The Short-term Effects of Artificial Tears on the Tear Film Assessed by a Novel High-Resolution Tear Film Imager: A Pilot Study.

PURPOSE: The purpose of this study was to investigate the effects of artificial tears (AT) on the sublayers of the tear film assessed by a novel tear film imaging (TFI) device. METHODS: The mucoaqueous layer thickness (MALT) and lipid layer thickness (LLT) of 198 images from 11 healthy participants, 9 of whom had meibomian gland disease, were prospectively measured before and after exposure to 3 different AT preparations (Refresh Plus; Retaine [RTA]; Systane Complete PF [SYS]), using a novel nanometer resolution TFI device (AdOM, Israel). Participants were assessed at baseline and at 1, 5, 10, 30, and 60 minutes after instilling 1 drop of AT during 3 sessions on separate days. Repeated-measures analysis of variances were used for comparisons with P < 0.05 considered significant. RESULTS: For all ATs, the mean MALT was greatest 1 minute after drop instillation, with an increase of 67%, 55%, and 11% above the baseline for SYS, Refresh Plus, and RTA, respectively. The SYS formulation demonstrated the highest percentage increases in mean MALT and LLT at most postdrop time points. The MALT differences were significantly higher in the SYS than in the RTA ( P = 0.014). After 60 minutes, no AT group demonstrated statistically significant changes in MALT or LLT compared with baseline. CONCLUSIONS: We report, for the first time, the effects of AT on MALT and LLT using a high-resolution TFI. A substantial acute mean MALT increase occurs 1 minute after AT instillation with all agents tested, but there were clear differences in response and durability, suggesting the benefits of choosing specific AT according to the needs of each patient.

High Resolution Images of Human Meibum Spread on Saline.

Purpose: Understanding of the role of the tear film lipid layer (TFLL) in evaporative dry eye requires knowledge of its structure. X-ray studies show 11.1-nm thick lamellae in meibum at tear film temperature (approximately 35°C), whereas below 30°C, 4.88-nm thick lamellae predominate. Here, high resolution microscopy of meibum spread on saline is studied as a function of temperature, to compare with x-ray results. Methods: A purpose-built high resolution color microscope, previously used to study the TFLL, was used to study meibum from 10 subjects. It was spread on buffered saline at near 40°C, and allowed to cool to room temperature. Analytical methods from previous studies were applied to measure meibum and lamellar thickness. Results: Initially, an irregular "island" was formed, surrounded by a "background layer" of 7.8 ± 0.3 nm thickness. Dewetting of the meibum layer always occurred, leading to the formation of lens-shaped droplets. Below 30°C, the lenses start to emit "tails" having a multilamellar structure containing up to about 49 lamellae superimposed on the background layer, each lamella being 4.82 ± 0.13 nm thick. Conclusions: Below 30°C, meibum spread on saline shows a multilamellar structure like the 4.88 nm thickness in x-ray studies, demonstrating the ability to observe and measure tightly stacked lamellae. In contrast, above 30°C, the 11.1 nm lamellae were not observed as in x-ray studies, indicating that these lamellae were not tightly stacked but may be separated by disordered lipid. The role of these findings in evaporative dry eye is discussed.

The Short-term Effects of Artificial Tears on the Tear Film Assessed by a Novel High-Resolution Tear Film Imager: A Pilot Study.

PURPOSE: The purpose of this study was to investigate the effects of artificial tears (AT) on the sublayers of the tear film assessed by a novel tear film imaging (TFI) device. METHODS: The mucoaqueous layer thickness (MALT) and lipid layer thickness (LLT) of 198 images from 11 healthy participants, 9 of whom had meibomian gland disease, were prospectively measured before and after exposure to 3 different AT preparations (Refresh Plus; Retaine [RTA]; Systane Complete PF [SYS]), using a novel nanometer resolution TFI device (AdOM, Israel). Participants were assessed at baseline and at 1, 5, 10, 30, and 60 minutes after instilling 1 drop of AT during 3 sessions on separate days. Repeated-measures analysis of variances were used for comparisons with P < 0.05 considered significant. RESULTS: For all ATs, the mean MALT was greatest 1 minute after drop instillation, with an increase of 67%, 55%, and 11% above the baseline for SYS, Refresh Plus, and RTA, respectively. The SYS formulation demonstrated the highest percentage increases in mean MALT and LLT at most postdrop time points. The MALT differences were significantly higher in the SYS than in the RTA (P = 0.014). After 60 minutes, no AT group demonstrated statistically significant changes in MALT or LLT compared with baseline. CONCLUSIONS: We report, for the first time, the effects of AT on MALT and LLT using a high-resolution TFI. A substantial acute mean MALT increase occurs 1 minute after AT instillation with all agents tested, but there were clear differences in response and durability, suggesting the benefits of choosing specific AT according to the needs of each patient.

Optical Analysis and Reappraisal of the Peripheral Light Focusing Theory of Nasal Pterygia Formation.

Purpose: Pterygia are much more common nasally than temporally. Ultraviolet (UV) radiation is a major risk factor. Coroneo proposed that the nasal preference is caused by the "peripheral light focusing effect," (PLF), in which UV at an oblique angle passes through temporal cornea and is concentrated on and damages nasal limbal stem cells. This study evaluates whether the PLF is sufficient to explain the nasal preference. Methods: Whereas Coroneo and colleagues derived the maximum PLF intensity gain (UV concentration factor) as a function of incident angle (i.e., different nasal limbal positions were used for different incident angles) the current analysis derived intensity gain at a fixed position such at the nasal corneo-limbal junction (CLJ). This provided a measure of the total PLF irradiation at this position, which was compared to total direct irradiation of nasal and temporal limbus at the corresponding positions (e.g., CLJs). In Part 1, analysis was performed like that of Coroneo, using horizontally incident UV; in Part 2, the analysis was extended to include incident rays above and below the horizontal. Results: In both part 1 and part 2 of the study, the limbal UV irradiation of the nasal limbus from the PLF was not sufficient to explain the strong nasal location preference of pterygia. Conclusions: The analysis calls into question the PLF explanation of nasal location preference. Other explanations of the nasal preference, and of pterygium pathogenesis, should be considered, such as temporal to nasal tear flow carrying substances such as cytokines to the nasal limbus.

Changes in Tear Lipid Layer Thickness and Symptoms Following the Use of Artificial Tears with and Without Omega-3 Fatty Acids: A Randomized, Double-Masked, Crossover Study.

PURPOSE: To determine if an eye drop containing omega-3 fatty acids (Refresh Optive MEGA-3®, Allergan plc, Dublin, Ireland) increases the lipid layer thickness (LLT) of the tear film versus a non-emollient eye drop (Refresh Optive, Allergan plc). METHODS: Patients (≥30 years) with baseline LLT ≤75 nm completed the Current Symptoms Survey (CSS - a visual analog survey of dry eye symptoms), and LLT was measured pre- and post-instillation (15 and 60 mins) of their randomly assigned treatment. After washout, patients were tested with the other treatment. Primary endpoint: change in LLT from baseline. Secondary endpoint: CSS results. RESULTS: Of 21 patients enrolled, 19 completed the study. With the omega-3-containing eye drop, the mean (standard deviation) LLT increase from baseline at 15 mins was statistically significant in the overall field (8.8 [11.5] nm; P<0.001), and in each individual zone (superior, central, and inferior). At 1 hr, the LLT change from baseline was statistically significant overall (4.4 [9.7] nm; P<0.02) and in the inferior and central zones. With the aqueous eye drop, LLT change from baseline was only significant at 15 mins in the inferior field. The CSS analysis revealed a ≥8.68-unit decrease in mean average dryness score from baseline at 15 and 60 mins post-instillation of the lipid-based treatment (P≤0.03). CONCLUSION: The eye drop containing omega-3 fatty acids increased LLT at 15 mins, maintaining it at 1 hr post-instillation. Dryness symptoms also improved and maintained improved levels 1 hr after instillation, indicating that the product may benefit symptomatic patients with evaporative dry eye.

On tear film breakup (TBU): dynamics and imaging.

We report the results of some recent experiments to visualize tear film dynamics. We then study a mathematical model for tear film thinning and tear film breakup (TBU), a term from the ocular surface literature. The thinning is driven by an imposed tear film thinning rate which is input from in vivo measurements. Solutes representing osmolarity and fluorescein are included in the model. Osmolarity causes osmosis from the model ocular surface, and the fluorescein is used to compute the intensity corresponding closely to in vivo observations. The imposed thinning can be either one-dimensional or axisymmetric, leading to streaks or spots of TBU, respectively. For a spatially-uniform (flat) film, osmosis would cease thinning and balance mass lost due to evaporation; for these space-dependent evaporation profiles TBU does occur because osmolarity diffuses out of the TBU into the surrounding tear film, in agreement with previous results. The intensity pattern predicted based on the fluorescein concentration is compared with the computed thickness profiles; this comparison is important for interpreting in vivo observations. The non-dimensionalization introduced leads to insight about the relative importance of the competing processes; it leads to a classification of large vs small TBU regions in which different physical effects are dominant. Many regions of TBU may be considered small, revealing that the flow inside the film has an appreciable influence on fluorescence imaging of the tear film.

Mechanisms, imaging and structure of tear film breakup.

Tear film breakup (BU) is an important aspect of dry eye disease, as a cause of ocular aberrations, irritation and ocular surface inflammation and disorder. Additionally, measurement of breakup time (BUT) is a common clinical test for dry eye. The current definition of BUT is subjective; here, a more objective concept of "touchdown" - the moment when the lipid layer touches down on the corneal surface - is proposed as an aid to understanding processes in early and late stages of BU development. Models of BU have generally been based on the assumption that a single mechanism is involved. In this review, it is emphasized that BU does not have a single explanation but it is the end result of multiple processes. A three-way classification of BU is proposed - "immediate," "lid-associated," and "evaporative." Five different types of imaging systems are described, which have been used to help elucidate the processes involved in BU and BUT; a new method, "high resolution chromaticity images," is presented. Three directions of tear flow - evaporation, osmotic flow out of the ocular surface, and "tangential flow" along the ocular surface - determine tear film thinning between blinks, leading to BU. Ten factors involved in BU and BUT, both before and after touchdown, are discussed. Future directions of research on BU are proposed.

Tear lipid layer thickness with eye drops in meibomian gland dysfunction.

PURPOSE: The aim of this study was to evaluate the efficacy of a lipid containing emollient eye drop, Soothe XP, which was reformulated in 2014 with a more stable preservative and buffer system, compared to a control, non-emollient, eye drop (Systane Ultra) in improving lipid layer thickness (LLT) in subjects with dry eye due to meibomian gland dysfunction (MGD). PATIENTS AND METHODS: This prospective single-center, open-label, cross-over, examiner masked-study enrolled subjects aged 30-75 years with lipid-deficient dry eye and a clinical diagnosis of MGD as determined by a slit lamp examination, an evaluation of meibomian gland drop out with meibography, and a standard patient evaluation of eye dryness questionnaire of >5. Eligibility was then determined by a LLT of <75 nm at baseline and the inability to increase LLT ≥15 nm with three blinks, as determined by interferometric methods. Subjects were randomized to receive a single emollient or non-emollient eye drop at Visit 1 and were crossed over for the alternate treatment at Visit 2. At each visit, LLT was measured prior to and 15 minutes following the instillation of the assigned eye drop. The primary endpoint was the change in LLT from baseline. RESULTS: Subjects (n=40) were enrolled and 35 completed the two study arms. Mean (±SD) patient age was 55.7 years (10.9) and 69% were female. Mean (±SD) LLT at baseline was 49.5 nm (9.2). Instillation of Soothe XP resulted in an increase in LLT to 77.5 nm (29.3) 15 minutes following drop instillation, which is an increase of 28.0 nm (27.4) (P<0.001). In contrast, LLT 15 minutes after the instillation of Systane Ultra was 50.8 nm (14.1), which was not statistically significant when compared to the baseline LLT. CONCLUSION: In this study of subjects with MGD, the emollient, or lipid containing eye drop, increased the LLT of tears when measured 15 minutes after instilling a single eye drop.

Computed tear film and osmolarity dynamics on an eye-shaped domain.

The concentration of ions, or osmolarity, in the tear film is a key variable in understanding dry eye symptoms and disease. In this manuscript, we derive a mathematical model that couples osmolarity (treated as a single solute) and fluid dynamics within the tear film on a 2D eye-shaped domain. The model includes the physical effects of evaporation, surface tension, viscosity, ocular surface wettability, osmolarity, osmosis and tear fluid supply and drainage. The governing system of coupled non-linear partial differential equations is solved using the Overture computational framework, together with a hybrid time-stepping scheme, using a variable step backward differentiation formula and a Runge-Kutta-Chebyshev method that were added to the framework. The results of our numerical simulations provide new insight into the osmolarity distribution over the ocular surface during the interblink.

Can Binocular Vision Disorders Contribute to Contact Lens Discomfort?

PURPOSE: To determine the relationship between binocular vision (BV) disorder and dry eye symptoms and the frequency of BV disorders in subjects with contact lens-induced dry eye symptoms. METHODS: Subjects recruited for a larger dry eye study (n = 104) completed the Ocular Surface Disease Index (OSDI) and Convergence Insufficiency Symptom Survey (CISS) to determine if symptoms assessed on these two surveys were related. Also, myopic soft contact lens wearers (n = 29) with self-reported dry eye symptoms were recruited. Subjects completed the OSDI and CISS to assess severity of dry eye and BV disorder symptoms. Basic BV and dry eye testing was performed on each subject. RESULTS: Severity of symptoms assessed on the OSDI and CISS was found to be significantly correlated in the larger subject group (ρ = 0.68, p = 0.0001). This significant correlation warranted further investigation of both symptoms and clinical signs. In the group of myopic soft contact lens wearers, 48.3% had a BV disorder. This proportion appeared to be higher than previously reported prevalence estimates of BV disorders. Accommodative lag greater than or equal to 1.00 diopter was the most common BV disorder sign encountered (48.3%), and pseudo-convergence insufficiency was the most common BV disorder (31.0%). CONCLUSIONS: Symptoms related to dry eye and BV disorders overlap. Subjects with symptoms of discomfort while wearing soft contact lenses may be experiencing a concurrent or stand-alone BV disorder. Accommodative insufficiency and pseudo-convergence insufficiency were common in the sample of myopic soft contact lens wearers. Clinicians should screen symptomatic contact lens-induced dry eye patients for BV disorders. Dry eye studies should assess basic BV function.

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Tear film interferometry and corneal surface roughness.

PURPOSE: Previous studies of optical interference from the whole thickness of the precorneal tear film showed much lower contrast than from the pre-contact lens tear film. It is hypothesized that the recorded low contrast is related to roughness of the corneal surface compared with the smooth contact lens surface. This hypothesis is tested, and characteristics of this roughness are studied. METHODS: Reflectance spectra were recorded from 20 healthy individuals using a silicon-based sensor used in previous studies (wavelength range, 562-1030 nm) and an indium-gallium-arsenide (InGaAs) sensor responding at longer wavelengths (912-1712 nm). Interference from the whole thickness of the precorneal tear film caused oscillations in the reflectance spectra. RESULTS: Spectral oscillations recorded with the InGaAs sensor were found to decay as a Gaussian function of wave number (1/wavelength). This is consistent with a rough corneal surface, whose distribution of surface height is also a Gaussian function. Contrast of spectral oscillations for the InGaAs sensor was, on average, approximately four times greater than that for the silicon sensor. CONCLUSIONS: For the Gaussian roughness model based on InGaAs spectra, the corneal surface was characterized by a surface height SD of 0.129 µm. Spectral oscillations recorded with a silicon-based camera can have higher contrast than expected from this Gaussian roughness model, indicating some reflectance from a smoother or more compact surface. The results also indicate that InGaAs cameras could provide whole-thickness interference images of higher contrast than silicon-based cameras.

A model for tear film thinning with osmolarity and fluorescein.

PURPOSE: We developed a mathematical model predicting dynamic changes in fluorescent intensity during tear film thinning in either dilute or quenching regimes and we model concomitant changes in tear film osmolarity. METHODS: We solved a mathematical model for the thickness, osmolarity, fluorescein concentration, and fluorescent intensity as a function of time, assuming a flat and spatially uniform tear film. RESULTS: The tear film thins to a steady-state value that depends on the relative importance of the rates of evaporation and osmotic supply, and the resulting increase of osmolarity and fluorescein concentrations are calculated. Depending on the initial thickness, the rate of osmotic supply and the tear film thinning rate, the osmolarity increase may be modest or it may increase by as much as a factor of eight or more from isosmotic levels. Regarding fluorescent intensity, the quenching regime occurs for initial concentrations at or above the critical fluorescein concentration where efficiency dominates, while lower concentrations show little change in fluorescence with tear film thinning. CONCLUSIONS: Our model underscores the importance of using fluorescein concentrations at or near the critical concentration clinically so that quenching reflects tear film thinning and breakup. In addition, the model predicts that, depending on tear film and osmotic factors, the osmolarity within the corneal compartment of the tear film may increase markedly during tear film thinning, well above levels that cause marked discomfort.

Four characteristics and a model of an effective tear film lipid layer (TFLL).

It is proposed that a normal, effective tear film lipid layer (TFLL) should have the following four characteristics: 1) high evaporation resistance to prevent water loss and consequent hyperosmolarity; 2) respreadability, so it will return to its original state after the compression-expansion cycle of the blink; 3) fluidity sufficient to avoid blocking secretion from meibomian glands; 4) gel-like and incompressible structure that can resist forces that may tend to disrupt it. These characteristics tend to be incompatible; for example, lipids that form good evaporation barriers tend to be disrupted by compression-expansion cycles. It is noted that clues about the function and organization of the TFLL can be obtained by comparison with other biological lipid layers, such as lung surfactant and the lipid evaporation barrier of the skin. In an attempt to satisfy the conflicting characteristics, a "multilamellar sandwich model" of the TFLL is proposed, having features in common with the skin evaporation barrier.

Tear film images and breakup analyzed using fluorescent quenching.

PURPOSE: Tear evaporation should increase fluorescein concentration, causing fluorescence dimming from self-quenching for high but not low fluorescein concentration. This prediction was tested and compared to the predicted effect of "tangential flow" that fluorescence dimming should be similar for high and low concentrations. METHODS: A custom optical system was used for video recording of tear film fluorescence in 30 subjects. The subjects were asked to blink at the start of the recording and try to keep their eyes open for the rest of the 60-second recording. An initial recording was made after instillation of 1 µL 0.1% fluorescein followed by further recordings at 5-minute intervals using 0.5% and 5% fluorescein. RESULTS: Decay of fluorescence was considerably greater for the high (5%) concentration condition than for the low (0.1%) concentration. This is shown by "ratio images" (ratio of the intensity of a fluorescence image at a later time divided by that of an earlier image), fluorescence decay curves, fluorescence decay rates, and histograms of estimated tear thickness decrease. For example, for the high concentration condition, decay rates were higher than for the low concentration for all 30 subjects (P < 0.0001, binomial test). Additionally, breakup time was significantly reduced for the high compared to the low concentration condition. CONCLUSIONS: The greater fluorescence decay and more rapid breakup for the high concentration condition are the results expected if thinning and breakup are mainly due to evaporation, hence causing self-quenching. Fluorescence decay rate for the low concentration condition was not significantly greater than zero.

Tear film breakup and structure studied by simultaneous video recording of fluorescence and tear film lipid layer images.

PURPOSE: The thinning of the precorneal tear film between blinks and tear film breakup can be logically analyzed into contributions from three components: evaporation, flow into the cornea, and tangential flow along the corneal surface. Whereas divergent tangential flow contributes to certain types of breakup, it has been argued that evaporation is the main cause of tear thinning and breakup. Because evaporation is controlled by the tear film lipid layer (TFLL) it should therefore be expected that patterns of breakup should match patterns in the TFLL, and this hypothesis is tested in this study. METHODS: An optical system is described for simultaneous video imaging of fluorescein tear film breakup and the TFLL. Recordings were made from 85 subjects, including both with healthy and dry eyes. After instillation of 5 µL2% fluorescein, subjects were asked to blink 1 second after the start of the recording and try to maintain their eyes open for the recording length of 30 or 60 seconds. RESULTS: Areas of tear film thinning and breakup usually matched corresponding features in the TFLL. Whereas thinning and breakup were often matched to thin lipid, surprisingly, the corresponding lipid region was not always thinner than the surrounding lipid. Occasionally, a thin lipid region caused a corresponding region of greater fluorescence (thicker aqueous layer), due to convergent tangential flow. CONCLUSIONS: Areas of tear thinning and breakup can generally be matched to corresponding regions of the TFLL as would be expected if breakup is largely due to evaporation. Surprisingly, in some examples, the corresponding lipid area was not thinner and possibly thicker than the surrounding lipid. This indicates that the lipid was a poor barrier to evaporation, perhaps because of deficiency in composition and/or structure. For example, bacterial lipases may have broken down esters into component acids and alcohols, causing a defective TFLL structure with increased evaporation.

The use of fluorescent quenching in studying the contribution of evaporation to tear thinning.

PURPOSE: The purpose of our study was to test the prediction that if the tear film thins due to evaporation, rather than tangential flow, a high concentration of fluorescein in the tear film would show a greater reduction in fluorescent intensity compared to a low concentration of fluorescein due to self-quenching at high concentrations. METHODS: Tear film thickness, thinning rate, and fluorescent intensity were measured continuously and simultaneously with a modified spectral interferometer in 30 healthy subjects with two different concentrations (2% followed by 10%) of 1 µL of liquid fluorescein on the eye. Measurements of fluorescein self-quenching (fluorescent efficiency as a function of fluorescein concentration) are described in an Appendix and are reported in arbitrary units. RESULTS: Under low and high fluorescein concentration conditions, there were no differences in tear film thickness (P = 0.09) or thinning rates (P = 0.76). While the mean initial fluorescent intensity was similar between groups (637.47 ± 381.47 vs. 672.09 ± 649.72, P = 0.55), the mean rate of fluorescent decay was 4-fold faster in the high (16.57 ± 29.34) than in the low (4.11 ± 6.78) concentration group (P < 0.01). CONCLUSIONS: The large difference in the rate of fluorescent decay between groups can be explained by the effects of evaporation and self quenching of fluorescein; the latter is expected to be greater for high than for low fluorescein concentration. Fluorescence decay due to tangential flow would be expected to be similar at high and low fluorescein concentrations. This supports previous evidence that evaporation has the primary role in normal tear thinning between blinks.

Analysis of Comparison of Human Meibomian Lipid Films and Mixtures with Cholesteryl Esters In Vitro Films using High Resolution Color Microscopy.

PURPOSE: The lipid layer of the tears has been studied in vivo using high resolution color microscopy (HRCM). The purpose of these experiments was to gain further insight into the structure of the lipid layer by applying HRCM to in vitro meibomian lipid films. METHODS: Films of human meibomian lipids, cholesteryl nervonate, cholesteryl palmitate, or their mixtures, were spread on a Langmuir trough. Changes to the films were monitored using HRCM as the films were compressed to different surface pressures. The penetration of albumin into a meibomian lipid film also was studied. RESULTS: Small amounts of meibomian lipids at low pressures formed very thin films estimated to be 5.2 nm thick. Compression caused spots to appear in the films. At higher concentrations, micro lenses were a feature of the film. Cholesteryl nervonate formed a multilayered oil slick that did not change with surface pressure. Cholesteryl palmitate formed a stiff film that collapsed at high compression. Mixtures of cholesteryl nervonate and meibomian lipids showed that they mixed to increase surface pressures above that of the individual components. HRCM also allowed albumin to be seen penetrating the meibomian lipid film. CONCLUSIONS: HRCM combined with in vitro surface pressure measurements using a Langmuir trough is useful for modeling meibomian lipid films. The films often resemble the appearance of the lipid layer of in vivo films. The data indicate that the lipid layer might be modeled best as a duplex film containing an array of liquid crystals.