Norihiko Yokoi

The International Workshop on Meibomian Gland Dysfunction: Report of the Diagnosis Subcommittee

Diagnostic tests of meibomian gland dysfunction (MGD) and of MGD-related disorders are based on the demonstration of abnormal anatomy and physiology of the glands and the detection of specific pathologic events. For this reason, this subcommittee report is divided into two sections. In part I, those aspects of meibomian anatomy and physiology that are relevant to currently available tests are described; a fuller account of the anatomy and physiology is provided in the report of the Anatomy Subcommittee of this workshop. In part II, each test and its performance is described in detail. In part III, the practical application of selected tests is summarized and recommendations for future approaches are made. Additional recommendations and a summary of pertinent literature and concepts are presented in Appendices 1 to 17.

Predicted Phenotypes of Dry Eye: Proposed Consequences of Its Natural History

This paper reviews current knowledge of the pathophysiology of dry eye and predicts that the clinical picture in late disease differs in both severity and quality from that in early disease. It is hypothesized that hybrid forms evolve, in which aqueous-deficient dry eye (ADDE) takes on features of evaporative dry eye (EDE) and vice versa. As a consequence, early and late forms may require different diagnostic criteria and respond to different therapeutic regimes. Tear hyperosmolarity plays a key role in the damage mechanism of dry eye, and ADDE is recognized to be a low-volume, hyperosmolar state. As ADDE advances, a progressive decrease in lacrimal secretion occurs, exacerbated by loss of the corneal reflex. This causes a decrease in tear volume, thinning of the aqueous tear film, and retarded spreading of the tear film lipid layer. The latter is hypothesized to cause an increase in evaporative water loss and an added evaporative component to the dry eye. Thus, in advanced disease, the hybrid state would be an organic ADDE, accompanied by a functional EDE in the absence of meibomian gland dysfunction. This functional EDE would respond to agents that expand the tear volume, restore corneal sensitivity, or provide an artificial tear film lipid layer.

A mass and solute balance model for tear volume and osmolarity in the normal and the dry eye

Tear hyperosmolarity is thought to play a key role in the mechanism of dry eye, a common symptomatic condition accompanied by visual disturbance, tear film instability, inflammation and damage to the ocular surface. We have constructed a model for the mass and solute balance of the tears, with parameter estimation based on extensive data from the literature which permits the influence of tear evaporation, lacrimal flux and blink rate on tear osmolarity to be explored. In particular the nature of compensatory events has been estimated in aqueous-deficient (ADDE) and evaporative (EDE) dry eye. The model reproduces observed osmolarities of the tear meniscus for the healthy eye and predicts a higher concentration in the tear film than meniscus in normal and dry eye states. The differential is small in the normal eye, but is significantly increased in dry eye, especially for the simultaneous presence of high meniscus concentration and low meniscus radius. This may influence the interpretation of osmolarity values obtained from meniscus samples since they need not fully reflect potential damage to the ocular surface caused by tear film hyperosmolarity. Interrogation of the model suggests that increases in blink rate may play a limited role in compensating for a rise in tear osmolarity in ADDE but that an increase in lacrimal flux, together with an increase in blink rate, may delay the development of hyperosmolarity in EDE. Nonetheless, it is predicted that tear osmolarity may rise to much higher levels in EDE than ADDE before the onset of tear film breakup, in the absence of events at the ocular surface which would independently compromise tear film stability. Differences in the predicted responses of the pre-ocular tears in ADDE compared to EDE or hybrid disease to defined conditions suggest that no single, empirically-accessible variable can act as a surrogate for tear film concentration and the potential for ocular surface damage. This emphasises the need to measure and integrate multiple diagnostic indicators to determine outcomes and prognosis. Modelling predictions in addition show that further studies concerning the possibility of a high lacrimal flux phenotype in EDE are likely to be profitable.

Rheology of tear film lipid layer spread in normal and aqueous tear-deficient dry eyes.

PURPOSEnTo analyze the relationship between tear volume and tear film lipid layer (TFLL) spread.nnnMETHODSnTwenty-nine eyes from 22 subjects, including normal eyes and eyes with aqueous tear-deficient dry eye, were enrolled in this study. In all eyes, the radius of curvature (R: mm) of the central lower tear meniscus was measured with a video-meniscometer, and interference images from the TFLL were recorded with a video-interferometer. Interference images were captured as still images every 0.05 second, and the relationship between the acquisition time for each image after a blink and the averaged heights of the spreading TFLL in the upstroke of the blink were calculated.nnnRESULTSnIn all cases, the time-dependent changes in TFLL spread could be described by the expression H(t) - H(0) = rho[1 - exp(-t/lambda)], where H(t) is the averaged height in millimeters at time t, H(0) is the averaged height at t = 0, rho is a constant, t is time in seconds, and lambda is the characteristic time in seconds. A statistically significant correlation was found between those changes and the initial upward velocity of the spreading TFLL [H(0) = dH(0)/dt] and R (r = 0.573; P = 0.003).nnnCONCLUSIONSnThis study demonstrated that the time-dependent changes of TFLL spread are compatible with the Voigt model of viscoelasticity and that the initial velocity of TFLL spread after a blink decreased in proportion to the decrease of tear volume. There is potential interest in using this parameter to diagnose and evaluate the severity of aqueous tear deficiency.

A Solute Gradient in the Tear Meniscus. I. A Hypothesis to Explain Marx's Line

Marxs line is a line of mucosal staining behind the mucocutaneous junction. It can be demonstrated throughout life in all normal lids by staining with lissamine green and related dyes. Of all the body orifices, only the mucosae of the eye and mouth are directly exposed to the atmosphere. In this paper, we suggest that for the eye, this exposure leads to the formation of Marxs line. The tear meniscus thins progressively toward its apex, where it is pinned at the mucocutaneous junction of the lid. It also thins toward the black line, which segregates the meniscus from the tear film after the blink. We predict that, because of the geometry of the tear meniscus, evaporation generates a solute gradient across the meniscus profile in the anteroposterior plane, which peaks at the meniscus apices at the end of the interblink. One outcome would be to amplify the level of tear molarity at these sites so that they reach hyperosmolar proportions. Preliminary mathematical modeling suggests that dilution of this effect by advection and diffusion of solute away from the meniscus apex at the mucocutaneous junction will be restricted by spatial constraints, the presence of tear and surface mucins at this site, and limited fluid flow. We conclude that evaporative water loss from the tear meniscus may result in a physiological zone of hyperosmolar and related stresses to the occlusal conjunctiva, directly behind the mucocutaneous junction. We hypothesize that this stimulates a high epithelial cell turnover at this site, incomplete epithelial maturation, and a failure to express key molecules such as MUC 16 and galectin-3, which, with the tight junctions between surface epithelial cells, are necessary to seal the ocular surface and prevent penetration of dyes and other molecules into the epithelium. This is proposed as the basis for Marxs line. In Part II of this paper (also published in this issue of The Ocular Surface), we address additional pathophysiological consequences of this mechanism, affecting lid margins.

Sutureless amniotic membrane transplantation for ocular surface reconstruction with a chemically defined bioadhesive

The purpose of this study was to evaluate the efficiency and safety of a sutureless amniotic membrane transplantation (AMT) for ocular surface reconstruction with a chemically defined bioadhesive (CDB). The CDB was synthesized from aldehyded polysaccharides and epsilon-poly(L-lysine), two kinds of medical and food additives, as starting materials. Biocompatibility assay indicated that the CDB showed excellent biocompatibility with in vitro and in vivo ocular surface tissues and most of the CDB was histologically degraded within 4 weeks. Sutureless AMT using the CDB was safely and successfully performed onto a rabbit scleral surface. Transplanted amniotic membrane (AM) evaluated by histological, electron microscopic- and immunohistochemical examination indicated that the CDB did not affect normal differentiation of the cells or the integrity of the surrounding tissue. Thus, this newly developed CDB was found to be very useful for sutureless AMT for ocular surface reconstruction, without considering the risk of infection. It has the ability to fix AM to the ocular surface for a long time-period without additional inflammation, scarring, or damage to the surrounding tissues.

Surgery of the Conjunctiva

BACKGROUNDnDry eye is characterized by aqueous tear deficiency or excessive tear evaporation at the ocular surface, both leading to tear film instability that results in ocular surface epithelial damage. In addition to the lacrimal gland, the meibomian gland, cornea, and conjunctiva also contribute to the formation of the tear film via the production of goblet-cellderived mucin and the expression of membrane-associated mucin. The conjunctiva can be linked with dry eye through various mechanisms such as inflammation, disturbance of the tear film, and conjunctival fibrosis. Thus, normalization of the conjunctiva is important for the management of dry eye.nnnMATERIALS AND METHODSnConjunctival diseases associated with dry eye include conjunctivochalasis, superior limbic keratoconjunctivitis, pterygium and pinguecula, and severe ocular surface diseases such as Stevens-Johnson syndrome and ocular cicatricial pemphigoid. The associated pathophysiology and surgical procedures for these disorders are analyzed and described. The major concept of conjunctival surgery for dry eye is to smoothen the surface in order (1) to reduce blink-associated microtrauma, (2) to reconstruct the tear meniscus and conjunctival fornix and their respective functions as reservoirs for tears, and (3) to reduce conjunctival inflammation by the removal of abnormal fibrous tissue combined with the use of mitomycin C and/or amniotic membrane.nnnRESULTSnConjunctivochalasis and pterygium result in signs and symptoms of dry eye by inducing dysfunction of the tear meniscus and/or an ectopic tear meniscus. Therefore, the resection of redundant conjunctiva and abnormal tissue in pterygium is an effective procedure for normalizing the tear film. If cicatrizing conjunctivitis results in tear-film instability due to conjunctival inflammation and squamous metaplasia, reconstruction of ocular surface epithelium is vital for its resolution.nnnCONCLUSIONnIn order to effectively manage dry eye due to conjunctival disease, it is important to understand not only the surgical procedure but also the pathomechanisms of conjunctival changes leading to signs and symptoms of tear-film deficiencies.

Hyperexpression of the High-Affinity IgE Receptor-β Chain in Chronic Allergic Keratoconjunctivitis

PURPOSEnAlthough the existence of Fc(epsilon)RI-alphabetagamma(2) and Fc(epsilon)RI-alphagamma(2) receptor subtypes was reported, there has been no direct evidence of these two subtypes of Fc(epsilon)RI in vivo. To investigate the existence of these two subtypes of Fc(epsilon)RI in vivo, the authors evaluated the expression of Fc(epsilon)RI-beta in the giant papillae of chronic allergic conjunctivitis and compared the expression level of Fc(epsilon)RI-beta with control conjunctivae using the anti-human Fc(epsilon)RI-beta antibody.nnnMETHODSnFc(epsilon)RI-beta expression in giant papillae obtained from patients with atopic keratoconjunctivitis and vernal keratoconjunctivitis in control conjunctivae was evaluated by immunohistochemistry using anti-Fc(epsilon)RI-beta, -alpha, -gamma, and anti-human mast cell tryptase, anti-chymase, anti-basophil, and anti-CD1a antibodies.nnnRESULTSnStatistical analyses revealed that the densities of Fc(epsilon)RI-beta(+) cells, Fc(epsilon)RI-alpha(+) cells, tryptase(+) cells, and Fc(epsilon)RI-beta(+)/tryptase(+) cells were significantly increased in giant papillae compared with controls. There were two types of Fc(epsilon)RI (alphabetagamma(2) and alphagamma(2)) on the mast cells of the giant papillae. The ratio of the Fc(epsilon)RI-beta(+) cell number/Fc(epsilon)RI-alpha(+) cell number in the giant papillae (0.69 +/- 0.08 [mean +/- SD]) was significantly higher than that of the controls (0.07 +/- 0.16). Fc(epsilon)RI-beta/tryptase double immunostaining revealed that 81% +/- 13% of tryptase(+) cells expressed Fc(epsilon)RI-beta. Fc(epsilon)RI-beta(+) cells were preferentially localized within and around epithelial tissue. The authors also found that Fc(epsilon)RI-beta was expressed by basophils but not by Fc(epsilon)RI-alphagamma(2)-positive Langerhans cells in the giant papillae samples.nnnCONCLUSIONSnPreferential Fc(epsilon)RI-beta expression observed in the mast cells and basophils of giant papillae suggests important roles of Fc(epsilon)RI-beta in the pathophysiology of atopic keratoconjunctivitis and vernal keratoconjunctivitis.