John M. Tiffany

The thickness of the tear film

Measurements of the thickness of the pre-corneal tear film, pre-lens tear film, post-lens tear film, and the lipid layer on the surface of the tear film are summarized. Spatial and temporal variations in tear film thickness are described. Theoretical predictions of tear film thickness are discussed. Mechanisms involved in the upward drift of the tear film after a blink, and in the formation of dry spots, are considered.

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.

The Lipid Secretion of the Meibomian Glands

Publisher Summary The outer surface of mammalian skin and hair is covered by the lipid secretion of the sebaceous glands; in birds, this function is fulfilled by the secretion of the large uropygeal or preen gland, sebaceous glands are numerous around all body apertures, and might be modified in form or nature of secretion to suit the special conditions of these sites. Meibomian glands are found in well-developed form in mammals. They appear to be elongated sebaceous glands, embedded in the fibrous tarsal plate of upper and lower eyelids. Meibomian secretions have much in common with sebaceous lipids, and similar analytical techniques can be used for both. Many of these are similar to the techniques that are used for analysis of a variety of other biological lipids; however, the “differentness” of sebaceous-type lipids means that additional methods must be used to cope with chain branching, wax esters of high molecular weight, a variety of unusual steryl esters, complex diesters, and other unique factors.

Individual variations in human meibomian lipid composition.

Abstract Samples of meibomian lipid from several human donors were analyzed by thin-layer chromatography. Great variations were seen between individual samples in the relative proportions of the different lipid classes present, although all contained the three principal classes of wax esters, cholesteryl esters and triglycerides. Appreciable amounts of hydrocarbons and free fatty acids were seen in some cases, but the fatty acid did not seem to be derived by hydrolysis from triglycerides as in skin surface lipid. Samples from individual donors were also hydrolysed and the fatty acids and fatty alcohols (minus cholesterol) analysed by gas-liquid chromatography. The results were broadly similar for all samples. The fatty acids were of both odd and even carbon numbers, and both straight and branched-chain isomers were present in most cases; the unsaturated chain content was low. A characteristic pattern of chain length distribution was seen over the range C 8 –C 30 , and a similar pattern was noted for alcohols, but about four carbon atoms per chain longer. The significance of these and earlier results is discussed. It is concluded that no single composition exists for human meibomian oil, and that the results from pooled material from many individuals may be misleading as an indicator of ocular function.

Tear film stability and tear surface tension

Surface tension has been measured by the method of Ferguson and Kennedy on small (0.3-0.4 microliter) samples of tears from 65 normal and 35 dry eyes. Non-invasive break-up time (NIBUT) was also measured on the same patients as an indication of tear film stability. The mean (+/- SD) surface tension value was 43.6 +/- 2.7 mN/m for normals, and 49.6 +/- 2.2 mN/m for dry eyes. All NIBUT values for dry eyes were below 20 sec (8.9 +/- 5.1 sec, mean +/- SD, n = 35) while 53% of normal values were 30 sec or over. A negative correlation was found between surface tension and NIBUT for both dry eyes and normals. Comparison of surface tension results for tears and a variety of standard solutions indicated that mucus makes the greatest contribution, even at low concentrations, but the effect of proteins can be large, especially in inflammatory states where serum proteins leak from conjunctival vessels. The measurement of surface tension is simple and direct, and in conjunction with the NIBUT value can help in classification of tear quality in questionably dry eye cases.

The viscosity of human tears.

Blinking involves high rates of shear within the tear film, requiring a low tear viscosity to avoid damage to epithelial surfaces. Conversely, in the open eye, a higher viscosity is desirable to resist drainage and film break-up. Samples of human tears were collected with moderate stimulation from 5 adult males, 3 with normal and 2 with marginally-dry eyes. The apparent viscosity at 22° C was found using a Couette-type rheometer over the range of shear rate 2–160 sec-1. Marked shear-thinning was apparent in all samples, with little apparent difference between normal and dry-eye tears. Although a power-law equation could be fitted over part of the range, analyses according to either the Casson plastic model as used for rabbit tears (with a low yield-point indicative of some very loose initial gel-like structure) or the Steiger-Ory model (a true pseudoplastic model with no initial yield point) were inconclusive over the range of shear rate studied. The descriptive model of Cross gave zero-shear viscosity values of 4.4, 7.1 and 8.3 mPa. sec for normal tears, and 27.1 and 31.1 mPa.sec for dry-eye tears; the corresponding time constants were 0.13, 0.27 and 0.38 sec for normal tears, and 2.7 and 2.9 sec for dry-eye tears. These time-constants can be considered as an approximate relaxation time, indicating the time taken for the tear film to stabilise after a blink.

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.

The casual level of meibomian lipids in humans.

Using a modified skin surface lipid measuring instrument, the Meibometer, the amounts of meibomian lipid on the lid margins (the casual levels) of 421 subjects aged 1 to 94 years were measured. The lowest levels were found in children younger than 14 years (means +/- S.E.: males = 1.48 +/- 0.17, females = 1.53 +/- 0.17 micrograms lipid/mm2 lid margin surface) and rose with age, the highest levels being found in males aged 60-69 years (mean +/- S.E. = 3.26 +/- 0.18 micrograms lipid/mm2 lid margin surface). Male levels were higher than females in the 20-29 years age group but male and female levels became indistinguishable above the age of 50. These age- and sex-related changes differed markedly from those seen in skin surface lipid levels. The age-related changes in the casual levels of lid lipids remain unexplained although an endocrinological mechanism modified by morphological factors is considered.

Reflective meniscometry: a non-invasive method to measure tear meniscus curvature.

AIMS To devise a method to measure tear meniscus curvature by a non-invasive specular technique. METHODS A photographic system was devised. The system consisted of a camera and an illuminated target with a series of black and white stripes oriented parallel to the axis of the lower tear meniscus. The target was mounted on a flash gun close to the objective of a Brown macrocamera and calibrated using a graduated series of glass capillaries of known diameter, ground down to expose the inner wall. It was then applied to normal human eyes (n=45) to measure the tear meniscus curvature. A video system was also assessed which provided qualitative online information about the tear meniscus. RESULTS Using the photographic system, measured values for capillary radii were in excellent agreement with theoretical calculations (r 2=0.996, p<0.0001). The radii of curvature of lower tear menisci in normal human subjects (mean 0.365 (SD 0.153) mm, range 0.128–0.736; n=45) were similar to those reported in the literature. Both systems demonstrated variations in meniscus shape. The video system provided stable images of human menisci over prolonged periods of time and promises to be useful for the analysis of dynamic changes in meniscus volume. CONCLUSIONS Reflective meniscometry is a non-invasive technique providing quantitative information about tear meniscus shape and volume and of potential value in the study of ocular surface disease.

An instrument for quantifying meibomian lipid on the lid margin: the Meibometer

An instrument, the Meibometer, is described for estimating the casual level of meibomian lipid on the human eyelid margins, adapted from a commercially-available instrument used for measurement of skin surface lipid. A loop of plastic tape is pressed onto the everted lower lid margin to lift off a blot of lipid. The resultant change in light transmission of the tape is read by a photometer. Readings are not affected by side (R or L), time of day or lid surface temperature. After cleaning lipid from the lid margins with hexane, the rate of recovery per 10 blinks, as a percentage of the pre-cleaned level, was measured as 33.7 +/- 5.8 (mean +/- SE). This rate of delivery appears to provide enough lipid for complete resurfacing of the preocular tear film with every blink. Over short periods no detectable lipid was delivered in the absence of blinking.