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Huub J Poelman, Roger CW Wolfs, Wishal D Ramdas Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the NetherlandsCorrespondence: Wishal D RamdasDepartment of Ophthalmology, Erasmus Medical Center, Rotterdam, ‘S Gravendijkwal 230, CE 3015, Rotterdam, The NetherlandsEmail w.ramdas@erasmusmc.nlObjective: This review summarizes published findings concerning the Baerveldt-350 glaucoma drainage device (GDD). Most studies focus on the comparison between different treatments; in this review, the primary focus is efficacy, safety, and place in therapy for the Baerveldt implant.Methods: A systematic review was performed using the PubMed database for literature on March 13th, 2020. Efficacy was estimated by performing multiple meta-analyses to calculate the weighted mean difference in intraocular pressure (IOP) and IOP-lowering medication after surgery. In order to get an indication of the safety of the Baerveldt implant, all recorded peri- and postoperative complication were summarized.Results: A total of 21 studies, including 12 randomized controlled trials, were included with a follow-up up to 5 years, covering a mix of glaucoma types. At the last follow-up point, at 5 years postoperative, the mean (95% confidence interval) reduction in IOP was 15.57 mmHg (14.43– 16.71) and the mean (95% confidence interval) reduction in IOP-lowering medication after surgery was 1.81 (1.61– 2.01). Most frequently observed postoperative complications were corneal edema (2– 34%) and tube complications (4– 33%). Rates of required re-intervention ranged from 0% to 51% across all included studies.Conclusion: The efficacy of the Baerveldt implant is a significant reduction in IOP in the long term. The safety profile of the Baerveldt implant in terms of complication incidence is similar to those reported for other GDD’s. For treatment of secondary glaucoma, we suggest the Baerveldt (or any other similar GDD) as the choice of treatment in patients where highest IOP reduction is desired.Keywords: Baerveldt implant, glaucoma drainage device, glaucoma, intraocular pressure

Fundus images allow for non-invasive assessment of the retinal vasculature whose features provide important information on health. Using a fully automated image processing pipeline, we extract 17 different morphological vascular phenotypes, including median vessels diameter, diameter variability, main temporal angles, vascular density, central retinal equivalents, the number of bifurcations, and tortuosity, from over 130,000 fundus images of close to 72,000 UK Biobank subjects. We perform genome-wide association studies of these phenotypes. From this, we estimate their heritabilities, ranging between 5 and 25%, and genetic cross-phenotype correlations, which mostly mirror the corresponding phenotypic correlations, but tend to be slightly larger. Projecting our genetic association signals onto genes and pathways reveals remarkably low overlap suggesting largely decoupled mechanisms modulating the different phenotypes. We find that diameter variability, especially for the veins, associates with diseases including heart attack, pulmonary embolism, and age of death. Mendelian Randomization analysis suggests a causal influence of blood pressure and body mass index on retinal vessel morphology, among other results. We validate key findings in two independent smaller cohorts. Our analyses provide evidence that large-scale analysis of image-derived vascular phenotypes has sufficient power for obtaining functional and causal insights into the processes modulating the retinal vasculature., (© 2024. The Author(s).)

Purpose: We used a polygenic risk score (PRS) to identify high-risk groups for primary open-angle glaucoma (POAG) within population-based cohorts., Design: Secondary analysis of 4 prospective population-based studies., Participants: We included four European-ancestry cohorts: the United States-based Nurses' Health Study, Nurses' Health Study 2, and the Health Professionals Follow-up Study and the Rotterdam Study (RS) in The Netherlands. The United States cohorts included female nurses and male health professionals ≤ 55 years of age. The RS included residents ≤ 45 years of age living in Rotterdam, The Netherlands., Methods: Polygenic risk score weights were estimated by applying the lassosum method on imputed genotype and phenotype data from the UK Biobank. This resulted in 144 020 variants, single nucleotide polymorphism and insertions or deletions, with nonzero βs that we used to calculate a PRS in the target populations. Using multivariable Cox proportional hazard models, we estimated the relationship between the standardized PRS and relative risk for POAG. Additionally, POAG prediction was tested by calculating these models' concordance (Harrell's C statistic). Finally, we assessed the association between PRS tertiles and glaucoma-related traits., Main Outcome Measures: The relative risk for POAG and Harrell's C statistic., Results: Among 1046 patients and 38 809‬ control participants, the relative risk (95% confidence interval) for POAG for participants in the highest PRS quintile was 3.99 (3.08-5.18) times higher in the United States cohorts and 4.89 (2.93-8.17) times higher in the RS, compared with participants with median genetic risk (third quintile). Combining age, sex, intraocular pressure of more than 25 mmHg, and family history resulted in a meta-analyzed concordance of 0.75 (95% CI, 0.73-0.75). Adding the PRS to this model improved the concordance to 0.82 (95% CI, 0.80-0.84). In a meta-analysis of all cohorts, patients in the highest tertile showed a larger cup-to-disc ratio at diagnosis, by 0.10 (95% CI, 0.06 0.14), and a 2.07-fold increased risk of requiring glaucoma surgery (95% CI, 1.19-3.60)., Conclusions: Incorporating a PRS into a POAG predictive model improves identification concordance from 0.75 up to 0.82, supporting its potential for guiding more cost-effective screening strategies., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2024 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To determine the thickness of the conjunctiva, episclera and sclera in healthy individuals using anterior segment optical coherence tomography (AS-OCT)., Methods: We prospectively included 107 healthy individuals of different age groups (18-39 years, 40-54 years, 55-69 years and ≥70 years). For each eye, AS-OCT scans of four quadrants (temporal, nasal, superior and inferior) were acquired. The thickness of the conjunctiva, episclera and sclera was measured for each scan. In addition, the axial length of both eyes was measured, and general characteristics, including smoking, allergies and contact lens use, were collected., Results: The mean conjunctival thickness was significantly different between the nasal and superior quadrants (87 ± 30 μm vs. 77 ± 16 μm; p < 0.001), as well as the superior and inferior quadrants (77 ± 16 μm vs. 86 ± 19 μm; p = 0.001). The mean episcleral thickness was larger in the superior (174 ± 54 μm) and inferior (141 ± 43 μm) quadrants, compared to the nasal (83 ± 38 μm) and temporal quadrants (90 ± 44 μm). The mean scleral thickness of the inferior quadrant was the largest (596 ± 64 μm), followed by the nasal (567 ± 76 μm), temporal (516 ± 67 μm) and superior (467 ± 52 μm) quadrants (all p < 0.001). The averaged scleral thickness increased 0.96 μm per age year (0.41-1.47 μm, p < 0.001)., Conclusions: This study provides an assessment of the thickness of scleral and adjacent superficial layers in healthy individuals determined on AS-OCT, which could enable future research into the use of AS-OCT in diseases affecting the anterior eye wall., (© 2023 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Purpose: Glaucoma is an eye disease that is the most common cause of irreversible blindness worldwide. It has been suggested that gut microbiota can produce reactive oxygen species and pro-inflammatory cytokines that may travel from the gastric mucosa to distal sites, for example, the optic nerve head or trabecular meshwork. There is evidence for a gut-eye axis, as microbial dysbiosis has been associated with retinal diseases. We investigated the microbial composition in patients with glaucoma and healthy controls. Moreover, we analyzed the association of the gut microbiome with intraocular pressure (IOP; risk factor of glaucoma) and vertical cup-to-disc ratio (VCDR; quantifying glaucoma severity)., Methods: The discovery analyses included participants of the Rotterdam Study and the Erasmus Glaucoma Cohort. A total of 225 patients with glaucoma and 1247 age- and sex-matched participants without glaucoma were included in our analyses. Stool samples were used to generate 16S rRNA gene profiles. We assessed associations with 233 genera and species. We used data from the TwinsUK and the Study of Health in Pomerania (SHIP) to replicate our findings., Results: Several butyrate-producing taxa (e.g. Butyrivibrio, Caproiciproducens, Clostridium sensu stricto 1, Coprococcus 1, Ruminococcaceae UCG 007, and Shuttleworthia) were less abundant in people with glaucoma compared to healthy controls. The same taxa were also associated with lower IOP and smaller VCDR. The replication analyses confirmed the findings from the discovery analyses., Conclusions: Large human studies exploring the link between the gut microbiome and glaucoma are lacking. Our results suggest that microbial dysbiosis plays a role in the pathophysiology of glaucoma.

Background & Aims: Inflammation is involved in the pathogenesis of cataract, age-related macular degeneration (AMD), and possibly open-angle glaucoma (OAG). We assessed whether the inflammatory potential of diet (quantified using the dietary inflammatory index; DII) affects the incidence of these common blinding age-related eye diseases. Serum inflammation markers were investigated as possible mediators., Methods: Participants aged >45 years were selected from the prospective, population-based Rotterdam Study. From 1991 onwards, every 4-5 years, participants underwent extensive eye examinations. At baseline, blood samples and dietary data (using food frequency questionnaires) were collected. The DII was adapted based on the data available. Of the 7436 participants free of eye diseases at baseline, 4036 developed incident eye diseases during follow-up (cataract = 2895, early-intermediate AMD = 891, late AMD = 81, OAG = 169)., Results: The adapted DII (aDII) ranged from -4.26 (i.e., anti-inflammatory) to 4.53 (i.e., pro-inflammatory). A higher aDII was significantly associated with increased inflammation. A higher neutrophil-lymphocyte ratio (NLR) was associated with an increased risk of cataract and AMD. Additionally, complement component 3c (C3c) and systemic immune-inflammation index (SII) were associated with increased risks of cataract and late AMD, respectively. Every point increase in the aDII was associated with a 9% increased risk of cataract (Odds ratio [95% confidence interval]: 1.09 [1.04-1.14]). The NLR and C3c partly mediated this association. We also identified associations of the aDII with risk of AMD (early-intermediate AMD, OR [95% CI]: 1.11 [1.03-1.19]; late AMD, OR [95% CI]: 1.24 [1.02-1.53]). The NLR partly mediated these associations. The aDII was not associated with OAG., Conclusions: A pro-inflammatory diet was associated with increased risks of cataract and AMD. Particularly the NLR, a marker of subclinical inflammation, appears to be implicated. These findings are relevant for patients with AMD and substantiate the current recommendations to strive for a healthy lifestyle to prevent blindness., Competing Interests: Conflicts of interest CCWK: Consultant – Bayer, Laboratoires Théa, Novartis., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: The worldwide incidence of ocular melanoma (OM), uveal melanoma (UM), and conjunctival melanoma has last been reported on 15 years ago. Recently, light iris color and four specific single-nucleotide-polymorphisms (SNPs) have been identified as a UM-risk factor. Furthermore, six iris color predicting SNPs have been discovered (IrisPlex). Interestingly, two of these (rs129138329 and rs12203592) are also UM-risk factors. We collected worldwide incidence data of OM and investigated its correlations with iris color, IrisPlex SNPs, and UM-risk SNPs., Methods: Cases of OM, as defined by the International Classification of Diseases Oncology C69 (eye), 8720/3 to 8790/3 (malignant melanoma), and 8000 to 8005 (malignant neoplasm), between 1988 and 2012, were extracted from the Cancer Incidence in Five Continents. Incidence rates were age-standardized and their trends were analyzed with joinpoint regression and age period cohort modeling. Frequencies for each country of iris color, IrisPlex SNPs, and UM-risk SNPs were collected from the literature., Results: Incidence rates were generally ≥8.0 cases per million person-years in Northern Europe, Western Europe, and Oceania; 2.0 to 7.9 in North America, Eastern Europe, and Southern Europe; and <2.0 in South America, Asia, and Africa. OM incidence correlated with latitude (r = 0.77, P ≤ 0.001) and is expressed as a north-to-south decreasing gradient in Europe. SNP rs12913832 correlated with OM incidence (r = 0.83, P ≤ 0.001), blue iris color (r = 0.56, P ≤ 0.05), green iris color (r = 0.51, P ≤ 0.05), and brown iris color (r = -0.64, P ≤ 0.01). Trends were stable for most countries (28/35)., Conclusions: OM incidence is highest in populations of European ancestry and lowest in populations of Asian and African ancestry. Overall, trends are stable, and the spatial correlation among OM incidence, iris color, and rs12913832 may support the role of pigmentation-related risk factors in OM development.

Purpose: To investigate the association of commonly used systemic medications with glaucoma and intraocular pressure (IOP) in the European population., Design: Meta-analysis of 11 population-based cohort studies of the European Eye Epidemiology Consortium., Participants: The glaucoma analyses included 143 240 participants and the IOP analyses included 47 177 participants., Methods: We examined associations of 4 categories of systemic medications-antihypertensive medications (β-blockers, diuretics, calcium channel blockers [CCBs], α-agonists, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers), lipid-lowering medications, antidepressants, and antidiabetic medications-with glaucoma prevalence and IOP. Glaucoma ascertainment and IOP measurement method were according to individual study protocols. Results of multivariable regression analyses of each study were pooled using random effects meta-analyses. Associations with antidiabetic medications were examined in participants with diabetes only., Main Outcome Measures: Glaucoma prevalence and IOP., Results: In the meta-analyses of our maximally adjusted multivariable models, use of CCBs was associated with a higher prevalence of glaucoma (odds ratio [OR], 1.23; 95% confidence interval [CI], 1.08 to 1.39). This association was stronger for monotherapy of CCBs with direct cardiac effects (OR, 1.96; 95% CI, 1.23 to 3.12). No other antihypertensive medications, lipid-lowering medications, antidepressants, or antidiabetic medications were associated with glaucoma. Use of systemic β-blockers was associated with a lower IOP (β coefficient, -0.33 mmHg; 95% CI, -0.57 to -0.08 mmHg). Monotherapy of both selective systemic β-blockers (β coefficient, -0.45 mmHg; 95% CI -0.74 to -0.16 mmHg) and nonselective systemic β-blockers (β coefficient, -0.54 mmHg; 95% CI, -0.94 to -0.15 mmHg) was associated with lower IOP. A suggestive association was found between use of high-ceiling diuretics and lower IOP (β coefficient, -0.30 mmHg; 95% CI, -0.47 to -0.14 mmHg) but not when used as monotherapy. No other antihypertensive medications, lipid-lowering medications, antidepressants, or antidiabetic medications were associated with IOP., Conclusions: We identified a potentially harmful association between use of CCBs and glaucoma prevalence. Additionally, we observed and quantified the association of lower IOP with systemic β-blocker use. Both findings potentially are important, given that patients with glaucoma frequently use systemic antihypertensive medications. Determining causality of the CCB association should be a research priority., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background: Testosterone may be a possible modifiable risk factor for open-angle glaucoma (OAG) and intraocular pressure (IOP), but evidence has been scarce and conflicting. In this study we evaluated the association of testosterone and its genetic predisposition with incident (i) OAG, IOP, retinal nerve fiber layer (RNFL), and ganglion cell-inner plexiform layer (GCL +)., Methods: Participants aged 45-100 years were derived from the prospective, population-based Rotterdam Study. Ophthalmic examinations and serum testosterone measurements (including bioavailable and free testosterone) were performed from 1991 onwards. Follow-up took place every 4-5 years. A total of 187 out of 7898 participants were diagnosed with incident (i) OAG during follow-up. Genotyping was performed in 165 glaucoma cases and 6708 controls. We calculated sex-specific weighted genetic risk scores (GRS) for total and bioavailable testosterone. Associations with iOAG were analyzed using multivariable logistic regression. Associations with IOP, RNFL, and GCL + were analyzed with multivariable linear regression. Analyses were stratified on sex and adjusted for at least age, body mass index, and follow-up duration., Results: In men, testosterone was not associated with iOAG. However, the GRS for higher total testosterone was associated with an increased iOAG risk (odds ratio [OR] with 95% confidence interval [95% CI]: 2.48 [1.18; 5.22], per unit). In women, higher values of bioavailable testosterone (2.05 [1.00; 4.18] per nmol/L) and free testosterone (1.79 [1.00; 3.20] per ng/dL) were significantly associated with increased risk of iOAG. Moreover, the GRS for higher bioavailable testosterone was associated with an increased iOAG risk (2.48 [1.09; 5.65], per unit). Higher bioavailable and free testosterone were adversely associated with IOP (0.58 [0.05; 1.10] per nmol/L and 0.47 [0.04; 0.90] per ng/dL). Higher total testosterone was inversely associated with peripapillary RNFL and GCL + (Beta [95% CI]: - 3.54 [- 7.02; - 0.06] per nmol/L and - 2.18 [- 4.11; - 0.25] per nmol/L, respectively)., Conclusions: In women, higher testosterone levels increased the risk of iOAG. Both IOP-dependent and IOP-independent mechanisms may underlie this association. Managing testosterone levels may be particularly relevant for the prevention of neurodegeneration in the eye. Future research should confirm these findings., (© 2023. The Author(s).)

Purpose: The purpose of this study was to describe the genetic relationship between smoking and glaucoma., Methods: We used summary-level genetic data for smoking initiation, smoking intensity (cigarettes per day [CPD]), intraocular pressure (IOP), vertical cup-disc ratio, and open-angle glaucoma (OAG) to estimate global genetic correlations (rg) and perform two-sample Mendelian randomization (MR) experiments that explored relations between traits. Finally, we examined associations between smoking genetic risk scores (GRS) and smoking traits with measured IOP and OAG in Rotterdam Study participants., Results: We identified weak inverse rg between smoking- and glaucoma-related traits that were insignificant after Bonferroni correction. However, MR analysis revealed that genetically predicted smoking initiation was associated with lower IOP (-0.18 mm Hg per SD, 95% confidence interval [CI] = -0.30 to -0.06, P = 0.003). Furthermore, genetically predicted smoking intensity was associated with decreased OAG risk (odds ratio [OR] = 0.74 per SD, 95% CI = 0.61 to 0.90, P = 0.002). In the Rotterdam Study, the smoking initiation GRS was associated with lower IOP (-0.09 mm Hg per SD, 95% CI = -0.17 to -0.01, P = 0.04) and lower odds of OAG (OR = 0.84 per SD, 95% CI = 0.73 to 0.98, P = 0.02) in multivariable-adjusted analyses. In contrast, neither smoking history nor CPD was associated with IOP (P ≥ 0.38) or OAG (P ≥ 0.54). Associations between the smoking intensity GRS and glaucoma traits were null (P ≥ 0.13)., Conclusions: MR experiments and GRS generated from Rotterdam Study participants support an inverse relationship between smoking and glaucoma., Translational Relevance: Understanding the genetic drivers of the inverse relationship between smoking and glaucoma could yield new insights into glaucoma pathophysiology.

Purpose: To assess the association between the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet and the incidence of open-angle glaucoma (iOAG), as well as the association between iOAG and two other well-established diets in the Netherlands, i.e., the Mediterranean diet and Dutch dietary guidelines., Methods: In the Rotterdam Study, participants were followed for iOAG since 1991, with intervals of approximately 5 years. A total of 170 participants developed iOAG during follow-up. Participants with iOAG were matched with healthy controls on age and sex in a case:control ratio of 1:5. The associations between food frequency questionnaire-derived diet adherences (baseline) and iOAG were analyzed using multivariable conditional logistic regression analyses. The associations between the diet adherences and intraocular pressure (IOP; a risk factor for OAG) were assessed using multivariable linear regression analyses., Results: Greater adherence to the MIND diet was associated with a decreased iOAG risk (odds ratio [95% confidence interval]: 0.80 [0.66 to 0.96], for each 10-percent increase in adherence). Food component analyses showed that, in particular a higher intake of green leafy vegetables, berries and fish tended to be protective for iOAG. No significant associations were observed between adherence to the Mediterranean diet or Dutch dietary guidelines and iOAG. Moreover, none of the three examined diets were associated with IOP., Conclusion: Adherence to the MIND diet was significantly associated with a lower incidence of OAG in contrast to adherence to the Mediterranean diet or the Dutch dietary guidelines. As this association was IOP-independent, the MIND diet may be particularly relevant for the prevention of neurodegeneration in the eye., (© 2022. The Author(s).)

Background: Trabeculectomy is the "gold standard" initial surgical procedure for open-angle glaucoma worldwide. During the last decade, the introduction of less invasive procedures, including new bleb-forming surgery such as the MicroShunt, has altered the approach of glaucoma management. At present, there is insufficient evidence comparing the effectiveness between these procedures nor versus trabeculectomy. Furthermore, there is no data available on patient impact and cost-effectiveness. This study aims to address this gap in evidence and establish whether MicroShunt implantation is non-inferior compared to trabeculectomy with regard to effectiveness and whether it is cost-effective., Methods: A multicentre, non-inferiority, randomised controlled trial (RCT) studying open-angle glaucoma with an indication for surgery will be conducted. Patients with previous ocular surgery except for phacoemulsification are excluded, as are patients with ocular comorbidity compromising the visual field or requiring a combined procedure. After informed consent is obtained, patients will be randomly allocated to the intervention, a PRESERFLO™ MicroShunt implantation, or the control group, trabeculectomy, using block randomisation (blocks of 2, 4 or 6 patients). In total, 124 patients will be randomised in a 1:1 ratio, stratified by centre. The primary endpoint will be intraocular pressure (IOP) one year after surgery. Secondary outcomes include IOP-lowering medication use, treatment failure, visual acuity, visual field progression, additional interventions, adverse events, patient-reported outcome measures (PROMs), and cost-effectiveness. Study outcomes will be measured up to 12 months postoperatively., Discussion: This study protocol describes the design of a multicentre non-inferiority randomised controlled trial. To this date, cost-effectiveness studies evaluating the MicroShunt have not been undertaken. This multicentre RCT will provide more insight into whether MicroShunt implantation is non-inferior compared to standard trabeculectomy regarding postoperative IOP and whether MicroShunt implantation is cost-effective., Trial Registration: ClinicalTrials.gov, Identifier: NCT03931564 , Registered 30 April 2019., (© 2023. The Author(s).)

Background: Recent studies on the PRESERFLO MicroShunt suggest that it may be effective in lowering intraocular pressure (IOP); however, the number of studies on this device remains limited. Therefore, we assessed the efficacy of the PRESERFLO MicroShunt in patients with glaucoma and performed a meta-analysis of published results. Methods: Prospective study including all patients that underwent PRESERFLO MicroShunt surgery from 2018 onwards. Sub-analyses were performed for cataract-combined procedures. To compare our results, we performed a systematic review and meta-analysis. IOP, IOP-lowering medication and surgical complications reported in the retrieved studies were assessed. Results: A total of 72 eyes underwent PRESERFLO-implant surgery (59 as standalone procedure and 13 as cataract-combined procedure). No significant differences were found in IOP and IOP-lowering medication between both groups. The mean ± standard deviation IOP and IOP-lowering medications of both groups taken together declined from 21.72 ± 8.35 to 15.92 ± 8.54 mmHg (p < 0.001, 26.7% reduction) and 3.40 to 0.93 (p < 0.001, 72.6% reduction) at 1 year follow-up, respectively. Secondary surgeries were required in 19.4% of eyes, the majority (71.4%) within 6 months. The meta-analysis including 14 studies (totaling 1213 PRESERFLO MicroShunt surgeries) from the systematic review showed a mean preoperative IOP and IOP-lowering medication of 22.28 ± 5.38 and 2.97 ± 1.07, respectively. The three-years postoperative pooled mean was (weighted mean difference, 95% CI) 11.07 (10.27 [8.23−12.32], p < 0.001) mmHg and 0.91 (1.77 [1.26−2.28], p < 0.001) for IOP and IOP-lowering medication, respectively. The most common reported complication was hypotony (2−39%). Conclusion: The PRESERFLO MicroShunt is effective and safe in lowering IOP and the number of IOP-lowering medications.

Purpose: To obtain pediatric normative reference values and determine whether optical coherence tomography (OCT) corresponds better with clinical signs of intracranial hypertension (ICH) compared to the traditional screening method fundoscopy in a large cohort of one type of single suture craniosynostosis., Methods: Control subjects without optic nerve diseases and isolated sagittal synostosis patients aged 3-10 years who underwent fundoscopy and OCT were included in this prospective cohort study. Normative reference values were obtained through bootstrap analysis. Main outcome was the association between peripapillary total retinal thickness (TRT) and total retinal volume (TRV) and appearance on fundoscopy. Signs and symptoms suggestive of ICH, including skull growth arrest, fingerprinting, and headache, were scored., Results: Sixty-four healthy controls and 93 isolated sagittal synostosis patients were included. Normative cut-off values for mean TRT are < 256 μm and > 504 μm and for mean TRV < 0.21 mm 3 and > 0.39 mm 3 . TRT was increased in 16 (17%) and TRV in 15 (16%) of 93 patients, compared to only 4 patients with papilledema on fundoscopy (4%). Both parameters were associated with papilledema on fundoscopy (OR = 16.7, p = 0.02, and OR = 18.2, p = 0.01). Skull growth arrest was significantly associated with abnormal OCT parameters (OR = 13.65, p < 0.01)., Conclusions: The established cut-off points can be applied to screen for ICH in pediatrics. The present study detected abnormalities with OCT more frequent than with fundoscopy, which were associated with skull growth arrest. Therefore, a combination of OCT, fundoscopy, and skull growth arrest can improve clinical decision-making in craniosynostosis., (© 2022. The Author(s).)

Importance: Recent studies suggest that the diabetes drug metformin has a protective effect on open-angle glaucoma (OAG) and age-related macular degeneration (AMD). However, studies have not addressed the critical issue of confounding by indication, and associations have not been evaluated in a large prospective cohort., Objective: To determine the association between diabetes medication and the common eye diseases OAG, AMD, and cataract and to evaluate their cumulative lifetime risks in a large cohort study., Design, Setting, and Participants: This cohort study included participants from 3 independent cohorts from the prospective, population-based Rotterdam Study between April 23, 1990, and June 25, 2014. Participants were monitored for incident eye diseases (OAG, AMD, cataract) and had baseline measurements of serum glucose. Data on diabetes medication use and data from ophthalmologic examinations were gathered., Exposures: Type 2 diabetes (T2D) and the diabetes medications metformin, insulin, and sulfonylurea derivatives., Main Outcomes and Measures: Diagnosis and cumulative lifetime risk of OAG, AMD, and cataract., Results: This study included 11 260 participants (mean [SD] age, 65.1 [9.8]; 6610 women [58.7%]). T2D was diagnosed in 2406 participants (28.4%), OAG was diagnosed in 324 of 7394 participants (4.4%), AMD was diagnosed in 1935 of 10 993 participants (17.6%), and cataract was diagnosed in 4203 of 11 260 participants (37.3%). Untreated T2D was associated with a higher risk of OAG (odds ratio [OR], 1.50; 95% CI, 1.06-2.13; P = .02), AMD (OR, 1.35; 95% CI, 1.11-1.64; P = .003), and cataract (OR, 1.63; 95% CI, 1.39-1.92; P < .001). T2D treated with metformin was associated with a lower risk of OAG (OR, 0.18; 95% CI, 0.08-0.41; P < .001). Other diabetes medication (ie, insulin, sulfonylurea derivates) was associated with a lower risk of AMD (combined OR, 0.32; 95% CI, 0.18 to 0.55; P < .001). The cumulative lifetime risk of OAG was lower for individuals taking metformin (1.5%; 95% CI, 0.01%-3.1%) than for individuals without T2D (7.2%; 95% CI, 5.7%-8.7%); the lifetime risk of AMD was lower for individuals taking other diabetes medication (17.0%; 95% CI, 5.8%-26.8% vs 33.1%; 95% CI, 30.6%-35.6%)., Conclusions and Relevance: Results of this cohort study suggest that, although diabetes was clearly associated with cataract, diabetes medication was not. Treatment with metformin was associated with a lower risk of OAG, and other diabetes medication was associated with a lower risk of AMD. Proof of benefit would require interventional clinical trials.

Previous studies suggest that nitric oxide is involved in the regulation of the intraocular pressure (IOP) and in the pathophysiology of open-angle glaucoma (OAG). However, prospective studies investigating the association between dietary nitrate intake, a source of nitric oxide, and incident (i)OAG risk are limited. We aimed to determine the association between dietary nitrate intake and iOAG, and to evaluate the association between dietary nitrate intake and IOP. From 1991 onwards, participants were followed each five years for iOAG in the Rotterdam Study. A total of 173 participants developed iOAG during follow-up. Cases and controls were matched on age (mean ± standard deviation: 65.7 ± 6.9) and sex (%female: 53.2) in a case:control ratio of 1:5. After adjustment for potential confounders, total dietary nitrate intake was associated with a lower iOAG risk (odds ratio (OR) with corresponding 95% confidence interval (95% CI): 0.95 (0.91-0.98) for each 10 mg/day higher intake). Both nitrate intake from vegetables (OR (95% CI): 0.95 (0.91-0.98) for each 10 mg/day higher intake) and nitrate intake from non-vegetable food sources (OR (95% CI): 0.63 (0.41-0.96) for each 10 mg/day higher intake) were associated with a lower iOAG risk. Dietary nitrate intake was not associated with IOP. In conclusion, dietary nitrate intake was associated with a reduced risk of iOAG. IOP-independent mechanisms may underlie the association with OAG.

Background: Early studies have shown that micropulse transscleral cyclophotocoagulation (MP-TSCPC) might be an effective and safe treatment option for lowering intraocular pressure (IOP). These studies were, however, somewhat limited, in particular by their retrospective nature and the length of follow-up. Therefore, we assessed the efficacy and safety of this novel treatment in a large cohort for up to 4 years. Methods: We performed a prospective cohort study, including all patients who were treated with MP-TSCPC since November 2017. The primary outcome was a reduction of IOP and the number of IOP-lowering medications. Results: The mean ± standard deviation baseline IOP and number of IOP-lowering medications were 26.6 ± 10.8 mmHg and 3.3 ± 1.3. IOP was reduced by 8.2 ± 7.9 (31.8% reduction), 6.9 ± 8.7 (28.1% reduction), and 7.1 ± 8.4 (30.2% reduction) mmHg after 6, 12, and 24 months, respectively (p < 0.001). The mean postoperative number of IOP-lowering medications was significantly reduced after 6 months by 0.6 ± 1.5 (p = 0.002) but was not significantly different after 12 or 24 months. Oral acetazolamide was significantly reduced from 28 (29%) eyes before treatment, to 9 (9%) at the last follow-up visit (p < 0.001). No major complications were observed after treatment. Conclusions: MP-TSCPC is a safe and effective treatment option for lowering IOP, but only reduced IOP-lowering medications in the first 6 months after treatment. However, MP-TSCPC is especially effective in getting patients off oral IOP-lowering drugs.

Importance: Approximately twenty per cent of Von Hippel-Lindau patients with retinal haemangioblastomas (RH) suffer from visual impairment. Various treatment options are available for peripheral RH. However, management of peripheral RH is complex due to multifocality and bilaterality., Objective: To summarize published evidence on efficacy and safety of different interventions for peripheral RH and to provide treatment recommendations for specialists., Evidence Review: Comprehensive searches were performed using Medline, Embase, Web of Science and Google Scholar database on 4 March 2020. English publications that described outcomes related to efficacy or complications in at least two patients with peripheral RH were included. Efficacy and safety were estimated by complete tumour eradication rate, pretherapeutic and treatment-related complication rate. Odds ratios (OR) with 95% confidence intervals (CI) were calculated to calculate the risk estimate of complications between treatment options., Findings: Twenty-seven articles were included in this review describing nine different treatment options for peripheral RH: laser photocoagulation (n = 230), cryotherapy (n = 50), plaque radiotherapy (n = 27), vitreoretinal surgery (n = 88), photodynamic therapy (PDT; n = 14), transpupillary thermotherapy (TTT; n = 10), external beam radiotherapy (n = 3), systemic treatment (n = 7) and intravitreal anti-VEGF (n = 2). Complete tumour eradication was achieved in 86.7% (95% CI: 83.5-89.9%) of all eyes. For the different treatments, this was after laser photocoagulation 89.9% (86.1-93.7%), cryotherapy 70.2% (57.0-83.4%), plaque radiotherapy 96.3% (89.1-100.0%), vitreoretinal surgery (100.0%), PDT 64.3% (38.3-90.3%) and TTT 80.0% (53.8-100.0%). No complete tumour eradication was achieved after systemic therapy, external beam radiotherapy or intravitreal anti-VEGF. Photodynamic therapy and vitreoretinal surgery showed the highest complication rate after treatment compared to the other treatments (OR 10.5 [95% CI: 2.9-38.4]) and (OR 5.9 [95% CI: 3.4-9.9]), respectively. Cases that had pretherapeutic complications showed a higher treatment-related complication rate (OR 14.8 [95% CI: 7.3-30.0]) than cases without complications before treatment., Conclusions and Relevance: These findings suggest that laser photocoagulation is the safest and most effective treatment method for peripheral RH up to 1.5 mm in diameter. Vitreoretinal surgery has the highest success rate for complete tumour eradication and may be the most suitable treatment option in the presence of pretherapeutic complications and for larger tumours., (© 2021 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Background: There has been speculation that IOP-lowering medication, which increases aqueous humor outflow, increases the risk of metastatic uveal melanoma (UM). This hypothesis has not been studied previously but is relevant for UM patients who use IOP-lowering medication. The aim of the current study is to assess the association between the use of intraocular pressure (IOP)-lowering medication and the risk of metastatic UM, and mortality., Methods: A retrospective cohort study, in which patients from the Rotterdam Ocular Melanoma Study were included from 1986 onwards. Medical records were evaluated for use of IOP-lowering medication at baseline (i.e., before diagnosis). For each IOP-lowering medication, we divided patients into two groups for comparison (e.g., patients with alpha2-agonist use and patients without alpha2-agonist use). All patients underwent regular ophthalmic examinations and routine screening for metastasis. Survival analyses were initiated to compare groups in each IOP-lowering medication group. In addition, secondary analyses were performed to examine the association between IOP and the development of metastatic UM, and mortality., Results: A total of 707 patients were included of whom 13 patients used prostaglandin or pilocarpine at baseline. For alpha2-agonist, beta-blocker, carbonic anhydrase inhibitor, and oral IOP-lowering medication these were 4, 14, 11, and 12 patients, respectively. The risk of metastatic UM (choroid and ciliary body melanoma) among the prostaglandin/pilocarpine users was significantly higher than controls (HR [95% CI]: 4.840 [1.452-16.133]). Mortality did not differ significantly among the IOP-lowering medications groups, except for the prostaglandin or pilocarpine group (HR [95% CI]: 7.528 [1.836-30.867]). If we combined all IOP-lowering medication that increase aqueous humor outflow, the risk (HR [95% CI]) of metastatic UM and mortality was 6.344 (1.615-24.918) and 9.743 (2.475-38.353), respectively. There was an association between IOP and mortality, but not for the onset of metastatic UM., Conclusion: The use of topical prostaglandin or pilocarpine may increase the risk of metastatic UM and mortality compared to patients without prostaglandin or pilocarpine use. Therefore, use of IOP-lowering medication which increases aqueous humor outflow, should be avoided in patients with (presumed) UM.

Purpose: To evaluate the long-term efficacy and safety of two minimally invasive glaucoma surgery implants with a subconjunctival drainage approach: the XEN45 Gel Stent ® (Xen) implant and the PRESERFLO™ MicroShunt (MicroShunt)., Methods: Retrospective comparative case series of primary open-angle glaucoma (POAG) patients with at least 6 months of follow-up after a MicroShunt or Xen implantation augmented with mitomycin C., Results: Forty-one eyes of 31 patients underwent Xen implantation, and 41 eyes of 33 patients, MicroShunt implantation. Baseline characteristics were similar, except for more combined surgeries with phacoemulsification in the Xen group (37% vs. 2%). Mean baseline IOP ± standard deviation dropped from 19.2 ± 4.4 to 13.8 ± 3.8 mmHg (n = 26) in the Xen group and from 20.1 ± 5.0 to 12.1 ± 3.5 (n = 14) in the MicroShunt group at 24 months of follow-up (p = 0.19, t-test). The number of IOP-lowering medications dropped from 2.5 ± 1.4 to 0.9 ± 1.2 in the Xen group and from 2.3 ± 1.5 to 0.7 ± 1.1 in the MicroShunt group. The probability of qualified success was 73% and 79% at 24 months of follow-up for the Xen and MicroShunt groups, respectively. Postoperative complications were usually mild and self-limiting. The number of bleb needling and secondary glaucoma surgery procedures was similar in both groups; however, in the Xen group more additional MicroPulse ® transscleral cyclophotocoagulation procedures were performed., Conclusion: Xen Gel Stent and PreserFlo MicroShunt implantations achieved comparable results in POAG eyes in terms of IOP-lowering and surgical success, with a similar high safety profile., (© 2020 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Purpose: To compare the adverse side effects of fractionated stereotactic photon beam radiotherapy (fSRT) with proton beam radiotherapy (PBR) in patients with uveal melanoma (UM)., Methods: A retrospective study investigating 306 UM patients treated with fSRT (N=153) by the Rotterdam Ocular Melanoma Study group (ROMS), The Netherlands, between 1999-2014 or with PBR (N=153) at the Royal Liverpool University Hospital and the Clatterbridge Cancer Centre, Bebington, United Kingdom, between 1993-2014. The tumours treated with fSRT were matched with tumours treated with PBR based on sex, left or right eye, TNM classification, posterior margin ≤ or > 3mm of the fovea and of the optic disc., Results: The five-year actuarial rates of tumour recurrence were 4.5% for fSRT and 6.1% for PBR. For fSRT and PBR, the five-year actuarial rates of maculopathy were 14.9% and 12.4%, and for vitreous haemorrhage were 29.4% and 4.7%, respectively. Only vitreous haemorrhage (HR: 0.19, 95% CI: 0.07-0.56) was more common after fSRT compared to PBR. Overall, larger tumours were risk factors for maculopathy and secondary enucleation., Conclusions: Both treatments have excellent local tumour control. In matched groups, vitreous haemorrhage was the only adverse side effect showing a significant difference between groups., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: To assess the efficacy of XEN-implant surgery in patients with glaucoma, and to perform a meta-analysis of previously published results and compare these to our data., Methods: Prospective case-control study, in which all eyes that underwent XEN-implant surgery were included from 2015 onwards. Sub-analyses were performed for eyes that underwent XEN-implant as standalone procedure and as cataract-combined procedure. To compare our results, a systematic review was performed using the Embase, PubMed, Web of Science, and Cochrane database. Meta-analyses were performed by combining data (intraocular pressure (IOP), IOP-lowering medication, and complications) from the retrieved studies., Results: A total of 221 eyes underwent XEN-implant surgery (124 standalone and 97 cataract-combined). The mean ± standard deviation IOP declined from 18.8 ± 6.5 to 13.5 ± 4.3 mmHg at the last follow-up ( p < 0.001; 28.9%). Postoperative, no significant differences in IOP or IOP-lowering medication were found between patients with and without combined procedure. Secondary surgeries were performed in 20.8% of eyes, most of them (63.0%) within six months. A meta-analysis of 19 studies retrieved from the systematic review showed a two-years postoperative pooled mean (weighted mean difference) of 14.5 (7.3) mmHg and 1.0 (1.6) for IOP and IOP-lowering medications, respectively (compared to 13.5 (5.3) mmHg and 3.2 (2.4) in the current study)., Conclusion: XEN-implant surgery was effective and safe in lowering IOP and the number of IOP-lowering medications. There were no differences between standalone and combined procedures.

Keratoconus is characterised by reduced rigidity of the cornea with distortion and focal thinning that causes blurred vision, however, the pathogenetic mechanisms are unknown. It can lead to severe visual morbidity in children and young adults and is a common indication for corneal transplantation worldwide. Here we report the first large scale genome-wide association study of keratoconus including 4,669 cases and 116,547 controls. We have identified significant association with 36 genomic loci that, for the first time, implicate both dysregulation of corneal collagen matrix integrity and cell differentiation pathways as primary disease-causing mechanisms. The results also suggest pleiotropy, with some disease mechanisms shared with other corneal diseases, such as Fuchs endothelial corneal dystrophy. The common variants associated with keratoconus explain 12.5% of the genetic variance, which shows potential for the future development of a diagnostic test to detect susceptibility to disease.

Analysis of the proteins of the aqueous humor can help to elucidate the complex pathogenesis of primary open angle glaucoma. Thanks to advances in liquid chromatography tandem mass spectrometry (LC-MS/MS) it is now possible to identify hundreds of proteins in individual aqueous humor samples without the need to pool samples. We performed a systematic literature search to find publications that performed LC-MS/MS on aqueous humor samples of glaucoma patients and of non-glaucomatous controls. Of the seven publications that we found, we obtained the raw data of three publications. These three studies used glaucoma patients that were clinically similar (i.e. undergoing glaucoma filtration surgery) which prompted us to reanalyse and combine their data. Raw data of each study were analysed separately with the latest version of MaxQuant (version v1.6.11.0). Outcome files were exported to Microsoft Excel. Samples belonging to the same patient were averaged to obtain peptide expression values per individual. We compared the overlap of identified proteins using the VLOOKUP function of Excel and a publicly available Venn diagram software. For the peptide sequences that can belong to multiple proteins (usually of the same protein family), we initially included all possibly identified proteins. This ensured that we would not miss a potential overlap between the studies due to differences in identified peptide counts. Next, of those peptides of which we compared multiple proteins, only one unique protein was included in our analysis i.e. either the protein overlapping between studies or in case of no overlap, the protein that had the highest identified peptide count. This yielded 639 unique proteins detected in aqueous humor of either glaucoma patients or non-glaucomatous controls. In our manuscript entitled "The aqueous humor proteome of primary open angle glaucoma: An extensive review" [1], we further analysed this dataset. The dataset was exported to Perseus (version 1.6.5.0). We removed contaminants and filtered for proteins detected with high confidence, i.e. in more than 70% of the samples of at least one study. This yielded 248 proteins of which we compared the expression in glaucoma patients against control patients. Gene ontology enrichment analysis and pathway analysis was used to interpret the results. The unfiltered dataset reported in this data article and the approach reported here to reanalyse and combine raw data of different studies can be applied by other glaucoma researchers to gain more insight in the pathogenesis of glaucoma., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships which have, or could be perceived to have, influenced the work reported in this article., (© 2020 The Author(s).)

The number of eye diseases treated with intravitreal injections is increasing. Obviously, an injection of fluid into the eye results in an increase of intraocular pressure (IOP), the main risk factor for glaucoma. However, the effect of these repeated IOP increases on the eye is unclear. Therefore, we performed a systematic review with meta-analyses. PubMed, Embase and Clinical Trials Registries were searched for articles investigating the relationship between intravitreal injections (anti-vascular endothelial growth factor [anti-VEGF] or steroids) and either IOP, retinal nerve fiber layer (RNFL)-thickness and glaucoma. Multiple meta-analyses were performed, combining data on intravitreal injection of anti-VEGF medication and dexamethasone implants. A total of 74 articles were eligible for meta-analyses. The short-term effect of an intravitreal injection of anti-VEGF showed a statistically significant increase in IOP. One day after injection of anti-VEGF, however, IOP was significantly lower than baseline. The long-term time-intervals showed no significant difference in IOP. After intravitreal injection of a dexamethasone implant, IOP was significantly higher than baseline 1 month post-injection. RNFL-thickness was significantly reduced 6 and 12 months post-injection of anti-VEGF, as well as at end of follow up. Caution is advised when using intravitreal medication, especially when treating patients with advanced glaucoma; in these cases, prophylactic IOP-lowering medication may be considered.

Background: We reviewed the literature on the aqueous humor (AH) proteome of primary open angle glaucoma (POAG) patients in order to obtain deeper insight into the pathophysiology of POAG., Methods: We searched Pubmed and Embase up to May 2019 for studies that compared AH protein composition between POAG (cases) and cataract (controls). Untargeted studies (measuring the whole proteome, by LC-MS/MS) were divided into two subgroups depending on the type of surgery during which POAG AH was collected: glaucoma filtration surgery (subgroup 1) or cataract surgery (subgroup 2). We reanalyzed the raw data (subgroup 1) or combined the reported data (subgroup 2) to perform GO enrichment (GOrilla) and pathway analysis (Pathvisio)., Results: Out of 93 eligible proteomic studies, seven were untargeted studies that identified 863 AH proteins. We observed 73 differentially expressed proteins in subgroup 1 and 87 differentially expressed proteins in subgroup 2. Both subgroups were characterized by activation of the acute immune response, dysregulation of folate metabolism and dysregulation of the selenium micronutrient network. For subgroup 1 but not for subgroup 2, proteins of the complement system were significantly enriched., Conclusion: AH proteome of POAG patients shows strong activation of the immune system. In addition, analysis suggests dysregulation of folate metabolism and dysregulation of selenium as underlying contributors. In view of their glaucoma surgery, POAG patients of subgroup 1 most likely are progressive whereas POAG patients in subgroup 2 most likely have stable POAG. The proteome difference between these subgroups suggests that the complement system plays a role in POAG progression., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose/Aim: Many genes have been associated with primary open-angle glaucoma (POAG). Knowing exactly where they are expressed in the eye helps to unravel POAG pathology and to select optimal targets for intervention. We investigated whether RNA in situ hybridization (RNA-ISH) is a convenient technique to obtain detailed pan-ocular expression data of these genes. We tested this for four diverse candidate POAG genes, selected because of unclear ocular distribution ( F5 and Dusp1) and relevance for potential new therapies ( Tnf, Tgfβr3 ). Optn , a POAG gene with well-known ocular expression pattern served as control. Methods: We made a list of candidate glaucoma genes reported in genetic studies. A table of their ocular expression at the tissue level was compiled using publicly available microarray data (the ocular tissue database). To add cellular detail we performed RNA-ISH for Optn, Tnf, Tgfβr3, F5 , and Dusp1 on eyes of healthy, 2-month-old, pigmented, and albino mice. Results: Expression of the Optn control matched with published immunohistochemistry data. Ocular expression of Tnf was generally low, with patches of higher Tnf expression, superficially in the corneal epithelium. F5 had a restricted expression pattern with high expression in the nonpigmented ciliary body epithelium and moderate expression in the peripapillary region. Tgfβr3 and Dusp1 showed ubiquitous expression. Conclusions: RNA-ISH is a suitable technique to determine the ocular expression pattern of POAG genes, adding meaningful cellular detail to existing microarray expression data. For instance, the high expression of F5 in the nonpigmented ciliary body epithelium suggests a role of this gene in aqueous humor dynamics and intraocular pressure. In addition, the ubiquitous expression of Tgfβr3 has implications for designing TGF-β-related glaucoma therapies, with respect to side effects. Creating pan-ocular expression maps of POAG genes with RNA-ISH will help to identify POAG pathways in specific cell types and to select targets for drug development.

Background: To assess the relationship between different indications for trans pars plana vitrectomies (PPV's) and the intraocular pressure (IOP), and the effect of multiple PPV's on the IOP. We also examined whether there were differences in the number of IOP-lowering medications or surgeries before and after PPV., Methods: A retrospective study including all patients that underwent at least one PPV in the period from 2001 till 2014 at our clinic. Medical records of all patients were reviewed and clinically relevant data were entered in a database. Generalized estimating equations models for repeated measurements were used to examine the effect of the number of PPV's on the IOP and on the risk of undergoing glaucoma surgery, for each of the indications for PPV., Results: Of 1072 PPV's 447 eyes fulfilled the inclusion criteria. The IOP increased with 3.0 mmHg after a PPV with indication retinal detachment (p < 0.001), but remained stable after PPV for epiretinal membrane (p = 0.555), macular hole (p = 0.695), and vitreous hemorrhage (p = 0.787). At the end of the follow-up period the number of IOP-lowering medications was significantly higher compared to baseline, except in the macular hole group (p = 0.103). Also, the number of eyes that underwent glaucoma surgery was significantly higher compared to the fellow (not-operated) eyes (p < 0.001). There was a significant association between the number of PPV's and the final IOP for the indication retinal detachment (p = 0.009), and between the number of PPV's and glaucoma surgery (odds ratio [95% confidence interval]: 2.60 [1.62-4.15])., Conclusions: The IOP rises significantly after PPV with indication retinal detachment. This association was not found for other indications for PPV. Also, the risk of IOP-lowering surgeries was higher after PPV, but not different between the PPV indications. The IOP should be monitored carefully after PPV, since there may be a higher risk of secondary glaucoma.

Aim: To investigate the changes in intraocular pressure (IOP) before and after intraocular surgery measured with Goldmann applanation tonometry (GAT) and pascal dynamic contour tonometry (PDCT), and assessed their agreement., Methods: Patients who underwent trans pars plana vitrectomy (TPPV) with or without cataract extraction (CE) were included. The IOP was measured in both eyes with GAT and PDCT pre- and postoperatively, where the non-operated eyes functioned as control., Results: Preoperatively, mean IOP measurements were 16.3±6.0 mm Hg for GAT and 12.0±2.8 mm Hg for PDCT for the operated eyes. Postoperatively, the mean IOP dropped to 14.3±5.6 mm Hg for GAT ( P =0.011) and rose up to 12.7±2.6 mm Hg for PDCT ( P =0.257). Bland-Altman analysis showed a poor agreement between GAT and PDCT with a mean difference of 2.9 mm Hg preoperatively and 95% limits of agreement ranging from -3.2 to 9.0 mm Hg. Postoperatively, the mean difference was 1.2 mm Hg with 95% limits of agreement ranging from -8.3 to 10.7 mm Hg. There were no significant differences between the TPPV and TPPV+CE group, except when measured with PDCT postoperatively ( P =0.012)., Conclusion: The IOP is reduced after surgery when measured with GAT and remained stable when measured with PDCT. However, the agreement between GAT and PDCT is poor. Although PDCT may be a more accurate predictor of the true IOP, it seems less suitable for daily use in the clinical practice.

Purpose: To assess the efficacy of glaucoma drainage devices (GDD) in uveitic glaucoma and non-uveitic glaucoma, and to perform a meta-analysis of previously published results to compare with our data., Methods: Retrospective case-control study, in which all eyes that underwent GDD surgery were included from 2015 onwards. Cases were defined as patients with uveitic glaucoma. Patients with non-uveitic glaucoma served as controls. To compare our results, a review of the literature was performed using PubMed database., Results: A total of 99 eyes were included (38 with uveitic glaucoma). The preoperative IOP was 25.9 ± 7.7 mmHg and 27.9 ± 9.6 mmHg for patients with and without uveitis (p = 0.277). No significant differences were found between patients with and without uveitis in the final IOP or reduction in IOP (44.9% vs. 42.8%, respectively). Within the first year after surgery, 13.2% of cases developed macular edema (vs. 6.6%; p = 0.267) and 15.8% a transient hypotony (vs. 8.2%; p = 0.242). A meta-analysis of 24 studies showed a postoperative weighted mean difference of - 17.8 mmHg and 2.2 lower number of IOP-lowering medications in uveitic glaucoma (compared to - 13.2 mmHg and 3.5 in the current study, respectively)., Conclusion: GDD surgery in patients with uveitis has a similar effect on IOP as in patients without uveitis. The risks of developing macular edema and hypotony were slightly higher in patients with uveitis, but the results were not statistically significant. These findings are in line with previous reports, though data on the efficacy of GDD surgery and macular edema in uveitic glaucoma is scarce.

Purpose: A common question of patients to their physician is what they can do themselves against glaucoma, except taking their daily medication. However, for ophthalmologists, it is often hard to give their patients an advice on their dietary intake. To help ophthalmologists in answering this question, an overview of the current scientific literature on the association of nutrients with glaucoma is presented., Methods: A comprehensive systematic review was conducted in which articles published up to September 2017 were identified in PubMed and reference lists. Nutrients were categorized into minerals and trace elements, nutrition with antioxidative properties and omega-fatty acids., Results: The literature search revealed a total of 407 articles of which a total of 46 met the inclusion criteria. Most of these articles studied the effect of nutrients on open-angle glaucoma. Many trace elements have been investigated in the literature, but the most interesting are selenium and iron (both may increase the risk of glaucoma). Investigated nutrients with antioxidative properties and omega-fatty acids included glutathione, nitric oxide, carotenoids, flavonoids, and omega-3 and omega-6 fatty acids. Of these, glutathione, nitric oxide, and flavonoids had a significant protective effect on glaucoma., Conclusion: Intake of selenium and iron may increase the risk of glaucoma, though, only few studies have been done on this topic. Nitric oxide present in other dark green leafy vegetables seems to have a beneficial effect on glaucoma. However, the evidence for an association of dietary intake with glaucoma is still not strong. More (longitudinal and randomized clinical trials) studies are required to make the presented findings clinically applicable., (© 2018 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Background: The aim of is to determine the association of vitamins with glaucoma by performing a systematic review and meta-analyses., Methods: Studies on the relation of vitamins and glaucoma published up to December 2017 were identified in the PubMed and Embase database. Data on vitamins (method of assessment), glaucoma (type and method of assessment), study characteristics and quality were recorded. In case of multiple studies for one nutrient a meta-analysis was performed., Results: A total of 629 articles were identified of which 36 were included in the systematic review. The meta-analysis included five of them (940 open-angle glaucoma (OAG) cases and 123,697 controls in total) and resulted in an odds ratio [95% confidence interval] (OR [95% CI]) of 0.58 [0.37-0.91] for dietary vitamin A, though heterogeneity was high (I² = 51%). After omitting studies that contributed significantly to the heterogeneity, the pooled OR [95% CI] was 0.45 [0.30-0.68] for dietary vitamin A on OAG (I² = 0%). For vitamin B1, C and E no significant association with OAG was found (OR [95% CI]: 0.84 [0.47-1.51]; 0.68 [0.38-1.22]; 0.95 [0.75-1.19]; respectively). However, after addressing heterogeneity, vitamin C showed a protective effect as well. Especially, foods high in these vitamins (e.g., dark green vegetables) were protective for OAG., Conclusions: Dietary intake of vitamin A and C showed a beneficial association with OAG; however, findings on blood levels of vitamins do not show a clear relation with OAG., Competing Interests: The authors declare no conflict of interest.

To determine the incidence of glaucomatous visual field loss (GVFL) two decades after the start of the Rotterdam Study, and to compare known risk factors for open-angle glaucoma (OAG) between different clinical manifestations of OAG. Of 6806 participants aged 55 years and older from the population-based Rotterdam Study, 3939 underwent visual field testing at baseline and at least one follow-up round. The ophthalmic examinations included optic disc assessment and measurements of intraocular pressure (IOP), refractive error, diastolic blood pressure (DBP), and height and weight. The incidence rate of GVFL was calculated. Associations with the risk factors age, gender, baseline IOP, family history, myopia, DBP, and body-mass index [BMI] were assessed using Cox regression, with different clinical manifestations of OAG as outcome measure (glaucomatous optic neuropathy (GON), GVFL, GVFL and GON, GVFL without GON, and GON without GVFL). Median follow-up was 11.1 (IQR 6.8-17.2; range 5.0-20.3) years. The incidence rate of GVFL was 2.9 (95% confidence interval 2.4-3.4) per 1000 person years (140 cases with incident GVFL in one (n = 113) or both (n = 27) eyes). Baseline IOP and age were significantly associated with all OAG outcomes (all p < 0.001); BMI showed a non-significant protective effect in all outcomes (p = 0.01 to p = 0.09). Gender, myopia, and DBP were not associated with any outcome. Our study provides an estimate of the long-term incidence of GVFL in a predominantly white population. The development of GVFL was strongly associated with baseline IOP and age. Risk factor profiles were similar for the different outcomes.

Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a heritable disease. Siblings of POAG cases have a ten-fold increased risk of developing the disease. Intraocular pressure (IOP) and optic nerve head characteristics are used clinically to predict POAG risk. We conducted a genome-wide association meta-analysis of IOP and optic disc parameters and validated our findings in multiple sets of POAG cases and controls. Using imputation to the 1000 genomes (1000G) reference set, we identified 9 new genomic regions associated with vertical cup-disc ratio (VCDR) and 1 new region associated with IOP. Additionally, we found 5 novel loci for optic nerve cup area and 6 for disc area. Previously it was assumed that genetic variation influenced POAG either through IOP or via changes to the optic nerve head; here we present evidence that some genomic regions affect both IOP and the disc parameters. We characterized the effect of the novel loci through pathway analysis and found that pathways involved are not entirely distinct as assumed so far. Further, we identified a novel association between CDKN1A and POAG. Using a zebrafish model we show that six6b (associated with POAG and optic nerve head variation) alters the expression of cdkn1a. In summary, we have identified several novel genes influencing the major clinical risk predictors of POAG and showed that genetic variation in CDKN1A is important in POAG risk., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Glaucoma is an optic neuropathy characterized by loss of retinal ganglion cells (RGCs) and consequently visual field loss. It is a complex and heterogeneous disease in which both environmental and genetic factors play a role. With the advent of genome-wide association studies (GWASs), the number of loci associated with primary open-angle glaucoma (POAG) have increased greatly. There has also been major progress in understanding the genes determining the vertical cup-disc ratio (VCDR), disc area (DA), cup area (CA), intraocular pressure (IOP), and central corneal thickness (CCT). In this review, we will update and summarize the genetic loci associated so far with POAG, VCDR, DA, CA, IOP, and CCT. We will describe the pathways revealed and supported by genetic association studies, integrating current knowledge from human and experimental data. Finally, we will discuss approaches for functional genomics and clinical translation.

Keratoconus is a degenerative eye condition which results from thinning of the cornea and causes vision distortion. Treatments such as ultraviolet (UV) cross-linking have proved effective for management of keratoconus when performed in early stages of the disease. The central corneal thickness (CCT) is a highly heritable endophenotype of keratoconus, and it is estimated that up to 95% of its phenotypic variance is due to genetics. Genome-wide association efforts of CCT have identified common variants (i.e. minor allele frequency (MAF) >5%). However, these studies typically ignore the large set of exonic variants whose MAF is usually low. In this study, we performed a CCT exome-wide association analysis in a sample of 1029 individuals from a population-based study in Western Australia. We identified a genome-wide significant exonic variant rs121908120 (P = 6.63 × 10(-10)) in WNT10A. This gene is 437 kb from a gene previously associated with CCT (USP37). We showed in a conditional analysis that the WNT10A variant completely accounts for the signal previously seen at USP37. We replicated our finding in independent samples from the Brisbane Adolescent Twin Study, Twin Eye Study in Tasmania and the Rotterdam Study. Further, we genotyped rs121908120 in 621 keratoconus cases and compared the frequency to a sample of 1680 unscreened controls from the Queensland Twin Registry. We found that rs121908120 increases the risk of keratoconus two times (odds ratio 2.03, P = 5.41 × 10(-5))., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Primary open-angle glaucoma (POAG) is a blinding disease. Two important risk factors for this disease are a positive family history and elevated intraocular pressure (IOP), which is also highly heritable. Genes found to date associated with IOP and POAG are ABCA1, CAV1/CAV2, GAS7 and TMCO1. However, these genes explain only a small part of the heritability of IOP and POAG. We performed a genome-wide association study of IOP in the population-based Rotterdam Study I and Rotterdam Study II using single nucleotide polymorphisms (SNPs) imputed to 1000 Genomes. In this discovery cohort (n = 8105), we identified a new locus associated with IOP. The most significantly associated SNP was rs58073046 (β = 0.44, P-value = 1.87 × 10(-8), minor allele frequency = 0.12), within the gene ARHGEF12. Independent replication in five population-based studies (n = 7471) resulted in an effect size in the same direction that was significantly associated (β = 0.16, P-value = 0.04). The SNP was also significantly associated with POAG in two independent case-control studies [n = 1225 cases and n = 4117 controls; odds ratio (OR) = 1.53, P-value = 1.99 × 10(-8)], especially with high-tension glaucoma (OR = 1.66, P-value = 2.81 × 10(-9); for normal-tension glaucoma OR = 1.29, P-value = 4.23 × 10(-2)). ARHGEF12 plays an important role in the RhoA/RhoA kinase pathway, which has been implicated in IOP regulation. Furthermore, it binds to ABCA1 and links the ABCA1, CAV1/CAV2 and GAS7 pathway to Mendelian POAG genes (MYOC, OPTN, WDR36). In conclusion, this study identified a novel association between IOP and ARHGEF12., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Primary open-angle glaucoma is the most common optic neuropathy and an important cause of irreversible blindness worldwide. The optic nerve head or optic disc is divided in two parts: a central cup (without nerve fibers) surrounded by the neuroretinal rim (containing axons of the retinal ganglion cells). The International Glaucoma Genetics Consortium conducted a meta-analysis of genome-wide association studies consisting of 17,248 individuals of European ancestry and 6,841 individuals of Asian ancestry. The outcomes of the genome-wide association studies were disc area and cup area. These specific measurements describe optic nerve morphology in another way than the vertical cup-disc ratio, which is a clinically used measurement, and may shed light on new glaucoma mechanisms. We identified 10 new loci associated with disc area (CDC42BPA, F5, DIRC3, RARB, ABI3BP, DCAF4L2, ELP4, TMTC2, NR2F2, and HORMAD2) and another 10 new loci associated with cup area (DHRS3, TRIB2, EFEMP1, FLNB, FAM101, DDHD1, ASB7, KPNB1, BCAS3, and TRIOBP). The new genes participate in a number of pathways and future work is likely to identify more functions related to the pathogenesis of glaucoma., (© 2015 Wiley Periodicals, Inc.)