Sustained release of brimonidine from conjunctival sac insert to reduce intraocular pressure for glaucoma treatment.

BACKGROUND: Glaucoma is one of the major irreversible blinding eye diseases in the world. Reducing intraocular pressure (IOP) is the primary treatment option, and taking eye drops daily is the common method. However, short drug duration and poor bioavailability of eye drops may lead to unsatisfied therapeutic effects and inadequate patient compliance. METHODS: A brimonidine-loaded silicone rubber insert (BRI@SR@PT) was prepared by loading brimonidine into a surface-modified silicone rubber ring, followed by polydopamine/thermoplastic polyurethane coatings. The physical properties, in vitro cytocompatibility and drug release of BRI@SR@PT were investigated. The BRI@SR@PT was administrated in the conjunctival sac of rabbit eyes, and its in vivo drug release, IOP-lowering efficacy and biosafety were assessed. RESULTS: The BRI@SR@PT presented great thermal stability and excellent elasticity. The BRI@SR@PT was able to release BRI sustainably for 28 days with little toxicity in vitro. Compared to BRI eye drops, the BRI@SR@PT effectively lowered IOP for 21 days based on the sustained BRI release with great biosafety when administrated in conjunctival sac of rabbit eyes in a noninvasive fashion. CONCLUSIONS: The conjunctival sac insert (BRI@SR@PT), as a promising drug-delivery platform, may provide a sustained IOP-lowering treatment for patients with ocular hypertension or glaucoma, without the need for invasive procedures.

The association between airborne particulate matter (PM2.5) exposure level and primary open-angle glaucoma.

The eye is vulnerable to the adverse effects of air pollution. Previous experimental study found that fine particulate matter (PM2.5) had a direct toxic effect on intraocular tissues. However, clinical evidence for the impact of air pollutants exposure on functional and structural changes in glaucoma remains scarce. A total of 120 patients with primary open-angle glaucoma (POAG) who met the inclusion criteria were included in this retrospective study. The standardized ophthalmic examination, such as intraocular pressure (IOP), visual field, optical coherence tomography, and comprehensive physical examination, were performed. The air pollution data, including PM2.5 concentration and air quality index (AQI), were collected. PM2.5 and AQI for the day of the medical examination, as well as one month, and three months before the medical examination date, were investigated. In our results, higher average exposure levels for one-month and three-month, were associated with increased IOP (r=0.229, P=0.013; r=0.204, P=0.028, respectively) and decreased visual field mean sensitivity (MS) (r=-0.212, P=0.037; r=-0.305, P=0.002, respectively). PM2.5 concentrations for the day of the medical examination was not significantly associated with ocular parameters. In multiple linear regression analysis adjusted for demographic and clinical factors, higher PM2.5 exposure for one month was associated with elevated IOP (P=0.040, ß=0.173, 95 %CI=0.008-0.337). We also found an association between PM2.5 and MS (one-month exposure: ß=-0.160, P=0.029; three-month exposure: ß=-0.238, P=0.002). The logistic regression analysis found that three-month average PM2.5 exposure level was significantly associated with the disease severity (ß=0.043, P=0.025, 95 %CI=1.005-1.084). In conclusion, this study is the first to investigate the relationship between air pollution and detailed ocular parameters of POAG patients in Shanghai over a three-year period, and to explore the effects of different exposure times of PM2.5 on glaucoma. This study found that PM2.5 exposure was correlated with elevated IOP and decreased MS. The one-month PM2.5 exposure level had the most significant effects on IOP. The three-month PM2.5 exposure level was an independent risk factor for POAG severity. Current evidence suggests there may be an association between PM2.5 exposure and POAG.

MicroRNA-146a-5p protects retinal ganglion cells through reducing neuroinflammation in experimental glaucoma.

Neuroinflammation plays important roles in retinal ganglion cell (RGC) degeneration in glaucoma. MicroRNA-146 (miR-146) has been shown to regulate inflammatory response in neurodegenerative diseases. In this study, whether and how miR-146 could affect RGC injury in chronic ocular hypertension (COH) experimental glaucoma were investigated. We showed that in the members of miR-146 family only miR-146a-5p expression was upregulated in COH retinas. The upregulation of miR-146a-5p was observed in the activated microglia and Müller cells both in primary cultured conditions and in COH retinas, but mainly occurred in microglia. Overexpression of miR-146a-5p in COH retinas reduced the levels pro-inflammatory cytokines and upregulated the levels of anti-inflammatory cytokines, which were further confirmed in the activated primary cultured microglia. Transfection of miR-146a-5p mimic increased the percentage of anti-inflammatory phenotype in the activated BV2 microglia, while transfection of miR-146a-5p inhibitor resulted in the opposite effects. Transfection of miR-146a-5p mimic/agomir inhibited the levels of interleukin-1 receptor associated kinase (IRAK1) and TNF receptor associated factor 6 (TRAF6) and phosphorylated NF-κB subunit p65. Dual luciferase reporter gene assay confirmed that miR-146a-5p could directly target IRAK1 and TRAF6. Moreover, downregulation of IRAK1 and TRAF6 by siRNA techniques or blocking NF-κB by SN50 in cultured microglia reversed the miR-146a-5p inhibitor-induced changes of inflammatory cytokines. In COH retinas, overexpression of miR-146a-5p reduced RGC apoptosis, increased RGC survival, and partially rescued the amplitudes of photopic negative response. Our results demonstrate that overexpression of miR-146a-5p attenuates RGC injury in glaucoma by reducing neuroinflammation through downregulating IRAK1/TRAF6/NF-κB signaling pathway in microglia.

Primary congenital glaucoma: We are always on the way.

Primary congenital glaucoma (PCG), a developmental glaucoma occurring due to angle anomaly, earns growing concerns among ophthalmologists for its vision-damaging attribute. The incidence of PCG varies among races and geographic regions and is mostly genetically associated. Theories have been posed in attempt to address the etiology of this congenital maldevelopment and in the meanwhile providing evidence for feasibility of PCG surgeries. In regard to the clinical aspects of this entity, both the clinical characteristics and general principals of management are introduced, with angle surgeries highlighted for clarifying details including their success rates, key points for a successful surgical intervention, postoperative management, and follow-up strategies. Taking patients' vision-associated quality of life into consideration, we stressed that further perceptual learning and low vision rehabilitation are momentous. However, much has yet to be elucidated in respect of the truly comprehensive pathogenesis underneath as well as means by which clinical outcomes of PCG can be further improved. We are now looking forward to innovative therapeutic approaches like gene therapy in specific genes in the future, with the hope of improving their life-long visual quality in those young patients.

Eight Years and Beyond Longitudinal Changes of Peripapillary Structures on OCT in Adult Myopia.

PURPOSE: To investigate the long-term changes of peripapillary structures detected by enhanced depth imaging of optical coherence tomography (OCT) in adult myopia. DESIGN: Observational case series. METHODS: Myopic participants who had undergone a full baseline ophthalmologic examination and had been followed up for a minimum of 8 years were included. Using enhanced depth imaging of OCT, scans around the optic disc in the Spectralis software Follow-up mode, which enabled capturing of the same positions, were performed in 65 eyes. The peripapillary parameters including the size of border tissue, Bruch membrane opening (BMO), peripapillary choroidal thickness, and the angle between peripapillary Bruch membrane (BM) and anterior sclera were manually delineated and measured. RESULTS: The axial length showed a significant elongation after a mean follow-up of 9.46 ± 0.92 years. The rates of changes were 0.015 ± 0.011 mm/y in the medium myopia group and 0.057 ± 0.039 mm/y in the high myopia group. At the last visit, the average border tissue length and BMO diameter were increased. The angle between peripapillary BM did not show significant change, while the angle between the peripapillary sclera showed a significant rise. On multivariate analysis, the border tissue elongation, BMO enlargement, and increased sclera angle were all associated with a change in axial length. The development of a BM defect and inward protrusion of sclera in the temporal peripapillary region was observed on 8 eyes (34.8%) in the high myopia group, along with an extreme thinning or disappearing of the peripapillary choroid. CONCLUSION: Marked longitudinal changes in peripapillary structures including border tissue, BM, choroid, and sclera could be observed in adult myopic eyes, which may impact the biomechanical environment around the optic nerve head.

Association of Long-Term Exposure to Ambient Air Pollution With the Risk of Acute Primary Angle Closure.

Purpose: The purpose of this study was to investigate the association between long-term exposure to ambient air pollutants and the risk of acute primary angle closure (APAC). Methods: Two hundred eighty-one (281) patients with APAC and 730 age- and sex-matched controls hospitalized between January 2017 and December 2019 were enrolled in this retrospective case-control study. Residential exposure to ambient air pollutants, including fine particulate matter (PM2.5), inhalable particulate (PM10), nitrogen dioxide (NO2), sulfur dioxide (SO2), and ozone were estimated by satellite-models or ground measurement. Multivariate regression analyses explored the association between annual air pollutants exposure and the risk of APAC. Results: Of the 1011 participants (31.1% were male subjects), the average age was 64.0 years. Long-term exposure to PM2.5, PM10, and SO2 were significantly associated with an increased risk of APAC. The adjusted odds ratios (aORs) for each interquartile range (IQR) increment of PM2.5, PM10, and SO2 were 1.28 (95% confidence interval [CI] = 1.06-1.57), 1.26 (95% CI = 1.06-1.50), and 1.30 (95% CI = 1.04-1.62) separately, after controlling for confounders. Robust associations were observed for a longer lag 2-year exposure. Conclusions: Long-term exposure to PM2.5, PM10, and SO2 was associated with an increased risk of APAC in a Chinese population. Our findings provide epidemiological implications on the adverse effects of air pollution on ocular diseases. Translational Relevance: Long-term exposure to ambient air pollutants increased the risk of APAC.

Transfer RNA derived fragment, tRF-Glu-CTC, aggravates the development of neovascular age-related macular degeneration.

Rationale: Angiogenesis expedites tissue impairment in many diseases, including age-related macular degeneration (AMD), a leading cause of irreversible blindness in elderly. A substantial proportion of neovascular AMD patients, characterized by aberrant choroidal neovascularization (CNV), exhibit poor responses or adverse reactions to anti-VEGF therapy. Herein, we aimed to unveil the function of newly identified transfer RNA-derived small RNA, tRF-Glu-CTC, in the pathology of CNV and determine its potential in inhibiting angiogenesis. Methods: Small non-coding RNA sequencing and quantitative polymerase chain reaction were conducted to detect expression pattern of tRF-Glu-CTC in CNV development. Immunofluorescence staining, fundus fluorescein angiography and ex vivo choroidal sprouting assays were employed for the evaluation of tRF-Glu-CTC's function in CNV development. The role of tRF-Glu-CTC in endothelial cells were determined by in vitro endothelial cell proliferation, migration and tube formation assays. Transcriptome sequencing, dual-luciferase reporter assay and in vitro experiments were conducted to investigate downstream mechanism of tRF-Glu-CTC mediated pathology. Results: tRF-Glu-CTC exhibited substantial up-regulation in AMD patients, laser-induced CNV model, and endothelial cells under hypoxia condition, which is a hallmark of CNV. Inhibiting tRF-Glu-CTC reduced angiogenesis and hypoxia stress in the neovascular region without neuroretina toxicity in laser-induced CNV model, showing an anti-angiogenic effect comparable to bevacizumab, while overexpression of tRF-Glu-CTC significantly augmented CNV. Mechanically, under hypoxia condition, angiogenin was involved in the production of tRF-Glu-CTC, which in turn triggered endothelial cell tubulogenesis, migration and promoted the secretion of inflammatory factors via the suppression of vasohibin 1 (VASH1). When downregulating VASH1 expression, the inhibition of tRF-Glu-CTC showed minimal suppression on angiogenesis. Conclusions: This study demonstrated the important role of tRF-Glu-CTC in the progression of angiogenesis. Targeting of tRF-Glu-CTC may be an alternative to current anti-VEGF therapy for CNV in AMD and other conditions with angiogenesis.

Clinical analysis of infectious endophthalmitis following glaucoma filtration surgery.

BACKGROUND: This study aimed to evaluate the clinical correlative factors and outcomes of treatment of bleb-associated endophthalmitis (BAE) following glaucoma filtration surgery in a Chinese population from the year 2012 to 2022, and to compare them with the clinical course during the coronavirus disease (COVID-19) pandemic period. METHODS: This was a retrospective analysis of consecutive cases of BAE treated at the Eye & ENT Hospital of Fudan University, Shanghai, China, between January 1, 2012, and December 31, 2022. The clinical presentation, treatment modality, microbiological data, clinical course, and outcomes of visual acuity (VA) and intraocular pressure (IOP) in all BAE cases were collected and analyzed. RESULTS: A total of 28 eyes with BAE were examined, predominantly in male patients (71.4%, p = 0.023). Most patients underwent trabeculectomy (89.3%, p ≤ 0.001), while a smaller proportion underwent Ex-PRESS implantation (10.7%). Primary open-angle glaucoma (POAG) was the most common type of glaucoma (39.3%, p ≤ 0.001). Most patients (96.4%) presented with poor visual acuity, worse than 20/400, and IOP ranged from 3-60 mmHg. Treatment, including initial tap-and-inject procedure of antibiotics (Ceftazidime and Norvancomycin) or initial pars plana vitrectomy (PPV), was initiated 5.0 ± 7.1 days after BAE onset. Streptococcus was the most common causative organism (53.6% of cases, p ≤ 0.001). The visual acuity significantly improved from 2.58 ± 0.27 to 2.14 ± 0.85 (reported in logMAR) after treatment (p ≤ 0.001), and most patients maintained normal tension during follow-up. Poisson regression model analysis showed the annual incidence of BAE during the COVID-19 pandemic period was significantly twice greater than that of previous years. CONCLUSIONS: BAE may cause irreversible visual impairment. POAG filtering surgery with male sex and the COVID-19 pandemic period might be potentially relevant factors for BAE. Culture positivity was closely related to BAE prognosis, with Streptococcus species being the leading pathogenic organisms. Online outpatient services, early diagnosis, and timely treatment may rescue vision and maintain IOP control in the presence of BAE.

Metabolomics identifies and validates serum androstenedione as novel biomarker for diagnosing primary angle closure glaucoma and predicting the visual field progression.

Background: Primary angle closure glaucoma (PACG) is the leading cause of irreversible blindness in Asia, and no reliable, effective diagnostic, and predictive biomarkers are used in clinical routines. A growing body of evidence shows metabolic alterations in patients with glaucoma. We aimed to develop and validate potential metabolite biomarkers to diagnose and predict the visual field progression of PACG. Methods: Here, we used a five-phase (discovery phase, validation phase 1, validation phase 2, supplementary phase, and cohort phase) multicenter (EENT hospital, Shanghai Xuhui Central Hospital), cross-sectional, prospective cohort study designed to perform widely targeted metabolomics and chemiluminescence immunoassay to determine candidate biomarkers. Five machine learning (random forest, support vector machine, lasso, K-nearest neighbor, and GaussianNaive Bayes [NB]) approaches were used to identify an optimal algorithm. The discrimination ability was evaluated using the area under the receiver operating characteristic curve (AUC). Calibration was assessed by Hosmer-Lemeshow tests and calibration plots. Results: Studied serum samples were collected from 616 participants, and 1464 metabolites were identified. Machine learning algorithm determines that androstenedione exhibited excellent discrimination and acceptable calibration in discriminating PACG across the discovery phase (discovery set 1, AUCs=1.0 [95% CI, 1.00-1.00]; discovery set 2, AUCs = 0.85 [95% CI, 0.80-0.90]) and validation phases (internal validation, AUCs = 0.86 [95% CI, 0.81-0.91]; external validation, AUCs = 0.87 [95% CI, 0.80-0.95]). Androstenedione also exhibited a higher AUC (0.92-0.98) to discriminate the severity of PACG. In the supplemental phase, serum androstenedione levels were consistent with those in aqueous humor (r=0.82, p=0.038) and significantly (p=0.021) decreased after treatment. Further, cohort phase demonstrates that higher baseline androstenedione levels (hazard ratio = 2.71 [95% CI: 1.199-6.104], p=0.017) were associated with faster visual field progression. Conclusions: Our study identifies serum androstenedione as a potential biomarker for diagnosing PACG and indicating visual field progression. Funding: This work was supported by Youth Medical Talents - Clinical Laboratory Practitioner Program (2022-65), the National Natural Science Foundation of China (82302582), Shanghai Municipal Health Commission Project (20224Y0317), and Higher Education Industry-Academic-Research Innovation Fund of China (2023JQ006).

Three-dimensional choroidal vascularity index and choroidal thickness in fellow eyes of acute and chronic primary angle-closure using swept-source optical coherence tomography.

AIM: To compare the three-dimensional choroidal vascularity index (CVI) and choroidal thickness between fellow eyes of acute primary angle-closure (F-APAC) and chronic primary angle-closure glaucoma (F-CPACG) and the eyes of normal controls. METHODS: This study included 37 patients with unilateral APAC, 37 with asymmetric CPACG without prior treatment, and 36 healthy participants. Using swept-source optical coherence tomography (SS-OCT), the macular and peripapillary choroidal thickness and three-dimensional CVI were measured and compared globally and sectorally. Pearson's correlation analysis and multivariate regression models were used to evaluate choroidal thickness or CVI with related factors. RESULTS: The mean subfoveal CVIs were 0.35±0.10, 0.33±0.09, and 0.29±0.04, and the mean subfoveal choroidal thickness were 315.62±52.92, 306.22±59.29, and 262.69±45.55 µm in the F-APAC, F-CPACG, and normal groups, respectively. All macular sectors showed significantly higher CVIs and choroidal thickness in the F-APAC and F-CPACG eyes than in the normal eyes (P<0.05), while there were no significant differences between the F-APAC and F-CPACG eyes. In the peripapillary region, the mean overall CVIs were 0.21±0.08, 0.20±0.08, and 0.19±0.05, and the mean overall choroidal thickness were 180.45±54.18, 174.82±50.67, and 176.18±37.94 µm in the F-APAC, F-CPACG, and normal groups, respectively. There were no significant differences between any of the two groups in all peripapillary sectors. Younger age, shorter axial length, and the F-APAC or F-CPACG diagnosis were significantly associated with higher subfoveal CVI and thicker subfoveal choroidal thickness (P<0.05). CONCLUSION: The fellow eyes of unilateral APAC or asymmetric CPACG have higher macular CVI and choroidal thickness than those of the normal controls. Neither CVI nor choroidal thickness can distinguish between eyes predisposed to APAC or CPACG. A thicker choroid with a higher vascular volume may play a role in the pathogenesis of primary angle-closure glaucoma.

Adult-onset neuronal intranuclear inclusion disease related retinal degeneration: a Chinese case series.

Purpose: To evaluate adult-onset neuronal intranuclear inclusion disease (NIID)-related retinopathy with guanine-guanine-cytosine repeat expansions in NOTCH2NLC. Materials and methods: Neuro-ophthalmic evaluations, including best-corrected visual acuity, slit-lamp biomicroscopy, intraocular pressure (IOP), ultrasound biomicroscopy, pupillometry, fundus photography, fundus autofluorescence (FAF), optical coherence tomography (OCT), Humphrey visual field, full-field electroretinography (ERG), and multifocal ERG (mf-ERG) were performed in patients with gene-proven NIID. Results: Nine patients (18 eyes) were evaluated, with a median age of 62 years (55-68) and only one man was included in our study. Six patients presented with decreased visual acuity or night blindness, whereas the other three were asymptomatic. The visual acuity was measured from 20/200 to 20/20. Miosis was present in eight patients, four of whom had ciliary process hypertrophy and pronation, and three of whom had shallow anterior chambers. Fundus photography, FAF, and OCT showed consistent structural abnormalities mainly started from peripapillary areas and localized in the outer layer of photoreceptors and inner ganglion cell layer. ERG and mf-ERG also revealed retinal dysfunction in the corresponding regions. Conclusion: Patients with NIID showed both structural and functional retinopathies which were unique and different from common cone-rod dystrophy or retinitis pigmentosa. Patients with miosis may have a potential risk of an angle-closure glaucoma attack. Neuro-ophthalmic evaluations is essential for evaluating patients with NIID, even without visual symptom.

Outcomes of Filtering Surgery Versus Clear Lens Extraction in Young Patients With Angle-Closure Glaucoma.

PURPOSE: To compare the effect of filtering surgery versus clear lens extraction in young patients with medically uncontrolled angle-closure glaucoma (ACG). DESIGN: Retrospective, nonrandomized, comparative, interventional study. METHODS: We reviewed the medical charts of patients with the following scenarios: (1) age ≤40 years; (2) diagnosis of ACG without cataract, including primary angle-closure glaucoma (PACG), nanophthalmic ACG, and ACG combined with retinal dystrophies; and (3) ACG undergoing filtering surgery or clear lens extraction. The main outcomes including intraocular pressure (IOP), number of medications, best-corrected visual acuity, and severe complications were extracted at the postoperative early (within 1 week) and late stage (>3 months) follow-up. RESULTS: Data from 160 eyes of 130 young patients with ACG were available. Eyes with 76 PACG, 12 nanophthalmic ACG, and 26 ACG with retinal diseases underwent filtering surgery, whereas eyes with 22 PACG, 12 nanophthalmic ACG, and 12 ACG with retinal diseases received clear lens extraction. Overall, filtering surgery and clear lens extraction resulted in significant but comparable IOP and drug reductions at the postoperative late stage in each ACG subgroup, with similar complete success rates between 2 treatments (all P > .05). Regarding the safety, filtering surgery and patients with retinal diseases were independent factors associated with postoperative malignant glaucoma (P < .05 in both multivariable logistic regression models). CONCLUSIONS: This study highlights that the efficacy of clear lens extraction is comparable to that of filtering surgery in medically uncontrolled ACG in young patients, but clear lens extraction is safer, especially for young patients with ACG comorbid with retinal diseases.

The correlation of anterior segment structures in primary congenital glaucoma by ultrasound biomicroscopy with disease severity and surgical outcomes.

PURPOSE: To evaluate the anterior segment structures using ultrasound biomicroscopy (UBM) in primary congenital glaucoma (PCG) and explore their correlation with disease severity and surgical outcomes. METHODS: Clinical information of PCG patients who underwent UBM prior to their first glaucoma surgeries from September 2014 to March 2021 were reviewed. The study included 214 UBM images of 154 PCG eyes and 60 fellow unaffected eyes. Anterior segment characteristics were analyzed. UBM parameters, including the iris thickness (IT) at variant distances from the pupil edge and iris root, anterior chamber depth (ACD), and pupil diameter (PD), were compared between two groups and their relationship with clinical factors and surgical outcomes were analyzed in PCG eyes. RESULTS: PCG eyes had unclear scleral spur, thin iris, wide anterior chamber angle, deep anterior chamber, rarefied ciliary body, elongated ciliary processes, and abnormal anterior iris insertion. ITs were thinner, ACD was deeper, and PD was larger in PCG eyes than fellow unaffected eyes (all P < 0.001). In PCG eyes, thinner ITs correlated with bilateral involvement and earlier age at presentation, and larger PD correlated with earlier age at presentation (P = 0.030) and higher intraocular pressure (P < 0.001). Thinner IT2 (P = 0.046) and larger PD (P = 0.049) were identified as risk factors for surgical failure. CONCLUSION: UBM is a powerful technique to exam anterior segment structures in PCG. The anatomical features are associated with disease severity and surgical outcomes, providing essential clinical insights.

Abnormal Topological Organization of White Matter Structural Networks in Normal Tension Glaucoma Revealed via Diffusion Tensor Tractography.

BACKGROUND: Normal tension glaucoma (NTG) is considered a neurodegenerative disease with glaucomatous damage extending to diffuse brain areas. Therefore, this study aims to explore the abnormalities in the NTG structural network to help in the early diagnosis and course evaluation of NTG. METHODS: The structural networks of 46 NTG patients and 19 age- and sex-matched healthy controls were constructed using diffusion tensor imaging, followed by graph theory analysis and correlation analysis of small-world properties with glaucoma clinical indicators. In addition, the network-based statistical analysis (NBS) method was used to compare structural network connectivity differences between NTG patients and healthy controls. RESULTS: Structural brain networks in both NTG and NC groups exhibited small-world properties. However, the small-world index in the severe NTG group was reduced and correlated with a mean deviation of the visual field (MDVF) and retinal nerve fiber layer (RNFL) thickness. When compared to healthy controls, degree centrality and nodal efficiency in visual brain areas were significantly decreased, and betweenness centrality and nodal local efficiency in both visual and nonvisual brain areas were also significantly altered in NTG patients (all p < 0.05, FDR corrected). Furthermore, NTG patients exhibited increased structural connectivity in the occipitotemporal area, with the left fusiform gyrus (FFG.L) as the hub (p < 0.05). CONCLUSIONS: NTG exhibited altered global properties and local properties of visual and cognitive-emotional brain areas, with enhanced structural connections within the occipitotemporal area. Moreover, the disrupted small-world properties of white matter might be imaging biomarkers for assessing NTG progression.

En face optical coherence tomography detection of Schlemm's canal in primary open angle glaucoma.

Purpose: To compare the morphological characteristics of Schlemm's canal (SC) in patients with primary open-angle glaucoma (POAG) and healthy controls, using swept-source optical coherence tomography (SS-OCT) with en face reconstruction. Methods: In this Prospective comparative study, we included 100 eyes from 50 patients diagnosed with POAG and 50 healthy controls. Three-dimensional cube and line scans of the temporal and nasal quadrants of the anterior segment of the limbus were acquired using SS-OCT. SC was identified using en face and cross-sectional images. The diameter and area of SC in cross-sectional images and the visible percentage and area of SC in en face images were measured using ImageJ. Results: SC was observed in 84% of en face images and 81% of cross-sectional images in eyes with POAG but in 92% of en face images and 86% of cross-sectional images in control eyes. Significant differences between the POAG and normal control eyes were found in the en face area (0.35 ± 0.14 mm2 vs. 0.56 ± 0.22 mm2 in the temporal quadrant and 0.36 ± 0.14 mm2 vs. 0.58 ± 0.23 mm2 in the nasal quadrant; both p < 0.001) and visible percentage of SC (85.71% vs. 94.91% and 87.10% vs. 95.52% in the temporal and nasal quadrant respectively, both p < 0.001) in en face images as well as the cross-sectional area (2790.9 ± 942.2 µm2 vs. 4138.6 ± 2027.8 µm2 in the temporal quadrant and 2805.7 ± 947.2 µm2 vs. 4224.0 ± 2002.2 µm2 in the nasal quadrant, both p < 0.001) and diameter of SC (123.1 ± 25.4 µm vs. 149.5 ± 34.7 µm in the temporal quadrant and 126.3 ± 28.9 µm vs. 155.3 ± 36.0 µm in the nasal quadrant, both p < 0.001) in cross-section images. In addition, the mean intraocular pressure (IOP) significantly correlated with the en face area, visible percentage of SC, and cross-sectional area in the temporal and nasal quadrants. Conclusion: SS-OCT can obtain high-quality en face images of SC without post-acquisition processing. Eyes with POAG had a decreased en face SC area compared with normal eyes. A correlation between SC area, visible percentage of en face images, and IOP was also observed.

The morphology of angle dysgenesis assessed by ultrasound biomicroscopy and its relationship with glaucoma severity and mutant genes in Axenfeld-Rieger syndrome.

Background: Axenfeld-Rieger syndrome (ARS), a developmental disorder, involves anterior segment abnormalities and can lead to glaucoma. However, limited research has addressed the ultrasound biomicroscopy (UBM) characteristics of ARS. This study aimed to assess the anterior chamber angle features using UBM in ARS and determine their correlation with glaucoma severity and mutant genes. Methods: UBM examination was conducted for 42 patients diagnosed with ARS and glaucoma. The morphology of the anterior chamber angle was classified into 6 types (type A, pure high iris insertion; type B, posterior embryotoxon; type C, iris process; type D, trabecular-iris synechia; type E, peripheral iridocorneal adhesion; type F, goniodysgenesis). Candidate genes were sequenced with next-generation sequencing. Correlations of clinical characteristics with angle dysgenesis types and mutant genes were analyzed. Results: Among the 42 patients recruited, 6 eyes were excluded for poor quality UBM images or lack of glaucoma development. The remaining 78 eyes were categorized into 6 groups according to their dominant type of anterior chamber angle (>2 quadrants). There were statistically significant differences in onset age of glaucoma (P<0.001), untreated intraocular pressure (IOP) (P=0.016), vertical cup to disc ratio (P=0.001), and age at surgery (P<0.001) among the groups. Eyes in the type C and D groups developed glaucoma and underwent surgery at an earlier age, while eyes in the type B, E, and F groups developed glaucoma at a relatively later age. Eyes in type A group developed glaucoma and underwent surgery at the latest age, and had the lowest untreated IOP compared to the other groups. Patients with FOXC1 defects were more likely to have angle type B, type C, and type D (accounting for 93.8% of the total), whereas patients with PITX2 defects were more likely to have angle type A, type E, and type F (accounting for 92.1% of the total). Conclusions: UBM is powerful for evaluating the anterior segment abnormalities in ARS. Combined with genetic testing results, the morphological classification helps to assess the severity of glaucoma.

Reduction-responsive polymeric micelles for trans-corneal targeted delivery of microRNA-21-5p and glaucoma-specific gene therapy.

The therapeutic value of microRNA (miRNA) for the treatment of glaucoma has become a focus of attention. However, naked miRNA cannot cross the corneal barrier and reach the target tissue by itself. Thus, the precise transport of miRNA to the target sites is key to the success of gene therapy. Herein, we selected a miRNA, namely miR-21-5p, based on its unique intraocular pressure (IOP) mechano-sensing property. Moreover, a biocompatible polymeric poly(L-lysine) (PLL) micelle conjugated with collagenase and ABCA1 antibody was judiciously constructed to achieve the trans-corneal and target delivery of miR-21-5p to the trabecular meshwork (TM) and Schlemm's canal (SC) tissues inside the eye. The topically administrated PLL micelles as an eye drop successfully crossed the cornea with the help of collagenase and then preferentially accumulated in the target TM/SC tissues under the guidance of the ABCA1 antibody. When endocytosed by TM/SC cells, the PLL micelles could be decomposed in the reductive lysosomal environment to release miR-21-5p for successfully lowering the IOP by activating the miR-21-5p/eNOS/MMP9 signaling axis, which will open new prospects for glaucoma-specific gene therapy.

Peroxynitrite-Scavenging Organosilica Nanomedicines for Light-Controllable NO Release and Precision On-Demand Glaucoma Therapy.

Nitric oxide (NO) is a promising approach for treating ocular hypertension and glaucoma. However, its clinical application is limited by its uncontrollable release and the unwanted overproduction of peroxynitrite. Herein, a denitrifying hollow mesoporous organosilica nanoparticle (HMMN) with framework cohybridization is first constructed to encapsulate S-nitroso-N-acetyl-d,l-penicillamine (SNAP) to produce SNAP@HMMN with dual capacities of selective peroxynitrite removal and controllable NO release. Featuring a large corneal permeability, the well-designed SNAP@HMMN can achieve trans-corneal delivery to reach the target trabecular meshwork (TM)/Schlemm's canal (SC) site. Upon light irradiation, the intraocular pressure (IOP) is appropriately lowered in an adjustable and long-lasting manner while the outflow tissues are protected from nitrative damage, which is expected to realize precision on-demand glaucoma therapy with little biosafety concern, promising significant clinical translational potential.

Binocular head-mounted chromatic pupillometry can detect structural and functional loss in glaucoma.

Aim: The aim of this study is to evaluate the utility of binocular chromatic pupillometry in detecting impaired pupillary light response (PLR) in patients with primary open-angle glaucoma (POAG) and to assess the feasibility of using binocular chromatic pupillometer in opportunistic POAG diagnosis in community-based or telemedicine-based services. Methods: In this prospective, cross-sectional study, 74 patients with POAG and 23 healthy controls were enrolled. All participants underwent comprehensive ophthalmologic examinations including optical coherence tomography (OCT) and standard automated perimetry (SAP). The PLR tests included sequential tests of full-field chromatic stimuli weighted by rods, intrinsically photosensitive retinal ganglion cells (ipRGCs), and cones (Experiment 1), as well as alternating chromatic light flash-induced relative afferent pupillary defect (RAPD) test (Experiment 2). In Experiment 1, the constricting amplitude, velocity, and time to maximum constriction/dilation were calculated in three cell type-weighted responses, and the post-illumination response of ipRGC-weighted response was evaluated. In Experiment 2, infrared pupillary asymmetry (IPA) amplitude and anisocoria duration induced by intermittent blue or red light flashes were calculated. Results: In Experiment 1, the PLR of POAG patients was significantly reduced in all conditions, reflecting the defect in photoreception through rods, cones, and ipRGCs. The variable with the highest area under the receiver operating characteristic curve (AUC) was time to max dilation under ipRGC-weighted stimulus, followed by the constriction amplitude under cone-weighted stimulus and the constriction amplitude response to ipRGC-weighted stimuli. The impaired PLR features were associated with greater visual field loss, thinner retinal nerve fiber layer (RNFL) thickness, and cupping of the optic disk. In Experiment 2, IPA and anisocoria duration induced by intermittent blue or red light flashes were significantly greater in participants with POAG than in controls. IPA and anisocoria duration had good diagnostic value, correlating with the inter-eye asymmetry of visual field loss. Conclusion: We demonstrate that binocular chromatic pupillometry could potentially serve as an objective clinical tool for opportunistic glaucoma diagnosis in community-based or telemedicine-based services. Binocular chromatic pupillometry allows an accurate, objective, and rapid assessment of retinal structural impairment and functional loss in glaucomatous eyes of different severity levels.