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.PurposeUnderstanding 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.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.MethodsA 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.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.ResultsInitially, 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.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.ConclusionsBelow 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.
TFOS DEWS II pain and sensation report Belmonte, Carlos; Nichols, Jason J.; Cox, Stephanie M. ...
The ocular surface,
July 2017, 2017-07-00, 20170701, Letnik:
15, Številka:
3
Journal Article
Recenzirano
Odprti dostop
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.
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.
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.
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).
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.
Abstract Purpose To validate a subset of Dry Eye Questionnaire (DEQ) items that discriminate across self-assessed severity and various diagnoses of dry eye (DE). Methods Subjects ( n = 260) in 2 ...studies received a clinical DE diagnosis, completed the 6-page DEQ and self-assessment of DE severity (SA-Sev). SA-Sev ratings were: 46 Severe, 107 Moderate, 77 Mild, and 46 None. Dry eye diagnoses were: 48 asymptomatic controls (C), 155 non-SS KCS, and 57 Sjögren Syndrome (SS). All DEQ items were correlated to SA-Sev by Spearman. Groups of highly correlated DEQ items were tested to discriminate SA-Sev; and the subset tested to distinguish across DE diagnosis. Results The DEQ-5 comprises: frequency of watery eyes ( r = 0.48), discomfort ( r = 0.41), and dryness ( r = 0.35), and late day (PM) intensity of discomfort and dryness ( r = 0.42, 0.36) all significantly correlated to SA-Sev ( p < 0.01). Mean DEQ-5 scores by SA-Sev: Severe 14.9 ± 2.3, Moderate 11.4 ± 3.3, Mild 8.6 ± 3.1 and None 2.7 ± 3.2 (ANOVA, p < 0.0001) and by DE diagnosis: C 2.7 ± 2.9, non-SS KCS10.5 ± 4.5 and SS14.0 ± 3.4, differing significantly overall ( Z = −8.6, p = 0.000) and between diagnoses ( X2 = 116.3, p = 0.000). Watery eyes were reported primarily by non-SS KCS. Proposed screening criteria for the DEQ-5 are >6 for DE and >12 for suspected SS. Conclusions The DEQ-5, the sum of scores for frequency and PM intensity of dryness and discomfort plus frequency of watery eyes, effectively discriminated across self-assessed severity ratings and between patients with DE diagnoses. These results indicate that DEQ-5 scores >6 suggest DE and scores >12 may indicate further testing to rule out SS–DE.
To develop and validate a comprehensive patient-reported outcomes instrument focusing on the impact of dry eye on everyday life (IDEEL).
Development and validation of the IDEEL occurred in four ...phases: 1) focus groups with 45 dry eye patients to develop a draft instrument, 2) item generation, 3) pilot study to assess content validity in 16 patients and 4) psychometric validation in 210 subjects: 130 with non-Sjögren's keratoconjunctivitis sicca, 32 with Sjögren's syndrome and 48 controls, and subsequent item reduction.
Focus groups identified symptoms and the associated bother, the impact of dry eye on daily life and the patients' satisfaction with their treatment as the central concepts in patients' experience of dry eye. Qualitative analysis indicated that saturation was achieved for these concepts and yielded an initial 112-item draft instrument. Patients understood the questionnaire and found the items to be relevant indicating content validity. Patient input, item descriptive statistics and factor analysis identified 55 items that could be deleted. The final 57-item IDEEL assesses dry eye impact constituting 3 modules: dry eye symptom-bother, dry eye impact on daily life comprising impact on daily activities, emotional impact, impact on work, and dry eye treatment satisfaction comprising satisfaction with treatment effectiveness and treatment-related bother/inconvenience. The psychometric analysis results indicated that the IDEEL met the criteria for item discriminant validity, internal consistency reliability, test-retest reliability and floor/ceiling effects. As expected, the correlations between IDEEL and the Dry Eye Questionnaire (a habitual symptom questionnaire) were higher than between IDEEL and Short-Form-36 and EuroQoL-5D, indicating concurrent validity.
The IDEEL is a reliable, valid and comprehensive questionnaire relevant to issues that are specific to dry eye patients, and meets current FDA patient-reported outcomes guidelines. The use of this questionnaire will provide assessment of the impact of dry eye on patient dry eye-related quality of life, impact of treatment on patient outcomes in clinical trials, and may aid in treatment effectiveness evaluation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
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.
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).
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.
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.
To explore the effect of time on grading corneal fluorescein and conjunctival lissamine green staining in dry eye disease (DED).
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.
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).
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.
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).
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).
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).
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.
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.
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.
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.
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.
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