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.

Safety and efficacy of UV application for superficial infections in humans: A systematic review and meta-analysis.

BACKGROUND: Ultraviolet (UV) light is naturally antimicrobial, but risks associated with UV overexposure have limited its clinical application. This systematic review evaluates the safety and efficacy of UV light treatment of superficial human infections. METHODS: MEDLINE, Embase, Cochrane CENTRAL, ANZCTR and US National Library of Medicine were searched (March 25, 2020). Clinical studies applying UV light (200-400 nm) for superficial infections and non-clinical studies evaluating the antimicrobial effects of UV light on human samples were included. Randomised controlled trials (RCTs) and non- RCTs were appraised using the Cochrane risk of bias and the ROBINS-I tools, respectively. RESULTS: Eleven RCTs, seven non-RCTs, 24 case studies, and 11 in vitro studies were included. Most clinical studies (34/42) evaluated UVA treatment for microbial keratitis (MK) using cross-linking (UVA-CXL) methods. Six clinical studies assessed UVC; one, UVB; and one, broadband UV for chronic skin infections. Pooled data analysis showed no difference in the time to wound resolution with UVA-CXL relative to standard treatment (mean difference [MD]: -18.20 [95% CI: -39.04 to 2.65] days; p = 0.09). Adverse event incidence was similar to control for UVA-CXL in MK (RR: 0.70 [95%CI: 0.32-1.79]; 5 RCTs) and UVC in skin infections (RR: 0.63 [95%CI: 0.25-1.54]; 2 RCTs). CONCLUSION: Alone or as an adjunct to standard therapy, UV light shows promise as a safe and effective treatment for a wide range of infections. Applications of UV light as an anti-infective agent are deserving of further evaluation, especially in the context of growing antibiotic resistance. REGISTRATION: PROSPERO registration number CRD42020176510.

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.

Omega-3 Fatty Acids and Eye Health: Opinions and Self-Reported Practice Behaviors of Optometrists in Australia and New Zealand.

This study investigated optometrists' attitudes and self-reported practice behaviors towards omega-3 fatty acids for eye health, and knowledge and understanding of their potential risks and benefits. An anonymous online survey was distributed to optometrists in Australia and New Zealand. Questions included practitioner demographics and practice modality; self-reported practices and recommendations relating to diet, nutritional supplements, and omega-3 fatty acids for age-related macular degeneration (AMD) and dry eye disease (DED); and practitioner knowledge about omega-3 fatty acids. Of 206 included surveys, most respondents (79%) indicated recommending for their patients to consume omega-3 fatty acids to improve their eye health. Sixty-eight percent of respondents indicated recommending omega-3-rich foods for AMD management, while 62% indicated recommending omega-3 supplements. Most respondents (78%) indicated recommending omega-3-rich foods or supplements for DED. For DED, recommended omega-3 supplement dosages were (median [inter-quartile range, IQR]) 2000 mg [1000-2750 mg] per day. The main sources of information reported by respondents to guide their clinical decision making were continuing education articles and conferences. In conclusion, optometrists routinely make clinical recommendations about diet and omega-3 fatty acids. Future education could target improving optometrists' knowledge of differences in the evidence for whole-food versus supplement sources of omega-3 fatty acids in AMD. Further research is needed to address uncertainties in the evidence regarding optimal omega-3 dosage and formulation composition in DED.

Corneal Epithelial "Neuromas": A Case of Mistaken Identity?

Laser scanning in vivo confocal microscopy is a useful clinical tool to assess the corneal nerves in human and laboratory animals. With this new technology, the use of terms such as "neuromas" and "microneuromas" is becoming popular to describe nerve structures seen in humans. Here, we point out that the sites where stromal nerves enter the corneal epithelium are often hyperreflective and can appear dysmorphic when imaged using in vivo confocal microscopy. Furthermore, we clarify what is known anatomically about how the nerves enter the corneal epithelium from the stroma, and we urge colleagues to differentiate between hyperreflective foci at the corneal stromal-epithelial nerve penetration sites and alterations in nerve morphology secondary to injury or disease.

Intense pulsed light (IPL) therapy for the treatment of meibomian gland dysfunction.

BACKGROUND: Meibomian gland dysfunction (MGD) is the major cause of evaporative dry eye disease, which is the more prevalent form of dry eye disease. Intense pulsed light (IPL) therapy, involving treatment of the skin near the eyelids, has emerged as a potential treatment for MGD. OBJECTIVES: To evaluate the effectiveness and safety of intense pulsed light (IPL) for the management dry eye disease resulting from meibomian gland dysfunction (MGD). SEARCH METHODS: We searched CENTRAL, MEDLINE (Ovid), Embase Ovid and three trial registers for eligible clinical trials on 1 August 2019. There were no restrictions on publication status, date or language. SELECTION CRITERIA: We included randomised controlled trials (RCTs) studying the effectiveness or safety of IPL for treating MGD. DATA COLLECTION AND ANALYSIS: Our outcomes of interest were the change from baseline in subjective dry eye symptoms, adverse events, changes to lipid layer thickness, tear break-up time (TBUT), tear osmolarity, eyelid irregularity, eyelid telangiectasia, meibomian gland orifice plugging, meibomian gland dropout, corneal sodium fluorescein staining and conjunctival lissamine green staining. Two review authors independently screened abstracts and full-text articles, extracted data from eligible RCTs and judged the risk of bias using the Cochrane tool. We reached consensus on any disagreements by discussion. We summarised the overall certainty of the evidence using the GRADE Working Group approach. MAIN RESULTS: We included three RCTs, one from New Zealand, one from Japan and one from China, published between 2015 and 2019. Together, these trials enrolled 114 adults (228 eyes). Two studies used a paired-eye (inter-eye comparison) design to evaluate the effects of a sham (control) IPL treatment relative to an actual IPL treatment. One study randomised individuals to either an IPL intervention combined with meibomian gland expression (MGX), or MGX alone (standard therapy). The study follow-up periods ranged from 45 days to nine months. None of the trials were at low risk of bias in all seven domains. The first authors of two included studies were in receipt of funding from patents or the manufacturers of IPL devices. The funding sources and declaration of interests were not given in the report of the third included trial. All three trials evaluated the effect of IPL on dry eye symptoms, quantified using the Standard Patient Evaluation of Eye Dryness (SPEED) questionnaire. Pooling data from two trials that used a paired-eye design, the summary estimate for these studies indicated little to no reduction in dry eye symptoms with IPL relative to a sham intervention (mean difference (MD) -0.33 units, 95% confidence interval (CI) -2.56 to 1.89; I² = 0%; 2 studies, 144 eyes). The other study was not pooled as it had a unit-of-analysis error, but reported a reduction in symptoms in favour of IPL (MD -4.60, 95% CI -6.72 to -2.48; 84 eyes). The body of evidence for this outcome was of very low certainty, so we are uncertain about the effect of IPL on dry eye symptoms. There were no relevant combinable data for any of the other secondary outcomes, thus the effect of IPL on clinical parameters relevant to dry eye disease are currently unclear. For sodium fluorescein TBUT, two studies indicated that there may be an improvement in favour of IPL (MD 2.02 seconds, 95% CI 0.87 to 3.17; MD 2.40 seconds, 95% CI 2.27 to 2.53; 172 eyes total; low-certainty evidence). We are uncertain of the effect of IPL on non-invasive tear break-up time (MD 5.51 seconds, 95% CI 0.79 to 10.23; MD 3.20, 95% CI 3.09 to 3.31 seconds; two studies; 140 eyes total; very low-certainty evidence). For tear osmolarity, one study indicated that there may be an improvement in favour of IPL (MD -7.00 mOsmol/L, 95% -12.97 to -1.03; 56 eyes; low-certainty evidence). We are uncertain of the effect of IPL on meibomian gland orifice plugging (MD -1.20 clinical units, 95% CI -1.24 to -1.16; 84 eyes; very low-certainty evidence). We are uncertain of the effect of IPL on corneal sodium fluorescein staining. One study reported no evidence of a difference between the IPL and sham intervention arms at three months of follow-up (P = 0.409), and a second study reported data favouring IPL (MD -1.00 units, 95% CI -1.07 to -0.93 units; 172 eyes in total; very low-certainty evidence). We considered the incidence of adverse events at the study endpoint, as a measure of safety. As most trials did not specifically report adverse events, the safety of IPL as a treatment for MGD could also not be determined with any certainty. Very low-certainty results from individual studies suggest some adverse effects that may be experienced by participants, include mild pain and burning, and the potential for partially losing eyelashes (due to clinician error). AUTHORS' CONCLUSIONS: This systematic review finds a scarcity of RCT evidence relating to the effectiveness and safety of IPL as a treatment for MGD. Whether IPL is of value for modifying the symptoms or signs of evaporative dry eye disease is currently uncertain. Due to a lack of comprehensive reporting of adverse events, the safety profile of IPL in this patient population is also unclear. The current limitations in the evidence base should be considered by clinicians using this intervention to treat MGD, and outlined to individuals potentially undergoing this procedure with the intent of treating dry eye disease. The results of the 14 RCTs currently in progress will be of major importance for establishing a more definitive answer regarding the effectiveness and safety of IPL for treating MGD. We intend to update this review when results from these trials become available.

Corneal Epithelial Dendritic Cell Response as a Putative Marker of Neuro-inflammation in Small Fiber Neuropathy.

We report a case of a 41-year old female with systemic lupus erythematosus and Sjögren's syndrome, who developed symptoms of painful small fiber neuropathy (SFN). Examination using in vivo confocal microscopy (IVCM) revealed dense accumulations of putative dendritic cells in the central cornea that was postulated to represent a peripheral neuro-inflammatory response. Interventions with higher dose prednisolone, and then intravenous immunoglobulin resulted in substantial, progressive improvements in her symptoms, which were paralleled by cumulative reductions in corneal dendritic cell density (DCD). This case identifies corneal DCD as a potential non-invasive marker of symptomatic SFN due to inflammatory causes.

Omega-3 polyunsaturated fatty acid oral supplements for improving peripheral nerve health: a systematic review and meta-analysis.

CONTEXT: Peripheral nerve damage can occur in a variety of systemic conditions and can have a profound impact on functional and psychological health. Currently, therapeutic interventions for peripheral nerve damage are limited. OBJECTIVE: The aim of this systematic review, conducted in accordance with the Cochrane Collaboration's handbook and reported according to the PRISMA checklist, was to evaluate the efficacy and safety of omega-3 oral supplements for improving peripheral nerve structure and function. DATA SOURCES: PubMed, Embase, and Cochrane databases, along with clinical trial registries, were searched from inception to February 2019. Evidence was identified, critically appraised, and synthesized, and the certainty of evidence was appraised using the Grading of Recommendations Assessment, Development and Evaluation approach. STUDY SELECTION: Randomized controlled trials assessing the effects of omega-3 oral supplementation on outcomes of peripheral nerve structure, peripheral nerve function, or both were eligible for inclusion. Titles and abstracts of identified articles were independently assessed for potential eligibility by 2 review authors. For studies judged as eligible or potentially eligible, full text articles were retrieved and independently assessed by 2 review authors to determine eligibility; disagreements were resolved by consensus. DATA EXTRACTION: Fifteen trials were included. Two clinically similar studies that investigated the effect of omega-3 supplementation in individuals receiving chemotherapy were meta-analyzed. Pooled data showed a reduced incidence of peripheral neuropathy (RR = 0.58; 95%CI, 0.43-0.77) and a preservation of sensory nerve action potential amplitudes with omega-3 supplementation compared with placebo (MD = 4.19 µV; 95%CI; 2.19-6.19). CONCLUSION: This review finds, with low certainty, that omega-3 supplementation attenuates sensory loss and reduces the incidence of neuropathy secondary to oxaliplatin and paclitaxel treatment relative to placebo. There is currently limited evidence to ascertain whether omega-3 supplementation is beneficial in other systemic conditions characterized by peripheral nerve damage. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number CRD 42018086297.

Preliminary Validation of a Food Frequency Questionnaire to Assess Long-Chain Omega-3 Fatty Acid Intake in Eye Care Practice.

Clinical recommendations relating to dietary omega-3 essential fatty acids (EFAs) should consider an individual's baseline intake. The time, cost, and practicality constraints of current techniques for quantifying omega-3 levels limit the feasibility of applying these methods in some settings, such as eye care practice. This preliminary validation study, involving 40 adults, sought to assess the validity of a novel questionnaire, the Clinical Omega-3 Dietary Survey (CODS), for rapidly assessing long-chain omega-3 intake. Estimated dietary intakes of long-chain omega-3s from CODS correlated with the validated Dietary Questionnaire for Epidemiology Studies (DQES), Version 3.2, (Cancer Council Victoria, Melbourne, Australia) and quantitative assays from dried blood spot (DBS) testing. The 'method of triads' model was used to estimate a validity coefficient (ρ) for the relationship between the CODS and an estimated "true" intake of long-chain omega-3 EFAs. The CODS had high validity for estimating the ρ (95% Confidence Interval [CI]) for total long-chain omega-3 EFAs 0.77 (0.31-0.98), docosahexaenoic acid 0.86 (0.54-0.99) and docosapentaenoic acid 0.72 (0.14-0.97), and it had moderate validity for estimating eicosapentaenoic acid 0.57 (0.21-0.93). The total long-chain omega-3 EFAs estimated using the CODS correlated with the Omega-3 index (r = 0.37, p = 0.018) quantified using the DBS biomarker. The CODS is a novel tool that can be administered rapidly and easily, to estimate long-chain omega-3 sufficiency in clinical settings.

Omega-3 polyunsaturated fatty acid supplementation for improving peripheral nerve health: protocol for a systematic review.

INTRODUCTION: Damage to peripheral nerves occurs in a variety of health conditions. Preserving nerve integrity, to prevent progressive nerve damage, remains a clinical challenge. Omega-3 polyunsaturated fatty acids (PUFAs) are implicated in the development and maintenance of healthy nerves and may be beneficial for promoting peripheral nerve health. The aim of this systematic review is to assess the effects of oral omega-3 PUFA supplementation on peripheral nerve integrity, including both subjective and objective measures of peripheral nerve structure and/or function. METHODS AND ANALYSIS: A systematic review of randomised controlled trials that have evaluated the effects of omega-3 PUFA supplementation on peripheral nerve assessments will be conducted. Comprehensive electronic database searches will be performed in Ovid MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), US National Institutes of Health Clinical Trials Registry and the WHO International Clinical Trials Registry Platform. The title, abstract and keywords of identified articles will be assessed for eligibility by two reviewers. Full-text articles will be obtained for all studies judged as eligible or potentially eligible; these studies will be independently assessed by two reviewers to determine eligibility. Disagreements will be resolved by consensus. Risk of bias assessment will be performed using the Cochrane Collaboration risk of bias tool to appraise the quality of included studies. If clinically meaningful, and there are a sufficient number of eligible studies, a meta-analysis will be conducted and a summary of findings table will be provided. ETHICS AND DISSEMINATION: This is a systematic review that will involve the analysis of previously published data, and therefore ethics approval is not required. A manuscript reporting the results of this systematic review will be published in a peer-reviewed journal and may also be presented at relevant scientific conferences. PROSPERO REGISTRATION NUMBER: CRD42018086297.

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.