Identification of presumed corneal neuromas and microneuromas using laser-scanning in vivo confocal microscopy: a systematic review.

BACKGROUND/AIMS: This systematic review critically evaluated peer-reviewed publications describing morphological features consistent with, or using terms related to, a 'neuroma' or 'microneuroma' in the human cornea using laser-scanning in vivo confocal microscopy (IVCM). METHODS: The review was prospectively registered on PROSPERO (CRD42020160038). Comprehensive literature searches were performed in Ovid MEDLINE, Ovid Embase and the Cochrane Library in November 2019. The review included primary research studies and reviews that described laser-scanning IVCM for examining human corneal nerves. Papers had to include at least one of a pre-specified set of keyword stems, broadly related to neuromas and microneuromas, to describe a corneal nerve feature. RESULTS: Twenty-five papers (20 original studies; 5 reviews) were eligible. Three original studies evaluated corneal nerve features in healthy eyes. Most papers assessed corneal nerves in ocular and systemic conditions; seven studies did not include a control/comparator group. There was overlap in terminology used to describe nerve features in healthy and diseased corneas (eg, bulb-like/bulbous, penetration, end/s/ing). Inspection of IVCM images within the papers revealed that features termed 'neuromas' and 'microneuromas' could potentially be physiological corneal stromal-epithelial nerve penetration sites. We identified inconsistent definitions for terms, and limitations in IVCM image acquisition, sampling and/or reporting that may introduce bias and lead to inaccurate representation of physiological nerve characteristics as pathological. CONCLUSION: These findings identify a need for consistent nomenclature and definitions, and rigorous IVCM scanning and analysis protocols to clarify the prevalence of physiological, as opposed to pathological, corneal nerve features.

Tear film inflammatory cytokine upregulation in contact lens discomfort.

PURPOSE: To investigate the ocular inflammatory response, using clinical and immunological techniques, in people experiencing contact lens (CL) discomfort. METHODS: This study involved 38 adults who were full-time, silicone-hydrogel CL wearers. Participants were categorized into groups based upon a validated CL dry-eye questionnaire (CLDEQ-8) (n = 17 'asymptomatic', CLDEQ-8 score <9; n = 21 'symptomatic', CLDEQ-8 score ≥13). Examinations were performed at two visits (one with, and one without, CL wear), separated by one-week. Testing included: tear osmolarity, ocular redness, tear stability, ocular surface staining, meibography, tear production and tear collection. Tear osmolarity was taken from the inferior-lateral and superior-lateral menisci. The 'Inferior-Superior Osmotic Difference', I-SOD, was the absolute osmolarity difference between these menisci. Concentrations of seven cytokines (IL-2, IL-4, IL-6, IL-10, IL-17A, IFN-gamma, TNF-alpha) were assayed from basal tears using multiplex cytometric bead array. RESULTS: At baseline, there was no significant difference in key clinical signs between asymptomatic and symptomatic CL wearers (p > 0.05). The I-SOD was greater in symptomatic than asymptomatic CL wearers (23.1 ±â€¯2.6 versus 11.3 ±â€¯1.4 mOsmol/L, p = 0.001). People experiencing CL discomfort had higher tear IL-17A (122.6 ±â€¯23.7 versus 44.0 ±â€¯10.0 pg/mL, p = 0.02) and reduced tear stability (6.3 ±â€¯1.1 versus 10.4 ±â€¯1.6 s, p = 0.03) after several hours of CL wear. Tear IL-17A levels correlated with both the I-SOD (r = 0.43, p = 0.01) and CLDEQ-8 score (r = 0.40, p = 0.01). CONCLUSIONS: CL discomfort occurs in individuals having no clinical dry eye signs, and is associated with higher tear levels of the pro-inflammatory cytokine IL-17A. These findings support an association between the discomfort response and low-grade, ocular surface inflammation.

Oral Omega-3 Supplementation Lowers Intraocular Pressure in Normotensive Adults.

PURPOSE: Elevated intraocular pressure (IOP) is the major modifiable risk factor for the sight-threatening eye disease, glaucoma. We investigated whether oral omega-3 supplements affect IOP in normotensive adults. METHODS: We undertook a pooled analysis of data from two double-masked, placebo-controlled randomized trials (Australian New Zealand Clinical Trials Registry, ACTRN12614001019695, ACTRN12615000173594) that investigated the efficacy and safety of oral omega-3 supplementation for treating ocular surface inflammation. Recruitment involved adults (n = 105) with IOP <21 mm Hg, and without a current or prior glaucoma diagnosis. Participants were randomly allocated to either an oral omega-3 (∼1000 mg/day eicosapentaenoic acid + ∼500 mg/day docosahexaenoic acid ± 900 mg/day α-linolenic acid) or placebo (olive oil, 1500 mg/day) supplement. IOP was quantified at baseline and after 3 months of supplementation (day 90). Change in IOP, relative to baseline, was compared between groups. RESULTS: At baseline, participants were of similar age (omega-3/placebo groups: mean ± SEM, 33.7 ± 1.7, n = 72/35.6 ± 3.0 years, n = 33), sex (65%/79% female), and had similar IOP (14.3 ± 0.3/13.8 ± 0.5 mm Hg). At day 90, IOP was reduced to 13.6 ± 0.3 mm Hg in the omega-3 group; controls had a slight IOP increase to 14.2 ± 0.4 mm Hg (P < 0.05). CONCLUSIONS: Oral omega-3 supplementation for 3 months significantly reduced IOP in normotensive adults. To our knowledge, this is the first study to report that omega-3 fatty acids lower IOP in humans. TRANSLATIONAL RELEVANCE: These findings justify further investigation into the therapeutic potential of omega-3 supplementation for reducing IOP, to prevent and/or treat conditions with IOP elevation, including ocular hypertension and glaucoma.

Laser scanning in vivo confocal microscopy (IVCM) for evaluating human corneal sub-basal nerve plexus parameters: protocol for a systematic review.

INTRODUCTION: Laser scanning in vivo confocal microscopy (IVCM) enables non-invasive, high-resolution imaging of the cornea. In recent years, there has been a vast increase in researchers using laser scanning IVCM to image and quantify corneal nerve parameters. However, a range of methodological approaches have been adopted. The primary aim of this systematic review is to critically appraise the reported method(s) of primary research studies that have used laser scanning IVCM to quantify corneal sub-basal nerve plexus (SBNP) parameters in humans, and to examine corneal nerve parameters in healthy individuals. METHODS AND ANALYSIS: A systematic review of primary studies that have used laser scanning IVCM to quantify SBNP parameters in humans will be conducted. Comprehensive electronic searches will be performed in Ovid MedLine, Embase and the Cochrane Library. Two reviewers will independently assess titles and abstracts, and exclude studies not meeting the inclusion criteria. For studies judged eligible or potentially eligible, full texts will be independently assessed by two reviewers to determine eligibility. A third reviewer will resolve any discrepancies in judgement. Risk of bias will be assessed using a custom tool, covering five methodological domains: participant selection, method of image capture, method of image analysis, data reporting and other sources of bias. A systematic narrative synthesis of findings will be provided. A multilevel random-effects meta-analysis will be performed for corneal nerve parameters derived from healthy participants. This review will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. ETHICS AND DISSEMINATION: As this review considers published data, ethical approval is not required. We foresee that this synthesis will serve as a reference for future studies, and can be used to inform best practice standards for using IVCM in clinical research. A manuscript reporting the results of the review will be published and may also be presented at scientific conferences.

Optical Coherence Tomography Reveals Changes to Corneal Reflectivity and Thickness in Individuals with Tear Hyperosmolarity.

PURPOSE: To investigate whether tear hyperosmolarity, a feature of dry eye disease (DED), affects central corneal thickness (CCT), corneal light reflectivity, and/or tear film reflectivity. METHODS: This prospective, cross-sectional study involved 48 participants (38 with hyperosmolar tears and 10 controls with normo-osmolar tears). Symptoms and signs of DED (tear osmolarity, sodium fluorescein tear break-up time, ocular surface staining, Schirmer test) were assessed. CCT, and the reflectivity of the cornea and the tear-epithelial interface were quantified relative to background noise using Fourier-domain optical coherence tomography (FD-OCT). RESULTS: CCT of eyes with severe tear hyperosmolarity, defined as eyes in the upper quartile of the hyperosmolar group, was less than control eyes (539.1 ± 7.4 vs. 583.1 ± 15.0 µm, P = 0.02) and eyes with less severe tear hyperosmolarity, defined as hyperosmolar eyes in the lower quartile (622.7 ± 5.8 µm, P < 0.0001). CCT showed a negative linear relationship with tear osmolarity for values above 316 mOsmol/L (R2 = 0.17, P = 0.01). Central corneal reflectivity was lower in hyperosmolar eyes than normo-osmolar eyes (45.1 ± 0.3 vs. 48.1 ± 0.6 pixels, P = 0.02); the greatest relative difference was in the anterior stroma, where corneal reflectivity was 4.7 ± 1.9% less in hyperosmolar eyes (P < 0.01). Peak reflectivity of the tear-epithelial interface was 4.8% ± 3.5% higher in the hyperosmolar group than the normo-osmolar tear group (P = 0.04). CONCLUSION: Individuals with significant tear hyperosmolarity and clinical signs of symptoms of DED show reduced CCT and altered corneal reflectivity. TRANSLATIONAL RELEVANCE: Anterior segment FD-OCT provides novel insight into corneal microstructural differences in individuals with DED.

Tear Interferon-Gamma as a Biomarker for Evaporative Dry Eye Disease.

Purpose: To assess whether tear hyperosmolarity, being diagnostic of dry eye disease (DED), is associated with specific alterations to the cytokine content of human tears that may provide a biomarker for DED. Methods: In this prospective, cross-sectional, clinical study, participants (n = 77) were recruited from a single clinical site and categorized into groups based upon tear osmolarity status (n = 62 hyperosmolar, n = 15 normo-osmolar). Comprehensive anterior eye clinical assessments were undertaken. Concentrations of seven cytokines (IL-2, IL-4, IL-6, IL-10, IL-17A, IFN-γ, and TNF-α) in basal tears were assayed using multiplex cytometric bead array. The main outcome measure was difference in cytokine concentration between groups. Group comparisons were undertaken using 2-tailed t-tests. Cohen's effect size was calculated for each finding. Spearman correlations between cytokine concentrations, clinical symptoms, and clinical parameters of DED were calculated. Results: Tear hyperosmolarity was specifically associated with increased tear IFN-γ levels (13.3 ± 2.0 vs. 4.4 ± 1.4 pg/mL, P = 0.03). Cohen's effect size was large (0.8) for changes to tear IFN-γ levels. Significant correlations were observed between IFN-γ concentration and each of: tear osmolarity (r = 0.34; P = 0.007), total ocular surface staining (r = 0.56, P < 0.0001), and Schirmer test score (r = -0.33, P = 0.003). Conclusions: Tear hyperosmolarity is specifically associated with higher levels of the proinflammatory cytokine IFN-γ, which correlate with key clinical parameters of DED. The calculated effect size (0.8) suggests that this assay has diagnostic power as a biomarker for evaporative DED.

Automated Tear Film Surface Quality Breakup Time as a Novel Clinical Marker for Tear Hyperosmolarity in Dry Eye Disease.

PURPOSE: To assess the diagnostic performance of a novel, automated, noninvasive measure of tear film stability derived from Placido disc videokeratography, the tear film surface quality breakup time (TFSQ-BUT), as a clinical marker for diagnosing dry eye disease (DED) relative to a standard of tear hyperosmolarity. METHODS: This prospective, cross-sectional study involved 45 participants (28 DED, 17 controls). Symptoms (Ocular Surface Disease Index) and signs (tear osmolarity, TFSQ-BUT, tear breakup time measured with sodium fluorescein [NaFl-BUT], ocular surface staining and Schirmer test with topical anesthesia) of DED were assessed. Three measures of TFSQ-BUT and NaFl-BUT were taken per eye; "first," "average," and "shortest" BUT were analyzed separately. Optimal diagnostic cutoff values were determined using the Youden Index. The repeatability and agreement of the TFSQ-BUT was compared with two clinicians who manually assessed noninvasive BUT (CNI-BUT). Repeatability of methods was assessed using the geometric coefficient of variation (gCoV, %). Agreement between methods was considered with Bland-Altman analysis. RESULTS: Eyes with DED had significantly shorter TFSQ-BUTs than controls (P < 0.05). There was a significant, moderate correlation between both shortest and average TFSQ-BUT and NaFl-BUT (r = 0.35, P = 0.02 and r = 0.38, P = 0.01, respectively). The receiver-operator characteristic (ROC) curve for shortest TFSQ-BUT showed an area under the curve of 0.92 (P < 0.0001). Shortest TFSQ-BUT with a criterion of 12.1 seconds had a sensitivity of 82% and specificity of 94% for diagnosing DED against tear hyperosmolarity. Automated TFSQ-BUT showed less variability (gCoV = 9.4%, 95% confidence interval [CI]: 7.1%-14.0%) than CNI-BUT (gCoV = 27.0%, 95% CI: 19.62%-41.06%, P < 0.05). CONCLUSIONS: Automated TFSQ-BUT is a repeatable, noninvasive clinical marker with both high sensitivity and specificity for tear hyperosmolarity.

The self-reported clinical practice behaviors of Australian optometrists as related to smoking, diet and nutritional supplementation.

OBJECTIVE: The primary aim of this study was to examine the self-reported, routine clinical practice behaviors of Australian optometrists with respect to advice regarding smoking, diet and nutritional supplementation. The study also sought to assess the potential influence of practitioner age, gender, practice location (major city versus regional), therapeutic-endorsement status and personal nutritional supplementation habits upon management practices in these areas. METHODS: A survey was electronically distributed to Australian optometrists (n = 4,242). Respondents anonymously provided information about their personal demographics and lifestyle behaviors (i.e., age, gender, practice location, therapeutic-endorsement status, smoking status, nutritional supplement intake) and routine patient management practices with respect to advice across three domains: smoking, diet and nutritional supplementation. Multivariate logistic regression analyses were performed to assess for potential effects of the listed factors on practitioner behavior. RESULTS: A total of 283 completed surveys were received (completed survey response rate: 6.7%). Fewer than half of respondents indicated routinely asking their patients about smoking status. Younger practitioners were significantly (p < 0.05) less likely to enquire about patients' smoking behaviors, but this did not extend to counseling for smoking cessation. Almost two-thirds of respondents indicated routinely counseling patients about diet. About half of practitioners specified routinely asking their patients about nutritional supplement intake; this form of questioning was significantly more likely if the respondent was female (p < 0.05). Practitioners who recommended nutritional supplements most commonly did so for age-related macular degeneration (91.2%) and dry eye disease (63.9%). The primary source of evidence used to guide practitioners' nutrition-related patient management was reported to be peer-reviewed publications. CONCLUSIONS: These findings demonstrate that there are no clear predictors of practitioner behavior across the three domains. Overall, this study suggests that there is scope for Australian optometrists to improve their routine engagement by questioning patients, as well as providing evidence-based clinical advice, about smoking status, diet and nutritional supplement behaviors, being key modifiable lifestyle risk factors with long-term implications for eye health.

Monitoring of strain-dependent responsiveness to TLR activation in the mouse anterior segment using SD-OCT.

PURPOSE: To determine whether spectral-domain optical coherence tomography (SD-OCT) can be used to longitudinally monitor inflammation in the mouse anterior segment and to identify any strain-dependent differences in responsiveness to distinct toll-like receptor (TLR) ligands. METHODS: Corneal inflammation was induced in BALB/c and C57BL/6 mice following central corneal abrasions and topical application of saline, TLR-4 ligand, lipopolysaccharide (LPS), or TLR-9 ligand, CpG-oligodeoxynucleotide (CpG-ODN; CpG). Anterior-segment images were captured using SD-OCT at baseline, 24 hours, and 1 week post treatment. Corneal thickness, stromal haze, and the number of keratic precipitates (KP) and anterior chamber (AC) cells were longitudinally compared to determine differences between mouse strains, time points, and TLR activation. RESULTS: In both mouse strains, treatment with CpG, but not saline or LPS, resulted in a similar number of KPs and AC cells. In C57BL/6 mice, central corneal thickness (CCT) increased in CpG- and LPS-treated eyes at 24 hours, which normalized by 1 week. In BALB/c mice, a significant increase in CCT occurred in eyes treated with CpG at 1 week. Stromal haze peaked in C57BL/6 eyes treated with LPS- or CPG-treatment at 24 hours; however, BALB/c eyes showed persistent and marked increases in corneal haze compared with baseline at 1 week post treatment. CONCLUSIONS: Spectral-domain OCT enables high-resolution, longitudinal, in vivo imaging of anterior segment inflammation in mice and revealed novel strain- and time-dependent differences in response to distinct TLR activation in the cornea.

Nutrition and age-related macular degeneration: research evidence in practice.

Age-related macular degeneration (AMD) is the leading cause of irreversible visual impairment in developed countries. In the absence of effective treatments to slow AMD progression, it is predicted that the prevalence of AMD will double over the next 20 years. One area of significant interest is the potential role that nutrition may play in preventing and/or delaying the progression of AMD. Specifically, is there any benefit in oral antioxidant and/or mineral supplementation? This review critically evaluates the currently available evidence relating to nutrition and AMD, with particular reference to the key findings of two large National Eye Institute-sponsored clinical studies, namely, the Age-Related Eye Disease Study (AREDS) and AREDS2. Topical controversies relating to nutrition and AMD are considered and analyzed in the context of the published literature to guide practitioners through assessing the merit, or otherwise, of common claims. This article provides a foundation for clinicians to provide informed advice to AMD patients based on available research evidence.