Parameter Estimation for Mixed-Mechanism Tear Film Thinning.

Etiologies of tear breakup include evaporation-driven, divergent flow-driven, and a combination of these two. A mathematical model incorporating evaporation and lipid-driven tangential flow is fit to fluorescence imaging data. The lipid-driven motion is hypothesized to be caused by localized excess lipid, or "globs." Tear breakup quantities such as evaporation rates and tangential flow rates cannot currently be directly measured during breakup. We determine such variables by fitting mathematical models for tear breakup and the computed fluorescent intensity to experimental intensity data gathered in vivo. Parameter estimation is conducted via least squares minimization of the difference between experimental data and computed answers using either the trust-region-reflective or Levenberg-Marquardt algorithm. Best-fit determination of tear breakup parameters supports the notion that evaporation and divergent tangential flow can cooperate to drive breakup. The resulting tear breakup is typically faster than purely evaporative cases. Many instances of tear breakup may have similar causes, which suggests that interpretation of experimental results may benefit from considering multiple mechanisms.

Parameter Estimation for Evaporation-Driven Tear Film Thinning.

Many parameters affect tear film thickness and fluorescent intensity distributions over time; exact values or ranges for some are not well known. We conduct parameter estimation by fitting to fluorescent intensity data recorded from normal subjects' tear films. The fitting is done with thin film fluid dynamics models that are nonlinear partial differential equation models for the thickness, osmolarity and fluorescein concentration of the tear film for circular (spot) or linear (streak) tear film breakup. The corresponding fluorescent intensity is computed from the tear film thickness and fluorescein concentration. The least squares error between computed and experimental fluorescent intensity determines the parameters. The results vary across subjects and trials. The optimal values for variables that cannot be measured in vivo within tear film breakup often fall within accepted experimental ranges for related tear film dynamics; however, some instances suggest that a wider range of parameter values may be acceptable.

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.

Scale and spatial distribution of aberrations associated with tear breakup.

PURPOSE: We examined the spatial correlation between tear breakup (TBU) and the associated optical anomalies on multiple spatial scales. METHODS: Five subjects refrained from blinking while the time course and patterns of TBU were sequentially observed using fluorescein, retroillumination, and Shack-Hartmann (SH) aberrometry. Wavefront error maps were developed using Zernike polynomials, as well as local zonal analysis of measured wavefront slopes. The difference between these maps reveals the presence of very high-order aberrations missed by standard modal fitting methods. Size of SH spots was also quantified to estimate optical perturbations on a microscopic scale. The spatial correlation between TBU and optical aberrations was also computed. RESULTS: Degradation of the tear film increased wavefront aberrations over all spatial scales measured. Consistent with tear thinning, blink suppression induced an irregular pattern of phase advances in regions of TBU. SH spot size also increased in regions of TBU, which indicates the presence of optical aberrations on a scale smaller than individual lenslets. CONCLUSIONS: The optical signature of TBU caused by blink suppression is a combination of wavefront aberrations on macroscopic and microscopic scales due to non-uniform tear film thinning and possible exposure of a rough epithelial surface. Localized optical defects correspond temporally and spatially with TBU revealed by fluorescein and retroillumination. In addition to gross wavefront aberrations, scatter develops in areas of TBU that will further contribute to image degradation and visual disturbances after TBU.

Contact Lens Dry Eye Questionnaire-8 (CLDEQ-8) and opinion of contact lens performance.

PURPOSE: To report on the development and validation of a short form of the Contact Lens Dry Eye Questionnaire (the CLDEQ-8) to enable it to reflect status of and change in overall opinion ("opinion") of soft contact lenses (SCLs). METHODS: Item reduction for the CLDEQ was achieved by correlation with overall opinion of SCLs at follow-up visits in a sample of 38 SCL wearers at one academic clinical site. The CLDEQ-8 score (frequency plus late day intensity of dryness, discomfort, and "blurry vision"; frequency of "closing eyes to rest them" and "removing CLs to relieve discomfort") was then tested in 379 SCL wearers in a multicenter study with analysis stratified by opinion ratings at baseline and 2 weeks postrandomization to new silicone hydrogel SCLs. The sum of CLDEQ-8 scores (maximum 37) was correlated with opinion by Spearman's rank correlation coefficient and analyzed for change in opinion by analysis of variance (ANOVA). RESULTS: The CLDEQ-8 scores in the validation sample were highly correlated with habitual baseline opinion (-0.44, p < 0.0001) and responsive to change in opinion postrandomization (-0.58, p < 0.0001). Baseline CLDEQ-8 scores by opinion status were as follows: Fair: 17.4 ± 8.7, Good 13.7 ± 6.4, Very Good 9.1 ± 4.7, and Excellent 6.4 ± 3.7 (ANOVA, F = 291.1, p < 0.0001). After 2 weeks, change in CLDEQ-8 scores by improvement status was as follows: Much Improved: -16.7 ± 10.0, Unchanged: -2.3 ± 5.0, to Much Worse +8.5 ± 5.8 (ANOVA, F = 16.5, p < 0.001). CONCLUSIONS: The CLDEQ-8 score significantly reflected baseline status and change in overall opinion after refitting with two types of silicone hydrogels. The CLDEQ-8 score is a valid outcome measure in SCL clinical trials to reflect opinion of SCLs.

Report of the TFOS/ARVO Symposium on global treatments for dry eye disease: an unmet need.

In September 2010, a Symposium in Florence, Italy, was held to address the unmet need for global treatments for dry eye disease (DED). It was sponsored by The Tear Film & Ocular Surface Society (TFOS; www.TearFilm.org) and co-sponsored by the Association for Research in Vision & Ophthalmology (www.arvo.org). The Symposium objectives were two-fold: first, to discuss accepted and emerging clinical endpoints of DED with regulatory experts from around the world; and second, to consider how to improve clinical trials of treatments for DED. The Symposium focused on the personal and collective burden of DED, as well as the developmental and regulatory challenges associated with generating new DED therapeutics. This article provides a synopsis of many of the presentations, discussions and recommendations of this Symposium.

The effect of time on grading corneal fluorescein and conjunctival lissamine green staining.

PURPOSE: To explore the effect of time on grading corneal fluorescein and conjunctival lissamine green staining in dry eye disease (DED). METHODS: Photographs of 68 subjects with non-Sjogren's DED (nSS DED) and 32 with Sjogren's DED (SS DED) were taken of corneal fluorescein staining, then conjunctival lissamine green staining every 30 s for at least 5 min. Photographs of one randomly selected eye were then randomly ordered and graded on a scale from 0 to 5 (severe staining) by two clinicians, masked to both site and subject. The average time required to reach the maximum grade of staining (Gmax) was calculated. RESULTS: The median time (upper and lower quartiles) to corneal fluorescein Gmax was 2.6 (1.3-5.3) minutes for nSS DED and 3.8 (2.6-5.4) minutes for SS DED, a statistically significant difference (Mann Whitney U test, p = 0.018). In contrast, the median time to the Gmax for lissamine green staining of the nasal and temporal conjunctiva was 0.5 (0.5-1.1 nasal, 0.5-0.8 temporal) minutes for nSS DED and 0.5 (0.5-0.8 nasal, 0.5-0.5 temporal) minutes for SS DED subjects, which was not statistically significant (p ≥ 0.383). CONCLUSIONS: The time required to reach the maximum grade of corneal fluorescein staining, but not conjunctival lissamine green staining, varied widely and was significantly longer in subjects with Sjögren's Syndrome. Early observation of corneal fluorescein staining can lead to under-grading, which may impact the diagnosis and assessment of treatment in DED. Further study of the best time to assess corneal fluorescein staining in various DED populations is warranted.

Dynamics and mechanisms for tear breakup (TBU) on the ocular surface.

The human tear film is rapidly established after each blink, and is essential for clear vision and eye health. This paper reviews mathematical models and theories for the human tear film on the ocular surface, with an emphasis on localized flows where the tear film may fail. The models attempt to identify the important physical processes, and their parameters, governing the tear film in health and disease.

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.

Effect of contact lens wear and a near task on tear film break-up.

PURPOSE: To study the effect of extrinsic controls on blinking by examining blink parameters and tear stability among adapted soft contact lens (CL) wearers performing tasks that require varying amounts of visual concentration. METHODS: The Demographic Questionnaire, Contact Lens Dry Eye Questionnaire, and Current Symptoms Questionnaire were completed by 15 adapted soft CL wearers (nine females). Three 55 s simultaneous measurements of tear film stability via retroillumination and blinking were obtained with a slit-lamp biomicroscope and 200 Hz video camera while subjects listened to music and played a video game with and without their habitual CLs. Interblink interval (IBI) and blink amplitude (BA) were calculated. The area of break-up (AB) was calculated for the retroillumination image before each blink. The Current Symptoms Questionnaire was completed four times throughout testing. RESULTS: With the game compared to music, IBI was significantly longer and BA significantly decreased without CLs (p < or = 0.001). With CLs, the IBI did not significantly change between tasks but the BA significantly decreased (p = 0.100). The AB significantly increased with CL and the game (paired t-test, p < or = 0.001). The BA was significantly correlated with self-reported severity of dry eye for all testing scenarios (Spearman r > or = 0.5579, p < 0.0001) and several symptom measures (Spearman r > or = 0.6262, p < 0.0001). The AB was significantly correlated with symptom measures including bothersome discomfort for the game with and without CLs (Spearman r > or = 0.5064, p < 0.0001). CONCLUSIONS: During tasks requiring concentration, the IBI increased (blink rate decreased) and many blinks were incomplete without CLs. With CLs, tear film instability increased. Blinking frequency also increased, but it remained high when subjects played the game, and symptoms of ocular irritation increased. This suggests that wearing soft CLs, even when fully adapted, provides enough extrinsic ocular surface stimulation to override internal controls and affect blink parameters.

Role of diurnal variation of corneal sensory processing in contact lens discomfort.

PURPOSE: To examine the diurnal variation of corneal threshold and suprathreshold sensory processing, symptoms, and tear secretion in symptomatic and asymptomatic contact lens (CL) wearers and controls. METHODS: 26 symptomatic and 25 asymptomatic CL wearers and 15 asymptomatic non-CL wearing controls participated. Cooling thresholds, symptoms and tear meniscus height (TMH) were measured on each of 3 measurement days (random order) on the following schedules; Day-1 within 1 h of awakening (Baseline) and 3, 6 and 9 h later, Day-2 baseline and 9 h later (CLs worn in CL group) and Day-3 baseline and 9 h later. Magnitudes estimates for threshold-scaled suprathreshold stimuli were also estimated on Day-3. Data were analyzed using mixed models and repeated measures ANOVA. RESULTS: Cooling thresholds for the symptomatic group were lower and decreased over Day-1 (p < 0.008) and after 8 h of CL wear on Day-2 (p < 0.001) and were paralleled by increased symptoms (all p < 0.001), whereas minimal variations were found in the asymptomatic and control groups. Magnitude estimates for suprathreshold stimuli were higher (p ≤ 0.002) in the symptomatic group but did not differ significantly over the day. TMH varied little over time and was lower in the symptomatic group, but the difference was not statistically significant. CONCLUSION: Corneal sensitivity and symptoms, but not TMH, increased diurnally irrespective of CL wear in symptomatic CL wearers. These results reveal the essential role of neurosensory abnormalities in CL discomfort and suggest involvement of a central mechanism in the diurnally increased symptoms of these patients.

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.

Blinking and tear break-up during four visual tasks.

PURPOSE: This study investigates the relationship between blinking, tear film break-up, and ocular symptoms for normal and dry eye subjects performing four different visual tasks. METHODS: Sixteen control and sixteen dry eye subjects performed four visual tasks (looking straight ahead, watching a movie, identifying rapidly changing letters, and playing a computer game) while blink patterns and fluorescein images of the tear film were videotaped. Pre and posttesting symptom questionnaires, querying the intensity of nine symptoms of ocular irritation, were completed by all subjects. Blink rate and blink amplitude were computed from digitized videos. The percentage of tear film break-up before the blink was calculated. RESULTS: Dry eye subjects had a significantly higher blink rate (p = 0.017, t-test). Both groups blinked significantly less during the game and letter tasks (p < 0.04, t-test). Partial blinks were common as were clusters or "flurries" of rapid blinks, but there was no significant difference in blink amplitude for control and dry eye subjects. Tear film break-up in normal subjects was typically inferior; whereas dry eye subjects showed more tear break-up centrally and superiorly. Real-time video recording of tear break-up and blink behavior pointed to complex interaction between the two. Dry eye subjects shifted more toward intense ocular symptoms at posttesting (p < 0.05, Wilcoxon signed rank) than controls. Both groups showed a shift toward more corneal staining at posttesting (p < 0.05, Wilcoxon signed rank), which was typically inferior. CONCLUSIONS: Reduced and incomplete blinking along with increased tear film break-up during normal visual tasks may explain the increased level of ocular discomfort symptoms reported at the end of the day, particularly in dry eye patients.

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.

A simple and cost effective method for preparing FL and LG solutions.

PURPOSE: The purpose of this study was to develop a clinically feasible method for obtaining dye concentrations of 2% fluorescein (FL) and 1% lissamine green (LG) by soaking commercially available dye impregnated strips in saline. METHODS: Calibration curves were established to related known concentrations of dye to prepared FL fluorescence and LG absorbance. To determine the optimum number of dye strips and soaking times (preliminary testing), 1, 2, 3 FL or LG strips were soaked in 200 µl commercially available saline for 0.5, 1, 2, 3, 4 and 5 min, using calibration curves to determine FL and LG concentrations. The best combination of number of dye strips and soaking time was soaking 3FL and 3LG strips for 5 min and these were finally tested in 2 ml centrifuge tubes, selected for ease of use in a clinical setting. RESULTS: Preliminary testing indicated that soaking 3 FL or 3 LG strips for 5 min in saline yielded an average (±standard deviation) of 2.0 ± 0.000% FL and 0.93 ± 0.010% LG. Final testing of FL in centrifuge tubes (strips soaked for 3-15 min) yielded an average of 1.99 ± 0.040% FL, with no significant difference among time periods or dye lots tested. However, LG showed more variable results with an average of 0.80 ± 0.160% LG (5-15 min), with significant differences among dye lots and times (2-way ANOVA, p < 0.05). CONCLUSIONS: This simple, reliable and relatively inexpensive method involves soaking 3 FL or LG strips in saline solution, yielding concentrations close to the 2%FL and 1%LG recommended for clinical trials, although LG showed more variability.

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.

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.

A link between tear breakup and symptoms of ocular irritation.

PURPOSE: We used the presence or absence of a soft contact lens (CL) as a barrier to test the hypothesis that tear breakup (TBU) presents a direct noxious stimulus to the ocular surface. METHODS: Ten subjects kept one eye open as long as possible, termed sustained tear exposure (STARE), for 10 consecutive trials while discomfort was monitored with and without a CL in place. The area of TBU was quantified in each frame. Discomfort was measured during and after each STARE trial and symptoms of ocular irritation were assessed before and after all testing. RESULTS: TBU increased at the end of trials to an average of 19.89% ± 17.91% and 20.58% ± 15.33% and discomfort to 9.09 ± 1.44 and 1.97 ± 2.19 in trials without and with a CL, respectively. Discomfort was significantly higher during trials without CLs (Friedman test, p < 0.005), but there was no significant difference in the area of TBU between trials (Friedman test, p = 0.296) with and without a CL (Friedman test, p = 0.527). Discomfort after each STARE trial increased significantly across trials (Friedman, p < 0.005). Symptoms of ocular irritation increased significantly from pre- to post-testing (Wilcoxon signed rank test, p < 0.005). CONCLUSIONS: TBU during STARE trials was associated with increasing ocular discomfort, which was partially blocked by wearing a CL, supporting the hypothesis that TBU directly stimulates the corneal surface. Repeated STARE trials led to increasing discomfort and dry-eye like symptoms of ocular irritation, suggesting that repeated bouts of TBU can lead to alterations in ocular surface sensory processing.

TFOS DEWS II pain and sensation report.

Pain associated with mechanical, chemical, and thermal heat stimulation of the ocular surface is mediated by trigeminal ganglion neurons, while cold thermoreceptors detect wetness and reflexly maintain basal tear production and blinking rate. These neurons project into two regions of the trigeminal brain stem nuclear complex: ViVc, activated by changes in the moisture of the ocular surface and VcC1, mediating sensory-discriminative aspects of ocular pain and reflex blinking. ViVc ocular neurons project to brain regions that control lacrimation and spontaneous blinking and to the sensory thalamus. Secretion of the main lacrimal gland is regulated dominantly by autonomic parasympathetic nerves, reflexly activated by eye surface sensory nerves. These also evoke goblet cell secretion through unidentified efferent fibers. Neural pathways involved in the regulation of meibomian gland secretion or mucin release have not been identified. In dry eye disease, reduced tear secretion leads to inflammation and peripheral nerve damage. Inflammation causes sensitization of polymodal and mechano-nociceptor nerve endings and an abnormal increase in cold thermoreceptor activity, altogether evoking dryness sensations and pain. Long-term inflammation and nerve injury alter gene expression of ion channels and receptors at terminals and cell bodies of trigeminal ganglion and brainstem neurons, changing their excitability, connectivity and impulse firing. Perpetuation of molecular, structural and functional disturbances in ocular sensory pathways ultimately leads to dysestesias and neuropathic pain referred to the eye surface. Pain can be assessed with a variety of questionaires while the status of corneal nerves is evaluated with esthesiometry and with in vivo confocal microscopy.