Effect of recombinant human nerve growth factor treatment on corneal nerve regeneration in patients with neurotrophic keratopathy.

Introduction: Neurotrophic Keratopathy (NK) is a neurodegenerative corneal disease that results in diminished corneal sensation. Previous studies have found that Cenegermin 0.002%, a recombinant human nerve growth factor (rhNGF), improves corneal epithelial healing in stage 2 and 3 NK patients. However, rhNGF effect on corneal sensation and nerve regeneration has not been well established. Thus, this study aims to analyze the effect of rhNGF on corneal nerve regeneration using in vivo confocal microscopy (IVCM) and on corneal sensitivity in NK patients. Methods: This is a retrospective, longitudinal, case-control study that included patients with NK, treated with rhNGF for at least 4 weeks, with pre- and post-treatment IVCM images available for analysis. Chart reviews were conducted documenting prior medical and surgical history, clinical signs and symptoms, and corneal sensation using Cochet-Bonnet esthesiometry. Corneal nerve parameters were assessed by IVCM. Sex- and age-matched reference controls were selected from a database of healthy subjects for comparison. Results: The study included 25 patients, with 22 (88%) stage 1, two (8%) stage 2, and 1 (4%) stage 3 NK patients, with a median age of 64 years (range: 30-93 years). Total, main, and branch nerve densities [median (range) in mm/mm2] were lower in the NK group pre-treatment [2.3 (0.0-21.1); 1.7 (0.0-13.0); 0.5 (0.0-10.2); respectively] vs. controls [22.3 (14.9-29.0); 10.1 (3.2-15.4); and 12.1 (6.2-18.4), (p < 0.0001 for all), respectively]. Post-treatment nerve densities increased compared to pre-treatment to 5.3 (0.0-19.4, p = 0.0083) for total, 3.5 (0.0-13.2, p = 0.0059) for main, and 2.0 (0.0-10.4, p = 0.0251) for branch nerves, but remained lower than controls (p < 0.0001 for all). Corneal sensation increased from 2.3 ± 1.1 cm pre-treatment to 4.1 ± 1.4 cm post-treatment (p = 0.001). Median best corrected visual acuity significantly increased following rhNGF treatment from 0.4 (0.0-1.6) to 0.12 (-0.1 to 1.6) (p = 0.007). Conclusion: Patients with NK treated with at least 4 weeks of rhNGF, showed a significant increase in corneal nerve densities after treatment. A significant increase in corneal sensation, as well as best corrected visual acuity, was observed following treatment.

Corneal nerve regeneration is affected by scar location in herpes simplex keratitis: A longitudinal in vivo confocal microscopy study.

PURPOSE: To assess the effect of corneal scar location on corneal nerve regeneration in patients with herpes simplex virus (HSV) keratitis in their affected and contralateral eyes over a 1-year period by in vivo confocal microscopy (IVCM), and to correlate these findings to corneal sensation measured by Cochet-Bonnet Esthesiometer. METHODS: Prospective, longitudinal, case-control study. Bilateral corneal nerve density and corneal sensation were analyzed centrally and peripherally in 24 healthy controls and 23 patients with unilateral HSV-related corneal scars using IVCM. RESULTS: In the central scar (CS) group, total nerve density in the central cornea remained significantly lower compared to controls at follow-up (11.05 ± 1.97mm/mm2, p < 0.001), and no significant nerve regeneration was observed (p = 0.090). At follow-up, total nerve density was not significantly different from controls in the central and peripheral cornea of the peripheral scar (PS) group (all p > 0.05), but significant nerve regeneration was observed in central corneas (16.39 ± 2.39mm/mm2, p = 0.007) compared to baseline. In contralateral eyes, no significant corneal nerve regeneration was observed in central or peripheral corneas of patients with central scars or peripheral scars at 1-year follow-up, compared to baseline (p > 0.05). There was a positive correlation between corneal nerve density and sensation in both central (R = 0.53, p < 0.0001) and peripheral corneas (R = 0.27, p = 0.0004). In the CS group, the corneal sensitivity was <4 cm in 4 (30.8%) and 7 (53.8%) patients in the central and peripheral corneas at baseline, and in 5 (38.5%) and 2 subjects (15.4%) at follow-up, whereas in the PS group only 1 patient (10%) showed a corneal sensation < 4 cm in the central cornea at baseline, and only 1 (10.0%), 3 (30.0%) and 1 (10.0%) patients at follow-up in the central, affected and opposite area of the cornea, respectively. CONCLUSION: The location of HSV scarring in the cornea affects the level of corneal nerve regeneration. Eyes with central corneal scar have a diminished capacity to regenerate nerves in central cornea, show a more severe reduction in corneal sensation in the central and peripheral corneas that persist at follow-up, and have a reduced capability to restore the corneal sensitivity above the cut-off of 4 cm. Thus, clinicians should be aware that CS patients would benefit from closer monitoring for potential complications associated with neurotrophic keratopathy, as they have a lower likelihood for nerve regeneration.

A Single Administration of OC-01 (Varenicline Solution) Nasal Spray Induces Short-Term Alterations in Conjunctival Goblet Cells in Patients with Dry Eye Disease.

INTRODUCTION: Dry eye disease is characterized by a persistently unstable or deficient tear film causing discomfort or visual impairment. Varenicline is a small-molecule nicotinic acetylcholine receptor agonist recently approved for use as a preservative-free nasal spray (OC-01 [varenicline solution] nasal spray [OC-01 VNS]) to treat signs and symptoms of dry eye disease, but its effect on conjunctival goblet cells has not been studied. METHODS: In this phase 2, single-center, vehicle-controlled study, patients aged 18 years or more with a diagnosis of dry eye disease and Ocular Surface Disease Index© score of at least 23 were randomized 2:1 to receive a 50-µL single dose of OC-01 0.06 mg VNS or vehicle nasal spray in each nostril. Image assessments for area and perimeter were performed pre and 10 min post treatment for goblet cells by in vivo confocal microscopy and for meibomian glands by infrared meibography. Non-parametric Wilcoxon signed-rank test compared pre- and post-treatment measurements for each treatment group. Treatment-emergent adverse events (TEAEs) were assessed. RESULTS: The study randomized 18 patients (mean age 61 years); 6 received vehicle (3/6 [50%] female) and 12 patients received OC-01 VNS (11/12 [92%] female). OC-01 VNS treatment decreased mean goblet cell area (pre-treatment, 106.4 µm2; post-treatment, 67.6 µm2; p = 0.02) and perimeter (pre-treatment, 38.9 µm; post-treatment, 31.2 µm; p = 0.03) but not vehicle did not (p = 0.25). There were no significant changes in mean meibomian gland area with either treatment (p ≥ 0.05). All TEAEs were non-ocular, non-serious, and mild. CONCLUSIONS: This study demonstrated that a single administration of OC-01 0.06 mg VNS in patients with dry eye disease reduced conjunctival goblet cell area and perimeter, suggesting goblet cell degranulation and associated release of lubricating mucin. By activating the natural tear film, OC-01 VNS may provide benefits over topical medications. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03688802.

Alterations in corneal nerves in different subtypes of dry eye disease: An in vivo confocal microscopy study.

PURPOSE: To evaluate corneal subbasal nerve alterations in evaporative and aqueous-deficient dry eye disease (DED) as compared to controls. METHODS: In this retrospective, cross-sectional, controlled study, eyes with a tear break-up time of less than 10 s were classified as DED. Those with an anesthetized Schirmer's strip of less than 5 mm were classified as aqueous-deficient DED. Three representative in vivo confocal microscopy images were graded for each subject for total, main, and branch nerve density and numbers. RESULTS: Compared to 42 healthy subjects (42 eyes), the 70 patients with DED (139 eyes) showed lower total (18,579.0 ± 687.7 µm/mm2 vs. 21,014.7 ± 706.5, p = 0.026) and main (7,718.9 ± 273.9 vs. 9,561.4 ± 369.8, p < 0.001) nerve density, as well as lower total (15.5 ± 0.7/frame vs. 20.5 ± 1.3, p = 0.001), main (3.0 ± 0.1 vs. 3.8 ± 0.2, p = 0.001) and branch (12.5 ± 0.7 vs. 16.5 ± 1.2, p = 0.004) nerve numbers. Compared to the evaporative DED group, the aqueous-deficient DED group showed reduced total nerve density (19,969.9 ± 830.7 vs. 15,942.2 ± 1,135.7, p = 0.006), branch nerve density (11,964.9 ± 749.8 vs. 8,765.9 ± 798.5, p = 0.006), total nerves number (16.9 ± 0.8/frame vs. 13.0 ± 1.2, p = 0.002), and branch nerve number (13.8 ± 0.8 vs. 10.2 ± 1.1, p = 0.002). CONCLUSIONS: Patients with DED demonstrate compromised corneal subbasal nerves, which is more pronounced in aqueous-deficient DED. This suggests a role for neurosensory abnormalities in the pathophysiology of DED.

Low-dose naltrexone is effective and well-tolerated for modulating symptoms in patients with neuropathic corneal pain.

PURPOSE: Neuropathic corneal pain (NCP) is caused by damage or disease of the somatosensory nervous system that innervates the cornea and presents with symptoms of pain or persistent unpleasant sensations, such as burning, dryness, or light sensitivity. This retrospective study aims to assess the efficacy and tolerability of low-dose naltrexone (LDN) in refractory NCP patients. METHODS: Fifty-nine NCP patients with a centralized component treated with oral LDN 4.5  mg at bedtime for at least four weeks were identified. Thirty out of 59 patients who had a baseline pain score ≥4 on the visual analogue scale had completed the ocular pain assessment survey (OPAS) and presented persistent pain, despite instillation of topical anesthetic drops, were included. Changes in pain scores, comorbidities, side effects, among others, were analyzed. Change in ocular pain scores (scale 0-10) and quality of life (QoL) scores (scale 0-100%) were the main endpoints. RESULTS: Mean age (years ± SD) was 45.60 ± 19.30 with a white (80.00%) female (73.33%) predominance. Duration of LDN use was 14.87 ± 11.25 months, and the duration of NCP before treatment was 17.53 ± 17.29 months. Eight patients used LDN as a monotherapy, whereas the remaining used it as an adjunct therapy. LDN resulted in a 49.22% decrease in mean pain score from 6.13 ± 1.93 to 3.23 ± 2.60 (p < 0.001). Mean QoL scores by the OPAS were 5.84 ± 2.57 at the first visit and improved to 3.77 ± 2.91 at the last visit (p = 0.023). Common side effects were vivid dreams, headaches, and stomachache. CONCLUSION: LDN was effective and well-tolerated for NCP treatment.

Efficacy and tolerability of nortriptyline in the management of neuropathic corneal pain.

PURPOSE: Neuropathic corneal pain (NCP) is a recently acknowledged disease entity. However, there is no consensus in potential treatment strategies, particularly in patients with a centralized component of pain. This study aims to assess the efficacy and tolerability of the tricyclic antidepressant, nortriptyline, among NCP patients. METHODS: Patients with clinically diagnosed NCP and a centralized component of pain, treated with oral nortriptyline, who had recorded pain scores as assessed by the ocular pain assessment survey at the first and last visit were included. Patients were excluded if they had any other ocular pathology that might result in pain or had less than 4 weeks of nortriptyline use. Demographics, time between visits, concomitant medications, systemic and ocular co-morbidities, duration of NCP, side effects, ocular pain scores, and quality of life (QoL) assessment were recorded. RESULTS: Thirty patients with a mean age of 53.1 ± 18.5 were included. Male to female ratio was 8:22. Mean ocular pain in the past 24 h improved from 5.7 ± 2.1 to 3.6 ± 2.1 after 10.5 ± 9.1 months (p < 0.0001). Twelve patients (40.0%) had equal to or more than 50% improvement, 6 patients (20.0%) had 30-49% improvement, 6 patients (20.0%) had 1-29% improvement, 4 patients (13.3%) did not improve, while 2 patients (6.7%) reported increase in pain levels. Mean QoL improved from 6.0 ± 2.5 to 4.3 ± 2.4 (p = 0.019). Eight patients (26.6%) discontinued treatment due to persistent side effects, despite improvement by 22.4%. CONCLUSION: Nortriptyline was effective in relieving NCP symptoms in patients with centralized component and insufficient response to other systemic and topical therapies who tolerated the drug for at least 4 weeks. Nortriptyline may be used in the management of patients with NCP.

Dry Eye Disease Practice in Ghana: Diagnostic Perspectives, Treatment Modalities, and Challenges.

SIGNIFICANCE: There is a dearth of studies investigating the challenges encountered in dry eye practice. Profiling these barriers is crucial to improving dry eye diagnosis and patient care. PURPOSE: This study aimed to examine the diagnostic and treatment perspectives, and challenges in dry eye practice in Ghana. METHODS: An anonymous paper-based or web survey regarding dry eye practice pattern, practice challenges, and access to diagnostic tools was distributed to 280 potential participants. RESULTS: One hundred thirteen respondents completed the survey. Case history (92.5%), fluorescein tear breakup time (87.5%), and corneal fluorescein staining (72.5%) were the topmost procedures used for dry eye diagnosis. A preserved lubricant drop was the most commonly prescribed treatment of mild, moderate, and severe dry eye at the rates of 77.0, 83.2, and 77.0%, respectively. A few respondents prescribed cyclosporine (2.7%) or punctal plugs (5.3%) across all disease severities, and none used scleral lens, autologous serum tears, or thermal pulsation. Graduate professional training influenced the practice pattern of 82.3% of respondents, whereas continuing professional education influenced less than 1%. Approximately 70.1 and 92.8% of optometrists considered referring dry eye in children and cases that are unresponsive to treatment, respectively. Eighty-eight percent of practitioners indicated they experience a challenge in dry eye practice, with limited access to diagnostic tools (77.9%) and limited availability of effective dry eye medication on the Ghanaian market (50.4%) being the most frequent challenges. More than 85% of respondents had access to a fluorescein dye or slit-lamp biomicroscope; however, none had access to a phenol red thread, lissamine green dye, osmolarity technology, or meibography device. CONCLUSIONS: Practitioners' limited access to diagnostic tools/techniques and the limited effective dry eye treatments are major challenges encountered in dry eye practice in Ghana. Addressing these will improve dry eye practice and treatment outcomes in the country.

A Review of Imaging Biomarkers of the Ocular Surface.

A biomarker is a "characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or responses to an exposure or intervention, including therapeutic interventions." Recently, calls for biomarkers for ocular surface diseases have increased, and advancements in imaging technologies have aided in allowing imaging biomarkers to serve as a potential solution for this need. This review focuses on the state of imaging biomarkers for ocular surface diseases, specifically non-invasive tear break-up time (NIBUT), tear meniscus measurement and corneal epithelial thickness with anterior segment optical coherence tomography (OCT), meibomian gland morphology with infrared meibography and in vivo confocal microscopy (IVCM), ocular redness with grading scales, and cellular corneal immune cells and nerve assessment by IVCM. Extensive literature review was performed for analytical and clinical validation that currently exists for potential imaging biomarkers. Our summary suggests that the reported analytical and clinical validation state for potential imaging biomarkers is broad, with some having good to excellent intra- and intergrader agreement to date. Examples of these include NIBUT for dry eye disease, ocular redness grading scales, and detection of corneal immune cells by IVCM for grading and monitoring inflammation. Further examples are nerve assessment by IVCM for monitoring severity of diabetes mellitus and neurotrophic keratitis, and corneal epithelial thickness assessment with anterior segment OCT for the diagnosis of early keratoconus. However, additional analytical validation for these biomarkers is required before clinical application as a biomarker.

Effect of the Bruder moist heat eye compress on contact lens discomfort in contact lens wearers: An open-label randomized clinical trial.

The purpose of this study was to investigate the effect of the Bruder Moist Heat Compress on contact lens (CL) discomfort in subjects with contact lens-related dry eye (CLDE). This was a 4-week, single-center, three-arm, randomized, open-label clinical trial in subjects diagnosed with CLDE using the Contact Lens Dry Eye Questionnaire. Fifty-one CL wearers were randomized to one of three treatment groups: application of the Bruder Compress twice a day, Bruder Compress once a day, or warm washcloth used for ten minutes twice a day without reheating. Subject diaries were monitored for compliance and collected data on daily CL comfort upon awakening and throughout the afternoon. Clinical assessments included tear film break-up time (TBUT), lipid layer thickness (LLT), and meibomian gland evaluation. Statistical tests included a generalized linear model and one-way analysis of variance (ANOVA) to investigate treatment effect on comfortable wear time. Fifty-one subjects (98% female) completed the study. After treatment, subjects using a washcloth reported more uncomfortable contact lens wear time on average (mean = 5.1 ± 2.8 h) when compared with subjects who had used the Bruder Compress in Group 1 (mean = 2.8 ± 1.6 h) (p = 0.02). In the Bruder Compress groups, there was a significant reduction in the blockage of meibomian glands (p < 0.01). No significant difference in uncomfortable wear time was found between subjects using the Bruder Compress twice daily versus once daily (p = 0.48). Subjects using the Bruder Compress once daily had the highest rate of compliance at 90.2% (p < 0.01). No significant improvements were observed in TBUT (p = 0.76) or LLT (p = 0.78). The Bruder Moist Heat Compress resulted in a significant improvement in comfortable CL wear time in subjects with CLDE.

A Randomized Trial to Evaluate the Effect of Toric Versus Spherical Contact Lenses on Vision and Eyestrain.

OBJECTIVES: To compare the effect of toric versus spherical soft contact lenses on objective measures of visual performance using visual acuity and electromyography of the orbicularis oculi muscle. METHODS: Current soft contact lens wearers with -0.75 to -1.75 D astigmatism in each eye were binocularly fitted with toric (1-Day ACUVUE MOIST for astigmatism) and spherical (1-Day ACUVUE MOIST) contact lenses in random order. After each fitting and at 1-week follow-up, high- and low-contrast visual acuities were measured. Electromyography was used to objectively evaluate eyestrain. Linear mixed models were used to assess differences between toric and spherical contact lenses. RESULTS: The mean age (±SD) of the 60 participants was 27.5±5.0 years, spherical refractive error was -3.68±2.01 D, and cylinder was -1.28±0.36 D. High- and low-contrast visual acuities with toric lenses were better than with spherical lenses at both fitting (toric high-contrast: -0.065±0.078 and low-contrast: 0.133±0.103 vs. spherical high-contrast: 0.001±0.104 and low-contrast: 0.224±0.107) and follow-up (toric high-contrast: -0.083±0.087 and low-contrast: 0.108±0.107 vs. spherical high-contrast: -0.015±0.095 and low-contrast: 0.211±0.104) (all P<0.0001). Electromyography-measured eyestrain was less with toric versus spherical contact lenses at fitting (least-square ratio of toric over spherical=0.72; P=0.0019) but not at follow-up (ratio=0.86; P=0.11). CONCLUSION: These results suggest that toric contact lenses provided improved objective measures of vision in a low-to-moderate astigmatic population.

Efficacy of Toric Contact Lenses in Fitting and Patient-Reported Outcomes in Contact Lens Wearers.

OBJECTIVES: To assess whether patient-reported measures are improved with soft toric contact lenses (TCLs) compared with soft spherical contact lenses (SCLs) and whether clinical time needed to fit TCL is greater than SCL. METHODS: Habitual contact lens wearers with vertexed spherical refraction +4.00 to +0.25 D or -0.50 to -9.00 D and cylinder -0.75 to -1.75 DC were randomly assigned to be binocularly fitted into a TCL or SCL, and masked to treatment assignment. Time to successful fit was recorded. After 5 days, the National Eye Institute Refractive Error Quality of Life Instrument (NEI-RQL-42) and modified Convergence Insufficiency Symptom Survey (CISS) were completed. After washout, subjects were fit into the alternative lens design (TCL or SCL). Outcomes were evaluated using linear mixed models for the time to fit and CISS score, generalized linear model for the successful fit, and Wilcoxon tests for the NEI-RQL-42. RESULTS: Sixty subjects (71.7% women, mean age [±SD] = 27.5±5.0 years) completed the study. The mean time to fit the TCL was 10.2±4.3 and 9.0±6.5 min for the SCL (least square [LS] mean difference (TCL-SCL)=1.2, P=0.22). Toric contact lens scored better than SCL in global NEI-RQL-42 score (P=0.006) and the clarity of vision (P=0.006) and satisfaction with correction subscales (P=0.006). CISS showed a 15% reduction in symptoms (LS mean difference [TCL-SCL]=-2.20, P=0.02). CONCLUSION: TCLs are a good option when trying to improve the vision of patients with low-to-moderate astigmatism given the subjective improvements in outcomes.

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.

Eyelid Margin and Meibomian Gland Characteristics and Symptoms in Lens Wearers.

PURPOSE: To describe the lid margin characteristics of contact lens wearers and relate them to comfort during lens wear. METHODS: Three study sites enrolled habitual contact lens wearers. Subjects completed the Comfort domain of the Contact Lens User Experience (CLUE) questionnaire, and each eye was graded for the presence of mucocutaneous junction (MCJ) displacement, lid margin irregularity, and lid margin vascularity. Examiners counted the number of meibomian gland (MG) orifices in the central centimeter of the lower eyelid and the number of those that showed pouting/plugging and vascular invasion. MG expressibility was graded according to the Shimazaki schema. Subjects were grouped based on presence/absence of each characteristic, total number of orifices (≥5 vs. <5), and expressibility (grade 0 vs. >0). Descriptive statistics are reported. A linear model was used to assess the fixed effect of each characteristic on combined CLUE score and each CLUE statement, if the effect on combined CLUE score showed p < 0.10. RESULTS: The study included 203 subjects (67.5% female) with mean age (±SD) of 30.3 ± 9.6 years. The most commonly observed characteristics were orifice pouting/plugging, compromised MG expressibility, and lid margin vascularity (35.0, 30.3, and 20.4%, respectively). MCJ displacement and MG expressibility had an effect on the combined CLUE score such that individual CLUE statements were analyzed (p = 0.01 and p = 0.06, respectively). MCJ displacement had an effect on comfort upon insertion (p = 0.01), comfort after 5 minutes (p = 0.03), end-of-day comfort (p = 0.01), and ability to maintain ocular moisture (p = 0.030). MG expressibility had a significant effect on general comfort (p = 0.01), comfort throughout the day (p = 0.02), and the ability to maintain ocular moisture (p = 0.02). CONCLUSIONS: MCJ displacement and MG expressibility have an effect on contact lens comfort.

Association Between Meibomian Gland Testing and Ocular Surface Sensitivity.

PURPOSE: To assess whether corneal sensitivity is associated with clinical tests assessing the tear film and meibomian glands. METHODS: Subjects were recruited based on the history of contact lens wear and the extent of meibomian gland dropout. Clinical examination included assessment of symptoms, redness of the lower eyelid margin, lipid layer thickness, esthesiometry of the inferior cornea and palpebral conjunctiva, noninvasive tear breakup time, Schirmer test assessment, and meibomian gland assessment through orifice count and expressed meibum quality grade. Subjects were grouped into a high corneal sensitivity (HS) group or low corneal sensitivity (LS) group, based on the median sensitivity measure. Groups for palpebral conjunctival sensitivity were created in the same manner. Mann-Whitney U tests were used for comparisons of sensitivity groups, and a Spearman rho correlation coefficient was used to study the associations between each tear film characteristic and the sensitivities. RESULTS: Fifty-seven subjects with an average age of 34.7 years (SD = 15.1) were included in the analysis, of which 63.2% were female. The median corneal and conjunctival thresholds for sensation were 0.5 and 1.4 g/mm, respectively. The average noninvasive tear breakup time [HS: 7.8 seconds [interquartile range (IQR) = 5.7]; LS: 11.6 seconds (IQR = 8.4); P = 0.05] and Schirmer test assessments [HS: 16.0 mm (IQR = 15.0); LS: 25.0 mm (IQR = 19.0); P = 0.04] were significantly different between the palpebral conjunctival HS and LS groups. All other group comparisons and correlations were not statistically significant. CONCLUSIONS: The palpebral conjunctival sensitivity may be more critical than the corneal sensitivity when assessing dry eye.

Agreement between Automated and Traditional Measures of Tear Film Breakup.

PURPOSE: To determine the repeatability and agreement between the noninvasive Keratograph tear break-up time (NIK-BUT) as measured by the Oculus Keratograph 4 and fluorescein tear break-up time (FBUT). METHODS: Sixty subjects were recruited for two study visits separated by 7 (± 2) days. At each visit, three NIK-BUT measures and FBUT measures were obtained. Each NIK-BUT measure from the Keratograph included a first and an average NIK-BUT. The means of the measures obtained, first NIK-BUT, and average NIK-BUT and FBUT were calculated for each visit. Between- and within-visit agreement was assessed using intraclass correlation coefficients (ICCs) and Bland-Altman 95% limits of agreement (LoA) analyses of log-transformed data. RESULTS: Between-visit ICCs were 0.53 [95% confidence interval (CI), 0.32 to 0.69] for first NIK-BUT, 0.59 (95% CI, 0.40 to 0.73) for average NIK-BUT, and 0.66 (95% CI, 0.49 to 0.78) for FBUT, whereas 95% LoA were -0.65 to 0.67, -0.44 to 0.48, and -1.14 to 1.10 [back transformed: (visit 1 + 0.01)/(visit 2 + 0.01) = 0.22 to 4.68, 0.36 to 3.02, and 0.07 to 12.59] for the aforementioned methods, respectively. The visit 1 within-visit ICC between first NIK-BUT and FBUT was 0.44 (95% CI, 0.21 to 0.62), whereas the 95% LoA was -0.84 to 1.18 [back transformed: (first NIK-BUT + 0.01)/(FBUT + 0.01) = 0.14 to 15.14]. Likewise, the visit 1 within-visit ICC between average NIK-BUT and FBUT was 0.41 (95% CI, 0.18 to 0.60), whereas the 95% LoA was -0.58 to 1.44 [back transformed: (average NIK-BUT + 0.01)/(FBUT + 0.01) = 0.26 to 27.54]. CONCLUSIONS: The 95% LoA suggest that the average NIK-BUT has better between-visit agreement compared with the first NIK-BUT or FBUT. The first NIK-BUT showed better within-visit agreement with the FBUT than the average NIK-BUT. In addition, there is better between- and within-visit agreement for all measures at lower values.

The neurobiology of the meibomian glands.

This article compiles research regarding the neuroanatomy of the meibomian glands and their associated blood vessels. After a review of meibomian gland morphology and regulation via hormones, a case for innervation is made based on anatomical findings whereby the nerves lack a myelin sheath and Schwann cells. The localization and co-localization of dopamine beta-hydroxylase, tyrosine hydroxylase, neuropeptide Y, vasoactive intestinal polypeptide, calcitonin gene-related peptide, and substance P are explored with emphasis on differences that exist between species. The presence of the various neuropeptides/neurotransmitters adjacent to the meibomian gland versus the vasculature associated with the meibomian gland is documented so that conclusions can be made with regard to direct and indirect effects. Research regarding the presence of receptors and receptor proteins for these neuropeptides is documented. Evidence supporting the influence of certain neurotransmitters and/or neuropeptides on the meibomian gland is given based on research that correlates changes in meibomian gland morphology and/or tear film with changes in neurotransmitter and/or neuropeptide presence. Conclusions are drawn related to direct and indirect regulation and differences between the various nervous systems.