Anthony J. Bron

Grading of corneal and conjunctival staining in the context of other dry eye tests.

Purpose To describe the Oxford Scheme for grading ocular surface staining in dry eye and to discuss optimization of stain detection using various dyes and filters. Also, to propose a sequence of testing for dry eye diagnosis. Methods The grading of corneal and conjunctival staining is described, using the Oxford Scheme, including biomicroscopy, optical filters, illumination conditions, and the characteristics of and instillation techniques used for, selected clinical dyes. Results A series of panels, labeled A–E, in order of increasing severity, reproducing the staining patterns encountered in dry eye, are used as a guide to grade the degree of staining seen in the patient. The amount of staining seen in each panel, represented by punctate dots, increases by 0.5 of the log of the number of dots between panels B to E. The use of the vital dyes fluorescein, lissamine green, and rose Bengal is described; fluorescein and lissamine green, used in conjunction with appropriate absorption filters, are recommended for use in clinical trials. The placement of staining in relation to the sequence of other diagnostic tests is discussed. Conclusions The monitoring and assessment of corneal and conjunctival staining can be greatly enhanced by the use of a grading scale, controlled instillation of dyes, and standard evaluation techniques. This is of particular benefit in clinical trials, where ocular surface staining is commonly employed as an outcome measure

Tear osmolarity in the diagnosis and management of dry eye disease.

PURPOSE To evaluate the use of tear osmolarity in the diagnosis of dry eye disease. DESIGN A prospective, observational case series to determine the clinical usefulness of tear osmolarity and commonly used objective tests to diagnose dry eye disease. METHODS A multicenter, 10-site study consisting of 314 consecutive subjects between 18 and 82 years of age. Bilateral tear osmolarity, tear film break-up time (TBUT), corneal staining, conjunctival staining, Schirmer test, and meibomian gland grading were performed. Diagnostic performance was measured against a composite index of objective measurements that classified subjects as having normal, mild or moderate, or severe dry eye. The main outcome measures were sensitivity, specificity, area under the receiver operating characteristic curve, and intereye variability. RESULTS Of the 6 tests, tear osmolarity was found to have superior diagnostic performance. The most sensitive threshold between normal and mild or moderate subjects was found to be 308 mOsms/L, whereas the most specific was found at 315 mOsms/L. At a cutoff of 312 mOsms/L, tear hyperosmolarity exhibited 73% sensitivity and 92% specificity. By contrast, the other common tests exhibited either poor sensitivity (corneal staining, 54%; conjunctival staining, 60%; meibomian gland grading, 61%) or poor specificity (tear film break-up time, 45%; Schirmer test, 51%). Tear osmolarity also had the highest area under the receiver operating characteristic curve (0.89). Intereye differences in osmolarity were found to correlate with increasing disease severity (r(2) = 0.32). CONCLUSIONS Tear osmolarity is the best single metric both to diagnose and classify dry eye disease. Intereye variability is a characteristic of dry eye not seen in normal subjects.

The International Workshop on Meibomian Gland Dysfunction: Executive Summary

DOI:10.1167/iovs.10-6997a Investigative Ophthalmology & Visual Science, Special Issue 2011, Vol. 52, No. 4 Copyright 2011 The Association for Research in Vision and Ophthalmology, Inc. 1922 ドライアイ疾患の原因としては、マイボーム腺機能不全 (MGD)がおそらく最も多い。この疾患によって数百万人 もの健康と幸福が損なわれているにもかかわらず、MGD の定 義、分類、診断、治療について世界的なコンセンサスはない。 そうしたコンセンサスに達する目的で、非営利団体である Tear Film and Ocular Surface Society( TFOS; http://www. tearfilm.org)が International Workshop on Meibomian Gland Dysfunction(国際マイボーム腺機能不全ワークショップ、 www.tearfilm.org/mgdworkshop/index.html)を起ち上げた。こ のワークショップの目的は以下の通りである:

Meibomian Gland Dysfunction: A Clinical Scheme for Description, Diagnosis, Classification, and Grading

Although meibomian gland disease (MGD) is one of the most common disorders encountered in ophthalmic practice, there has been no descriptive system consistently accepted to clinically characterize the anatomical and correlative biochemical alterations that occur in this condition. The purpose of this review is to synthesize a clinical description of meibomian gland disease and to provide a scheme for diagnosis, classification, and quantification that will be of value in the clinical setting and in the conduct of clinical trials.

The ageing lens.

The human lens grows by a process of epithelial cell division at its equator and the formation of generations of differentiated fibre cells. Despite the process of continuous remodelling necessary to achieve growth within a closed system, the lens can retain a high level of light transmission throughout the lifetime of the individual, with the ability to form sharp images on the retina. Continuous growth of the lens solves the problem imposed by terminal differentiation within a closed, avascular system, from which cells cannot be shed. The lens fibre tips arch over the equator to meet anteriorly and posteriorly and form branching sutures of increasing complexity. The stages of branching may create the optical zones of discontinuity seen on biomicroscopy. The lens is exposed to the cumulative effects of radiation, oxidation and postranslational modification. These later proteins and other lens molecules in such a way as to impair membrane functions and perturb protein (particularly crystallin) organisation, so that light transmission and image formation may be compromised. Damage is minimised by the presence of powerful scavenger and chaperone molecules. Progressive insolublisation of the crystallins of the lens nucleus in the first five decades of life, and the formation of higher molecular weight aggregates, may account for the decreased deformability of the lens nucleus which characterises presbyopia. Additional factors include: the progressive increase in lens mass with age, changes in the point of insertion of the lens zonules, and a shortening of the radius of curvature of the anterior surface of the lens. Also with age, there is a fall in light transmission by the lens, associated with increased light scatter, increased spectral absorption, particularly at the blue end of the spectrum, and increased lens fluorescence. A major factor responsible for the increased yellowing of the lens is the accumulation of a novel fluorogen, glutathione-3-hydroxy kynurenine glycoside, which makes a major contribution to the increasing fluorescence of the lens nucleus which occurs with age. Since this compound may also cross-link with the lens crystallins, it may contribute to the formation of high-molecular-weight aggregates and the increases in light scattering which occur with age. Focal changes of microscopic size are observed in apparently transparent, aged lenses and may be regarded as precursors of cortical cataract formation.

The Contribution of Meibomian Disease to Dry Eye

The tear film lipid layer is the major barrier to evaporation from the ocular surface. A decrease in its thickness or functional integrity may cause evaporative dry eye (EDE). Obstructive meibomian gland dysfunction (MGD) is the most common cause of EDE and occurs as a primary disorder or secondary to acne rosacea, seborrheic or atopic dermatitis, and with cicatrizing conjunctival disorders, such as trachoma, erythema multiforme, and cicatricial pemphigoid. MGD may be an incidental finding in asymptomatic eyes, or it may be responsible for irritative lid symptoms in the absence of dry eye. MGD-dependent EDE is diagnosed on the basis of a defined degree of MGD in a symptomatic patient showing typical ocular surface damage in the absence of an aqueous tear deficiency. When MGD occurs in a background of aqueous tear deficiency (ATD), then an additional evaporative component may assumed, depending on the extent of meibomian obstruction. However, definitive criteria are not yet established. The clinical severity of dry eye is greatest when ATD and EDE occur together, particularly in Sjogren syndrome. A hypothesis is proposed to explain the steps leading to primary, simple MGD and subsequent EDE.

A non-invasive instrument for clinical assessment of the pre-corneal tear film stability

A simple, non-invasive technique has been developed for assessment of the stability of the pre-corneal tear film. Changes are observed in the reflection of a grid pattern from the tear film surface. Breaks in the tear film appear as random discontinuities in the grid image. Using this non-invasive technique the stability of the pre-corneal tear film was assessed in nine normal subjects and twelve established dry-eye patients. The non-invasive tear film break-up time (NIBUT) of the dry-eye patients was on average only 25% to 32% of normal values. The non-invasive technique provides an alternative approach to diagnosing non-wetting disorders as well as a means of evaluating the efficacy of artificial tear solutions.

Diagnosis of Dry Eye

Dry eve disease is characterized by symptoms, ocular surface damage, reduced tear film stability, and tear hyperosmolarity. There are also inflammatory components. These features can be identified by various kinds of diagnostic tests (symptom questionnaires, ocular surface staining, tear break-up time, and osmometry), although there may not be a direct correlation between the number or severity of symptoms and the degree of ocular surface damage or tear deficiency. Once the diagnosis of dry eye disease has been established, further tests can be used to classify the condition into tear-deficient or evaporative dry eve. The two forms of dry eye are not mutually exclusive and often co-exist. The optimal diagnosis of dry eye disease, therefore, depends on the results of several tests, and this article suggests an appropriate order for performing these tests at a single clinic visit.

The Oxford Clinical Cataract Classification and Grading System

A composite slit-lamp based system for the clinical classification and grading of cataract is described. Cataract features are classified morphologically, and individual features are graded by comparison with standard diagrams mounted adjacent to the slit-lamp. Attention has been paid to relevant aspects of measurement theory, with equal interval steps between the grades. The image degrading effect of the cataract is assessed using a ‘resolution target projection ophthalmoscope’. The method may be used in conjunction with photographic and image analysing techniques.

The lens in diabetes

This paper reviews the changes which occur in the human lens in diabetes. They include refractive changes and cataract and age-related increases in thickness, curvatures, light scattering, autofluorescence and yellowing. The incidence of cataract is greatly increased over the age of 50 years, slightly more so in women, compared with non-diabetics. Experimental models of sugar cataract provide some evidence for the mechanism of the uncommon, but morphologically distinct, juvenile form of human diabetic cataract, where an osmotic mechanism due to sugar alcohol accumulation has been thoroughly studied in diabetic or galactose-fed rats. The discrepancy between the ready accumulation of sugar alcohol in the lens in model systems and the very slow kinetics of aldose reductase (AR) has not been satisfactorily explained and suggests that the mechanism of polyol formation is not yet fully understood in mammalian systems. The activity of AR in the human lens lies mainly in the epithelium and there appears to be a marginal expectation that sufficient sorbi-tol accumulates in cortical lens fibres to explain the lens swelling and cataract on an osmotic basis. This is even more so in the cataracts of adult diabetics, which resemble those of age-related non-diabetic cataracts in appearance. The very low levels of sorbitol in adult diabetic lenses make an osmotic mechanism for the increased risk of cataract even less likely. Other mechanisms, including glycation and oxidative stress, are discussed. The occurrence of cataract is a predictor for increased mortality in the diabetic.