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.

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.

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.

Tonometry after Intrastromal Corneal Ring Segments for Keratoconus.

SIGNIFICANCE: Reliable intraocular pressure (IOP) measurement after intrastromal corneal ring segments (ICRS) implantation is a challenge because of altered corneal morphology. In this study, IOP is measured with four tonometers, compared with Goldmann applanation tonometry (GAT) values and the influence of corneal parameters is established. PURPOSE: This study compares IOP measurements made using different tonometers in patients implanted with ICRS and assesses the effects of central corneal thickness (CCT), corneal curvature, and corneal astigmatism on the IOP measurements obtained. METHODS: In this cross-sectional study, IOP was measured using three different tonometers in 91 eyes of 91 patients with corneal ectasia implanted at least 6 months previously with ICRS. The tonometers tested were the TonoPen XL, Pascal dynamic contour tonometer (DCT), and iCare Pro rebound tonometer. GAT measurements were used as reference. Agreement among the IOPs provided by the different tonometers and the influence of corneal variables on the IOP measurements obtained were assessed using the Bland-Altman method, intraclass correlation coefficients, and multiple linear regression analysis. RESULTS: Mean IOP differences were GAT versus TonoPen XL -0.8 ± 3.07 mm Hg, GAT versus DCT -1.0 ± 3.26 mm Hg, and GAT versus iCare Pro 0.8 ± 2.92 mm Hg. Our multiple linear regression analysis identified CCT as a confounding factor affecting all the tonometer readings but DCT-IOP. CONCLUSIONS: In patients fitted with ICRS, IOP measurements made using the iCare Pro and TonoPen XL showed most agreement with GAT. Intraocular pressure measurements made by DCT were unaffected by corneal topographic factors though this procedure slightly overestimated GAT readings.

Agreement between Five Experts and the Laguna ONhE Automatic Colourimetric Application Interpreting the Glaucomatous Aspect of the Optic Nerve.

BACKGROUND: Optic nerve head (ONH) interpretation is a glaucoma screening method which may be influenced by criteria variability. Laguna ONhE software is a low-cost and non-invasive method of ONH analysis. METHODS: We analysed the results of the Laguna ONhE application, interpreting 552 ONH images from the ACRIMA database, publicly available on the Internet, and compared them with the opinion of five experts. Diagnostic agreement was investigated using Cohen's kappa (κ) with 95% confidence. RESULTS: The kappa concordance index obtained with Laguna ONhE and the majority of the experts' criterion (0.77) was significantly higher compared to that obtained with ACRIMA and the majority of the experts' criterion (0.61). In 44.7% of the cases there was absolute agreement among the 5 experts and the Laguna ONhE program. Removing borderline cases from the analysis yielded increased diagnostic agreement (0.81). The area under the receiver operating characteristic (AUROC) of the Laguna ONhE program (0.953, p < 0.001) was not significantly different than AUROC of the majority of the experts' criterion (0.925, p < 0.001), p = 0.052. Individually obtained expert's AUROCs were significantly lower (0.636 to 0.913; p < 0.01). CONCLUSIONS: Laguna ONhE's agreement with the experts is high, particularly where the diagnosis may be more obvious by the appearance of the ONH.

Peripapillary Vascular Density in Childhood Glaucoma: A Pilot Comparative Study with Age and Sex Matched Healthy Subjects.

PURPOSE: The aim of this study concerns the evaluation of peripapillary vessel indices in childhood glaucoma (CG) and healthy subjects. MATERIAL AND METHODS: In this prospective, unicenter, observational cross-sectional study, patients with CG and age and sex-matched healthy subjects were included. We compared retinal nerve fiber layer (RNFL) measurements in optical coherence tomography (OCT), peripapillary vessel density (PVD), and the flux index (FI) of the superficial vascular plexus from OCT angiography (OCT-A) between CG patients and control groups. RESULTS: We included 39 patients (68 eyes) with CG and 50 (95 eyes) healthy subjects. The peripapillary RNFL thickness, vessel density, and flux index were significantly lower in the CG group than in the control group. The mean PVD of CG patients was 0.52 ± 0.043%, compared with 0.55 ± 0.014%, p < 0.0001 in healthy subjects. The mean FI was 0.32 ± 0.054 versus 0.37 ± 0.028, p < 0.0001, in CG patients and healthy subjects, respectively. PVD and FI in the superior, inferior, and temporal sectors were significantly lower in CG. The peripapillary RNFL thickness showed a higher area under the ROC curve (AUROC) for discriminating healthy and CG eyes and was significantly different than the PVD (0.797, 95%CI 0.726-0.869; p < 0.0001 vs. 0.664, 95%CI 0.574-0.752; p 0.00037), p 0.012. CONCLUSIONS: PVD and FI show lower values in CG and correlate with RNFL thickness measurement but have lower diagnostic ability than RNFL thickness measurement. Our results reveal possible differences in the pathogenesis of microvascular compromise in childhood glaucoma patients.

Effect of Hypercholesterolemia, Systemic Arterial Hypertension and Diabetes Mellitus on Peripapillary and Macular Vessel Density on Superficial Vascular Plexus in Glaucoma.

BACKGROUND/AIMS: Vascular factors are involved in the development of glaucoma, including diseases such as hypercholesterolemia (HC), systemic arterial hypertension (SAH), and diabetes mellitus (DM). The aim of this study was to determine the effect of glaucoma disease on peripapillary vessel density (sPVD) and macular vessel density (sMVD) on the superficial vascular plexus, controlling differences on comorbidities such as SAH, DM and HC between glaucoma patients and normal subjects. METHODS: In this prospective, unicenter, observational cross-sectional study, sPVD and sMVD were measured in 155 glaucoma patients and 162 normal subjects. Differences between normal subjects and glaucoma patients' groups were analyzed. A linear regression model with 95% confidence and 80% statistical power was performed. RESULTS: Parameters with greater effect on sPVD were glaucoma diagnosis, gender, pseudophakia and DM. Glaucoma patients had a sPVD 1.2% lower than healthy subjects (Beta slope 1.228; 95%CI 0.798-1.659, p < 0.0001). Women presented 1.19% more sPVD than men (Beta slope 1.190; 95%CI 0.750-1.631, p < 0.0001), and phakic patients presented 1.7% more sPVD than men (Beta slope 1.795; 95%CI 1.311-2.280, p < 0.0001). Furthermore, DM patients had 0.9% lower sPVD than non-diabetic patients (Beta slope 0.925; 95%CI 0.293-1.558, p = 0.004). SAH and HC did not affect most of the sPVD parameters. Patients with SAH and HC showed 1.5% lower sMVD in the outer circle than subjects without those comorbidities (Beta slope 1.513; 95%CI 0.216-2.858, p = 0.021 and 1.549; 95%CI 0.240-2.858, p = 0.022 respectively. CONCLUSIONS: Glaucoma diagnosis, previous cataract surgery, age and gender seem to have greater influence than the presence of SAH, DM and HC on sPVD and sMVD, particularly sPVD.

Intervortex Venous Anastomosis in the Macula in Central Serous Chorioretinopathy Imaged by En Face Optical Coherence Tomography.

PURPOSE: To assess the presence of macular intervortex venous anastomosis in central serous chorioretinopathy (CSCR) patients using en face optical coherence tomography (EF-OCT). METHODS: A cross-sectional study where EF-OCT 6 × 6 and 12 × 12 mm macular scans of patients with unilateral chronic CSCR were evaluated for anastomosis between vortex vein systems in the central macula. The presence of prominent anastomoses was defined as a connection with a diameter ≥150 µm between the inferotemporal and superotemporal vortex vein systems which crossed the temporal raphe. Three groups were studied: CSCR eyes (with an active disease with the presence of neurosensorial detachment; n = 135), fellow unaffected eyes (n = 135), and healthy eyes as controls (n = 110). Asymmetries, abrupt termination, sausaging, bulbosities and corkscrew appearance were also assessed. RESULTS: In 79.2% of the CSCR eyes there were prominent anastomoses in the central macula between the inferotemporal and superotemporal vortex vein systems, being more frequent than in fellow eyes and controls (51.8% and 58.2% respectively). The number of anastomotic connections was higher in the affected eye group (2.9 ± 1.8) than in the unaffected fellow eye group (2.1 ± 1.7) and the controls (1.5 ± 1.6) (p < 0.001). Asymmetry, abrupt terminations and the corkscrew appearance of the choroidal vessels were more frequent in the affected eyes, although no differences in sausaging or bulbosities were observed. CONCLUSIONS: Intervortex venous anastomoses in the macula were common in CSCR, being more frequently observed in affected eyes than in fellow unaffected eyes and healthy controls. This anatomical variation could have important implications concerning the pathogenesis and classification of the disease.

Outcomes of Corneal Transplant in Childhood Glaucoma.

PRCIS: Childhood glaucoma produces alterations in the postnatal development and function of various ocular structures, including the cornea. Childhood glaucoma patients present lower corneal transplant survival rates. Our series shows outcomes of corneal transplant in childhood glaucoma with survival rates of 29% at 2 years. OBJECTIVE: To investigate the surgical outcome of different types of keratoplasty in eyes with childhood glaucoma. PATIENTS AND METHODS: A retrospective review was made of the medical records from 17 eyes of 15 patients who were diagnosed with childhood glaucoma and received a corneal transplantation between January 2010 and July 2020. Patient demographics, intraocular pressure, previous ocular surgery, comorbidities, corneal transplant surgery, and follow-up outcome were collected. The primary efficacy endpoint was graft survival (in months) until failure, the latter being considered as irreversible loss of corneal transparency. Secondary efficacy points were the need for an increase in topical hypotensive therapy and the need for additional surgery. RESULTS: Seventeen eyes of 15 patients were included, 11 eyes (10 patients) with primary congenital glaucoma and 6 with other types of childhood glaucoma. Corneal transplantation was performed at the mean age of 23.76 ± 14.86 years. At the time of the transplantation, the number of topical medications was 1.35 ± 1.27, intraocular pressure was 15.00 ± 8.34 mm Hg, and patients had received up to 7 glaucoma surgeries. Descemet stripping automated endothelial keratoplasty was performed in 13 eyes (76%) and penetrating keratoplasty in 4 (24%). After surgery, 7 (41%) eyes required increased topical treatment and 2 (12%) glaucoma surgery. Twelve eyes (71%) developed graft failure at 24 months, the mean time of survival being 13.88 ± 8.25 months. CONCLUSIONS: Management of corneal decompensation in childhood glaucoma poses a challenge. In this series of childhood glaucoma with corneal transplantations, the survival rate was 29% at 24 months.

Evaluation of a Novel Αb Εxterno MicroShunt for the Treatment of Glaucoma.

The surgical management of glaucoma has been revolutionized by the introduction of minimally invasive glaucoma surgery (MIGS). The various MIGS options aim to meaningfully lower intraocular pressure with a better safety profile than traditional glaucoma surgery. The key clinical attributes and the emerging potential of an ab externo MicroShunt (PreserFlo™) are reviewed in the context of published evidence and clinical experience. This novel MicroShunt consists of an 8.5-mm-long tube that is implanted in the eye via an ab externo approach enabling aqueous humor drainage into the sub-Tenon's space through the formation of a bleb, similar in appearance to that created by trabeculectomy. The efficacy and safety of this procedure, the concomitant use of antimetabolites, the impact of tube positioning, and its future value in clinical practice are critically reviewed. Recent evidence has demonstrated the MicroShunt to be less effective than traditional filtration surgery, but with a significant improvement in safety. Cumulative data suggest that the new implant provides tangible clinical benefits to selected patients with glaucoma in need of further intraocular pressure (IOP) lowering. Future research should delineate the precise role of this and other MIGS options in the rapidly evolving glaucoma treatment algorithm.

Safety and Effectiveness of the PRESERFLO® MicroShunt in Primary Open-Angle Glaucoma: Results from a 2-Year Multicenter Study.

PURPOSE: To assess the safety and effectiveness of the PRESERFLO® MicroShunt (formerly InnFocus MicroShunt) in patients with primary open-angle glaucoma (POAG). DESIGN: The MicroShunt, a controlled ab externo glaucoma filtration surgery device, was investigated in a 2-year, multicenter, single-arm study. PARTICIPANTS: Eligible patients were aged 18-85 years with POAG inadequately controlled on maximal tolerated medical therapy with intraocular pressure (IOP) ≥18 and ≤35 mmHg or when glaucoma progression warranted surgery. METHODS: The MicroShunt was implanted as a stand-alone procedure with adjunctive use of topical mitomycin C (MMC; 0.2-0.4 mg/ml) for 2-3 minutes. MAIN OUTCOME MEASURES: The primary effectiveness outcome was IOP reduction and success (not requiring reoperation or pressure failures [IOP > 21 mmHg and < 20% reduction in IOP]) at year 1. Additional end points at year 2 included IOP reduction, success, glaucoma medications, adverse events (AEs), and reoperations. Results are reported in the overall population and subgroups of patients receiving 0.2 or 0.4 mg/ml MMC. RESULTS: In 81 patients, mean (± standard deviation [SD]) IOP decreased from 21.7 ± 3.4 mmHg at baseline to 14.5 ± 4.6 mmHg at year 1 and 14.1 ± 3.2 mmHg at year 2 (P < 0.0001). Overall success (with and without supplemental glaucoma medication use) at year 1 was 74.1%. Mean (± SD) number of medications decreased from 2.1 ± 1.3 at baseline to 0.5 ± 0.9 at year 2 (P < 0.0001), and 73.8% of patients were medication free. Most common nonserious AEs were increased IOP requiring medication or selective laser trabeculoplasty (25.9%) and mild-to-moderate keratitis (11.1%). There were 6 (7.4%) reoperations and 5 (6.2%) needlings by year 2. In an analysis (post hoc) according to MMC concentration, overall success was 78.1% (0.2 mg/ml) and 74.4% (0.4 mg/ml; P = 0.710). In the 0.2 and 0.4 mg/ml MMC groups, 51.9% and 90.3% of patients were medication free, respectively (P = 0.001). There was a trend toward lower IOP and higher medication reduction in the 0.4 mg/ml MMC subgroup. CONCLUSIONS: In this study, mean IOP and glaucoma medication reductions were significant and sustained over 2 years postsurgery. No long-term, sight-threatening AEs were reported. Further studies may confirm potential risk/benefits of higher MMC concentration.

Diagnostic validity of optic nerve head colorimetric assessment and optical coherence tomography angiography in patients with glaucoma.

BACKGROUND/AIMS: The aim of this study was to assess the optic nerve head (ONH) and macular vessel density with optical coherence tomography angiography (OCT-A) and the ONH haemoglobin (ONH Hb) amount with Laguna ONhE program in open-angle glaucoma (OAG) patients. METHODS: In this prospective observational cross-sectional study, 67 OAG patients and 41 healthy age-sex frequency matched subjects were examined with OCT-A and retinal photos. The circumpapillary (wcpVD), optic nerve head (iVD) and macular (wmVD) capillary vessel density of OCT-A and ONH colorimetric assessment to determine the ONH Hb amount using the Laguna ONhE program were evaluated. RESULTS: Significant differences between normal subjects and glaucoma patients in the wcpVD (22.18±3.42 vs 16.03±2.89%; p<0.001), iVD (18.31±5.56 vs 12.52±4.67%; p<0.001), wmVD (15.60±2.34 vs 13.34±2.32%; p<0.001) and amount of ONH Hb (71.10±1.67 vs 68.86±2.46%; p<0.001) and in the papillary cup (68.14±5.25 vs 64.77±5.08%; p=0.001) were found. The Laguna ONhE glaucoma discriminant function (GDF) index had a negative value in the OAG patients and normal values in healthy subjects (-18.76±13.31 vs 7.98±14.09; p<0.001). The area under the receiver operating characteristic (ROC) curve (AUROC) for discriminating between healthy and glaucomatous eyes was highest for wcpVD (0.93; 95% CI 0.86 to 0.97, p<0.0001), followed by GDF (0.92; 95% CI 0.86 to 0.97, p<0.0001), iVD (0.79; 95% CI 0.70 to 0.86; p<0.0001) and ONH Hb (0.78; 95% CI 0.69 to 0.85, p<0.0001). Pair wise comparisons showed that the AUROC of wcpVD (0.93) was not significantly different than GDF (0.92) (p=0.855). CONCLUSION: Laguna ONhE program and OCT-A have similar diagnostic validity in open-angle glaucoma patients.

Optic Nerve Head Vessel Density Assessment in Recovered COVID-19 Patients: A Prospective Study Using Optical Coherence Tomography Angiography.

PRECIS: Vascular diseases have been linked to alterations in optic nerve head perfusion. PURPOSE: The main objective was to investigate the changes in peripapillary vessel density (VD) in post coronavirus disease (COVID-19) patients. METHODS: In this prospective pilot exploratory study, patients with COVID-19 that were attended in the Emergency Department of Hospital Clinico San Carlos (Madrid) were included. All patients underwent optic nerve head optical coherence tomography angiography using the Cirrus HD-OCT 500 with AngioPlex OCTA (Zeiss, Dublin, CA) 4 and 12 weeks after diagnosis by positive reverse transcriptase-polymerase chain reaction test from nasopharyngeal swab at the Emergency Department. Sociodemographic data, medical history, disease severity, and laboratory work-up were collected. RESULTS: One hundred and eighty eyes of 90 patients with severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection were included. None of the patients reported visual changes. Severe patients were older, more frequently hispanic, dyslipidemic, and presented lower lymphocytes counts, as well as increased ferritin, D-dimer, fibrinogen, and international normalized ratio levels. No changes in optic nerve head vascularization were observed when both visits were compared. No correlation was found between VD and clinical parameters, disease severity and laboratory work-up. CONCLUSIONS: Changes to peripapillary VD were not observed in patients with COVID-19 in the early months following diagnosis.

Influence of Axial Length on Intraocular Pressure Measurement With Three Tonometers in Childhood Glaucoma.

PURPOSE: To determine the agreement between intraocular pressure (IOP) measurements obtained using the handheld version of the Goldmann applanation (Perkins; Clement-Clarke, Haag-Streit, Harlow, United Kingdom), rebound Icare-Pro (Icare, Tiolat Oy, Helsinki, Finland), and Tonopen XL (Reichert Inc., Depew, NY) tonometers in children with childhood glaucoma and to identify factors that may affect those measurements. METHODS: Ninety-one eyes of 46 children with early-onset childhood glaucoma were included in this cross-sectional study in which IOP, ocular axial length, anterior chamber depth, lens thickness, vitreous length, and central corneal thickness measurements were obtained under general anesthesia. Agreement between tonometers was evaluated using intraclass correlation coefficients (ICCs) and the Bland-Altman method. The influence of ocular biometric parameters and central corneal thickness on IOP measurements was analyzed using multiple linear regression analysis. RESULTS: The mean age of the children in the current study was 29.1 months (range: 13 to 31 months). The Icare-Pro and Tonopen XL overestimated IOP measurements compared to the Perkins tonometer (Icare-Pro-Perkins mean IOP difference: 2.2 ± 3.4 mm Hg, P < .0001, 95% confidence interval [CI]: 1.5 to 2.9 vs Tonopen XL-Perkins mean IOP difference: 6.7 ± 7.1 mm Hg, P < .0001, 95% CI: 5.2 to 8.2). The Icare-Pro showed greater agreement with the Perkins tonometer than the Tonopen XL (ICC: 0.789, 95% CI: 0.697 to 0.856, P < .0001 vs 0.453, 95% CI: 0.272 to 0.603, P < .0001). Ocular axial length affected IOP measurements the most, finding increased impact on Tonopen XL (slope: 0.086, 95% CI: 0.013 to 0.16, P = .022 vs 0.997, 95% CI: 0.369 to 1.625, P = .002 vs 1.571, 95% CI: 0.541 to 2.602, P < .0001 for Perkins, Icare-Pro, and Tonopen XL IOP measurements, respectively). CONCLUSIONS: Ocular axial length affects IOP measured by the Perkins, Icare-Pro, and Tonopen XL devices in patients with childhood glaucoma. The Icare-Pro shows more agreement with the Perkins tonometer than the Tonopen XL; therefore, it seems to be a more suitable option for these patients. [J Pediatr Ophthalmol Strabismus. 2020;57(1):27-32.].

Gender-related Influences on Superficial Papillary Microcirculation Measured with Optical Coherence Tomography Angiography in Patients with Glaucoma.

Purpose: To evaluate the optic nerve head (ONH), macular vessel density, and retinal nerve fiber layer (RNFL) thickness differences between the genders. Material and methods: In this prospective case-control cross-sectional study 111 healthy subjects and 130 primary open-angle glaucoma (OAG) patients were examined with optical coherence tomography angiography (OCT-A (RS-3000 Advance (Nidek, Gamagori, Japan))). The vessel density in the peripapillary and macular area as well as the RNFL thickness was evaluated. Results: Men appeared to have less RNFL thickness compared with women in early glaucomatous group, being significant at the whole circumpapillary retinal nerve fiber layer (cpRNFL) thickness and inferior and nasal quadrants: (cpRNFL) (71.01 ± 9.32 vs 77.64 ± 9.95 µm; P = .001), superior quadrant (89.10 ± 16.63 vs 92.97 ± 17.53 µm; P = .284), inferior quadrant (83.03 ± 19.17 vs 95.07 ± 21.70 µm; P = .006), temporal quadrant (57.11 ± 10.36 vs 61.78 ± 11.37 µm; P = .043), nasal quadrant (54.81 ± 11.42 vs 60.73 ± 11.62 µm; P = .016). Circumpapillary (wcpVD) and macular (wmVD) vessel density values were lower in men than women in the early stage OAG group, being wmVD significantly lower: wcpVD (15.53 ± 2.45% vs 16.81 ± 3.17%, P = .032) and wmVD values (12.51 ± 2.21 vs 13.63 ± 2.28%, P = .019), but not in the moderate OAG group (wcpVD 14.46 ± 2.20% vs 16.61 ± 3.10%, P = .056 and wmVD 12.61 ± 2.40% vs 12.74 ± 2.54%, P = .870). There were no significant differences between men and women for RNFL thickness and the vessel density parameters in normal group. Conclusion: Both, the thickness of the nerve fiber layer and peripapillary and macular vessel density are lower in men than in women with glaucoma, more markedly in early stage glaucomatous patients.

Ocular Vascular Changes in Mild Alzheimer's Disease Patients: Foveal Avascular Zone, Choroidal Thickness, and ONH Hemoglobin Analysis.

In Alzheimer's disease (AD), vascular changes could be caused by amyloid beta (Aß) aggregates replacing the contractile smooth musculature of the arteriole walls. These changes happen in the brain vascular network, but also in the eye, and are related to decreased vascular density and low blood flow. In patients with Alzheimer's disease, thinning of the choroid and the retina has been shown. The aim of this prospective study was to assess the retinal and choroidal vascular systems, analyzing the choroidal thickness with optical coherence tomography (OCT), the foveal avascular zone (FAZ) with OCT-angiography (OCTA), and the optic nerve head (ONH) hemoglobin with the Laguna ONhE program, to evaluate which of the two ocular vascular systems shows earlier changes in mild AD patients. These patients, compared to controls, showed a significantly thinner choroid at all the analyzed points, with the exception of the temporal macula (at 1000 and 1500 µm from the fovea). On the other hand, the FAZ and ONH hemoglobin did not show significant differences. In conclusion, a thinner choroid was the main ocular vascular change observed in mild AD patients, while the retinal vessels were not yet affected. Therefore, choroidal thickness could be used an early biomarker in AD.

Role of FOXC2 and PITX2 rare variants associated with mild functional alterations as modifier factors in congenital glaucoma.

Congenital glaucoma (CG) is a severe and inherited childhood optical neuropathy that leads to irreversible visual loss and blindness in children. CG pathogenesis remains largely unexplained in most patients. Herein we have extended our previous studies to evaluate the role of FOXC2 and PITX2 variants in CG. Variants of the proximal promoter and transcribed sequence of these two genes were analyzed by Sanger sequencing in a cohort of 133 CG families. To investigate possible oligogenic inheritance involving FOXC2 or PITX2 and CYP1B1, we also analyzed FOXC2 and PITX2 variants in a group of 25 CG cases who were known to carry CYP1B1 glaucoma-associated genotypes. The functional effect of three identified variants was assessed by transactivation luciferase reporter assays, protein stability and subcellular localization analyses. We found eight probands (6.0%) who carried four rare FOXC2 variants in the heterozygous state. In addition, we found an elevated frequency (8%) of heterozygous and rare PITX2 variants in the group of CG cases who were known to carry CYP1B1 glaucoma-associated genotypes, and one of these PITX2 variants arose de novo. To the best of our knowledge, two of the identified variants (FOXC2: c.1183C>A, p.(H395N); and PITX2: c.535C>A, p.(P179T)) have not been previously identified. Examination of the genotype-phenotype correlation in this group suggests that the presence of the infrequent PITX2 variants increase the severity of the phenotype. Transactivation reporter analyses showed partial functional alteration of three identified amino acid substitutions (FOXC2: p.(C498R) and p.(H395N); PITX2: p.(P179T)). In summary, the increased frequency in PCG patients of rare FOXC2 and PITX2 variants with mild functional alterations, suggests they play a role as putative modifier factors in this disease further supporting that CG is not a simple monogenic disease and provides novel insights into the complex pathological mechanisms that underlie CG.