Eye (1989) 3, 428-437 The Ocular Surface in Keratoconjunctivitis Sicca A. J. BRON and L. S. MENGHER Oxford Summary The ocular surface is altered in kerato-conjunctivitis sicca, a disorder of aqueous tear production. Many of the factors leading to these surface changes are now more clearly understood and are discussed in this paper. The Epithelium of the Normal Ocular binding protein (pRBP) to a cellular retinol Surface binding protein (cRBP). The corneal epi­ The surface epithelial cells of the cornea and thelium is denied a direct vascular source and conjunctiva exhibit delicate microvilli. In the it is likely that this is supplied by the tears, conjunctiva they are coated with a glycocalyx which contain less than 0.4-10.6 ng/mLH which is in continuity with glycoprotein Recently it has been proposed that tear­ secreted into subsurface vesicles. I.2 This specific pre albumin may play the role as a glycocalyx interacts with tear mucin histo­ carrier for retinol in the tears, similar to that chemically stainable at the surface of the eye, of RBP in the plasma. 9 Tseng et al. in 1985 whose precise disposition in vivo is not yet have suggested on the basis of transdifferen­ known. tiation experiments that the degree of vas­ Goblet cell distribution is not uniform cularisation of the ocular surface influences across the globe and tarsus. Cell density is goblet cell density by modulating the delivery greater infranasally on the globe and is great­ of retinol. 10 If rabbit cornea including the lim­ est on the caruncle. Cell density peaks shortly bus, is denuded of epithelium it is resurfaced after birth and plateaus between the fourth by conjunctival epithelial cells which at first and eighth decade.3 Goblet cells are absent retain their biochemical and morphological from the limbus. features, including goblet cells. After a matter Inflammatory cells are present in the of weeks however they transdifferentiate and normal conjunctival epithelium and substan­ take on the appearance of corneal epithelial tia propria, with neutrophils and lymphocytes cells; the goblet cells are lost. II This process of in the epithelium and with neutrophils, lym­ transdifferentiation can be prevented by phocytes, plasma cells and mast cells in the topical treatment with retinoidsl2.13 or if the substantia propria. 4 Normal tears collected by cornea which is resurfaced is vascularised micropipettes from the marginal strip are (and therefore, it is presumed, provided with usually free of inflammatory cells; tears a source of retinol). sucked from the bulbar surface do contain Tseng et al. have also suggested that scar­ granulocytes. 5.6.7 ring may diminish conjunctival vascularity in Vitamin A is essential to the maintenance various forms of dry eye and contribute to the of the normal architecture of the surface epi­ accompanying squamous metaplasia of the thelia of the eye. As in other tissue it is ocular surface. III The alternative view has assumed in the conjunctiva, a vascular tissue, been proposed, that hyperosmolarity (vide that retinol is transferred from plasma retinol infra) may be the cause of metaplasia, includ- Correspondence to: A. 1. Bran, Nuffield Laboratory of Ophthalmology, Walton Street, Oxford OX2 6AW . THE OCULAR SURFACE IN KERATOCONJUNCTIVITIS SICCA 429 ing goblet cell loss. 14.15 This may be true but it the corneal surface by lowering the surface must be noted that in animal models in which tension. Recent studies by Cope et al. (1986) the lacrimal excretory duct is occluded, this attempting to reproduce the conditions of would let tear retinol as well as lead to these experiments, have shown that physical hyperosmolarity. and chemical treatment of the corneal epi­ thelium causes significant surface damage as Tear Mucin demonstrated by scanning electron micro­ The goblet cells are assumed to be the major scopy (SEM). 23 Thus the hydrophobic source of tear mucin (i.e. mucous glycopro­ behaviour of the cornea under these condi­ tein). There is immunoidentity between at tions may not reflect the native state of the least one mucin fraction of the tears and a epithelium in the absence of mucin. Prelimin­ component of conjunctival goblet cell secre­ ary studies by Tiffany have suggested that the tion. 16 No such immunoidentity was found native surface tension of the corneal epi­ between tear mucin and lacrimal secretory thelium, after removal of mucin by mild saline acini. Huang et al. in 1987 have confirmedthis washing is low, that is, it is a wettable, hydro­ in the rabbit using antibody against the core philic surface. 24 protein of a mucin fraction. 17 Holly has also proposed that dry spots would be initiated in dry eye by contamination Viscosity of the Tears of the epithelial surface by meibomian lipid. Mucus is responsible for the high viscosity of Mucin is envisaged as interacting with such the tears and their non-Newtonian or lipid to prevent dry spots forming in this way. pseudoplastic behaviour, that is, their vis­ On these grounds mucin deficiency would cosity is shear-dependent and they exhibit a encourage tear film instability. 25 fall in viscosity, at high shear rates ('shear If tear mucin is not essential to render the thinning'). 18 This property is thought to confer corneal or indeed the conjunctival surface the advantage of low viscosity during a blink wettable, studies which correlate a loss of gob­ or saccade and stability of the tear film when let cells with a reduction in tear stability must the eye is stationary, for example, during be interpreted with caution. If it is naturally fixation. IY•2o wettable, then early tear break up in the pres­ During reflex tearing in normal subjects ence of reduced goblet cell destiny may still tear viscosity falls, which supports the view imply the occurrence of a surface change in that the lacrimal gland is at least not the major KCS which renders it hydrophobic; the 'lipid source of tear mucin. The paper by Allen et a!' trapping' role for mucin may prove to be more (1972) identifiedthe presence of glycoprotein tenable than a primary role in maintaining a within storage granules of human lacrimal hydrophilic epithelium (see below). Another gland. However, although this was taken to be possibility would be that loss of tear mucin mucus glycoprotein at the time, the histo­ reduces stability by lowering tear viscosity, chemical techniques used are not able to dis­ since Benedetto et al. in 1975 demonstrated a tinguish between mucus and other types of relationship between viscosity of polymers glycoprotein. 21 used as tear substitutes and the thickness of the film formed. 26 Wetting of the Ocular Surface Holly and Lemp in 1971 proposed that the Changes in the Tears and Ocular Surface in corneal surface was non-wettable (hydro­ Kerato-conjunctivitis Sicca phobic) in vivo and that tear mucus served the Infiltration of the lacrimal gland with round role of rendering the epithelium hydrophilic. 22 cells occurs in KCS and is assoicated with This conclusion was based on studies in which acinar atrophy27 and reduced secretion of lac­ surface mucus was removed by gentle wiping rimal fluid28. This is the primary event from or by chemical treatment. The corneal surface which most if not all changes at the ocular was found in these circumstances to become surface follow. hydrophobic and the addition of mucus Many of the features of KCS are quantifia­ restored the normal hydrophilic properties of ble (Table I), but only a small number of 430 A. J. BRaN AND L S. MENGHER Table I correlated with the Schirmer value in normal subjects. Only 7% of the normal subjects A. Aqueous deficicncy * Flow show a meniscus height of less than * Volume 0.1 mm.34 Continued evaporation from a pre­ * Osmolarity ocular tear film of reduced volume leads to B. Mucin deficiency hyperconcentration of the tears. A rise in tear * Goblet cell loss osmolarity was anticipated by von Bahr in * Lowered viscosity 1941 and later confirmed by Mastmann et al. * Increased surface tension in 1961 and Mishima et al. in 1971."5,36,28 * Altered tear stability * Altered mucus ferning Gilbard et al., (1978) using a micropipetting technique and a depression of freezing point C. Lipid deficiency * Fatty acid changes method to determine osmolarity, found the * Interference microscopy osmolarity of normal tears to be * Meibomian morphology 302±6.3 mOsm/L while that in a group of D. Chemical changes patients with KCS was considerably higher, * e.g. Lysozyme, lactoferrin, ceruloplasmin 343±32.3 mOsm/LY Farris et at. in 1983 E. Surface cellular damage using a cut off value of >312 mOsm/L have * e. g. Fluorescein, Rose Bengal staining found that the test has a sensitivity of 76% and F. Inflammation a specificity of 84%.30 Further studies by this * Polymorphonuclear leucocytes group have shown hyperosmolarity in the * Prostaglandins range cncountered in KCS to be damaging to * Superoxide rabbit corneal epithelial cells in vitro and hyperosmolarity has been suggested as the basis of ocular surface damage in KCS.3 8.39 We assessable features have been assessed as have confirmed a rise in marginal strip diagnostic tests. osmolarity in KCS.5 Damage to the ocular It can be seen from the study of Van Bijster­ surface is detected clinically by staining with veld (1969) that the Schirmer test has a high fluorescein, which demonstrates corneal sensitivity (85%) and specificity(83%) using a staining most effectively, or by Bengal Rose value of <6 mm wetting as a cut off in the which demonstrates conjunctival surface diagnosis of KCS.29 Farris et al. in 1983 not damage better than corneal epithelial unexpectedly found a much lower sensitivity damage. However, Bengal Rose is poorly tol­ using a cut off of 3.5 mm wetting or less (Table erated by KCS patients because of its low pH 11).30 and the inability to wash away the compound Decreased flowis associated with decreased with time following instillation.