Ab-Externo MicroShunt versus Trabeculectomy in Primary Open-Angle Glaucoma: Two-Year Results from a Randomized, Multicenter Study.

PURPOSE: To compare the effectiveness and safety of the MicroShunt (Santen Inc) versus trabeculectomy in patients with primary open-angle glaucoma (POAG). DESIGN: Prospective, randomized, multicenter trial conducted in the United States and Europe. PARTICIPANTS: Adult patients (aged 40-85 years) with mild to severe POAG inadequately controlled on maximum tolerated medical therapy and intraocular pressure (IOP) ≥ 15 mmHg and ≤ 40 mmHg. METHODS: Patients were randomized 3:1 to stand-alone MicroShunt implantation (n = 395) or trabeculectomy (n = 132), both augmented with mitomycin C (MMC) 0.2 mg/ml for 2 minutes. MAIN OUTCOME MEASURES: The primary effectiveness end point was surgical success, defined as ≥ 20% reduction in mean diurnal IOP from baseline with no increase in glaucoma medications. Secondary end points included changes in mean IOP and medication use from baseline and the need for postoperative interventions. RESULTS: At 2 years, the rate of surgical success was lower in the MicroShunt group than in the trabeculectomy group (50.6% vs. 64.4%, P = 0.005). Mean diurnal IOP was reduced from 21.1 ± 4.9 mmHg at baseline to 13.9 ± 3.9 mmHg at 24 months in the MicroShunt group and from 21.1 ± 5.0 mmHg at baseline to 10.7 ± 3.7 mmHg at 24 months in the trabeculectomy group (P < 0.001 compared with baseline in both groups). Mean medication use decreased from 3.1 to 0.9 in the MicroShunt group and from 2.9 to 0.4 in the trabeculectomy group (P < 0.001 compared with baseline in both groups). Adverse events at 2 years were generally similar in the 2 groups, except that hypotony was more common in eyes undergoing trabeculectomy (51.1% vs. 30.9%, P < 0.001). Repositioning or explantation of the implant occurred in 6.8% of MicroShunt patients. The majority of these patients had device removal at the time of subsequent glaucoma surgery. Vision-threatening complications were uncommon in both groups. CONCLUSION: At 2 years, both the MicroShunt and trabeculectomy provided significant reductions in IOP and medication use, with trabeculectomy continuing to have greater surgical success. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

The Increased Burden of Rare Variants in Four Matrix Metalloproteinase-Related Genes in Childhood Glaucoma Suggests a Complex Genetic Inheritance of the Disease.

Childhood glaucoma encompasses congenital and juvenile primary glaucoma, which are heterogeneous, uncommon, and irreversible optic neuropathies leading to visual impairment with a poorly understood genetic basis. Our goal was to identify gene variants associated with these glaucoma types by assessing the mutational burden in 76 matrix metalloproteinase-related genes. We studied 101 childhood glaucoma patients with no identified monogenic alterations using next-generation sequencing. Gene expression was assessed through immunohistochemistry. Functional analysis of selected gene variants was conducted in cultured cells and in zebrafish. Patients presented a higher proportion of rare variants in four metalloproteinase-related genes, including CPAMD8 and ADAMTSL4, compared to controls. ADAMTSL4 protein expression was observed in the anterior segment of both the adult human and zebrafish larvae's eye, including tissues associated with glaucoma. In HEK-293T cells, expression of four ADAMTSL4 variants identified in this study showed that two variants (p.Arg774Trp and p.Arg98Trp) accumulated intracellularly, inducing endoplasmic reticulum stress. Additionally, overexpressing these ADAMTSL4 variants in zebrafish embryos confirmed partial loss-of-function effects for p.Ser719Leu and p.Arg1083His. Double heterozygous functional suppression of adamtsl4 and cpamd8 zebrafish orthologs resulted in reduced volume of both the anterior eye chamber and lens within the chamber, supporting a genetic interaction between these genes. Our findings suggest that accumulation of partial functional defects in matrix metalloproteinase-related genes may contribute to increased susceptibility to early-onset glaucoma and provide further evidence supporting the notion of a complex genetic inheritance pattern underlying the disease.

Glaucoma medical treatment as a predictor of XEN45 subconjunctival gel implant hypotensive efficacy.

PURPOSE: The aim of this study was to determine the preoperative characteristics influencing hypotensive efficacy of the XEN45 gel stent in patients with open-angle glaucoma at one-year follow-up. MATERIALS AND METHODS: This was a retrospective multicentre study. All patients who underwent XEN45 gel stent implantation between January 2017 and January 2021 were included. The main study outcome was the assessment of one-year postoperative intraocular pressure (IOP) and glaucoma medication differences according to the number and type of preoperative topical treatments or glaucoma surgery, glaucoma stage and time since diagnosis. Follow-up period was 1-year post-surgery in all cases. IOP reduction and surgery success (not requiring reoperation or pressure failures [IOP > 18 mmHg and < 20% reduction in IOP]), safety and cost savings in topical glaucoma therapy after surgery were secondarily assessed. Linear regression analysis to determine the preoperative parameters influence on 1-year postoperative results was performed. RESULTS: XEN45 gel stent was implanted in 85 patients. One-year postoperative mean IOP dropped from 20.6 ± 4.1 to 13.7 ± 2.8 mmHg (p < 0.0001). Likewise, mean number of topical treatments decreased from 2.05 ± 0.9 to 0.36 ± 0.65 (p < 0.001). Both were mainly influenced by the number of preoperative glaucoma treatments, such that for each one-glaucoma medication increase, postoperative intraocular pressure increased by 1.18 mmHg (95% CI 0.56-1.79, p < 0.0001) and number of glaucoma medications increased by 0.3 (95% CI 0.16-0.43, p < 0.001). Overall success rates (with and without supplemental glaucoma medication use) were 97.6% (95% CI 94.5-100%), 87.1% (95% CI 80.2-87.1%) and 61.2% (95% CI 51.6-72.5%) at 3, 6 months and 1 year after surgery. No sight-threatening adverse events were reported. Mean annual cost savings on medical treatment since surgery reached EUR 251.19 ± 169. 93 euros. CONCLUSIONS: One year after surgery, XEN45 gel implant significantly reduced IOP and number of topical medications with an adequate safety profile being both mainly influenced by the number of preoperative glaucoma treatments.

Efficacy and safety of the PreserFlo implant with mitomycin C in childhood glaucoma after previous failed glaucoma surgeries.

PURPOSE: This study aims to evaluate the efficacy and safety of the PreserFlo MicroShunt (Santen, Osaka, Japan) in lowering intraocular pressure (IOP) in childhood glaucoma patients with previous failed glaucoma surgeries. METHODS: This is a prospective case review of consecutive PreserFlo procedures performed in childhood glaucoma patients after failed surgeries. Age, sex, diagnosis, and previous glaucoma surgeries, as well as visual acuity, IOP, and treatment in the preoperative visit and all follow-up visits were collected. Outcome measures included IOP reduction from baseline, mean IOP change from baseline at month 6, medication use at 6 months, complications, adverse events, and need for further procedures. RESULTS: Fourteen patients were included, 8 (57%) males and 6 (43%) females; the mean age was 27.5 ± 13.5 years. Nine patients (64%) had at least two trabeculectomies, and 6 patients (43%) had at least one trabeculectomy and a glaucoma drainage implant. The mean IOP change from baseline was 11.3 ± 4.9 mmHg at 12 months. At 12 months, 12 patients (86%) presented ≥ 20% IOP lowering from baseline, and 11 patients (79%) presented ≥ 30%. The mean medication count decreased from 3.9 ± 0.7 (baseline) to 0.7 ± 1.3 (12 months). No intraoperative complications were reported. No adverse events were noted. No secondary filtration surgery was required, although bleb needling was required in one case, 1 month after the surgery. CONCLUSIONS: PreserFlo with MMC can be used successfully to treat uncontrolled IOP in childhood glaucoma cases with previous failed surgeries. Larger studies with longer follow-up are needed to further explore the role of the device in resistant childhood glaucoma cases.

Chronic Glaucoma Induced in Rats by a Single Injection of Fibronectin-Loaded PLGA Microspheres: IOP-Dependent and IOP-Independent Neurodegeneration.

To evaluate a new animal model of chronic glaucoma induced using a single injection of fibronectin-loaded biodegradable PLGA microspheres (Ms) to test prolonged therapies. 30 rats received a single injection of fibronectin-PLGA-Ms suspension (MsF) in the right eye, 10 received non-loaded PLGA-Ms suspension (Control), and 17 were non-injected (Healthy). Follow-up was performed (24 weeks), evaluating intraocular pressure (IOP), optical coherence tomography (OCT), histology and electroretinography. The right eyes underwent a progressive increase in IOP, but only induced cohorts reached hypertensive values. The three cohorts presented a progressive decrease in ganglion cell layer (GCL) thickness, corroborating physiological age-related loss of ganglion cells. Injected cohorts (MsF > Control) presented greater final GCL thickness. Histological exams explain this paradox: the MsF cohort showed lower ganglion cell counts but higher astrogliosis and immune response. A sequential trend of functional damage was recorded using scotopic electroretinography (MsF > Control > Healthy). It seems to be a function-structure correlation: in significant astrogliosis, early functional damage can be detected by electroretinography, and structural damage can be detected by histological exams but not by OCT. Males presented higher IOP and retinal and GCL thicknesses and lower electroretinography. A minimally invasive chronic glaucoma model was induced by a single injection of biodegradable Ms.

Comparison of intraocular pressure measurements between Easyton transpalpebral tonometry and Perkins, iCare iC100 and Corvis ST, and the influence of corneal and anterior scleral thickness.

PURPOSE: To compare intraocular pressure (IOP) measurements between Easyton transpalpebral tonometry and Perkins, iCare iC100 and Corvis ST. Also, to assess the influence of corneal characteristics and anterior scleral thickness (AST) on the IOP measurements. METHODS: Sixty-nine eyes from 69 healthy subjects were included. IOP was measured by Easyton, Perkins, iC100 and Corvis ST (corrected IOP, bIOP; and non-corrected IOP, IOPnct). Other variables studied were AST, axial length (AL), and Corvis parameters: Length 1, velocity 1, length 2, velocity 2, peak distance, radius, deformation amplitude, and central corneal thickness (CCT). Pearson correlation, limits of agreement (LoA), and multiple regression analysis were calculated. RESULTS: No significant differences in IOP between Easyton and Perkins, iC100, and bIOP were observed (all p > 0.05), being significant only between Perkins and IOPnct ( - 1.49 mmHg, p < 0.001). Bland-Altman graphs showed that the mean difference between Perkins and Easyton was 0.07 mmHg (p < 0.001), and LoA - 7.49 to + 7.39 mmHg. Significant correlations were found between the measurements of Perkins and iC100, IOPnct, bIOP (r = 0.710, 0.628, 0.539; p < 0.001 respectively), iC100 and IOPnct, bIOP (r = 0.627, 0.513; p < 0.001, respectively). The multivariate regression analysis revealed that differences between Perkins and Easyton (adjusted R2 = 0.25) were influenced by AL (B = 1.28, p < 0.008), length 1 (B = 3.13, p < 0.018), and the radius (B = 1.26, p < 0.010). Differences between Perkins and bIOP (adjusted R2 = 0.21) were affected by the CCT (B = 0.029, p < 0.003). CONCLUSIONS: There are no significant differences in the IOP measurements between Perkins and Easyton, iC100 or bIOP. Length 1, radius, and CCT have limited influence on these differences, while AST did not show any effect.

Easyton® transpalpebral versus Perkins applanation tonometry in different populations.

OBJECTIVE:  To compare intraocular pressure (IOP) measurements obtained using the new transpalpebral Easyton® tonometer and Perkins applanation tonometer (PAT) in three different clinical populations. METHODS: The participants of this prospective study were 84 subjects divided into the groups: 22 healthy children (G1), 42 healthy adults (G2), and 20 adult patients with primary open angle glaucoma (G3). The data recorded in 84 eyes of these subjects were age, sex, gender, central corneal thickness (CCT), and axial length (AL). In all eyes, IOP was determined in the same examination room by the same experienced examiner using Easyton® and PAT in random order. RESULTS:  Mean differences in IOP readings between Easyton® and PAT were 0.45 ± 1.97 (p = 0.295), - 0.15 ± 2.13 (p = 0.654), - 1.65 ± 3.22 (p = 0.033), and - 0.018 ± 2.50 mmHg (p = 0.500) in the groups G1, G2, G3, and whole sample (G4), respectively. Correlations between Easyton® and PAT IOP values were 0.668 (p = 0.001) for G1, 0.463 (p = 0.002) for G2, 0.680 (p < 0.001) for G3, and 0.605 (p < 0.001) for G4. Moderate to good agreement between the two tonometers was found in all groups according to intraclass correlation coefficients, which were 0.794 (p < 0.001) for G1, 0.632 (p < 0.001) for G2, 0.809 (p < 0.001) for G3, and 0.740 (p < 0.001) for G4. The lower and upper limits of agreement between the devices were - 5.1 and 4.7 mmHg, respectively, in the complete group. No correlation was noted between CCT or AL and the Easyton® IOP measurements. CONCLUSION: IOP measurements obtained with Easyton® and PAT show an acceptable level of agreement mainly in healthy individuals, recommending it for IOP screening in children and in patients in which PAT measurement may be impared as patients with hemifacial spasms, corneal irregularities, or reduced mobility. It is not recommended for glaucoma patients follow-up.

Proinflammatory Cytokine Profile Differences between Primary Open-Angle and Pseudoexfoliative Glaucoma.

INTRODUCTION: Few studies have investigated glaucoma biomarkers in aqueous humor and tear and have found elevations of proinflammatory cytokines in patients with primary open-angle glaucoma (POAG) and pseudoexfoliative glaucoma (PXG). In this study, we investigate differences in inflammatory cytokines between POAG and PXG patients to find specific disease biomarkers. METHODS: For this purpose, tear and aqueous humor samples of 14 eyes with POAG and 15 eyes with PXG undergoing cataract surgery were immunoassayed for 27 proinflammatory cytokines. The concentrations of cytokines in tear and aqueous humor and their association with clinical variables were analyzed, correlated, and compared between the groups. RESULTS: We found that the levels of three cytokines differed significantly in the aqueous humor of POAG and PXG patients: IL-12 and IL-13 were higher in the POAG group, while monocyte chemoattractant protein-1 (monocyte chemotactic and activating factor) was higher in the PXG group. The number of topical hypotensive medications was correlated with diminished levels of two cytokines (IL-7 and basic fibroblast growth factor) in aqueous humor in the POAG group and with diminished levels of IL-12 in tear in the PXG group. CONCLUSION: We conclude that both POAG and PXG show elevated concentrations of proinflammatory cytokines in tear and aqueous humor that could be used as biomarkers for these types of glaucoma and that the concentrations in aqueous humor of three cytokines, IL-12, IL-13, and monocyte chemoattractant protein-1 (monocyte chemotactic and activating factor), could be used to differentiate POAG and PXG.

One-Year Changes in Optic Nerve Head Parameters in Recovered COVID-19 Patients.

BACKGROUND: The main purpose was to evaluate the changes in peripapillary retinal nerve fiber layer (RNFL) thickness and vessel density (VD) in post-COVID-19 patients during 12-month follow-up. METHODS: In this prospective study, patients with COVID-19 who were attended in the Hospital Clinico San Carlos (Madrid, Spain) were included. All patients underwent a complete ophthalmological examination, optic nerve head optical coherence tomography (OCT), and OCT angiography (OCTA) using the Cirrus HD-OCT 5,000 with AngioPlex OCTA 1, 3, and 12 months after laboratory-confirmed diagnosis. Sociodemographic data, medical history, disease severity, and laboratory workup were registered. RESULTS: A total of 180 eyes of 90 patients with SARS-CoV-2 infection were included; the mean age was 55.5 ± 8.9 years, and 46 patients (51%) were females. The mean visual acuity was 0.76 ± 0.16, and no abnormalities attributable to SARS-CoV-2 were detected in the ocular or fundus examination. No differences in the OCT and OCTA data were found between severity groups in each visit (all P > 0.05). Overall, there was a decrease in RNFL global thickness ( P < 0.001) from the first to the last visit, and an increase in VD and flux index was noted in some sectors at the 12-month examination. A significant correlation was detected at 12 months between vascularization parameters and RNFL thickness. CONCLUSIONS: One year after SARS-CoV-2 infection, changes in peripapillary RNFL thickness and vascularization occur, possibly indicating a recovery in such parameters.

Detecting SARS-CoV-2 RNA in conjunctival secretions: Is it a valuable diagnostic method of COVID-19?

The main purpose of this study is to evaluate the presence of viral RNA of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in conjunctival swab specimen of coronavirus disease 2019 (COVID-19) patients with and without conjunctivitis to establish the diagnostic value of reverse transcription-polymerase chain reaction (RT-PCR) in each case and to describe its clinical characteristics. A cross-sectional study was conducted at the Hospital Clinico San Carlos of Madrid, Spain. Thirty-six subjects from the COVID admission unit with laboratory-confirmed SARS-CoV-2 infection were included. Conjunctival swabs were collected from 18 patients with conjunctivitis and 18 patients without conjunctivitis and RT-PCR was performed. Conjunctival swab was collected from both eyes of 36 patients (72 eyes), detecting SARS-CoV-2 RNA in conjunctival swab of two patients (5.5%). Among the 18 patients with conjunctivitis, only one of them (5.5%) showed positive results. Likewise, SARS-CoV-2 RNA was detected in one patient without conjunctivitis (5.5%). The mean age of the 36 patients was 67.9 years (range, 28-92 years) and the male-to-female ratio was 0.44 (16:20). The mean days since the onset of COVID-19 symptoms until conjunctivitis manifestation was 8 (range, 1-24 days). The mean duration of the conjunctivitis was 3 days (range, 1-7 days). SARS-CoV-2 RNA may be detected in conjunctival swabs of both patients with and without conjunctivitis. This study revealed the same rate of positive results amongst the group with and without conjunctivitis, suggesting that detecting SARS-CoV-2 in ocular fluids is not conditioned on the presence of conjunctivitis. The presence of SARS-CoV-2 RNA in ocular samples highlights the role of the eye as a possible route of transmission of the disease.

Systemic treatment with 7,8-Dihydroxiflavone activates TtkB and affords protection of two different retinal ganglion cell populations against axotomy in adult rats.

PURPOSE: To analyze responses of different RGC populations to left intraorbital optic nerve transection (IONT) and intraperitoneal (i.p.) treatment with 7,8-Dihydroxyflavone (DHF), a potent selective TrkB agonist. METHODS: Adult albino Sprague-Dawley rats received, following IONT, daily i.p. injections of vehicle (1%DMSO in 0.9%NaCl) or DHF. Group-1 (n = 58) assessed at 7days (d) the optimal DHF amount (1-25 mg/kg). Group-2, using freshly dissected naïve or treated retinas (n = 28), investigated if DHF treatment was associated with TrkB activation using Western-blotting at 1, 3 or 7d. Group-3 (n = 98) explored persistence of protection and was analyzed at survival intervals from 7 to 60d after IONT. Groups 2-3 received daily i.p. vehicle or DHF (5 mg/kg). Retinal wholemounts were immunolabelled for Brn3a and melanopsin to identify Brn3a+RGCs and m+RGCs, respectively. RESULTS: Optimal neuroprotection was achieved with 5 mg/kg DHF and resulted in TrkB phosphorylation. The percentage of surviving Brn3a+RGCs in vehicle treated rats was 60, 28, 18, 13, 12 or 8% of the original value at 7, 10, 14, 21, 30 or 60d, respectively, while in DHF treated retinas was 94, 70, 64, 17, 10 or 9% at the same time intervals. The percentages of m+RGCs diminished by 7d-13%, and recovered by 14d-38% in vehicle-treated and to 48% in DHF-treated retinas, without further variations. CONCLUSIONS: DHF neuroprotects Brn3a + RGCs and m + RGCs; its protective effects for Brn3a+RGCs are maximal at 7 days but still significant at 21d, whereas for m+RGCs neuroprotection was significant at 14d and permanent.

Synergic effect of corneal hysteresis and central corneal thickness in the risk of early-stage primary open-angle glaucoma progression.

PURPOSE: To evaluate corneal hysteresis (CH), acquired with ocular response analyzer (ORA), as a risk factor for glaucoma progression in early-stage primary open-angle glaucoma (POAG). METHODS: In a historical cohort study, patients diagnosed in 2011 with early-stage POAG according to the Hodapp, Parrish and Anderson classification modified for Octopus perimetry and followed up until glaucomatous progression development; otherwise, observations were censored in October 2018. Cox regression was used to obtain hazard ratios (HR) to evaluate baseline variables (CH, central corneal thickness, gender, age IOP and glaucoma family history) as risk factors for perimetric glaucoma progression. A likelihood ratio test for interaction was performed in order to assess the effect of the combination of CH and CCT on the risk of progression. RESULTS: Of the cohort of 1573 patients, 11.38% developed early-stage POAG progression during the follow-up. The mean follow-up time was 3.28 ± 1.92 years. Patients without progression had a higher CH (11.35 ± 1.43 vs 9.07 ± 1.69 mmHg; p < 0.001) and CCT (570.75 ± 17.71 vs 554.51 ± 23.20; p < 0.001). In the multivariate analysis, each 1 mmHg of lower CH was associated with an increase of 2.13 times in the HR of progression (95% CI: 1.92-2.32; p < 0.001). CH hazard ratio was modified by CCT, with higher values of CCT and CH resulting in a higher HR of early glaucoma progression (p < 0.001). CONCLUSIONS: CH can be considered as a risk factor of progression in early-stage POAG. The risk associated with CH changed depending on CCT values, acting synergistically slowing the risk of glaucoma progression with higher values.

Twelve-month results of ab interno trabeculectomy with Kahook Dual Blade: an interventional, randomized, controlled clinical study.

PURPOSE: To evaluate the efficacy and safety profile of Kahook Dual Blade ab interno trabeculectomy combined with phacoemulsification compared to stand-alone conventional cataract surgery. METHODS: A single-center longitudinal, randomized controlled trial was conducted. Patients older than 18 years with coexisting cataract and open-angle glaucoma or ocular hypertension were invited to participate. Preoperative and postoperative clinical data were collected and analyzed preoperatively and at months 1, 3, 6, and 12 after the procedure. Main outcome measures included best corrected visual acuity, intraocular pressure, number of glaucoma medications, endothelial cell count, and standard automated perimetry. RESULTS: Forty-two eyes from 33 patients were randomly allocated to the combined cataract and KDB (treatment, n = 21) or cataract alone (control, n = 21) groups. Intraocular pressure decreased from 17.9 ± 3.5 to 16.0 ± 2.2 mmHg and from 17.3 ± 2.5 to 15 ± 3.2 mmHg at the last visit in the treatment and control groups (p = 0.47). The use of glaucoma medications was reduced from a median (IQR) 1 (1-2) to 0 (0-0) in the treatment group and from 1 (1-2) to 0 (0-1) in the control group, with no significant differences between groups at the 12-month visit (p = 0.47). Best corrected visual acuity, endothelial cell count, and standard automated perimetry remained similar during follow-up in both groups. CONCLUSIONS: In patients with well-controlled, mild-to-moderate glaucoma, adding ab interno trabeculectomy with KDB to phacoemulsification might not be more effective than phacoemulsification alone to reach mid-teens IOP values. Both procedures showed similar safety profiles. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04202562, December 17, 2019 retrospectively registered.

Reduced macular vessel density in COVID-19 patients with and without associated thrombotic events using optical coherence tomography angiography.

PURPOSE: Thrombotic events (TE) represent one of the major complications of SARS-CoV-2 infection. The objective is to evaluate vessel density (VD) and perfusion density (PD) by optical coherence tomography angiography (OCTA) in COVID-19 patients, and compare the findings with healthy controls. The secondary objective is to evaluate if there are differences in OCTA parameters between COVID-19 patients with and without associated TE. METHODS: Cross-sectional case-control study that included patients with laboratory-confirmed diagnosis of COVID-19 with and without TE related to the infection and age-matched healthy controls. Ophthalmological examination and OCTA were performed 12 weeks after diagnosis. Demographic data and medical history were collected. Macular OCTA parameters in the superficial retinal plexus were analyzed according to ETDRS sectors. RESULTS: Ninety patients were included, 19 (20%) COVID-19 patients with associated TE, 47 (49.5%) COVID-19 patients without TE, and 29 (30.5%) healthy controls. Fifty-three (55.7%) were male, mean age 54.4 (SD 10.2) years. COVID-19 patients presented significantly lower VD than healthy controls: central (p = 0.003), inner ring (p = 0.026), outer ring (p = 0.001). PD was also significantly decreased: outer ring (p = 0.003), full area (p = 0.001). No differences in OCTA parameters were found between COVID-19 patients with and without TE. CONCLUSIONS: OCTA represents a promising tool for the in vivo assessment of microvascular changes in COVID-19. Patients with SARS-CoV-2 infection show lower VD and PD compared to healthy controls. However, no differences were found between COVID-19 when considering TE. Prospective studies are required to further evaluate the retinal microvascular involvement of SARS-CoV-2 and its impact on the vasculature of other organs.

CPAMD8 loss-of-function underlies non-dominant congenital glaucoma with variable anterior segment dysgenesis and abnormal extracellular matrix.

Abnormal development of the ocular anterior segment may lead to a spectrum of clinical phenotypes ranging from primary congenital glaucoma (PCG) to variable anterior segment dysgenesis (ASD). The main objective of this study was to identify the genetic alterations underlying recessive congenital glaucoma with ASD (CG-ASD). Next-generation DNA sequencing identified rare biallelic CPAMD8 variants in four patients with CG-ASD and in one case with PCG. CPAMD8 is a gene of unknown function and recently associated with ASD. Bioinformatic and in vitro functional evaluation of the variants using quantitative reverse transcription PCR and minigene analysis supported a loss-of-function pathogenic mechanism. Optical and electron microscopy of the trabeculectomy specimen from one of the CG-ASD cases revealed an abnormal anterior chamber angle, with altered extracellular matrix, and apoptotic trabecular meshwork cells. The CPAMD8 protein was immunodetected in adult human ocular fluids and anterior segment tissues involved in glaucoma and ASD (i.e., aqueous humor, non-pigmented ciliary epithelium, and iris muscles), as well as in periocular mesenchyme-like cells of zebrafish embryos. CRISPR/Cas9 disruption of this gene in F0 zebrafish embryos (96 hpf) resulted in varying degrees of gross developmental abnormalities, including microphthalmia, pharyngeal maldevelopment, and pericardial and periocular edemas. Optical and electron microscopy examination of these embryos showed iridocorneal angle hypoplasia (characterized by altered iris stroma cells, reduced anterior chamber, and collagen disorganized corneal stroma extracellular matrix), recapitulating some patients' features. Our data support the notion that CPAMD8 loss-of-function underlies a spectrum of recessive CG-ASD phenotypes associated with extracellular matrix disorganization and provide new insights into the normal and disease roles of this gene.

Hypercytokinemia in COVID-19: Tear cytokine profile in hospitalized COVID-19 patients.

The aim of this study is to analyze the concentrations of cytokines in tear of hospitalized COVID-19 patients compared to healthy controls. Tear samples were obtained from 41 healthy controls and 62 COVID-19 patients. Twenty-seven cytokines were assessed: interleukin (IL)-1b, IL-1RA, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL9, IL-10, IL-12, IL-13, IL-15, IL-17, eotaxin, fibroblast growth factor basic, granulocyte colony-stimulating factor (G-CSF), granulocyte-monocyte colony-stimulating factor (GM-CSF), interferon (IFN)-γ, interferon gamma-induced protein, monocyte chemo-attractant protein-1, macrophage inflammatory protein (MIP)-1a, MIP-1b, platelet-derived growth factor (PDGF), regulated on activation normal T cell expressed and secreted, tumor necrosis factor-α and vascular endothelial growth factor (VEGF).In tear samples of COVID-19 patients, an increase in IL-9, IL-15, G-CSF, GM-CSF, IFN-γ, PDGF and VEGF was observed, along with a decrease in eotaxin compared to the control group (p < 0.05). A poor correlation between IL-6 levels in tear and blood was found. IL-1RA and GM-CSF were significantly lower in severe patients and those who needed treatment targeting the immune system (p < 0.05). Tear cytokine levels corroborate the inflammatory nature of SARS-CoV-2.

Conjunctivitis in COVID-19 patients: frequency and clinical presentation.

PURPOSE: The purpose of this study was to evaluate the frequency and clinical presentation of conjunctivitis in hospitalized patients with COVID-19. METHODS: A cross-sectional study was conducted at the Hospital Clinico San Carlos of Madrid, Spain. A total of 301 subjects from the COVID admission unit with laboratory-confirmed SARS-CoV-2 infection were included. The presence and clinical characteristics of conjunctivitis were evaluated. Laboratory, radiological, and clinical results in patients with and without conjunctivitis stratified by sex were analyzed. RESULTS: Of the 301 subjects included, 180 patients (59.8%) were male and the median age was 72 years (IQ 59-82). Overall, 35 patients (11.6%) were diagnosed with acute conjunctivitis. We found no relationship between the COVID-19 severity score and the presence of conjunctivitis (P = 0.17). However, conjunctivitis was more frequent in males with moderate clinical severity and in women classified as clinically mild. The natural history of the disease seems to be a rapid self-limited conjunctivitis that improves without treatment and does not affect visual acuity nor associate short-term complications. CONCLUSIONS: Approximately, 1 out of 10 hospitalized non-critical COVID-19 patients presents conjunctivitis during the disease. Compared with other viral conjunctivitis, we found distinctive clinical findings that could guide defining and differentiating conjunctivitis in COVID-19 patients. TRIAL REGISTRATION NUMBER: 20/336_E_COVID.

Normative database and determinants of macular vessel density measured by optical coherence tomography angiography.

IMPORTANCE: To provide a normative vessel density (VD) database for the macula through swept-source optical coherence tomography angiography (OCTA) and to assess the main determinants of this measurement. BACKGROUND: In contrast with dye angiography, the recently introduced OCTA technique allows for the non-invasive measurement of retinal and choroidal VD metrics. DESIGN: Cross-sectional study. PARTICIPANTS: The right eyes of 346 healthy subjects were studied. In 105 subjects both eyes were imaged. METHODS: Foveal and parafoveal macular VD measurements were obtained in the retinal superficial capillary plexus (SCP), deep capillary plexus (DCP), and in the choriocapillaris (CC) layer. Also recorded were age, sex, axial length (AL), foveal and choroidal thickness (CT). MAIN OUTCOME MEASURES: Normative database and determinants of macular VD measured by OCTA. RESULTS: Mean participant age was 38.3 ± 20.1 years (mean ± SD) (range 5-83). Foveal VDs in the different plexuses were: SCP 22.1% ± 5.0% (7.3-35.1), DCP 19.9% ± 6.3% (6.9-51.2) and CC: 52.8% ± 4.3% (40.2-62.1). Parafoveal VDs ranged from 45.4% ± 3.7% to 51.8% ± 4.6%. Positive correlation was observed between foveal VD and foveal thickness (R = .327), as well as between parafoveal DCP VD and CT (R = .250;P ≤ .006), while correlation with age was negative in the SCP and CC (R = -.283;P < .001). No associations were detected between macular VD and sex or AL (P ≥ .05). CONCLUSION AND RELEVANCE: Macular VD showed wide individual variation, was positively correlated with foveal thickness and with CT, negatively correlated with age, and showed no correlation with AL or sex.

Ciliary muscle dimensions measured by swept-source optical coherence tomography in eyes with primary open-angle glaucoma and healthy eyes.

PURPOSE: To compare in vivo swept-source optical coherence tomography (SS-OCT) measurements of the ciliary muscle (CM) in patients with primary open-angle glaucoma (POAG) and healthy subjects, and examine correlations between CM dimensions and several covariates. METHODS: This was a cross-sectional study of the right eyes of 181 subjects: 89 POAG patients and 92 healthy subjects. Using the Triton SS-OCT device (Topcon, Tokyo, Japan), CM length (CML), area (CMA) and thickness measured 1000 µm (CMT1), 2000 µm (CMT2) and 3000 µm (CMT3) from the scleral spur were determined in the temporal and nasal quadrants. POAG patients were subjected to visual field (VF) and peripapillary retinal nerve fiber layer (RNFL) assessment. CM dimensions were then assessed for correlation with VF mean defect (MD), mean RNFL thickness and intraocular pressure (IOP). RESULTS: Mean CMLs were 4325 ± 340 µm and 4195 ± 843 µm for the healthy subjects and POAG patients, respectively (p = 0.17). Mean CM thicknesses were CMT1 = 546 ± 56 µm, CMT2 = 326 ± 44 µm and CMT3 = 174 ± 16 µm in the healthy eyes versus CMT1 = 534 ± 108, CMT2 = 332 ± 99 and CMT3 = 183 ± 74 in the POAG eyes, with no significant differences detected (all p ≥ 0.25). In the temporal quadrant, mean CMA was 1.12 ± 0.29 mm2 and 1.15 ± 0.24 mm2 for the healthy and POAG subjects, respectively (p = 0.45). No correlations were observed between CM measurements and RNFL thickness (p ≥ 0.15), IOP or VF MD (p ≥ 0.14) in POAG subjects irrespective of glaucoma severity (p ≥ 0.19). CONCLUSIONS: While SS-OCT proved useful to measure CM dimensions in vivo, these dimensions did not differ between healthy individuals and POAG subjects. In the patients with POAG, no correlations were detected between CM dimensions and VF, RNFL or IOP.

Long-term effect of intravitreal ranibizumab therapy on retinal nerve fiber layer in eyes with exudative age-related macular degeneration.

PURPOSE: To investigate long-term effect (96 months) of intravitreal ranibizumab administered for exudative age-related macular degeneration (AMD) on retinal nerve fiber layer (RNFL) thickness when used following a pro re nata regimen. METHODS: In this prospective study, 20 eyes of 20 patients diagnosed with exudative AMD were included. Contralateral non-exudative AMD eyes of nine of these patients were included as controls. Data on intraocular pressure (IOP) and number of injections were recorded. Spectralis optic coherence tomography (OCT) of the circumpapillary RNFL was performed under dilation when diagnosis was made and before the three loading injections. "Follow-up" software was selected to accurately compare baseline with subsequent images through the 8 years of the study. RESULTS: Baseline IOP was 14.1 mmHg both in study (standard deviation, SD: 0.8) and control eyes (SD: 0.9) and remained unchanged during the study. Mean number of injections was 21 (SD: 2.8) at the end of the study. Mean average thickness of RNFL in the study eye group at the end of the study was 96.5 µm (SD: 2.1). Mean loss for the study period was 5.3 µm (SD: 0.7; p < 0.0001). Corresponding RNFL values for controls were 92.9 (SD: 3.2) and 5.8 µm (SD: 1.2; p < 0.001). Superior temporal sector had the greatest loss in both groups, followed by inferior and nasal sectors. No statistically significant differences were found when comparing losses in injected eyes versus control eyes. CONCLUSIONS: RNFL thickness decreased both equally in injected eyes and control eyes. Thus, no long-term effects of intravitreal ranibizumab were observed on the retinal nerve fiber layer thickness.