an Indian population, the mean vertical dimension of the palpebral aperture was 12.3þ/1.7 mm for men and 11.7þ/1.6 mm for women.59 Differences in morphological types of upper lids may contribute to these variations,23 although they may have been influenced by measurement criteria and technique. Palpebral aperture depth may be affected by contact lens wear. Fonn et al found depth to be 9.76þ/0.99 mm for rigid lens wearers in Canada.60 This finding is significantly lower than the 10.24þ/0.94 mm found in soft lens wearers and 10.10þ/1.11 mm in non-contact lens wearers (the latter two findings not being significantly different).60 However, it seems that the average blink-related excursion for the upper lid wiper and the associated potential for accumulating friction-related damage, is at least three times greater than the average 3.3 mm excursion of the lower lid. However, movement of the upper lid wiper over an area covered by a thinner exposed tear layer and areas of tear breakup also appears likely to have more potential for friction-related damage. By comparison, the lower lid “wiper” makes a relatively better lubricated sliding movement over an area of unexposed ocular surface. For example, DED symptoms in soft contact lens wearers were found to be strongly associated
with upper lid wiper epitheliopathy.51 Only 20% of symptomatic soft lens wearers were found to be free of upper lid wiper staining compared to 87% of asymptomatic soft lens wearers.51 Sequential staining of the upper lid wiper in non-contact lens wearers had been found in only 12%51 and 20%52 of asymptomatic subjects. VI. OVER-EXPOSURE STAIN LOCATION Upper lid forces on the cornea cause topographic changes close to the interblink upper lid margin positions during visual tasks involving downgaze.37 It was concluded that passive compressive upper eyelid forces are capable of altering corneal topography, especially when the eyes look down during a sustained reading task.37 Similarly, it was found that the compressive loading by the lid wiper region of the lid margin creates an indentation and adjacent peaks in the epithelial surface.56 These epithelial changes56 could explain the altered topography previously observed under similar conditions.37 The mean width of contact between the eyelids and the ocular surface was estimated to be 0.60þ/0.16 mm.56 This finding is consistent with the 0.3-1.5 mm width found for the central upper lid wiper.61 Downgaze during reading could result in relative stability for the hyperosmolar black line. Its position on the ocular surface would be at a level above its position during primary gaze. As a region of greater increase in osmolarity,2,39,42 the black line, as well as the lower meniscus, may contribute to epitheliopathy over a wide area of the over-exposed cornea, depending on eye position. Thus, epitheliopathy that is observed lower on the cornea may be more likely to develop during activities using predominantly primary gaze, e.g., driving or watching television. However, a band of exposure epitheliopathy over a higher area of the over-exposed cornea may be more likely to develop during activities involving downgaze, e.g., reading and other tasks requiring lowered directions of gaze. In this case, the higher position of the lower lid relative to the cornea provides protection for the most inferior part of the cornea, which does not stain. For the superior cornea wiped by an incomplete blink, a stable tear film can be deposited by the upper meniscus alone, without a contribution from the lower meniscus, even in DED subjects.62 Increased tear stability over the less exposed upper surface following incomplete blinks in DED subjects might be due to less stretching of an already fragile tear film.62 By comparison, a complete blink requires a greater tear volume in the upper meniscus to cover (replenish) a greater area of the ocular surface.62 Consequently, significantly greater areas of tear breakup were observed following a full blink in DED subjects but not in controls.62 Meniscus height is reduced in DED subjects, especially perhaps those with aqueous-production deficiency but even more so if evaporation rates are also higher than normal.62 Consequently, reduced meniscus heights in DED subjects appear to help explain the increased rate of tear breakup observed following a complete blink. Reduced meniscus heights may significantly reduce the opportunity for mixing of the two menisci with any complete blinks.
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Table 1.
Proposed scheme for tear distribution over the ocular surface by sub-compartmentalizing according to variable levels of osmolarity
1. Isotonic tears in the superior conjunctival sac feed into the superior meniscus. 2. Although formed from isotonic tears, the osmolarity of the upper tear meniscus may become elevated according to the extent to which it mixes with tears on the interpalperbral surface, which are exposed to evaporative ambient conditions during interblink intervals. 3. Osmolarity increases in the exposed interpalpebral tears due to evaporation. Evaporation could be exacerbated by lipid layer dysfunction and shorter tear breakup times, air movement, increased temperature, and contact lens wear, for example. Ultra-thin tears indicated by the superior and inferior black lines, which are seen to form in sodium fluorescein stained tears after a blink, may be sites of greater osmolarity. 4. However, the inferior exposed area is over-exposed by incomplete blinks and may develop greater osmolarity than the superior exposed area. Epithelial stain due to hyperosmotic insult in the inferior (over-exposed) area fits this model. 5. The inferior meniscus is primarily formed from hyperosmotic tears delivered from the exposed areas by the top lid during a blink and is presumably more hypertonic than the superior meniscus for this reason. 6. Even though the tears in the inferior conjunctival sac are exposed to evaporation only during upgaze, their relative stagnancy may contribute to their even higher osmolarity.
VII. CONCLUSIONS This review of the evidence provides considerable support for compartmental variations in tear osmolarity.3 Upper and lower conjunctival sacs, upper and lower menisci, and exposed and over-exposed ocular surface appear to be useful subcompartmental classifications with corresponding differences in osmolarity. For example, in normal eyes there appears to be the basis for a progressive increase in osmolarity from the isotonic freshly produced tears in the upper conjunctival sac, to the upper meniscus, the upper exposed ocular surface, the lower over-exposed ocular surface, the lower meniscus, with highest osmolarity in the lower conjunctival sac (Table 1). Subcompartmental differences may be exaggerated in DED, especially when hyperosmotic tears are delivered to the upper conjunctival sac. Specification of tear osmolarity for any eye should be qualified according to which compartment or subcompartment has been assessed. Friction-related damage appears to be the primary basis for upper lid wiper epitheliopathy, but tear hyperosmolarity in the exposed areas may also have a role. Positive correlation was observed between staining of the upper lid margin and tear osmolarity measured in the inferior meniscus.63 Blink-related excursions for the lower “lid wiper” are much less than for the upper lid wiper. As a consequence, it has less opportunity for friction-related damage, and any epitheliopathy observed may more likely be due to hyperosmotic insult. Subcompartmental consideration of variation in osmolarity may contribute to the understanding of different forms of epitheliopathy. REFERENCES 1. Bron AJ. Eyelid secretions and the prevention and production of disease. Eye 1988;2:164-71 2. Bron AJ, Yokoi N, Gaffney EA, et al. A solute gradient in the tear meniscus. I. A hypothesis to explain Marx’s line. Ocul Surf 2011;9:70-91 3. Bron AJ, Tiffany JM, Yokoi N, et al. Using osmolarity to diagnose dry eye: a compartmental hypothesis and review of our assumptions. Adv Exp Med Biol 2002;506(Pt B):1087-94
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