How gut microbiota may impact ocular surface homeostasis and related disorders.

Changes in the bacterial flora in the gut, also described as gut microbiota, are readily acknowledged to be associated with several systemic diseases, especially those with an inflammatory, neuronal, psychological or hormonal factor involved in the pathogenesis and/or the perception of the disease. Maintaining ocular surface homeostasis is also based on all these four factors, and there is accumulating evidence in the literature on the relationship between gut microbiota and ocular surface diseases. The mechanisms involved are mostly interconnected due to the interaction of central and peripheral neuronal networks, inflammatory effectors and the hormonal system. A better understanding of the influence of the gut microbiota on the maintenance of ocular surface homeostasis, and on the onset or persistence of ocular surface disorders could bring new insights and help elucidate the epidemiology and pathology of ocular surface dynamics in health and disease. Revealing the exact nature of these associations could be of paramount importance for developing a holistic approach using highly promising new therapeutic strategies targeting ocular surface diseases.

Therapeutic Response After Immunosuppressive Drug Prescription in Non-infectious Uveitis: A Survival Analysis.

INTRODUCTION: To identify factors affecting the response rate to immunosuppressive drugs (ISDs) in patients with non-infectious uveitis (NIU). METHODS: This longitudinal retrospective cohort study included patients from the Hospital Clinico San Carlos Uveitis Clinic diagnosed with NIU from 1992 to 2016. Subjects were followed up from ISD prescription until the achievement of good therapeutic response (GTR), ISD treatment change, or up to 12 months. GTR was defined as the complete resolution of the eye inflammatory manifestations with a corticosteroid dose ≤ 10 or ≤ 5 mg per day of prednisone or equivalent (GTR10 and GTR5, respectively) maintained for at least 28 days. Kaplan-Meier curves were estimated for GTR. Demographic, clinical, and treatment-related factors were analyzed using Cox robust regression. RESULTS: A total of 73 patients (100 episodes of ISD prescription) were analyzed. In 44 and 41 episodes, GTR10 and GTR5 were achieved, respectively. A lower hazard for both GTRs was associated with uveitic macular edema at prescription and with a higher "highest oral corticosteroid dose prescribed in the year before ISD prescription". GTR10 was higher if cyclosporine was prescribed (compared to other ISDs), and if a higher number of ISDs had been previously prescribed. GTR5 hazard was lower for patients with posterior uveitis or if the ISDs were prescribed before 2008, and higher if periocular corticosteroids had been administered before ISD prescription, or if the duration of the posterior segment activity was shorter. CONCLUSIONS: Factors associated with GTR to ISDs may help to identify patients with NIUs who could benefit from a thorough follow-up.

Management of inflammation in dry eye disease: Recommendations from a European panel of experts.

INTRODUCTION: Early initiation of anti-inflammatory therapies is recommended for dry eye disease (DED) to break the vicious cycle of pathophysiology. However, there is limited guidance on how to implement topical ciclosporin (CsA) and corticosteroid treatment into clinical practice. This expert-led consensus provides practical guidance on the management of DED, including when and how to use topical CsA. METHODS: A steering committee (SC) of seven European DED experts developed a questionnaire to gain information on the unmet needs and management of DED in clinical practice. Consensus statements on four key areas (disease severity and progression; patient management; efficacy, safety and tolerability of CsA; and patient education) were generated based on the responses. The SC and an expanded expert panel of 22 members used a nine-point scale (1 = strongly disagree; 9 = strongly agree) to rate statements; a consensus was reached if ≥75% of experts scored a statement ≥7. RESULTS: A stepwise approach to DED management is required in patients presenting with moderate corneal staining. Early topical CsA initiation, alone or with corticosteroids, should be considered in patients with clinical risk factors for severe DED. Patient education is required before and during treatment to manage expectations regarding efficacy and tolerability in order to optimise adherence. Follow-up visits are required, ideally at Month 1 and every 3 months thereafter. Topical CsA may be continued indefinitely, especially when surgery is required. CONCLUSION: This consensus fills some of the knowledge gaps in previous recommendations regarding the use of topical corticosteroids and CsA in patients with DED.

Effect of face mask on topographic corneal parameters in healthy individuals.

PURPOSE: To evaluate whether the use of masks has an effect on the measurement of corneal topographic parameters. METHODS: A study including healthy patients with no previous ocular diseases or surgeries was conducted. Corneal topography was evaluated with an elevation topography Pentacam Scheimpflug. Four measurements were taken: two measurements with face mask and another two measurements after 10 min without wearing the face mask. The following parameters were evaluated: anterior topographic flat meridian (K1), anterior topographic steepest meridian (K2), mean keratometry (Km) and maximum keratometric point (Kmax). RESULTS: Thirty-five eyes of thirty-five healthy individuals were included; with a mean age of 33.5 ± 13.8 years (range 24-66) and 26 (74%) being female. Mean time with face-mask was 3.8 ± 2.2 h (range 1-8). No differences in mean K1, K2, Km and Kmax with and without face-mask were noted (paired t-test, all, p > 0.05). Intraclass correlation coefficients (ICC) were excellent for all four analyzed parameters (ICC > 0.914), although they were lower when measurements with face-mask were considered. CONCLUSIONS: Although tear film alterations with the use of face-mask have been described in the literature, no significant differences can be noted in topographic variables.

Tear and ocular surface disease biomarkers: A diagnostic and clinical perspective for ocular allergies and dry eye disease.

Validated biomarkers to be used as biological tools for managing ocular surface diseases (OSDs) are still an unmet need in daily clinical practice. Many studies have contributed to the already extensive list of candidate biomarkers for these disorders. Dry eye (DE) and ocular allergy (OA) are complex and multifactorial diseases, often coexisting and with overlapping symptoms. The purpose of this review is to present a comprehensive updated revision of the most relevant biomarkers of DE and OA, with an emphasis on quantitative analyses and correlations with clinical parameter data. Analysis of biomarkers common for these pathologies has highlighted an important physiological process. Namely, the interleukin proteins (IL-1α, IL-1ß and IL-17), tumour necrotic factor (TNFα) and interferon gamma (IFNγ; Th1-Th7 pathway) and IL-4, IL-5 and IL-13 (Th2 pathway) seem to represent similar inflammatory mechanisms. Moreover, changes in the levels of mucins (MUC1, MUC2, MUC4, MUC5 and MUC16) are common alterations in the tear film mucous layer. We also examine the current state of medical devices and the main limitations to their use in clinical practice. Translational research in biomarkers for clinical practice depends on a feasible transition from the laboratory to the point-of-care. This requires large-scale, coordinated clinical validation campaigns to select the biomarkers with the highest specificity and sensitivity and significant correlation with clinical parameters. Moreover, technical limitations of multiplexed quantitation systems must be overcome to detect and measure the levels of several biomarkers in very small samples. To ensure the future of biomarker research, significant progress is necessary in a number of fields. There is an urgent need for global unification of clinical classification and diagnostics criteria. Widespread integration of proteomic and transcriptomic data is paramount for performing meaningful analyses using appropriate bioinformatics tools and artificial intelligence systems.

Comparison of the efficacy of topical insulin with autologous serum eye drops in persistent epithelial defects of the cornea.

PURPOSE: To investigate the effect of topical insulin on epithelization in persistent epithelial defects (PED) refractory to usual treatment compared to autologous serum. DESIGN: Retrospective, consecutive case-control series. METHODS: The charts of 61 consecutive patients with PED treated with topical insulin (case group) and 23 treated with autologous serum (control group) were reviewed. Primary efficacy end points were the percentage of patients in which epithelization was achieved, as well as the rate and time until epithelization. Secondary efficacy point was need for amniotic membrane transplantation (AMT) or other surgeries. RESULTS: Mean time between PED diagnosis and start of topical insulin was 22.7 ± 18.5 days (range 13-115) and the mean area was 14.8 ± 16.2 mm2 (range 1.1-70.6). In the control group, mean time was 27.9 ± 16.8 days, mean epithelial defect area being 18.6 ± 15.0 mm2 (range 1.7-52.9). No differences in baseline characteristics were found between groups (p > 0.05). Epithelization was achieved in 51 patients (84%) on insulin and 11 patients (48%) on autologous serum (p = 0.002). In those patients, mean time until reepithelization was 32.6 ± 28.3 days (range 4-124) in the insulin group and 82.6 ± 82.4 days (range 13-231) in the autologous serum group (p = 0.011). The need for AMT was significantly lower in the insulin group (p = 0.005). PED recurrence was higher in patients treated on autologous serum (43%) compared with insulin (11%) (p = 0.002). CONCLUSIONS: Topical insulin is an effective treatment and safely promotes healing of PED. In our series, topical insulin presented better epithelization outcomes than autologous serum and could thus be considered as a first-line treatment.

Vogt-Koyanagi-Harada disease in Spain.

PURPOSE: To describe the clinical and epidemiological characteristics of patients with Vogt-Koyanagi-Harada (VKH) disease in Spain. METHODS: This was a retrospective multicenter analysis of data from VKH patients followed for at least 6 months. The data collected were related to demographics, clinical manifestations, treatments, and complications. RESULTS: Participants were 112 patients (224 eyes), from 13 tertiary referral centers, of mean age 37.5 ± 14.7 years; 83.9% were women. Ethnicities were 61.6% Caucasian and 30.4% Hispanic. The disease was classified as complete in 16.1%, incomplete in 55.4%, and probable in 28.6%. When seen for the first time, the clinical course was acute in 69.6%, recurrent chronic in 15.2%, and chronic in 14.3%. The most frequent treatment was corticosteroids (acute stage 42.2%, maintenance stage 55.6%). The most common complications were cataract (41.1%) and ocular hypertension (16.1%). In most eyes, visual acuity was improved (96.7%) or remained stable at the end of follow up. CONCLUSION: VKH in Spain mostly affects women and presents as incomplete acute stage disease. Visual prognosis is good. Cataract and glaucoma are the two most frequent complications.

The ocular microbiome and microbiota and their effects on ocular surface pathophysiology and disorders.

The ocular surface flora perform an important role in the defense mechanisms of the ocular surface system. Its regulation of the immunological activity and the barrier effect against pathogen invasion are remarkable. Composition of the flora differs according to the methods of investigation, because the microbiome, composed of the genetic material of bacteria, fungi, viruses, protozoa, and eukaryotes on the ocular surface, differs from the microbiota, which are the community of microorganisms that colonize the ocular surface. The observed composition of the ocular surface flora depends on harvesting and examining methods, whether with traditional culture or with more refined genetic analysis based on rRNA and DNA sequencing. Environment, diet, sex, and age influence the microbial flora composition, thus complicating the analysis of the baseline status. Moreover, potentially pathogenic organisms can affect its composition, as do various disorders, including chronic inflammation, and therapies applied to the ocular surface. A better understanding of the composition and function of microbial communities at the ocular surface could bring new insights and clarify the epidemiology and pathology of ocular surface dynamics in health and disease. The purpose of this review is to provide an up-to-date overview of knowledge about this topic.

Topical insulin for refractory persistent corneal epithelial defects.

PURPOSE: To evaluate insulin eye drops for persistent epithelial defects (PEDs) that are refractory to usual treatment in clinical practice and to analyze how it may improve epithelization. METHODS: A prospective non-randomized hospital-based study was performed. Patients with PEDs that were refractory to conventional treatment were treated with insulin eye drops four times a day. Patients' demographics, PED etiology, concomitant treatments, and comorbidities were reviewed. The rate of PED closure and epithelial healing time were considered the primary outcome measures. RESULTS: 21 patients were treated with insulin drops (12 females and 9 males; mean age 72.2 years). Mean PED area before treatment was 17.6 ± 16.5 mm2 (median 13.2; range 3.9-70.6). PED comorbidities included seven eyes with infectious keratitis (33%), five eyes with calcium keratopathy (24%), ocular surgery on three eyes (14%), three eyes with lagophthalmos (14%), two eyes with bullous keratopathy (10%), and one patient with herpetic eye disease (5%). The eyes of 17 patients (81%) with refractory PEDs had reepithelized and four patients (19%) had still presented an epithelial defect by the end of the study follow-up period, although it had decreased in size. In patients where PED closure was achieved, mean time until reepithelization was 34.8 ± 29.9 days (median 23; range 7-114). In the remaining patients, a mean area reduction of 91.5% was achieved for the PEDs. CONCLUSION: Topical insulin can promote and accelerate corneal reepithelization of refractory PEDs. It also offers many other advantages, including excellent tolerance, availability, and cost-effectiveness.

The HYLAN M Study: Efficacy of 0.15% High Molecular Weight Hyaluronan Fluid in the Treatment of Severe Dry Eye Disease in a Multicenter Randomized Trial.

The aim of the HYLAN M study was to investigate if symptoms and/or signs of patients suffering from severe dry eye disease (DED) can be improved by substituting individually optimized artificial tear therapy by high molecular weight hyaluronan (HMWHA) eye drops. In this international, multicenter study, patients with symptoms of at least ocular surface disease index (OSDI) 33 and corneal fluorescein staining (CFS) of at least Oxford grade 3 were included. A total of 84 per-protocol patients were randomized in two study arms. The control group continued to use their individual optimum artificial tears over the study period of eight weeks; in the verum group, the artificial tears were substituted by eye drops containing 0.15% HMWHA. At the week 8 visit, the average OSDI of the verum group had improved by 13.5 as compared to the control group (p = 0.001). The best corrected visual acuity (BCVA) had improved by 0.04 logMAR (p = 0.033). CFS, tear film break-up time (TBUT), Schirmer I, lid wiper epitheliopathy (LWE), mucocutaneous junction (Yamaguchi score), and tear osmolarity were not significantly different between the verum and control groups (p > 0.050). We conclude that for most patients with severe DED, 0.15% HMWHA eye drops provide excellent improvement of symptoms without impairment of dry eye signs.

Safety and Efficacy of a Preservative-Free Artificial Tear Containing Carboxymethylcellulose and Hyaluronic Acid for Dry Eye Disease: A Randomized, Controlled, Multicenter 3-Month Study.

PURPOSE: To compare the efficacy and safety of an artificial tear combining the polymers carboxymethylcellulose (CMC) and hyaluronic acid (HA), to a formulation of CMC alone in subjects with dry eye. METHODS: A preservative-free artificial tear (CMC-HA) was compared with an existing artificial tear (CMC). Subjects with mild-to-severe signs and symptoms of dry eye were enrolled in this double-masked, randomized, multicenter trial, and dosed at least twice daily for 90 days, with follow-up visits at Days 7, 30, 60, and 90. Ocular Surface Disease Index (OSDI) was the primary outcome measure. Secondary outcome measures were tear break-up time (TBUT), ocular surface staining, Schirmer test with anesthesia, and visual analog scale (VAS) scores of dry eye symptom severity and formulation acceptability. Safety measures included adverse events, biomicroscopy, and visual acuity. RESULTS: A total of 460 subjects were enrolled across 45 sites (38 in Europe; 7 in Australia), of whom 454 were randomized to receive treatment. The per-protocol (PP) population consisted of 394 subjects, 364 (92.4%) of whom completed the study. In the PP population, the mean ± SD change from baseline in OSDI score at the primary timepoint, Day 90, was -16.9±17.5 for CMC-HA and -16.0±16.1 for CMC. CMC-HA was non-inferior to CMC based upon a confidence interval method. Both treatments significantly improved (P<0.001) OSDI, symptom VAS scores, TBUT, and ocular surface staining from baseline at all follow-up visits, with minimal differences between groups. Greater reduction of overall ocular pain/discomfort was reported in subjects using CMC-HA versus CMC (P=0.048). Approximately 10% of subjects in each group reported treatment-related adverse events of generally mild to moderate severity. CONCLUSION: The new CMC-HA formulation was effective and well tolerated, and demonstrates a greater potential for symptom relief compared with CMC. These data support implementation of this formula for the management of dry eye patients.

Panuveitis and Optic Neuritis as a Possible Initial Presentation of the Novel Coronavirus Disease 2019 (COVID-19).

OBJECTIVE: To describe the ocular manifestations in a case of novel coronavirus disease 2019 (COVID-19). MATERIAL AND METHODS: A case of unilateral panuveitis and optic neuritis as initial presentation of COVID-19. RESULTS: As it is published, angiotensin-converting-enzyme-2 receptors can be found in many organs, such as the eyes, nerves, and vessels, so extrapulmonary involvement would be expected. According to current evidence and clinical characteristics of the patient, uveitis and optic neuritis could be produced by the virus. CONCLUSIONS: It is fundamental to consider panuveitis and optic neuritis as an unusual presentation of ocular involvement in COVID-19 so proper care can be given to the patients.

TFOS European Ambassador meeting: Unmet needs and future scientific and clinical solutions for ocular surface diseases.

The mission of the Tear Film & Ocular Surface Society (TFOS) is to advance the research, literacy, and educational aspects of the scientific field of the tear film and ocular surface. Fundamental to fulfilling this mission is the TFOS Global Ambassador program. TFOS Ambassadors are dynamic and proactive experts, who help promote TFOS initiatives, such as presenting the conclusions and recommendations of the recent TFOS DEWS II™, throughout the world. They also identify unmet needs, and propose future clinical and scientific solutions, for management of ocular surface diseases in their countries. This meeting report addresses such needs and solutions for 25 European countries, as detailed in the TFOS European Ambassador meeting in Rome, Italy, in September 2019.

Reconsidering the central role of mucins in dry eye and ocular surface diseases.

Mucins are key actors in tear film quality and tear film stability. Alteration of membrane-bound mucin expression on corneal and conjunctival epithelial cells and/or gel-forming mucin secretion by goblet cells (GCs) promotes in ocular surface diseases and dry eye disease (DED). Changes in the mucin layer may lead to enhanced tear evaporation eventually contributing to tear hyperosmolarity which has been associated with ocular surface inflammation. Inflammatory mediators in turn may have a negative impact on GCs differentiation, proliferation, and mucin secretion. This sheds new light on the position of GCs in the vicious circle of DED. As contributor to ocular surface immune homeostasis, GC loss may contribute to impaired ocular surface immune tolerance observed in DED. In spite of this, there are no tools in routine clinical practice for exploring ocular surface mucin deficiency/dysregulation. Therefore, when selecting the most appropriate treatment options, there is a clear unmet need for a better understanding of the importance of mucins and options for their replacement. Here, we comprehensively revisited the current knowledge on ocular surface mucin biology, including functions, synthesis, and secretion as well as the available diagnostic tools and treatment options to improve mucin-associated homeostasis. In particular, we detailed the potential link between mucin dysfunction and inflammation as part of the uncontrolled chronic inflammation which perpetuates the vicious circle in DED.

Neurotrophic keratopathy.

Neurotrophic Keratopathy (NK) refers to a condition where corneal epitheliopathy leading to frank epithelial defect with or without stromal ulceration (melting) is associated with reduced or absent corneal sensations. Sensory nerves serve nociceptor and trophic functions, which can be affected independently or simultaneously. Loss of trophic function and consequent epithelial breakdown exposes the stroma making it susceptible to enzymatic degradation. Nerve pathology can range from attrition to aberrant re-generation with corresponding symptoms from anaesthesia to hyperaesthesia/allodynia. Many systemic and ocular conditions, including surgery and preserved medications can lead to NK. NK can be mild (epithelium and tear film changes), moderate (non-healing epithelial defect) or severe (stromal melting and perforation). Moderate and severe NK can profoundly affect vision and adversely impact on the quality of life. Medical management with lubricating agents from artificial tears to serum/plasma drops, anti-inflammatory agents, antibiotics and anti-proteases all provide non-specific relief, which may be temporary. Contact lenses, punctal plugs, lid closure with botulinum toxin and surgical interventions like tarsorrhaphy, conjunctival flaps and amniotic membrane provide greater success but often at the cost of obscuring sight. Corneal surgery in a dry ocular surface with reduced sensation is at high risk of failure. The recent advent of biologicals such as biopolymers mimicking heparan sulfate; coenzyme Q10 and antisense oligonucleotide that suppress connexin 43 expression, all offer promise. Recombinant nerve growth factor (cenegermin), recently approved for human use targets the nerve pathology and has the potential of addressing the underlying deficit and becoming a specific therapy for NK.

Confocal Microscopy Observation of Cornea Verticillata After Vandetanib Therapy for Medullary Thyroid Carcinoma.

PURPOSE: To report 2 cases of cornea verticillata (CV) after vandetanib treatment for medullary thyroid carcinoma (MTC). METHODS: In this retrospective interventional, case-report study, 2 patients who under vandetanib treatment for MTC were referred to our ophthalmology department because of vision complaints. Both subjects underwent a complete ophthalmologic examination, including confocal microscopy (CM) using the Heidelberg Retina Tomograph and Rostock Cornea Module. RESULTS: A 70-year-old man and a 43-year-old woman, both with a history of MTC under treatment with vandetanib for 5 months and 30 months, respectively, presented with blurred vision. In both patients, a mild CV pattern was observed although deposits were more evident in the male patient. CM images showed hyperreflective deposits in the corneal epithelium and subepithelial nerve plexus. Bright microdots were also seen throughout the stroma, along with a few hyperreflective keratocytes in the anterior stroma. CONCLUSIONS: In both patients, vandetanib seemed to be the cause of CV. The CM images supported the idea of drug-lipid complex deposits in vandetanib-induced CV.

Clinical impact of inflammation in dry eye disease: proceedings of the ODISSEY group meeting.

Dry eye disease (DED) is a common, multifactorial ocular condition with major impact on vision and quality of life. It is now well recognized that the pathophysiology of chronic DED can include a cycle of inflammation involving both innate and adaptive immune responses. Recently, in vitro/in vivo models have been used to obtain a better understanding of DED-related inflammatory processes at molecular/cellular levels although they do not truly reproduce the complex and chronic hallmarks of human DED. In clinical DED research, advanced techniques such as impression cytology, conjunctival biopsy, in vivo confocal microscopy and multiplex tear analyses have allowed an improved assessment of inflammation in DED patients. This was supported by the identification of reliable inflammatory markers including matrix metalloproteinase-9, human leucocyte antigen-DR or intercellular adhesion molecule-1 in tears and impression cytology samples. One of the current therapeutic strategies focuses on breaking the inflammatory cycle perpetuating the ocular surface disease, and preclinical/clinical research has led to the development of promising anti-inflammatory compounds. For instance, cyclosporine, already approved in the United States, has recently been authorized in Europe to treat DED associated with severe keratitis. In addition, other agents such as corticosteroids, doxycycline and essential fatty acids, through their anti-inflammatory properties, show encouraging results. We now have a clearer understanding of the inflammatory processes involved in DED, and there is hope that the still emerging preclinical/clinical findings will be translated into new and highly effective therapies for patients in the near future.