Mechanistic determination of tear film thinning via fitting simplified models to tear breakup

Purpose: To determine whether evaporation, tangential flow, or a combination of the two cause tear film breakup in a variety of instances; to estimate related breakup parameters that cannot be measured in breakup during subject trials; and to validate our procedure against previous work. Methods: Five ordinary differential equation models for tear film thinning were designed that model evaporation, osmosis, and various types of flow. Eight tear film breakup instances of five healthy subjects that were identified in fluorescence images in previous work were fit with these five models. The fitting procedure used a nonlinear least squares optimization that minimized the difference of the computed theoretical fluorescent intensity from the models and the experimental fluorescent intensity from the images. The optimization was conducted over the evaporation rate and up to three flow rate parameters. The smallest norm of the difference was determined to correspond to the model that best explained the tear film dynamics. Results: All of the breakup instances were best fit by models with time-dependent flow. Our optimal parameter values and thinning rate and fluid flow profiles compare well with previous partial differential equation model results in most instances. Conclusion: Our fitting procedure suggests that the combination of the Marangoni effect and evaporation cause most of the breakup instances. Comparison with results from previous work suggests that the simplified models can capture the essential tear film dynamics in most cases, thereby validating this procedure as one that could be used on many other instances.Comment: 28 pages, 11 figures, 6 table

Fitting ODE models of tear film breakup

Several elements are developed to quantitatively determine the contribution of different physical and chemical effects to tear breakup (TBU) in normal subjects. Fluorescence (FL) imaging is employed to visualize the tear film and to determine tear film (TF) thinning and potential TBU. An automated system using a convolutional neural network was trained and deployed to identify multiple TBU instances in each trial. Once identified, extracted FL intensity data was fit by mathematical models that included tangential flow along the eye, evaporation, osmosis and FL intensity of emission from the tear film. Optimizing the fit of the models to the FL intensity data determined the mechanism(s) driving each instance of TBU and produced an estimate of the osmolarity within TBU. Initial estimates for FL concentration and initial TF thickness agree well with prior results. Fits were produced for $N=467$ instances of potential TBU from 15 normal subjects. The results showed a distribution of causes of TBU in these normal subjects, as reflected by estimated flow and evaporation rates, which appear to agree well with previously published data. Final osmolarity depended strongly on the TBU mechanism, generally increasing with evaporation rate but complicated by the dependence on flow. The method has the potential to classify TBU instances based on the mechanism and dynamics and to estimate the final osmolarity at the TBU locus. The results suggest that it might be possible to classify individual subjects and provide a baseline for comparison and potential classification of dry eye disease subjects

Effects of Tear Film Instability on Sensory Responses to Corneal Cold, Mechanical, and Chemical Stimuli

Purpose: To investigate the effects of tear film instability (TFI) induced by sustained tear exposure (STARE) on sensory responses to corneal cold, mechanical, and chemical stimuli. Methods: Fifteen normal subjects were enrolled. TFI was induced during 10 repeated trials of STARE. Pneumatic cold, mechanical, and chemical stimuli were delivered using a computer-controlled Belmonte esthesiometer on three separate visits. The magnitude of the sensory responses to threshold and suprathreshold (1.25 and 1.50 times threshold levels) stimuli were assessed for intensity, coolness or warmness, irritation and pain, using a 0 (none) to 100 (very strong) scale, before and after STARE trials. Symptoms of ocular discomfort were evaluated using the Current Symptom Questionnaire (CSQ). Repeated measures ANOVA was used for data analysis. Results: Following STARE trials, the intensity and coolness ratings to cooling stimuli decreased (P = 0.043 and 0.044 for intensity and coolness, respectively), while rated irritation to mechanical stimuli was increased (P = 0.024). The CSQ scores also increased regardless of visits (all P < 0.001). Intensity ratings, coolness to room temperature stimuli and irritation to mechanical and chemical stimuli increased for all suprathreshold stimuli with increasing stimulus levels (P ≤ 0.005). Conclusions: Repeated TFI induced by STARE affects neurosensory function of the ocular surface. The decrease in reports of cooling and increase in irritation after repeated TFI suggest a complex interaction of neural mechanisms (particularly nonnociceptive cold and nociceptive mechanical) giving rise to ocular surface sensation in humans

Changes in Corneal Detection Thresholds After Repeated Tear Film Instability

Purpose: To use a human-based model to study the effects of repeated tear film instability on corneal detection thresholds to cold, mechanical, and chemical stimuli. Methods: Twenty-five subjects participated in three study visits. A computer-controlled Belmonte esthesiometer was used to estimate corneal detection thresholds to cold, mechanical, and chemical stimuli before, after, and 30 minutes following 10 consecutive sustained tear exposure (STARE) trials. Subjects turned a pain knob (0–10) to indicate discomfort during STARE trials. The area of tear breakup and thinning in each trial was analyzed. Symptoms were evaluated by the Current Symptom Questionnaire (CSQ). Results: There was a significant time effect on CSQ symptoms during both visits (Friedman test, P < 0.001), with immediately after repeated STARE and 30 minutes later significantly differing from before STARE (Wilcoxon, P < 0.017). Tear breakup occurred in every trial, ranging from 25% to 88% of the exposed corneal area and all subjects indicated discomfort during trials. There was a significant time effect on mechanical thresholds between before STARE mechanical thresholds and 30 minutes later (repeated measures analysis of variance [ANOVA] P < 0.001), but not cold (P = 0.057) or chemical (P = 0. 565) thresholds. Conclusions: In this study, tear breakup during STARE trials was associated with discomfort, which when repeated, resulted in increased symptoms of ocular discomfort and alterations of mechanical sensory thresholds after 30 minutes. These results suggest that tear film instability, which is thought to occur repeatedly during normal blinking among dry eye patients over the day, can produce neurosensory alterations

Blink characterization using curve fitting and clustering algorithms

The motion of the upper eyelid during blinking can be important in identifying possible diseases and syndromes that affect the eye. Hypothesized lid motion functions are fit to the dynamic position of the center of the upper lid under four experimentally controlled conditions in a pilot study. The coefficients of these nonlinear fits are used to classify blinks. Agglomerative hierarchical and spectral clustering were used to attempt an automatic distinction between partial and full blinks as well as between normal and abnormal blinks. Results for both approaches are similar when the input data is suitably normalized. Clustering finds outlying blinks that do not fit the model functions for lid motion well and that differ from the majority of blinks in our sample; however, those blinks may not be outliers based on easily observed data such as blink amplitude and duration. This type of analysis has potential for studying blink dynamics under normal and pathological conditions, but more work is needed with larger sets of data from blinks

Review and analysis of grading scales for ocular surface staining

Vital dye staining has been used for over a century to assess the severity of ocular surface disease. However, despite common usage, a universally accepted “gold standard” grading scale does not exist for corneal and conjunctival staining, which can impact the ability to diagnose and monitor ocular surface conditions such as dry eye. The Food and Drug Administration (FDA) and other international regulatory agencies rely on ocular surface staining as a primary endpoint for new drug approvals, so that absence of a “gold standard” scale may affect approval of new drug treatments. To begin to address this problem, we review existing, published grading scales in an integrated fashion, highlighting their differences and similarities to emphasize common themes and the methods and elements that are important in creating a standardized scale. Our goal is to aid the field in moving towards an accepted standardized grading scale for ocular surface staining that can be applied in clinic and research settings for a variety of ocular conditions

The effects of increasing ocular surface stimulation on blinking and sensation. Invest Ophthalmol Vis Sci

PURPOSE. To investigate the effect of varying levels of ocular surface stimulation on the timing and amplitude of the blink and tear secretion. METHODS. Following instillation of fluorescein dye, increasing levels of air flow were directed toward the central corneas of 10 healthy subjects. Interblink interval (IBI), tear meniscus height (TMH), and fluorescence intensity were measured simultaneously. Because blinking can obscure changes in TMH, we developed novel measures of tear secretion by calculating tear meniscus fluorescein concentration (TMFC) from intensity using a mathematical model. The change of TMH and TMFC over trials and the slope of the TMFC within each IBI (IBI-TTR) were further calculated. RESULTS. The mean IBI was decreased by 8.08 6 8.54 seconds from baseline to maximum air stimulation. The TMH increase was highly variable (0.41 6 0.39 mm) among subjects, compared to the fluorescence tear turnover metrics: decrease in TMFC of 2.84 6 0.98 natural logarithm or ln(%) and IBI-TTR of 0.065 6 0.032 ln(%)/sec. Ocular surface stimulation was highly correlated with the TMFC and IBI-TTR, but less so with TMH (Pearson&apos;s r ¼ 0.71, 0.69, and 0.40, P &lt; 0.01, respectively). Blinking and tearing were significantly correlated with each other (Pearson&apos;s r ¼ 0.56, P &lt; 0.01), but tearing lagged behind by an average of 6.54 6 4.07 seconds. CONCLUSIONS. Blinking and tearing share a common origin with sensory stimulation at the ocular surface. Both showed a dose-response increase with surface stimulation and were correlated with each other. These methods can potentially be used to understand alterations in ocular surface sensory function and associated protective responses in dry eye and other disorders of the ocular surface

Canonical Grading Scales of Corneal and Conjunctival Staining Based on Psychophysical and Physical Attributes

Purpose: In this study, we apply psychophysical scaling principles based on physical (photometric) attributes of images to better understand the factors involved in clinician judgement of ocular surface staining and, using that knowledge, to develop photographic scales for the assessment of staining for dry eye (DE) and related conditions. Methods: Subjects with noninfectious ocular surface staining were enrolled at five clinical sites. Following instillation of fluorescein, photographs of corneal staining were taken every 30 seconds for at least 5 minutes. The same procedure was followed for conjunctival staining after instillation of 2 µl of 1% lissamine green. A subset of the best corneal and bulbar conjunctival staining images were anonymized and a spectroradiometer measured photometric attributes (luminance and chromaticity). The images were scaled psychophysically by study investigators, who participated in constructing grading scales based on physical and psychophysical analyses. The final grading scales were refined following consultation with outside DE experts. Results: Photographs were collected from 142 subjects (81% women), with an average age of 58 ± 17 years; 89% were diagnosed with DE. There was a monotonic relationship between between physical measurements and psychophysically scaled staining of both corneal (fluorescein) and bulbar (lissamine green) staining. Michelson contrast and u' (chromaticity) accounted for 66% and 64% of the variability in the psychophysically scaled images of fluorescein corneal and lissamine green conjunctival staining, respectively. Translational relevance: This paper provides examples of the first ever clinically usable ocular surface staining scales validated using psychophysical scaling and the physical attributes (luminance and chromaticity) of the staining itself. In addition, it provides a generalizable method for the development of other clinical scales of ocular appearance