NLRP3 Inflammasome as a Potential Therapeutic Target in Dry Eye Disease.

Dry eye disease (DED) is a multifactorial ocular surface disorder arising from numerous interrelated underlying pathologies that trigger a self-perpetuating cycle of instability, hyperosmolarity, and ocular surface damage. Associated ocular discomfort and visual disturbance contribute negatively to quality of life. Ocular surface inflammation has been increasingly recognised as playing a key role in the pathophysiology of chronic DED. Current readily available anti-inflammatory agents successfully relieve symptoms, but often without addressing the underlying pathophysiological mechanism. The NOD-like receptor protein-3 (NLRP3) inflammasome pathway has recently been implicated as a key driver of ocular surface inflammation, as reported in pre-clinical and clinical studies of DED. This review discusses the intimate relationship between DED and inflammation, highlights the involvement of the inflammasome in the development of DED, describes existing anti-inflammatory therapies and their limitations, and evaluates the potential of the inflammasome in the context of the existing anti-inflammatory therapeutic landscape as a therapeutic target for effective treatment of the disease.

Quantifying corneal immune cells from human in vivo confocal microscopy images: Can manual quantification be improved with observer training?

Manually quantifying immune cells (ICs), commonly considered dendritic cells, in the corneal epithelium from in vivo confocal microscopy (IVCM) images can be influenced by observer bias. This study sought to evaluate the repeatability of manual IC quantification. Cell counts were first performed for 184 non-overlapping IVCM images by a single observer. Quantifications were undertaken to establish the total cell numbers per image, and the numbers of three cell morphological subtypes: mature ICs (with elongated dendrites), immature ICs (with short- or non-discernible dendrites) and globular cells (with large bodies and no visible dendrites). Cell counts were then repeated by the same observer, and independently undertaken by a second observer. Prior to these counts, both observers undertook an agreement 'training' process to define IC appearance and delineate the morphological subtypes. Total IC counts demonstrated excellent intra- and inter-observer reliability (intraclass correlation coefficients (ICC) > 0.90). Bland-Altman plots showed that interobserver measurement bias increased as a function of the total IC number in the image prior to consensus training. For total IC counts after the observer training process, there was no significant interobserver measurement bias. For IC morphological subtypes, there was a positive relationship between the mean inter-observer difference and average cell count for mature ICs and globular cells, but not immature ICs. In conclusion, higher variability in manual corneal IC counts exists when more cells are present in an IVCM image. Implementing an observer training process reduced inter-observer variability and minimised systematic measurement error.

Ocular Demodex: a systematic review of the clinical literature.

PURPOSE: There is increasing clinical and research interest in the potential contribution of Demodex to ocular surface disease. The aim of this systematic review was to summarise and synthesise current clinical evidence relating to the aetiology, diagnosis and treatment of ocular Demodex. RECENT FINDINGS: A comprehensive literature search was performed in OVID Medline, OVID Embase, and clinical trial registries, for studies published between 1990 and August 2019, examining Demodex on the ocular surface. The review included primary clinical research studies and systematic reviews of primary clinical research studies, where Demodex was considered in the context of the ocular surface and/or adnexa. Studies were categorised using the National Health and Medical Research Council evidence hierarchy. Risk of bias assessment was performed using validated tools for studies categorised as providing Level I or II evidence. A total of 87 studies were eligible for inclusion, including two systematic reviews. Most studies (60%) were observational, describing the prevalence of ocular Demodex in different clinical populations. There was a high degree of variability in the epidemiological data derived from cross-sectional aetiology studies. There was mostly consistent evidence to support an association between ocular Demodex and chronic blepharitis. Seven diagnostic test-accuracy studies were identified, which considered a range of techniques, including slit lamp examination for cylindrical eyelash collarettes and/or eyelash manipulation techniques, light microscopic evaluation of epilated eyelashes and in vivo confocal microscopy. There is currently no accepted gold-standard diagnostic method for ocular Demodex. For intervention studies, there was one systematic review, 11 published randomised trials, six trial registry entries, and nine case series. Despite a number of recent trials, the appropriate treatment regimen for ocular Demodex (including the optimal criteria and timing of an intervention) is not clearly established. CONCLUSIONS: This comprehensive narrative synthesis has captured the landscape of clinical evidence relating to the prevalence, aetiology, diagnosis and treatment of ocular Demodex. There remain opportunities to enhance understanding of its role in ocular surface disease, best diagnostic approaches and optimal treatment protocols.

Randomized Trial of Desktop Humidifier for Dry Eye Relief in Computer Users.

SIGNIFICANCE: Dry eye is a frequently reported problem among computer users. Low relative humidity environments are recognized to exacerbate signs and symptoms of dry eye, yet are common in offices of computer operators. Desktop USB-powered humidifiers are available commercially, but their efficacy for dry eye relief has not been established. PURPOSE: This study aims to evaluate the potential for a desktop USB-powered humidifier to improve tear-film parameters, ocular surface characteristics, and subjective comfort of computer users. METHODS: Forty-four computer users were enrolled in a prospective, masked, randomized crossover study. On separate days, participants were randomized to 1 hour of continuous computer use, with and without exposure to a desktop humidifier. Lipid-layer grade, noninvasive tear-film breakup time, and tear meniscus height were measured before and after computer use. Following the 1-hour period, participants reported whether ocular comfort was greater, equal, or lesser than that at baseline. RESULTS: The desktop humidifier effected a relative difference in humidity between the two environments of +5.4 ± 5.0% (P < .001). Participants demonstrated no significant differences in lipid-layer grade and tear meniscus height between the two environments (all P > .05). However, a relative increase in the median noninvasive tear-film breakup time of +4.0 seconds was observed in the humidified environment (P < .001), which was associated with a higher proportion of subjects reporting greater comfort relative to baseline (36% vs. 5%, P < .001). CONCLUSIONS: Even with a modest increase in relative humidity locally, the desktop humidifier shows potential to improve tear-film stability and subjective comfort during computer use.Trial registration no: ACTRN12617000326392.

A comparison of the self-reported dry eye practices of New Zealand optometrists and ophthalmologists.

PURPOSE: The aim of this cross-sectional survey was to evaluate the self-reported clinical practices of New Zealand optometrists and ophthalmologists with respect to the diagnosis and management of dry eye disease. It also sought to compare these behaviours with the current research evidence base. METHODS: An anonymous survey was distributed electronically to New Zealand eye care clinicians (optometrists n = 614, ophthalmologists n = 113) to determine practitioner interest in dry eye disease, practice experience, practice modality, preferred diagnostic and management strategies, and information used to guide patient care. RESULTS: Respondents from both professions (response rates, optometrists: 26%, ophthalmologists: 26%) demonstrated similarly strong knowledge of tear film assessment. Ninety percent of respondents ranked patient symptoms and meibomian gland evaluation as the most valuable and common diagnostic approaches. Conversely, standardised grading scales and validated dry eye questionnaires were infrequently adopted. Both professions tailored dry eye management according to severity, indicating eyelid hygiene and non-preserved lubricants as mainstay therapies. Ophthalmologists prescribed systemic tetracyclines significantly more often than optometrists for moderate (48% vs 11%) and severe (72% vs 32%) dry eye (p < 0.05). Continuing education conferences were acknowledged as the primary information source used to guide dry eye management practices by both professions. CONCLUSIONS: Consistent with evidence-based guidelines, New Zealand eye care professionals combine subjective and objective techniques to diagnose and stratify dry eye management according to disease severity. There is potential to improve dissemination of research evidence into clinical practice, with continuing education via professional conferences the favoured mode of delivery.

Ocular surface microbiome in meibomian gland dysfunction.

BACKGROUND: To investigate the ocular microbiome in meibomian gland dysfunction in Auckland, New Zealand. DESIGN: Prospective, cross-sectional, observational, university-based study. PARTICIPANTS: Participants resident in New Zealand for ≥2 years (n = 157) were classified as normal (n = 66), mild (n = 41) or moderate-to-severe meibomian gland dysfunction (n = 50). Contact lens wear and anterior blepharitis status were recorded, as well as symptoms and clinical features. METHODS: Bacteria collected from lid margin swabs, before and after gland expression, were isolated and identified by conventional microbiological culture techniques. Aerobic isolates were identified in all 157 participants, and both aerobic and anaerobic bacteria isolated in a subset of 87 subjects. MAIN OUTCOME MEASURES: Bacterial incidence according to meibomian gland dysfunction status RESULTS: Symptoms, bulbar hyperaemia, conjunctival staining, lipid layer grade and tear film stability, but not corneal staining, showed moderate association with meibomian gland dysfunction severity. Participants with and without meibomian gland dysfunction showed a similar microbiome, unaffected by gland expression. Anterior blepharitis, a common co-morbidity, was not an independent predictor of the microbiome. Sterile cultures were more common in contact lens wearers than non-wearers. The incidence of Staphylococcus aureus was higher than anticipated across all severity groups, and that of coagulase-negative Staphylococcus, Corynebacterium and streptococci was lower. CONCLUSIONS: Modest differences in relative proportions of bacteria compared with other studies support climatic variations in the ocular surface microbiome. Similarity in microbiome profile, irrespective of meibomian gland dysfunction severity, anterior blepharitis presence or contact lens wear, suggests potential for commonality in treatment.

Comparison of Self-applied Heat Therapy for Meibomian Gland Dysfunction.

PURPOSE: To compare the effects on ocular temperature, lipid layer grade, tear film stability, and tear meniscus height after a single application of two commercially available warm compresses in mild-to-moderate dry eye and to report participant treatment preference. METHODS: Forty-one subjects with mild-to-moderate dry eye symptoms were enrolled in a randomized, paired-eye, investigator-masked trial. Heat was applied simultaneously to one eye (randomized) with a portable eye mask (EyeGiene) and to the contralateral eye with a microwave-heated flaxseed eye bag (MGDRx Eye Bag). Outer and inner eyelid temperatures, tear film lipid layer grade (LLG), and noninvasive tear film breakup time (NIBUT) were measured at baseline and immediately after 10 minutes of device application. RESULTS: Outer and inner eyelid temperatures, LLG, and NIBUT did not differ before treatment between eyes assigned to eye mask and eye bag therapy. All measurements were significantly increased from baseline, after warming with both devices (all p < 0.05). Outer and inner eyelid temperature changes were significantly greater with the eye bag than with the eye mask (outer eyelid, +3.5 ± 1.0°C vs. +2.4 ± 0.8°C; inner eyelid, +3.5 ± 1.0°C vs. +2.5 ± 0.9°C; all p < 0.001), although there was no significant difference in LLG and NIBUT improvement between treatments (all p > 0.05). A majority of subjects (78%) preferred the application of heat with the eye bag over the eye mask. CONCLUSIONS: Both the EyeGiene mask and the MGDRx Eye Bag are convenient eyelid warming devices that result in clinically and statistically significant increases in NIBUT and LLG in patients with mild-to-moderate dry eye symptoms. The MGDRx Eye Bag is more effective in raising ocular temperature and is the preferred treatment method among subjects.

Appropriateness of Questionnaires for the Diagnosis and Monitoring Treatment of Dry Eye Disease.

Objectives: If questionnaires contributing to the diagnosis of dry eye disease are to be recommended as alternatives to existing questionnaires, they must be comparable, with similar repeatability and treatment sensitivity. Comparability was thus examined for three common dry eye questionnaires along with identifying the individual questions that most strongly predicted overall scores. Methods: Anonymised data (n = 329) collected via the Ocular Surface Disease Index (OSDI), 5-item Dry Eye Questionnaire (DEQ-5) and Symptom Assessment in Dry Eye (SANDE) questionnaires (including responses to individual questions) from consenting patients were drawn from real-world dry eye clinics/registries in the United Kingdom, Australia and New Zealand; at follow-up, normalised changes were evaluated in 54 of these patients. Treatment data were also analysed from a 6-month, randomised controlled trial assessing artificial tear supplement treatments with 43 responders and 13 non-responders to treatment identified. The questions extracted from the OSDI which form the abbreviated 6-item OSDI were also analysed. Results: The agreement between the questionnaires ranged from r = 0.577 to 0.754 (all p < 0.001). For the OSDI, three questions accounted for 89.1% of the variability in the total score. The correlation between the OSDI and OSDI-6 was r = 0.939, p < 0.001. For the DEQ-5, two questions accounted for 88.5% of the variance in the total score. Normalised treatment changes were also only moderately correlated between the questionnaires (r = 0.441 to 0.595, p < 0.01). For non-responders, variability was 7.4% with both OSDI and OSDI-6, 9.7% with DEQ-5, 12.1% with SANDE-frequency and 11.9% with SANDE-severity scale. For responders, improvement with drops was detected with a 19.1% change in OSDI, 20.2% in OSDI-6, 20.9% in DEQ-5, and 27.5%/23.6% in SANDE-frequency/severity scales. Conclusions: Existing commonly used dry eye questionnaire scores do not show high levels of correlation. The OSDI was the least variable of the questionnaires and while displaying a slightly lower treatment effect than either the DEQ or SANDE, it was more sensitive to detection of a treatment effect. The quicker-to-complete OSDI-6 exhibited essentially the same outcome as the OSDI, with similar variability and treatment sensitivity.

Predictive performance of corneal and lid margin sensitivity for dry eye disease: An investigator-masked, prospective, prognostic accuracy study.

PURPOSE: To evaluate the prognostic ability of non-contact esthesiometry corneal and lid margin sensitivity measurements in detecting symptoms and signs of dry eye disease, as defined by the global consensus TFOS DEWS II criteria. METHODS: A total of 87 community residents (58 females; mean ± SD age, 53 ± 16 years) were recruited in an investigator-masked, prospective, prognostic accuracy study. Dry eye symptomology, tear film parameters, and ocular surface characteristics were evaluated in a single clinical session, and non-contact esthesiometry corneal and lid margin sensitivity measurements performed by an independent masked assessor. RESULTS: Overall, 49 (56%) participants fulfilled the TFOS DEWS II criteria for dry eye disease, while 57 (66%) exhibited clinical symptoms, and 67 (77%) had positive signs. The prognostic abilities of corneal and lid margin sensitivity measurements were significantly greater than chance for the detection dry eye signs (both p ≤ 0.03), but not for symptoms or overall disease diagnosis (all p > 0.10). The Youden-optimal prognostic cut-offs for corneal and lid margin sensitivity thresholds were both ≥0.8 mbar for the detection of clinical dry eye signs. Lid margin sensitivity demonstrated marginally higher predictive performance than corneal sensitivity (C-statistic, 0.688 versus 0.658), and was significantly correlated with tear film stability, corneal, conjunctival and lid wiper staining (all p < 0.05). CONCLUSIONS: Corneal and lid margin sensitivity demonstrated moderate prognostic utility for detecting clinical dry eye signs. Future research is warranted to investigate the utility of incorporating non-contact esthesiometry in the workup for dry eye disease and neurotrophic keratopathy.

BCLA CLEAR Presbyopia: Definitions.

Presbyopia is often the first sign of ageing experienced by humans. Standardising terminology and adopting it across the BCLA CLEAR Presbyopia reports, improves consistency in the communication of the evidence-based understanding of this universal physiological process. Presbyopia can be functionally and psychologically debilitating, especially for those with poor access to eyecare. Presbyopia was defined as occurring when the physiologically normal age-related reduction in the eye's focusing range reaches a point that, when optimally corrected for far vision, the clarity of vision at near is insufficient to satisfy an individual's requirements. Accommodation is the change in optical power of the eye due to a change in crystalline lens shape and position, whereas pseudo-accommodation is the attainment of functional near vision in an emmetropic or far-corrected eye without changing the refractive power of the eye. Other definitions specific to vision and lenses for presbyopia were also defined. It is recommended that these definitions be consistently adopted in order to standardise future research, clinical evaluations and education.

BCLA CLEAR Presbyopia: Management with corneal techniques.

Corneal techniques for enhancing near and intermediate vision to correct presbyopia include surgical and contact lens treatment modalities. Broad approaches used independently or in combination include correcting one eye for distant and the other for near or intermediate vision, (termed monovision or mini-monovision depending on the degree of anisometropia) and/or extending the eye's depth of focus [1]. This report provides an overview of the evidence for the treatment profile, safety, and efficacy of the range of corneal techniques currently available for managing presbyopia. The visual needs and expectations of the patient, their ocular characteristics, and prior history of surgery are critical considerations for patient selection and preoperative evaluation. Contraindications to refractive surgery include unstable refraction, corneal abnormalities, inadequate corneal thickness for the proposed ablation depth, ocular and systemic co-morbidities, uncontrolled mental health issues and unrealistic patient expectations. Laser refractive options for monovision include surface/stromal ablation techniques and keratorefractive lenticule extraction. Alteration of spherical aberration and multifocal ablation profiles are the primary means for increasing ocular depth of focus, using surface and non-surface laser refractive techniques. Corneal inlays use either small aperture optics to increase depth of field or modify the anterior corneal curvature to induce corneal multifocality. Presbyopia correction by conductive keratoplasty involves application of radiofrequency energy to the mid-peripheral corneal stroma which leads to mid-peripheral corneal shrinkage, inducing central corneal steepening. Hyperopic orthokeratology lens fitting can induce spherical aberration and correct some level of presbyopia. Postoperative management, and consideration of potential complications, varies according to technique applied and the time to restore corneal stability, but a minimum of 3 months of follow-up is recommended after corneal refractive procedures. Ongoing follow-up is important in orthokeratology and longer-term follow-up may be required in the event of late complications following corneal inlay surgery.

Nga whakaro hauora Maori o te karu: Maori thoughts and considerations surrounding eye health.

CLINICAL RELEVANCE: Research highlighting Indigenous patient perspectives is essential in the pursuit of understanding and addressing longstanding health inequities. BACKGROUND: Evidence indicates that disparities in ocular health outcomes between Maori and non-Maori are pervasive in the New Zealand health system. Evidence shows the cause of these inequities is often multifactorial; due to factors such as colonisation, ongoing marginalisation, racism, socioeconomic status, poverty and culturally unsafe practice between health professionals and Maori patients. METHODS: This project used kaupapa Maori methodology to identify the perceptions of Maori surrounding ocular healthcare within a Maori context in Aotearoa New Zealand. Three focus groups with Maori community members and three individual interviews with Maori eyecare practitioners were conducted. Participants discussed sub-topics relating to Maori health, ocular health consultations, ocular examination and access to ocular health services in Aotearoa New Zealand. Reflexive thematic analysis was undertaken using NVivo qualitative research software. RESULTS: Five key themes were derived from the data: (1) the importance of effective clinician-patient communication; (2) historical experiences of patients inform their health attitudes; (3) barriers to access are systemic; (4) Maori health is important to Maori and (5) Te Ao Maori, Tikanga and Tapu are significant cultural concepts for Maori. Overall, Maori patients recognise the value of ocular healthcare and the importance of acknowledging Maori models of health within services. CONCLUSION: The key issues Maori patients face within ocular health services resonate strongly with wider concepts intrinsically important to Maori. These are the right to cultural safety within clinical settings, the right to accurate and pertinent communication of information between clinician and patient and the respect of cultural beliefs and acknowledgement of power imbalances within the wider healthcare system. Participant discussions and suggestions raise possible pathways to begin addressing ocular ethnic disparities in healthcare delivery.

Omega-3 polyunsaturated fatty acids and corneal nerve health: Current evidence and future directions.

Corneal nerves play a key role in maintaining ocular surface integrity. Corneal nerve damage, from local or systemic conditions, can lead to ocular discomfort, pain, and, if poorly managed, neurotrophic keratopathy. Omega-3 polyunsaturated fatty acids (PUFAs) are essential dietary components that play a key role in neural development, maintenance, and function. Their potential application in modulating ocular and systemic inflammation has been widely reported. Omega-3 PUFAs and their metabolites also have neuroprotective properties and can confer benefit in neurodegenerative disease. Several preclinical studies have shown that topical administration of omega-3 PUFA-derived lipid mediators promote corneal nerve recovery following corneal surgery. Dietary omega-3 PUFA supplementation can also reduce corneal epithelial nerve loss and promote corneal nerve regeneration in diabetes. Omega-3 PUFAs and their lipid mediators thus show promise as therapeutic approaches to modulate corneal nerve health in ocular and systemic disease. This review discusses the role of dietary omega-3 PUFAs in maintaining ocular surface health and summarizes the possible applications of omega-3 PUFAs in the management of ocular and systemic conditions that cause corneal nerve damage. In examining the current evidence, this review also highlights relatively underexplored applications of omega-3 PUFAs in conferring neuroprotection and addresses their therapeutic potential in mediating corneal nerve regeneration.

Managing Corneal Infections: Out with the old, in with the new?

There have been multiple reports of eye infections caused by antibiotic-resistant bacteria, with increasing evidence of ineffective treatment outcomes from existing therapies. With respect to corneal infections, the most commonly used antibiotics (fluoroquinolones, aminoglycosides, and cephalosporines) are demonstrating reduced efficacy against bacterial keratitis isolates. While traditional methods are losing efficacy, several novel technologies are under investigation, including light-based anti-infective technology with or without chemical substrates, phage therapy, and probiotics. Many of these methods show non-selective antimicrobial activity with potential development as broad-spectrum antimicrobial agents. Multiple preclinical studies and a limited number of clinical case studies have confirmed the efficacy of some of these novel methods. However, given the rapid evolution of corneal infections, their treatment requires rapid institution to limit the impact on vision and prevent complications such as scarring and corneal perforation. Given their rapid effects on microbial viability, light-based technologies seem particularly promising in this regard.

Association between systemic omega-3 polyunsaturated fatty acid levels, and corneal nerve structure and function.

BACKGROUND: Omega-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have anti-inflammatory and neuroprotective properties. This study sought to determine the relationship between corneal parameters and systemic omega-3 fatty acid levels. METHODS: Forty-seven participants with no/mild peripheral neuropathy (26 with diabetes and 21 without) underwent comprehensive ocular surface and systemic PUFA assessments. Corneal anatomical parameters were assessed using in vivo confocal microscopy. Corneal sensitivity was measured using non-contact esthesiometry. Relationships between systemic PUFA levels and corneal parameters were evaluated with multiple linear regression, adjusted for age, sex, neuropathy symptom score, and presence of diabetes and dry eye disease. The relationship between corneal nerve fibre length (CNFL) and corneal sensitivity threshold was evaluated. RESULTS: The median Omega-3 Index, a measure of erythrocyte EPA and DHA, was 5.21% (interquartile range: 4.44-5.94%) in the study population. Mean ( ± SD) CNFL was 13.53 ± 3.37 mm/mm2. Multiple linear regression showed that Omega-3 Index (ß = 0.33; p = 0.02), age (ß = -0.46; p = 0.001) and diabetes (ß = -0.30; p = 0.03) were independently associated with CNFL (R2 = 0.39, p = 0.002). In a separate model, DHA (ß = 0.32; p = 0.027) and age (ß = -0.41; p = 0.003) were associated with CNFL (R2 = 0.37, p = 0.003). Neither systemic EPA nor omega-6 fatty acid levels correlated with CNFL. There was no association between PUFA levels and corneal sensitivity or corneal immune cell density. A negative correlation was found between CNFL and corneal sensation thresholds to a cooled stimulus in diabetes participants, in the central (ρ = -0.50; p = 0.009) and peripheral (ρ = -0.50; p = 0.01) cornea. CONCLUSIONS: A positive relationship between the systemic Omega-3 Index and corneal nerve parameters suggests omega-3 PUFA intake may influence corneal nerve architecture.