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.

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.

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.

Comparison in conjunctival-Tenon's capsule thickness, anterior scleral thickness and ciliary muscle dimensions between Caucasians and Hispanic by optical coherence tomography.

PURPOSE: To investigate the differences in the dimensions of the anterior ocular segment, and specifically in conjunctival-Tenon's capsule thickness (CTT), anterior scleral thickness (AST) and ciliary muscle thickness (CMT), between Caucasian and Hispanic subjects using swept-source optical coherence tomography (SS-OCT). METHODS: Cross-sectional study including 53 Hispanic and 60 Caucasian healthy participants, matched by age, sex and refractive error, who underwent a complete ophthalmological examination. CTT, AST and CMT were manually measured in the temporal and nasal quadrants at 0, 1, 2 and 3 mm from the scleral spur using SS-OCT. RESULTS: Mean age and refractive error were 38.7 ± 12.3 years and -1.05 ± 2.6 diopters, and 41.8 ± 11.7 years and -0.50 ± 2.6 diopters for the Hispanic and Caucasians, respectively (p = 0.165 and p = 0.244). The CTT was increased in the temporal quadrant in the Hispanic group in the three studied regions (CTT1, CTT2 and CTT3; being the means 223.0 ± 68.4, 215.3 ± 66.4 and 203.8 ± 67.1 µm versus 190.8 ± 51.0, 189.4 ± 53.2 and 187.4 ± 55.3 µm respectively; p < 0.001). Larger AST values were observed in the temporal quadrant in the Hispanic group (AST2: 559.8 ± 80.8 µm and AST3: 591.6 ± 83.0 µm) compared to the Caucasian group (520.7 ± 50.1 and 558.9 ± 54.7 respectively; p ≤ 0.022). No differences were observed in the nasal quadrant for CTT, AST1 and AST3 (p ≥ 0.076). No differences emerged in the CM dimensions (p ≥ 0.055). CONCLUSION: CTT and AST measurements were thicker in the temporal quadrant of Hispanic patients compared to Caucasians. This could have implications for the pathogenesis of different ocular diseases.

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.

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.

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.

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.

Fourier domain optical coherence tomography to assess the iridocorneal angle and correlation study in a large Caucasian population.

BACKGROUND: Recently, novel anatomic parameters that can be measured by optical coherence tomography (OCT), have been identified as a more objective and accurate method of defining the iridocorneal angle. The aim of the present study is to measure the iridocorneal angle by Fourier domain (FD) OCT and to identify correlations between angle measurements and subject factors in a large healthy Caucasian population. METHODS: A cross sectional study was performed in 989 left eyes of 989 healthy subjects. The iridocorneal angle measurements: trabecular-iris angle (TIA), angle opening distance (AOD500) and trabecular-iris space area (TISA500) 500 µm from the scleral spur, were made using the FD-OCT RTVue®. Iris thickness was also measured. Correlations were examined between angle measurements and demographic and ocular factors. The main determinants of angle width were identified by multivariate linear regression. RESULTS: TIA could be measured in 94% of the eyes, and AOD500 and TISA500 in 92%. The means recorded were TIA 35.8 ± 12.2 degrees (range 1.5 to 76.1), AOD500 542.6 ± 285.4 µm (range 15 to 1755), and TISA500 0.195 ± 0.104 mm(2) (range 0.02 to 0.62). The correlation between the temporal and nasal quadrant was R = 0.902 for TIA. The reproducibility of measurements was excellent (intraclass correlation coefficient >0.947). Mean angle width measurements were smaller in women (p = 0.02). Correlation was detected between angle means and anterior chamber volume (ACV; R = 0.848), anterior chamber depth (ACD; R = 0.818), spherical error (R = -0.619) and age (R = -0.487), while no correlation was observed with Intraocular pressure (R = -0.052). ACV emerged as the main determinant of TIA (R(2) = 0.705; p < 0.001). CONCLUSIONS: In this Caucasian population, strong correlation was detected between FD-OCT anterior angle measurements and ACV, ACD, spherical refractive error and sex, emerging the ACV as the main determinant of TIA.

Primary congenital glaucoma in two siblings with different compound heterozygous CYP1B1 genotypes.

OBJECTIVE: To describe the inheritance pattern and clinical variability of primary congenital glaucoma (PCG) in a family with two affected siblings. MATERIALS AND METHODS: Two sisters diagnosed at birth with bilateral PCG, whose father had bilateral PCG and mother had bilateral microphthalmus, were subjected to a familial genetic study and ophthalmologic follow-up including intraocular pressure (IOP) measurement, and collection of biometric and cup-to-disc ratio data. RESULTS: The inheritance pattern was autosomal recessive in compound heterozygosis. The sisters were found to be carriers of three pathogenic allele variants of the CYP1B1 gene: c.317C>A (p.Ala106Asp) and c.1345delG (p.Asp449MetfsTer8) in one patient (10 years) and c.1345delG (p.Asp449MetfsTer8) and c.202_209delCAGGCGGC (p.Gln68Serfs153Ter) in her older sister (12 years). Surgical histories included: three goniotomies and two Ahmed valves in each eye, and two trabeculectomies and a pupilloplasty in the right eye in the 10-year old; and one goniotomy, trabeculectomy and three Ahmed valves in each eye in the older sister. Currently, both sisters have a controlled intraocular pressure of 18-20 mmHg in both eyes. The father is blind in both eyes and carries two variants c.317C>A (p.Ala106Asp) and c.202_209delCAGGCGGC (p.Gln68Serfs153Ter). The mother with a single variant c.1345delG (p.Asp440MetfsTer8) has a prosthetic right eye and microphthalmus left eye. CONCLUSIONS: The sisters were found to show two different allelic CYP1B1 variants (compound heterozygosis) with different repercussions on the clinical severity of PCG. These findings highlight the importance of genetic screening of affected families.

Basal evaluation and rates of progression based on visual fields in six different glaucoma types of a large population.

PURPOSE: The aim of this study is to analyze the distribution of visual field (VF) mean defect (MD) in six subgroups of glaucoma patients at baseline and follow-up. METHODS: We assessed glaucoma patients treated in a Spanish tertiary care setting with a follow-up of at least 10 months. We have included 1036 visual fields and the following glaucoma subtypes: open-Angle Glaucoma (OAG); Angle-Closure Glaucoma (ACG); Congenital Glaucoma (CG); Ocular hypertension (OHT); Pseudoexfoliative Glaucoma (PSXG); Pigmentary Glaucoma (PG). We have calculated the baseline MD and the progression MD. We have stratified the MD progression in slow (MD rate > -0.5 dB/year); moderate (MD rate between -0.5 and -1 dB/year) fast (MD rate between -1 and -2 dB/year) and catastrophic (<-2 dB/year) progression and their glaucoma subtype. RESULTS: The glaucoma types with the worse baseline MD were CG and PG. We found significant differences after comparing the baseline MD of CG and OAG, ACG, OHT and between PG and OHT. Concerning the MD progression rate: OAG 73.54% showed slow MD progression rate; 9.85% fast; 7.3% moderate and 9.3% catastrophic. ACG 82.22% slow; 8.89% moderate; 2.22% fast and 6.67% catastrophic. CG 68.83% slow; 9.09% fast; 7.79% moderate and 14.29% catastrophic. OHT 88.6% slow; 6.14% moderate; 4.39% fast and 0.88% catastrophic. PSXG 63.24% slow, 13.24% moderate; 8.8% fast and 14.7% catastrophic. PG 89.29% slow; 3.57% moderate and 7.1% fast. CONCLUSIONS: The CG requires special attention because of its aggressive presentation and progression.

Improvement of objective ocular redness measured with Keratograph 5M in glaucoma patients after instilling brimonidine drops.

OBJECTIVE: To compare objective ocular redness measured using OCULUS Keratograph 5 M before and after 0.2% brimonidine instillation in glaucoma patients under topical hypotensive treatment. METHODS: 60 eyes from 60 subjects diagnosed with glaucoma or ocular hypertension under hypotensive ocular topical treatment were analyzed. Basal Ophthalmological examination was performed.Outcome variables were OCULUS Keratograph 5 M redness scores (RS) before and after 0.2% brimonidine instillation; overall, bulbar temporal (BT), bulbar nasal (BN), limbar temporal (LT), and limbar nasal (LN); non-invasive average tear film breakup time (Nia-BUT), non-invasive first tear film breakup time (Nif-BUT) and meibography. In addition, the following clinical data were collected: intraocular pressure, type, duration, amount, and preservatives/or not of hypotensive treatment, fluorescein corneal staining score and lower tear meniscus height. RESULTS: All eyes were under topical medication. All redness scores were reduced after brimonidine instillation, mean RS differences were BT 0.82 ± 0.62, BN hyperemia 1.03 ± 0.55, LN hyperemia 0.84 ± 0.49, LT hyperemia 0.71 ± 0.50 and total hyperemia 0.91 ± 0.52 (all p < 0.001). 30 min after brimonidine instillation mean overall RS reduction was 47.97 ± 12.39% (p < 0.001) and after 1 h there was a persistent reduction of overall RS of 45.92 ± 14.27% (p < 0.001). Hyperemia reduction was significant and comparable between preservative and preservative-free group 0.12 ± 0.14 (p > 0.392) and between patient with combination therapy and monotherapy 0.16 ± 0.14 (p > 0.258). CONCLUSION: A significant reduction of conjunctival hyperemia was objectively found in glaucoma patients under topical hypotensive treatment before and after brimonidine instillation. Its fast and long-lasting effect may be useful preoperatively in glaucoma patients to reduce intraoperative bleeding and associated complications.

Preserflo TM MicroShunt implantation combined with Ologen TM in primary and secondary glaucoma patients in a clinical setting.

PURPOSE: This study aims to assess the effectiveness and safety of combining the Preserflo™ MicroShunt implant (MicroShunt) with a simultaneous Ologen™ implant in patients with glaucoma. METHODS: We conducted a retrospective study on consecutive patients with medically uncontrolled glaucoma who underwent MicroShunt + Ologen implantation as a standalone procedure or in combination with phacoemulsification (combined procedure). Success was defined as achieving an intraocular pressure (IOP) of 6-15 mmHg at 18 months post surgery, with a preoperative IOP reduction of at least 20%, and without (complete success) or with (qualified success) the need for antiglaucoma medications. The primary endpoint was the success rate. RESULTS: Forty-eight eyes from 47 patients were included, with 28 eyes (58.3%) undergoing the standalone procedure and 20 eyes (41.7%) undergoing the combined procedure. Overall, there was a significant reduction in preoperative IOP from 19.7 ± 5.8 mmHg to 11.4 ± 2.6 mmHg at 18 months ( P < 0.0001). In the standalone procedure group, preoperative IOP decreased from 21.5 ± 5.2 mmHg to 11.7 ± 2.5 mmHg ( P < 0.0001), and in the combined procedure group, preoperative IOP decreased from 17.1 ± 5.8 mmHg to 10.9 ± 2.7 mmHg ( P = 0.0002), with no significant difference between the two groups regarding final IOP. The mean number of antiglaucoma medications significantly decreased from 3.2 ± 1.1 to 0.3 ± 0.7 in the overall study population ( P < 0.0001). At 18 months, 40 eyes (83.3%) were classified as successful. Regarding safety, out of the total number of eyes, two (4.2%) experienced choroidal detachment without visual impairment, two (4.2%) had transient hyphema, one (2.1%) showed reactivation of a corneal herpetic ulcer, one (2.1%) had diplopia, and one (2.1%) exhibited a shallow anterior chamber during the first week. CONCLUSION: The combination of Ologen™ and Preserflo™ MicroShunt, either alone or in conjunction with phacoemulsification, demonstrated a favorable profile in terms of IOP reduction and safety.

Prescription trends for preservative free glaucoma medication in a public health system.

PURPOSE: To analyze the prescribing trends over a 7-years period, between 2013 and 2020, in a tertiary hospital (Hospital Clinico San Carlos, Madrid, Spain) and its health area. MATERIAL AND METHODS: A retrospective study on the data collected from the information systems, "farm@web" and "Farmadrid", of glaucoma prescriptions in the framework of a public health system (Spanish National Health System) during the last seven years. RESULTS: Prostaglandin analogues were the most commonly used drugs in monotherapy during the study period (range: 36.82% - 47.07%). Fixed combinations of topical hypotensives had an upward trend since 2013 (range: 39.99% - 54.21%), becoming the most dispensed drugs in 2020 (48.99%). Preservative-free eye drops (lacking benzalkonium chloride, BAK) have displaced preservative containing topical treatments in all pharmacological groups. In 2013, BAK-preserved eye drops accounted for 91.1% of the total prescriptions, however in 2020 they only accounted for 34.2% of total prescriptions. CONCLUSIONS: The results of the present study highlight the current trend to avoid BAK-preserved eye drops for the treatment of glaucoma.

Effectiveness and safety of XEN63 in patients with primary-open-angle glaucoma.

This paper evaluates the effectiveness and safety of XEN63 stent, either standalone or in combination with phacoemulsification, in patients with primary open-angle glaucoma (POAG). Eighty eyes from 80 patients with medically uncontrolled POAG were assigned to undergo XEN63 implant. The primary outcome was the surgical success, defined as an intraocular pressure (IOP) lowering from preoperative values ≥ 20% and an IOP absolute value between 6 and 18 mmHg, with or without antiglaucoma medications. Forty-three (53.7%) eyes underwent XEN63-standalone and 37(46.2%) eyes a XEN63 + Phacoemulsification procedure. Success rate was 68.8% (55/80) eyes in the overall study sample, 69.8% (30/43) eyes in the XEN63-standalone group; and 67.6% (25/37) eyes in the XEN63 + Phaco group (p = 0.6133). Preoperative IOP was significantly lowered from 22.1 ± 4.9 mmHg and 19.8 ± 3.7 mmHg to 14.7 ± 5.3 mmHg and 13.8 ± 3.4 mmHg in the XEN63-standalone and XEN63 + Phaco groups, respectively (p < 0.0001 each, respectively); without significant differences between them at any of the time-points measured. Preoperative number of ocular-hypotensive drugs was significantly reduced from 2.3 ± 0.8 to 0.3 ± 0.7 drugs, from 2.5 ± 0.7 to 0.3 ± 0.7 drugs; and from 2.0 ± 0.8 to 0.3 ± 0.7 drugs, in the overall, XEN63-standalone, and XEN63 + Phaco groups, respectively. Regarding safety, 3(42.5%) eyes had transient hypotony at some point during the study, although only in one (1.2%) eye was clinically significant. Four (5.0%) eyes underwent a needling, 4 (5.0%) eyes underwent surgical-bleb-revision, 1 (1.2%) eye required a device replacement and 1 (1.2%) eye a device removal due to maculopathy. XEN63, either alone or in combination with phacoemulsification, significantly lowered IOP and reduced the number of ocular hypotensive medications. The rate of ocular hypotony was relatively high, although it was clinically relevant only in one eye.

European Glaucoma Society research priorities for glaucoma care.

BACKGROUND/AIMS: The goal of health research is to improve patients care and outcomes. Thus, it is essential that research addresses questions that are important to patients and clinicians. The aim of this study was to develop a list of priorities for glaucoma research involving stakeholders from different countries in Europe. METHODS: We used a three-phase method, including a two-round electronic Delphi survey and a workshop. The clinician and patient electronic surveys were conducted in parallel and independently. For phase I, the survey was distributed to patients from 27 European countries in 6 different languages, and to European Glaucoma Society members, ophthalmologists with expertise in glaucoma care, asking to name up to five research priorities. During phase II, participants were asked to rank the questions identified in phase I using a Likert scale. Phase III was a 1 day workshop with patients and clinicians. The purpose was to make decisions about the 10 most important research priorities using the top 20 priorities identified by patients and clinicians. RESULTS: In phase I, 308 patients and 150 clinicians were involved. In phase II, the highest-ranking priority for both patients and clinicians was 'treatments to restore vision'. In phase III, eight patients and four clinicians were involved. The top three priorities were 'treatments to stop sight loss', 'treatments to restore vision' and 'improved detection of worsening glaucoma'. CONCLUSION: We have developed a list of priorities for glaucoma research involving clinicians and patients from different European countries that will help guide research efforts and investment.

Null CYP1B1 genotypes in primary congenital and nondominant juvenile glaucoma.

PURPOSE: To assess the mutation spectrum, enzymatic activity, and phenotypic features associated with CYP1B1 genotypes in primary congenital glaucoma (PCG) and nondominant juvenile glaucoma (ndJG). DESIGN: CYP1B1 genotyping, segregation analysis, and functional evaluation of mutations in a cohort of patients. PARTICIPANTS: A total of 177 probands clinically diagnosed with PCG (161) or ndJG (16). METHODS: Automatic DNA sequencing of the promoter (-1 to -867) and the 3 CYP1B1 exons. CYP1B1 enzymatic activity was evaluated using an ethoxyresorufin O-deethylation assay in transfected HEK-293T cells. MAIN OUTCOME MEASURES: Screening and functional evaluation of CYP1B1 mutations. Glaucoma diagnosis based on slit-lamp examination, measurement of intraocular pressure, gonioscopy, and fundus examination. RESULTS: Thirty-one different mutations were identified in 56 PCG and 7 ndJG index cases. To the best of our knowledge, 3 of the identified mutations were novel (-337G>T, F123L, and I399_P400del). Approximately 56% of all mutation carriers were compound heterozygotes, 25% were homozygotes, and both groups inherited glaucoma as an autosomal recessive trait. Nineteen percent of carriers were heterozygotes and showed non-Mendelian segregation. In vitro and inferred functional analysis showed that no less than approximately 74% of the recessive genotypes result in null enzymatic activity. We detected variable expressivity in relation to age of onset and a possible case of incomplete penetrance in 3 of 6 families (50%), with more than 1 affected child or more than 1 subject carrying 2 CYP1B1 mutant alleles. Altogether, these data support that PCG is not a simple monogenic disease. In addition, most patients with PCG carrying null or putative null genotypes showed severe bilateral phenotypes featured by early disease onset, frequently at birth. The mean number of trabeculectomies per eye was significantly higher in carriers than in noncarriers. CONCLUSIONS: This is the largest analysis of CYP1B1 mutations performed in European patients with PCG to date. Our data show that null CYP1B1 genotypes, and therefore complete absence of CYP1B1 activity, frequently lead to severe phenotypes. Our results support that CYP1B1 glaucoma is not a simple monogenic disease and that CYP1B1 activity levels could influence the phenotype.