Management of corneal neovascularization: Current and emerging therapeutic approaches.

Corneal neovascularization (CoNV) is a sight-threatening condition affecting an estimated 1.4 million people per year, and the incidence is expected to rise. It is a complication of corneal pathological diseases such as infective keratitis, chemical burn, corneal limbal stem cell deficiency, mechanical trauma, and immunological rejection after keratoplasties. CoNV occurs due to a disequilibrium in proangiogenic and antiangiogenic mediators, involving a complex system of molecular interactions. Treatment of CoNV is challenging, and no therapy thus far has been curative. Anti-inflammatory agents such as corticosteroids are the mainstay of treatment due to their accessibility and well-studied safety profile. However, they have limited effectiveness and are unable to regress more mature neovascularization. With the advent of advanced imaging modalities and an expanding understanding of its pathogenesis, contemporary treatments targeting a wide array of molecular mechanisms and surgical options are gaining traction. This review aims to summarize evidence regarding conventional and emerging therapeutic options for CoNV.

Distinct diagnostic trajectories in NBAS-associated acute liver failure highlights the need for timely functional studies.

Variants of uncertain significance (VUS) are commonly found following genomic sequencing, particularly in ethnically diverse populations that are underrepresented in large population databases. Functional characterization of VUS may assist in variant reclassification, however these studies are not readily available and often rely on research funding and good will. We present four individuals from three families at different stages of their diagnostic trajectory with recurrent acute liver failure (RALF) and biallelic NBAS variants, confirmed by either trio analysis or cDNA studies. Functional characterization was undertaken, measuring NBAS and p31 levels by Western blotting, demonstrating reduced NBAS levels in two of three families, and reduced p31 levels in all three families. These results provided functional characterization of the molecular impact of a missense VUS, allowing reclassification of the variant and molecular confirmation of NBAS-associated RALF. Importantly, p31 was decreased in all individuals, including an individual with two missense variants where NBAS protein levels were preserved. These results highlight the importance of access to timely functional studies after identification of putative variants, and the importance of considering a range of assays to validate variants whose pathogenicity is uncertain. We suggest that funding models for genomic sequencing should consider incorporating capabilities for adjunct RNA, protein, biochemical, and other specialized tests to increase the diagnostic yield which will lead to improved medical care, increased equity, and access to molecular diagnoses for all patients.

Dysmotility in Eosinophilic Esophagitis.

Eosinophilic esophagitis (EoE) is an immune mediated chronic inflammatory disease resulting from antigen exposure and is characterized by mucosal inflammation with eosinophils. Diagnosis is based on the histological finding of at least 15 eosinophils per high power field in esophageal biopsy specimens from upper gastrointestinal endoscopies. These endoscopies are usually performed in the setting of esophageal dysfunction, however, EoE can occasionally be incidentally diagnosed during endoscopies performed for other indications like coeliac disease. The eosinophilia is in the absence of other causes of esophageal eosinophilia (e.g., parasitic infection, esophageal leiomyomatosis or Crohn's disease). Presentation can be wide ranging and often varies according to age. Infants and younger children can present with choking/gagging, feed refusal, failure to thrive, irritability and vomiting. Older children and adults commonly present with dysphagia, chest pain or food bolus obstruction. EoE was first described in the 1970s, but was only recognized as a distinct disease entity in the 1990s. It has been rising in incidence and prevalence, with reported prevalence ranging between 1 in 2,500 and 1 in 10,000. Although the diagnosis of EoE is dependent on clear histopathologic diagnostic criteria, there is a disconnect between the degree of esophageal eosinophilia and symptom severity especially that of reported dysphagia. Multiple anatomical changes can be seen in the spectrum of presentations of EoE which explain dysphagia, including isolated strictures, diffuse trachealisation, fixed rings, including Schatzki, as well as tissue remodeling and fibrotic changes. However, a majority of EoE patients do not have any of these findings and will still often report ongoing dysphagia. Some will report ongoing dysphagia despite histological remission. This suggests an underlying esophageal dysmotilty which cannot be assessed with endoscopy or correlated with histological changes seen in biopsies. This review will describe the types of motor disturbances seen and their prevalence, the pathophysiological basis of dysmotility seen in EoE, how best to investigate esophageal dysfunction in EoE and the role of manometry in the management of EoE.

The Effect of Patient Education and Telemedicine Reminders on Adherence to Eye Drops for Glaucoma.

PURPOSE: To determine the improvement in patient adherence to topical ocular hypotensive therapy by introducing a personalized illustrated medication reference chart and telereminder. DESIGN: Prospective randomized controlled clinical trial. PARTICIPANTS: Fifty-nine patients with glaucoma who were using at least 3 or more eye drops were recruited from the ophthalmology clinic at the National University Hospital of Singapore. METHODS: Participants were randomized into 3 groups: control, reference chart only, and reference chart with telereminder. They completed a survey on demographics, barriers to glaucoma medication adherence, and self-adherence (measured by the Morisky adherence scale) before and 6 weeks after intervention. Logistic regression analysis was performed on the barriers that contribute to nonadherence and paired t tests were conducted for the preimplementation and postimplementation effects of intervention on adherence score. MAIN OUTCOME MEASURES: Changes in mean adherence score based on the Morisky adherence scale before and after intervention in participants from all 3 groups. RESULTS: In our study, 71% of participants who were nonadherent to medications had multiple barriers to adherence, with lack of self-efficacy and forgetfulness being the most common factors. Only the reference chart with telereminder group showed a statistically significant increase in mean adherence score, from 7.18 to 7.69 (P = 0.047). CONCLUSIONS: Adherence to medication in chronic diseases like glaucoma is an important healthcare issue to address. Most of these patients have poor adherence because of multiple factors, and hence interventions aimed at improving adherence should be multifaceted to target these barriers.

A Pilot Study on MicroRNA Profile in Tear Fluid to Predict Response to Anti-VEGF Treatments for Diabetic Macular Edema.

(1) Background: Intravitreal anti-vascular endothelial growth factor (anti-VEGF) is an established treatment for center-involving diabetic macular edema (ci-DME). However, the clinical response is heterogeneous. This study investigated miRNAs as a biomarker to predict treatment response to anti-VEGF in DME. (2) Methods: Tear fluid, aqueous, and blood were collected from patients with treatment-naïve DME for miRNA expression profiling with quantitative polymerase chain reaction. Differentially expressed miRNAs between good and poor responders were identified from tear fluid. Bioinformatics analysis with the miEAA tool, miRTarBase Annotations, Gene Ontology categories, KEGG, and miRWalk pathways identified interactions between enriched miRNAs and biological pathways. (3) Results: Of 24 participants, 28 eyes received bevacizumab (15 eyes) or aflibercept (13 eyes). Tear fluid had the most detectable miRNA species (N = 315), followed by serum (N = 309), then aqueous humor (N = 134). MiRNAs that correlated with change in macular thickness were miR-214-3p, miR-320d, and hsa-miR-874-3p in good responders; and miR-98-5p, miR-196b-5p, and miR-454-3p in poor responders. VEGF-related pathways and the angiogenin-PRI complex were enriched in good responders, while transforming growth factor-ß and insulin-like growth factor pathways were enriched in poor responders. (4) Conclusions: We reported a panel of novel miRNAs that provide insight into biological pathways in DME. Validation in larger independent cohorts is needed to determine the predictive performance of these miRNA candidate biomarkers.

Systemic Factors Associated with Treatment Response in Diabetic Macular Edema.

PURPOSE: To identify systemic factors that may influence the response to anti-VEGF therapy in patients with diabetic macular edema (DME). METHODS: 35 patients undergoing anti-VEGF injections for centre-involving DME were studied in this prospective observational study. The primary outcome was change in macular thickness one month after treatment, measured using spectral-domain optical coherence tomography (OCT). At baseline, information on various systemic factors was collected including glycosylated hemoglobin (HbA1c), serum VEGF levels, lipid profile and markers of renal function, and blood pressure. Thirty-three of the 35 patients were included in this study. Nonparametric statistical tests were used for the analysis of the data in view of the nonnormal distribution of the outcome variables. Multivariate analysis was performed using logistic regression. Stata 12.1 software was used for the analysis. Main Outcome Measures. Reduction in macular central subfield thickness (on spectral-domain OCT) and change in logMAR visual acuity at one month after injection. RESULTS: Lower HbA1c levels (7% or less) were significantly associated with greater reduction in central macular subfield thickness at one month after injection of bevacizumab or ranibizumab on both univariate analysis (p=0.012) and multivariate analysis (p=0.012) and multivariate analysis (. CONCLUSIONS: Better glycemic control is associated with a greater reduction in central macular thickness after the first injection of bevacizumab or ranibizumab in diabetic macular edema. Patients with high levels of HbA1c and poor response to anti-VEGF may benefit from strict control of their blood glucose.

Three-year outcomes of Descemet's stripping endothelial keratoplasty in eyes with pre-existing glaucoma drainage devices.

BACKGROUND: Descemet's stripping endothelial keratoplasty (DSEK) is the most common procedure for corneal transplantation. The effect of a pre-existing glaucoma drainage device on long-term surgical outcomes is uncertain. METHODS: A retrospective chart review of all DSEK cases at an academic hospital over a 10-year period was conducted. RESULTS: 37 eyes who had undergone DSEK were included for analysis. These consist of 12 eyes with pre-existing GDD (GDD group), 13 eyes with glaucoma but no previous GDD (no-GDD group), and a control group of 12 patients with no ocular comorbidities apart from the indication for DSEK (control group). Visual acuity (VA) was significantly improved amongst all 3 groups, and there was no significant difference in VA between the GDD and no-GDD groups. There were no significant differences in absolute or increase in IOP between all three groups at 3 years. Graft survival rates of the 3 groups were not significantly different at 12 months. However, at 36 months, graft survival was 63% in the GDD group compared to 81% in the no-GDD group and 92% in the control group. In the GDD group, an increase in number of preoperative glaucoma drops, and a tube location in the anterior chamber were associated with an increased hazard ratio for failure. CONCLUSIONS: Presence of a GDD adversely affects graft survival whereas glaucomatous eyes which were medically managed or surgically managed without a GDD had survival rates comparable to controls. Glaucoma-filtering surgeries may confer graft survival advantage over tube shunt surgeries after DSEK.

Disease patterns of microbial keratitis in Singapore: A retrospective case series.

PURPOSE: To investigate the disease patterns of Microbial Keratitis(MK) in patients seen in a tertiary referral hospital, to evaluate the clinical outcomes of MK and the risk factors for poorer visual outcomes. METHODS: This is a retrospective case series of all culture-positive corneal scrapings between April 2012 and October 2016. A total of 230 patients(n = 230) were included into this study. Patient demographics, clinical information and microbiological characteristics of organisms are collected. RESULTS: 64.3% of patients with MK are contact lens(CL) users. Among CL users, there is a preponderance of females(68.9%) and they tend to be younger (27.1 ± 10.6 years). The most frequently isolated organism in this study is Pseudomonas aeruginosa(51.7%) with 69.6% of cases belonging to CL users. MK in non-CL users tend to involve other organisms, such as coagulase-negative Staphylococci, Staphylococcus aureus and Streptococcus pneumoniae. Pseudomonas aeruginosa exhibits good sensitivity rates to ciprofloxacin, levofloxacin and gentamicin. Non-Pseudomonas organisms display similar sensitivities to ciprofloxacin, levofloxacin and gentamicin. MK in non-CL users is related to predisposing factors of prior ocular trauma and concomitant ocular pathology. They tend to have worse visual acuity(VA) on presentation and after treatment compared to CL users. Poorer VA outcome is associated with larger ulcers, increasing age, trauma and non-CL wearers. Successful clinical outcome is achieved in 97.8% of patients, with only 2.2% requiring further surgical intervention. CONCLUSION: CL use alters the disease patterns of MK as well as the underlying microbiological etiology. Fluoroquinolones and aminoglycosides are good empirical antibiotics for MK treatment. Early referral to a tertiary centre will likely allow for earlier treatment, which can result in better VA outcome, especially so in patients who are older, non-CL wearers and have larger ulcers with associated trauma.

Optical and Tectonic Corneal Transplant Outcomes in a Tertiary Hospital in Singapore within the Singapore Corneal Transplant Registry.

INTRODUCTION: This study aimed to describe and compare corneal graft survival and optical outcomes following deep anterior lamellar keratoplasty (DALK) and Descemet's stripping automated endothelial keratoplasty (DSAEK) with penetrating keratoplasty (PK), and to document tectonic success of patch grafts. MATERIALS AND METHODS: This was a retrospective, non-randomised, comparative and descriptive cohort study. A total of 139 eyes that underwent primary keratoplasty between 2000 and 2016 were included, and the following data was extracted: demographics, clinical diagnosis and primary indication, pre- and intraoperative risk factors, postkeratoplasty outcomes, and complications. Optical success was defined as good graft clarity and best corrected visual acuity (BCVA) of 6/12 or better. Graft failure was defined as irreversible corneal oedema and loss of clarity. Tectonic success in patch grafts was defined as tectonic integrity with no repeat tectonic surgical procedure required in the postoperative period. RESULTS: The mean follow-up duration was 3.24 ± 3.47 years in the PK group (n = 16), 1.89 ± 0.86 years in the DALK group (n = 37), 2.36 ± 1.24 years in the DSAEK group (n = 53), and 2.17 ± 1.09 years in the patch graft group (n = 33). The 3-year probabilties of survival for PK, DALK, DSAEK and patch graft were 60.9%, 94.1%, 89.9%, and 67.1%, respectively. The overall percentage of complications was significantly higher for PK (81.3%), compared to DALK (48.6%), DSAEK (49.1%), and patch graft (21.2%). In the PK and DALK groups, 100% achieved DSAEK (49.1%), and patch graft (21.2%). In the PK and DALK groups, 100% achieved BCVA of 6/12 or better, while in the DSAEK group, 96.43% achieved BCVA of 6/12 or better. CONCLUSION: From a similar study cohort of Asian eyes, graft survival was superior and complications were reduced for DALK and DSAEK compared to PK, but optical outcomes were comparable. Graft survival for patch graft was expectedly lower, but the incidence of complications was low.

Primary external dacryocystorhinostomy versus primary endonasal dacryocystorhinostomy: a review.

This paper aims to compare the efficacy, mean operative time and adverse effects of primary external dacryocystorhinostomy (DCR) versus primary endonasal DCR in treating acquired nasolacrimal duct obstruction. Searches were performed for studies comparing the two procedures. Two reviewers independently extracted data from 14 eligible studies. A random effects model was used to analyse the studies. Outcome measures were defined as patency of the nasolacrimal canal and mean operative time,and adverse effects as cutaneous scarring and bleeding.Both procedures were comparable in efficacy in terms of full success, partial success and anatomic patency. Subgroup analysis showed no significant difference between prospective and retrospective studies as well as between non-laser endonasal DCR versus external DCR and laser endonasal DCR versus external DCR. Endonasal DCR had a significantly shorter mean operative duration, be it laser endonasal DCR (mean difference: 37.65 min, 95% confidence intervals:3.54-71.75 min, P: 0.03) or non-laser endonasal DCR (mean difference: 19.22 min, 95% confidence intervals: 2.15-36.28 min, P: 0.03). The odds of post-operative bleeding was not significantly different between the two procedures, whereas post-operative cutaneous scarring was unique to external DCR and occurred in 50 out of 402 (12.44%) external DCRs recorded. Endonasal DCR has comparable success rates with external DCR and has a shorter operative time and no cutaneous scar. However, drawbacks include the steep learning curve and higher costs.

Meta-analysis of viscocanalostomy versus trabeculectomy in uncontrolled glaucoma.

PURPOSE: Compare the efficacy and safety profile of viscocanalostomy versus trabeculectomy in uncontrolled glaucoma. PATIENTS AND METHODS: We looked through various search engines for randomized controlled trials directly comparing viscocanalostomy with trabeculectomy. Outcome measurements we examined were mean intraocular pressure difference at 6 months, 12 months, and 24 months, mean difference in postoperative number of antiglaucomatous medications and relative risk of adverse events. Subgroup analysis looked at studies that included 1 eye per patient, studies that included only white patients, studies with only primary open angle glaucoma, studies that did not allow the use of intraoperative mitomycin C in trabeculectomy treatment, studies that did not allow any postoperative use of antimetabolites, and studies with and without the use of postviscocanalostomy Nd:YAG goniopuncture. RESULTS: Ten randomized controlled trials were selected and included in the meta-analysis with a total of 458 eyes of 397 patients with medically uncontrolled glaucoma. At 6 months, mean intraocular pressure difference was 2.25 mm Hg (95% confidence interval 1.38-3.12), at 12 months it was 3.64 mm Hg (2.74, 4.54), whereas at 24 months it was 3.42 mm Hg (1.80, 5.03). Trabeculectomy was found to have a significantly better pressure-lowering outcome (P<0.0001). Relative risk of adverse events such as perforation of Descemet membrane, hypotony, hyphema, shallow anterior chamber, and cataract formation, were found to be 7.72 (2.37, 25.12), 0.29 (0.15, 0.58), 0.50 (0.30, 0.84), 0.19 (0.08, 0.45), and 0.31 (0.15, 0.64), respectively. Viscocanalostomy had a significantly higher relative risk of intraoperative perforation of Descemet membrane, whereas trabeculectomy had significantly more postoperative adverse events (P≤0.008). CONCLUSIONS: Trabeculectomy was found to have a greater pressure-lowering effect compared with viscocanalostomy. However, viscocanalostomy had a significantly better risk profile.