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Purpose The aim of this study was to investigate the association of diabetes mellitus (DM) and risk of open-angle glaucoma (OAG). Methods This population-based historic cohort consisted of individuals at age >= 40 years with DM treatment initiated 2001-2010 and a reference population matched by age, gender and hospital district. Incidence of OAG was compared between individuals with DM and their matched non-diabetic reference pairs. New glaucoma cases were identified from medication reimbursement certificates and hospital billing records. Incidence rate ratios (IRR) were analysed with Poisson regression models adjusted for age, sex, hospital district, socioeconomic status, systemic medications and chronic diseases. We analysed the sensitivity of the results with adapted input variables and performed a competing events analysis. Results Of the 244 100 study subjects meeting inclusion criteria, 2721 (1.1%) developed OAG. Follow-up spanned from 2001 to 2017. DM was associated with a modestly reduced incidence of OAG when adjusted for confounding factors (IRR 0.92, CI 0.85-0.99). Conclusions In our longitudinal population-based study, we found a modest decrease in the risk of OAG for individuals with DM.

PurposeVascular dysregulation seems to play a role in the pathogenesis of glaucoma, in particular normal tension glaucoma (NTG). The development of optical coherence tomography angiography (OCTA) enabled the measurement of the retinal microvasculature non-invasively and with high repeatability. Nonetheless, only a few studies transformed OCTA into a dynamic examination employing a sympathomimetic stimulus. The goal of this study was to use this dynamic OCTA exam (1) to differentiate healthy individuals from glaucoma patients and (2) to distinguish glaucoma subcategories, NTG and high-tension primary open angle glaucoma (POAG).MethodsRetinal vessel density (VD) in NTG patients (n = 16), POAG patients (n = 12), and healthy controls (n = 14) was compared before and during a hand grip test with a hydraulic dynamometer.ResultsAt baseline, mean peripapillary VD was lower in POAG and NTG (42.6 and 48.5%) compared to healthy controls (58.1%; p < 0.001) and higher in NTG compared to POAG (p = 0.024) when corrected for mean arterial pressure (MAP). Peripapillary and macular (superficial and deep) VD differences were found for gender, age, and baseline MAP. No change in VD occurred (pre-/post-stimulus) in any of the groups.ConclusionRetinal VD loss in glaucoma patients was confirmed and the necessity to correct for gender, age and especially MAP was established. Although replication in a larger population is necessary, OCTA might not be the most suitable method to dynamically evaluate the retinal microvasculature.

Glaucoma is a progressive optic neuropathy that is the second leading cause of preventable blindness worldwide, after cataract formation. A rise in the intraocular pressure (IOP) is considered to be a major risk factor for glaucoma and is associated with an abnormal increase of resistance to aqueous humour outflow from the anterior chamber. Glaucoma drainage devices have been developed to provide an alternative pathway through which aqueous humour can effectively exit the anterior chamber, thereby reducing IOP. These devices include the traditional aqueous shunts with tube-plate design, as well as more recent implants, such as the trabeculectomy-modifying EX-PRESS(R) implant and the new minimally invasive glaucoma surgery (MIGS) devices. In this review, we will describe each implant in detail, focusing on their efficacy in reducing IOP and safety profile. Additionally, a critical and evidence-based comparison between these implants will be provided. Finally, we will propose potential developments that may help to improve the performance of current devices.

BackgroundSystemic hypoperfusion plays a pivotal role in the pathogenesis of primary open-angle glaucoma (POAG). Extreme dips in mean arterial pressure (MAP) due to high 24-h variability are associated with POAG, however, whether this is driven by diurnal or nocturnal dips remains undocumented. We aimed this study to investigate the association of POAG damage with variability and dips in the diurnal and nocturnal MAP.MethodsWe conducted a retrospective longitudinal study that included 110 POAG patients who underwent 24-h ambulatory blood pressure monitoring. Our outcomes included (i) functional [visual field defects expressed as mean deviation (MD)] and (ii) structural (optic disc cupping obtained from cup-to-disc ratio) glaucoma damage. MAP variability independent of the mean (VIMmap) was computed for diurnal and nocturnal MAP. Dips were the five diurnal and three nocturnal lowest drops in MAP. We also calculated the night-to-day ratio. We applied mixed models to evaluate the progression of visual field defects and optic disc cupping in relation to diurnal and nocturnal MAP measures.ResultsThe mean age was 64.0 y (53% women). The median follow-up was 9 years. In adjusted mixed models, functional progression of glaucoma damage was associated with VIMmap (−2.57 dB change in MD per every 3 mmHg increase in VIMmap; P < 0.001) and diurnal MAP dips (changes in the MD ranged from −2.56 to −3.19 dB; P < 0.001). Every 5 mmHg decrease in the nocturnal MAP level was associated with −1.14 dB changes in MD [95% confidence interval (CI), −1.90 to −0.40] and 0.01 larger optic disc cupping (95% CI, 0.01–0.02). Lower night-to-day ratio was also related to both outcomes (P ≤ 0.012). Functional glaucoma damage worsened if nocturnal hypotension was combined with high variability or extreme dips in the diurnal MAP (P ≤ 0.022).ConclusionProgression of glaucoma damage in POAG associates with high variability and extreme dips in the diurnal MAP. Structural glaucoma damage seems more vulnerable to nocturnal hypotension. Ambulatory blood pressure monitoring allows the assessment of sporadic diurnal and persistent nocturnal hypotension episodes. These phenotypes might offer an opportunity to improve the risk-stratification of open-angle glaucoma (OAG).

Purpose: To date, population-based studies reporting associations between dry eye disease and medications were hypothesis-driven, did not take into account underlying comorbidities, and did not investigate individual drugs. The purpose of this study was to clarify the association of dry eye symptoms with medication classes and in-dividual drugs, using a hypothesis-free approach. Methods: 79,606 participants (age 20-97 years, 59.2% female) from the population-based Lifelines cohort in the Netherlands were cross-sectionally assessed for dry eye symptoms using the Womens' Health Study dry eye questionnaire. All medications used were coded with the ATC classification system. Logistic regression was used to assess the risk of the 59 most-used therapeutic/pharmacological subgroups and the 99 most-used individual drugs (all n > 200) on dry eye symptoms, correcting for age, sex, body mass index, and 48 comorbidities associated with dry eye. Results: Thirty-eight (64%) medication subgroups and fifty-two (53%) individual drugs were associated with dry eye symptoms (P < 0.05), after correction for age and sex only. A multivariable model correcting for comor-bidities revealed highly significant associations between dry eye symptoms and drugs for peptic ulcer (partic-ularly proton pump inhibitors (PPIs)), antiglaucoma and anticholinergic medications. Conclusions: This study underlines that medication use is highly informative of risk of dry eye symptoms. Correction for underlying comorbidities is critical to avoid confounding effects. This study confirms suggested associations between medications and dry eye symptoms at a population level and shows several new associa-tions. The novel link between PPIs and dry eye symptoms deserves particular attention given how commonly they are prescribed.

Purpose To investigate the association between different types of vitrectomy and risk of different types of glaucoma and to determine the effect of systemic medication and diabetes status on this risk. Methods A population-based nested case-control study included individuals of age >= 18 years who had undergone single vitrectomy, vitrectomy with retinal procedure, or combined phaco-vitrectomy between 2001 and 2010. End of follow-up was 2017. Odds ratio (OR) for the development of glaucoma after different types of vitrectomy and 95% confidence interval (CI) were based on conditional logistic regression models. For every glaucoma case, five controls were matched by age, sex, start of follow-up year, and hospital district. Results The cohort (n = 37 687), of which 52.8% was female, consisted of 6552 individuals diagnosed with glaucoma and 31 135 controls matched by age, sex, and hospital district. Vitrectomy was performed on 103 eyes in the glaucoma group and 158 eyes in the control group. As regards the risk of any glaucoma, the risk was lowest in eyes that underwent combined phaco-vitrectomy (OR: 2.7, 95% CI: 1.8-4.1), followed by single vitrectomy (OR: 3.15, 95% CI: 2.1-4.8), and highest in eyes that underwent vitrectomy with retinal procedure (OR: 4.5, 95% CI: 2.7-7.4). Diabetes had no effect (OR: 0.96, 95% CI: 0.92-1.01), but 5-year systemic statin use slightly decreased glaucoma risk (OR: 0.86, 95% CI: 0.77-0.97). Conclusions Vitreoretinal surgery was associated with an increased glaucoma risk; the risk being related to the complexity of vitrectomy. Long-term systemic statin therapy may decrease glaucoma risk, while diabetes had no association.

INTRODUCTION: Unexplained visual loss after removal of silicone oil from the eye has been described. The purpose of this study is to determine the incidence of unexplained loss of visual acuity after SO removal and to provide possible explanations for this phenomenon. METHODS: This retrospective study included patients that underwent vitreoretinal surgery, at Centro Hospitalar São João, between January of 2012 and October of 2018. Inclusion criterion was vitreoretinal surgery in which the chosen endotamponade was SO, followed by removal of SO and exchange with balanced salt solution (BSS) or air. After SO removal, patients with documented loss of best corrected visual acuity (BCVA) on two or more Snellen lines were analyzed and patients in which the cause of the visual loss was identified, namely OHT (intraocular pressure > 21 mmHg), retinal re-detachment, glaucoma, retinal proliferative membrane formation, or corneal decompensation, were excluded. All patients with unexplained visual loss underwent spectral domain optical coherence tomography (SD-OCT) to exclude causes of visual reduction such as cystoid macular edema, epiretinal membrane, or ellipsoid/interdigitation zone disruption. A p value less than 0.05 was considered statistically significant. RESULTS: A total of 46 eyes underwent SO tamponade and SO removal during the study period. In 34.8% of the cases (n = 16) there was visual acuity loss in at least two Snellen lines. Of 46 eyes, 23.9% (n = 11) showed vision loss due to known secondary causes. Unexplained loss of visual acuity after SO removal occurred in 10.9% of cases. OHT during silicone endotamponade (p = 0.046) and silicone emulsification (p = 0.001) were identified as factors associated with unexplained visual loss after SO removal. CONCLUSION: Unexplained loss of visual acuity after SO removal occurred in 10.9% of cases. OHT during silicone endotamponade and SO emulsification were identified as important factors in the ethology of this phenomenon. ispartof: OPHTHALMOLOGY AND THERAPY vol:9 issue:3 ispartof: location:England status: published

The present study involves the development of Dipivefrin hydrochloride (DV) containing Poloxamers (P407 and P188)-Carbopol-934 (CP) based thermoresponsive-gels for the management of elevated intraocular pressure (IOP). Optimal formulation was evaluated for gelation temperature (Tgel), physicochemical and viscoelastic properties, in-vitro gel dissolution and drug release studies. The in-vivo safety, precorneal retention, ocular pharmacokinetics and efficacy in reducing IOP were also evaluated. Tgel of DV-containing thermoresponsive-gels were between 35.1 and 38.9 °C and it was Poloxamers and CP concentrations dependent. The optimal formulation (F8), composed of 20% P407, 5% P188 and 0.15% CP (w/v), had a Tgel of 35 °C. Its viscosity indicated good flow at room temperature and ability to convert to gel at ocular temperature and the rheology studies revealed favorable characteristics for its ocular use. In precorneal retention experiment, F8 indicated significantly higher area under concentrations curves as compared to DV-aqueous suspension (DV-AqS). In-vivo ocular pharmacokinetics indicated a significant improvement in ophthalmic bioavailability of epinephrine (active form of DV). F8 was non-irritant to the eyes and showed a successful, continuous and superior ability to reduce IOP compared to DV-AqS in rabbits. In conclusion, our developed system could be an appropriate substitute to the conventional DV eye preparations in the management of elevated IOP.

Supplemental Digital Content is Available in the Text., Purpose: To identify risk factors for the development of ocular hypertension after keratoplasty. Methods: A systematic search in PubMed and Embase identified 67 relevant articles published between January 1990 and 2019. We preferentially searched for data on an intraocular pressure increase above 21 mmHg at 6 months or a threshold or time point close to that and reported whether the preoperative or intraoperative status of risk factors was defined. The results were presented in evidence tables, visualizing the direction of the association, whether univariate and/or multivariate analysis was performed, and the significance level (P < 0.05). Four researchers, blinded for the risk factors, independently assigned a level of evidence (definitely, probably, possibly, not associated). Consensus was met during group meetings. Results: From the 110 studied risk factors, pre-existing glaucoma, high preoperative IOP and combined keratoplasty with removal or exchange of an intraocular lens (IOL) were definitely associated with an increased risk. In addition, if the pre-or postoperative lens status was undefined, aphakia and pseudophakia with the IOL in the anterior or posterior chamber were also definitely associated with an increased risk when compared to phakia. Glaucoma in the contralateral eye, indication of bullous keratopathy, African American descent, preoperative treatment with cyclosporine or olopatadine 0.1%, postoperative treatment with prednisolone acetate 1%, and combined surgery in general (ie, the type of surgeries undefined in primary studies) were probably associated. Multiple other identified risk factors lack sufficient evidence and need additional investigation. Conclusions: Risk factors with a definite association can help clinicians select patients at risk and adjust their follow-up and treatment. The other factors need further investigation.

Purpose:To identify risk factors for the development of ocular hypertension after keratoplasty.Methods:A systematic search in PubMed and Embase identified 67 relevant articles published between January 1990 and 2019. We preferentially searched for data on an intraocular pressure increase above 21 mmHg at 6 months or a threshold or time point close to that and reported whether the preoperative or intraoperative status of risk factors was defined. The results were presented in evidence tables, visualizing the direction of the association, whether univariate and/or multivariate analysis was performed, and the significance level (P

Purpose Performing bioinformatics analyses using trabecular meshwork (TM) gene expression data in order to further elucidate the molecular pathogenesis of primary open-angle glaucoma (POAG), and to identify candidate target genes. Methods A systematic search in Gene Expression Omnibus and ArrayExpress was conducted, and quality control and preprocessing of the data was performed with ArrayAnalysis.org. Molecular pathway overrepresentation analysis was performed with PathVisio using pathway content from three pathway databases: WikiPathways, KEGG and Reactome. In addition, Gene Ontology (GO) analysis was performed on the gene expression data. The significantly changed pathways were clustered into functional categories which were combined into a network of connected genes. Results Ninety-two significantly changed pathways were clustered into five functional categories: extracellular matrix (ECM), inflammation, complement activation, senescence and Rho GTPase signalling. ECM included pathways involved in collagen, actin and cell-matrix interactions. Inflammation included pathways entailing NF-kappa B and arachidonic acid. The network analysis showed that several genes overlap between the inflammation cluster on the one hand, and the ECM, complement activation and senescence clusters on the other hand. GO analysis, identified additional clusters, related to development and corticosteroids. Conclusion This study provides an overview of the processes involved in the molecular pathogenesis of POAG in the TM. The results show good face validity and confirm findings from histological, biochemical, genome-wide association and transcriptomics studies. The identification of known points of action for drugs, such as Rho GTPase, arachidonic acid, NF-kappa B, prostaglandins and corticosteroid clusters, supports the value of this approach to identify potential drug targets.

Purpose: To evaluate corneal densitometry (CD) of patients with arcus senilis (AS) and its association with the serum lipid markers. Methods: This is a cross-sectional, case-control study. The AS diagnosis was made clinically. Forty-five eyes of 45 patients with AS and 38 eyes of 38 age-matched control subjects with no noticeable AS were enrolled in the study. All participants underwent detailed ophthalmologic examination along with corneal Scheimpflug imaging with CD measurement. The evaluated serum lipid markers of the participants included total cholesterol, triglyceride, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and very-low-density lipoprotein (VLDL). The Spearman correlation analysis was used to correlate the serum lipid values and the CD. P < 0.05 was defined as statistically significant. Results: The male to female ratio was 26/19 and 14/24 in the study and control groups, respectively (P = 0.057). The mean age was 59.56 +/- 8.7 and 56.47 +/- 8.6 years in the study and control groups, respectively (P = 0.117). The mean total CD values in the zones extending from 2 to 12 mm were higher in the study group than in the control group (P < 0.001). The serum HDL level was found to be significantly decreased in the study group compared to the control group (P = 0.048 and Z = -1.976). There was a significant positive correlation between the serum triglyceride level and the CD value of the outermost zone (10-12 mm) (r = 0.334 and P = 0.025). Conclusion: The CD of patients with AS was found to increase not only in the peripheral zone but also in the cornea's paracentral zone compared to the healthy controls. The serum triglyceride level should give an insight into the intensity of arcus senilis. The serum HDL levels were decreased in patients with AS.

Myopic eyes have an increased risk of glaucoma. However, glaucomatous changes in a myopic eye are often difficult to detect. Classic structural and functional investigations to diagnose glaucoma may be confounded by myopia. Here, we identify some of the common pitfalls in interpreting these structural parameters, and the possible solutions that could be taken to overcome them. For instance, in myopic eyes, we discuss the limitations and potential sources of error when using neuroretinal rim parameters, and retinal nerve fibre layer and ganglion cell-inner plexiform layer thickness measurements. In addition, we also review new developments and potential adjuncts in structural imaging such as the assessment of the retinal nerve fibre layer texture, and the examination of the microcirculation of the optic nerve head using optical coherence tomography angiography. For the functional assessment of glaucoma, we discuss perimetric strategies that may aid in detecting characteristic visual field defects in myopic glaucoma. Ultimately, the evaluation of glaucoma in myopia requires a multimodal approach, to allow correlation between structural and functional assessments. This review provides overview on how to navigate this diagnostic dilemma.

Myopic eyes have an increased risk of glaucoma. However, glaucomatous changes in a myopic eye are often difficult to detect. Classic structural and functional investigations to diagnose glaucoma may be confounded by myopia. Here, we identify some of the common pitfalls in interpreting these structural parameters, and the possible solutions that could be taken to overcome them. For instance, in myopic eyes, we discuss the limitations and potential sources of error when using neuroretinal rim parameters, and retinal nerve fibre layer and ganglion cell-inner plexiform layer thickness measurements. In addition, we also review new developments and potential adjuncts in structural imaging such as the assessment of the retinal nerve fibre layer texture, and the examination of the microcirculation of the optic nerve head using optical coherence tomography angiography. For the functional assessment of glaucoma, we discuss perimetric strategies that may aid in detecting characteristic visual field defects in myopic glaucoma. Ultimately, the evaluation of glaucoma in myopia requires a multimodal approach, to allow correlation between structural and functional assessments. This review provides overview on how to navigate this diagnostic dilemma.

International audience; Purpose Preservatives contained in glaucoma eye drops have been shown to have a deleterious impact on the ocular surface. We aimed to assess the association between preservative exposure and the occurrence of further glaucoma surgery among patients with glaucoma or ocular hypertension in France. Methods The study concerned all patients who first received glaucoma eye drop treatments in a French medical-administrative database (EGB) between 2008 and 2015. Three groups were created according to the level of preservative exposure during the whole follow-up: '0% preservatives', 'mixed' and '100% preservatives'. The occurrence of glaucoma surgery was estimated according to preservative exposure indicators in Cox multivariate models adjusted on age, sex, number of glaucoma eye drops simultaneously used, systemic antihypertensive treatment and duration of treatment. Results The sample consisted of 12 454 patients. The median (interquartile range) follow-up was 4.1 (1.7-6.1) years. A total of 231 (1.9%) patients underwent glaucoma surgery during follow-up. On multivariable analysis, the risk of glaucoma surgery was increased for the 'mixed' group (hazard ratio [HR] = 3.94 [95% CI, 1.54-10.05]) and for the '100% preservative' group (HR = 7.97 [95% CI, 3.07-20.67]) when compared with the 0% preservative group. Conclusion We found an association between exposure to glaucoma eye drop preservatives and the prevalence of further glaucoma surgery. While these data might be used to support the consideration of routine use of preservative-free drops, in the absence of a randomized clinical trial, they cannot prove a direct cause-and-effect relationship between preservative-free glaucoma eye drops and further glaucoma surgery.

Due to their similarities in anatomy, physiology, and pharmacology to humans, mice are a valuable model system to study the generation and mechanisms modulating conventional outflow resistance and thus intraocular pressure. In addition, mouse models are critical for understanding the complex nature of conventional outflow homeostasis and dysfunction that results in ocular hypertension. In this review, we describe a set of minimum acceptable standards for developing, characterizing, and utilizing mouse models of open-angle ocular hypertension. We expect that this set of standard practices will increase scientific rigor when using mouse models and will better enable researchers to replicate and build upon previous findings.

PurposeTo compare the corneal biomechanical parameters between pseudoexfoliation glaucoma (PXG), primary open-angle glaucoma (POAG) and healthy controls using Corvis ST.MethodsA prospective, cross-sectional study was conducted which included 132 treatment-naïve eyes which underwent Corvis ST. The study cohort comprised of 44 eyes with PXG, 42 eyes with POAG and 46 healthy controls. Corneal biomechanical parameters, which included corneal velocities, length of corneal applanated surface, deformation amplitude (DA), peak distance and radius of curvature, were compared between the groups using analysis of variance models.ResultsThe 3 groups were demographically similar. The mean IOP was 15.7 ±3 mmHg in the control group, 21.3 ±5 mmHg in the POAG group and 25.8 ±7 mmHg in the PXG group (pConclusionCorneal biomechanical parameters measured on Corvis ST are not different between eyes with PXG, POAG and healthy controls after adjusting for IOP.

Primary open-angle glaucoma is a progressive optic neuropathy which can lead to irreversible blindness if untreated. A number of studies have been published suggesting a correlation between the level of serum vitamin D3 and glaucoma or intraocular pressure (IOP). The latter is known to be a major risk factor for glaucoma and is the main target of glaucoma treatment. We give a critical review of the literature, exploring what is known about this matter. While some studies report an inverse association between serum vitamin D3 and IOP, others do not confirm this finding. Similar divergent conclusions came from studies regarding the association between serum vitamin D3 and the presence or severity of glaucoma. The effect of vitamin D3 on IOP decrease has been attributed to both aqueous humor production and trabecular meshwork outflow pathway increase. Vitamin D3 has been shown to play a major role in reducing inflammation, modulating the immune response, and decreasing angiogenesis in the eye and in other organs. It has been suggested that, through its neuroprotective effect, vitamin D3 could be a protective factor for glaucoma and that vitamin D3 deficiency could explain glaucoma occurrence or severity in some patients. Other neurodegenerative diseases such as Alzheimer's disease and multiple sclerosis have been similarly related to vitamin D3 deficiency. 1 alpha,25(OH)(2) vitamin D3 (calcitriol) supplementation has been shown to be beneficial for lowering IOP in monkeys. Although the studies highlighted in this review show interesting results, their limitations underscore the need for both population-based studies and larger randomized controlled trial with vitamin D3 supplementation. The specific role of vitamin D3 in the pathology of glaucoma remains to be elucidated, together with the possible therapeutic benefit of vitamin D3 supplementation.

In this study, we mathematically predict retinal vascular resistance (RVR) and retinal blood flow (RBF), we test predictions using laser speckle flowgraphy (LSFG), we estimate the range of vascular autoregulation, and we examine the relationship of RBF with the retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC). Fundus, optical coherence tomography (OCT), and OCT-angiography images, systolic/diastolic blood pressure (SBP/DBP), and intraocular pressure (IOP) measurements were obtained float 36 human subjects. We modeled two circulation markers (RVR and RBF) and estimated individualized lower/higher autoregula tion limits (LARL/HARL), using retinal vessel calibers, fractal dimen- sion, perfusion pressure, and population-based hematocrit values. Quantitative LSFG waveforms were extracted from vessels of the same eyes, before and during IOP elevation. LSFG metrics explained most variance in RVR (R-2 =0.77/P = 6.9.10(-9)) and RBF (R-2 =0.65/P = 1.0.10(-6)), suggesting that the markers strongly reflect blood flow physiology. Higher RBF was associated with thicker RNFL (P = 4.0.10(-4)) and GCC (P = 0.003), thus also verifying agreement with structural measurements. LARL was at SBP/DBP of 105/65 mmHg for the average subject without arterial hypertension and at 115/75 mmHg for the average hypertensive subject. Moreover, during IOP elevation, changes in RBF were more pronounced than changes in RVR. These observations physiologically imply that healthy subjects are already close to LARL, thus prone to hypoperfusion. In conclusion, we modeled two clinical markers and described a novel method to predict individualized autoregulation limits. These findings could improve understanding of retinal perfusion and pave the way for personalized intervention decisions, when treating patients with coexisting ophthalmic and cardiovascular pathologies.NEW & NOTEWORTHY We describe and test a new approach to quantify retinal blood flow, based on standard clinical examinations and imaging techniques, linked together with a physiological model. We use these findings to generate individualized estimates of the autoregulation range. We provide evidence that healthy subjects are closer to the lower autoregulation limit than thought before. This suggests that some retinas are less prepared to withstand hypoperfusion, even after small intraocular pressure rises or blood pressure drops.

Background. The aim of this study was to compare the daily costs and cost effectiveness of fixed combination glaucoma drugs in China. Methods. This study included the following fixed combination drugs: brinzolamide 1% and timolol 0.5% (Azarga; Alcon, Inc., Fort Worth, TX, USA), travoprost 0.004% and timolol 0.5% (DuoTrav; Alcon, Inc.), bimatoprost 0.03% and timolol 0.5% (Ganfort; Allergan, Inc., Dublin, Ireland), and latanoprost 0.005% and timolol 0.5% (Xalacom; Pfizer, Inc., New York, NY, USA). Five bottles of each drug were measured. The mean actual volume, mean actual number of drops, volume per drop, daily cost, yearly cost, and per mmHg reduction cost for each drug were calculated. Results. The volumes per drop ranged from 32.61 ± 2.90 μl (DuoTrav) to 24.38 ± 0.23 μl (Ganfort). The number of usage days per bottle varied from 36 days (DuoTrav) to 61 days (Ganfort). Azarga had the lowest daily cost ($0.23) and yearly cost ($84.72), while DuoTrav had the highest daily cost ($0.79) and yearly cost ($287.02). Azarga costed $2.17–$3.30 per mmHg intraocular pressure reduction, which was lower than the other three drugs. For the prostaglandin and ß-adrenergic blocker FCs, Ganfort had the lowest daily cost ($0.35) and per mmHg reduction cost (from $3.40 to $4.04). Conclusions. The daily costs of these drugs were significantly different, with Azarga having the lowest daily cost and best cost effectiveness. For the prostaglandin and β-adrenergic blocker fixed combinations, Ganfort was the most economical choice with its lower daily cost and per mmHg reduction cost. The results of this study could provide drug selection guidance from an economic perspective, but various factors should be considered when making a decision.

Irregular ocular pulsatility and altered mechanical tissue properties are associated with some of the most sight-threatening eye diseases. Here we present 4D optical coherence tomography (OCT) for the quantitative assessment and depth-resolved mapping of pulsatile dynamics in the murine retina and choroid. Through a pixel-wise analysis of phase changes of the complex OCT signal, we reveal spatiotemporal displacement characteristics across repeated frame acquisitions. We demonstrate in vivo fundus elastography (FUEL) imaging in wildtype mouse retinas and in a mouse model of retinal neovascularization and uncover subtle structural deformations related to ocular pulsation. Our data in mouse eyes hold promise for a powerful retinal elastography technique that may enable a new paradigm of OCT-based measurements and image contrast.

Primary open-angle glaucoma is one of the leading causes of irreversible blindness worldwide. Raised intraocular pressure is the most important modifiable risk factor and lowering it remains the mainstay therapeutic approach for slowing optic nerve damage and visual field progression in glaucoma patients. An intriguing finding of clinical retrospective and prospective studies is that intracranial pressure is lower in patients with glaucoma. Furthermore, in a recent study on monkeys subjected to an implantation of a lumboperitoneal cerebrospinal fluid shunt to lower intracranial pressure, chronic reduction in intracranial pressure was associated with the development of glaucoma-like pathology in half of the monkeys. In addition, a very recent study demonstrated that patients whose intracranial pressure has been lowered following ventriculoperitoneal shunt placement, as treatment for normal pressure hydrocephalus, have a significantly increased risk of developing normal-tension glaucoma. These findings suggest that a reduced intracranial pressure may play an important role in the pathogenesis of glaucoma. This may be due to an abnormally high pressure difference across the lamina cribrosa resulting in biomechanical changes of the optic nerve head and/or to a deficient clearance of toxic substances, particularly in the subarachnoid space of the optic nerve and/or in the 'ocular glymphatic system'. The search for drugs or medical devices useful to ameliorate glaucoma by lowering the trans-lamina cribrosa pressure difference and/or by facilitating cerebrospinal fluid circulation may therefore be an important area for future research. In this article, we propose that infusion of artificial cerebrospinal fluid through an implantable pump into the intrathecal space surrounding the spinal cord could be a new promising strategy for the treatment of glaucoma. Although the implantation of such a cerebrospinal fluid pump is a relatively invasive intervention, it seems worthwhile to make every effort to identify new therapies for patients who suffer from this devastating disease, especially given the significant number of patients for whom non-invasive treatment options are ineffective.

The trabecular meshwork (TM) and Schlemm’s canal generate the majority of outflow resistance; however, the distal regions of the conventional outflow pathway account for 25–50% of total resistance. Sections of distal vessels are surrounded by α-smooth muscle actin-containing cells, indicating that they may be vasoregulated. This study examined the effect of a potent vasodilator, nitric oxide (NO), and its physiological antagonist, endothelin-1 (ET-1), on the regulation of outflow resistance in the distal regions of the conventional outflow pathway. Using a physiological model of the conventional outflow pathway, human and porcine anterior segments were perfused in organ culture under constant flow conditions, while intrachamber pressure was continually monitored. For porcine anterior segments, a stable baseline outflow facility with TM intact was first achieved before anterior segments were removed and a trabeculotomy was performed. For human anterior segments, a trabeculotomy was immediately performed. In human anterior segments, 100 nM ET-1 significantly decreased distal outflow facility from 0.49 ± 0.26 to 0.31 ± 0.18 (mean ± SD) µl·min−1·mmHg, P < 0.01. Perfusion with 100 µM diethylenetriamine-NO in the presence of 1 nM ET-1 immediately reversed ET-1 effects, significantly increasing distal outflow facility to 0.54 ± 0.35 µl·min−1·mmHg, P = 0.01. Similar results were obtained in porcine anterior segment experiments. Therefore, data show a dynamic range of resistance generation by distal vessels in both the human and the porcine conventional outflow pathways. Interestingly, maximal contraction of vessels in the distal outflow tract of trabeculotomized eyes generated resistance very near physiological levels for both species having an intact TM.

PurposePhacoemulsification has been shown to reduce intraocular pressure (IOP). The mechanism of action is thought to be via increased trabecular outflow facility. However, studies on the relationship between phacoemulsification and outflow facility have been inconsistent. This study intended to examine the change in electronic Schiotz tonographic outflow facility (TOF) and IOP measurements following phacoemulsification.MethodsPatients who were due to undergo a standard clear corneal incision phacoemulsification with intraocular lens (IOL) implantation, at St Thomas’ Hospital, were invited to participate in this study. IOP was measured using Goldmann’s applanation tonometer, and TOF was measured by electronic Schiotz tonography at baseline and at 3, 6 and 12 months postoperatively.ResultsForty-one patients were recruited. Tonography data for 27 patients were reliable and available at all time points. Eleven cases had primary open angle glaucoma and cataract, while 16 patients had cataract only. Mean IOP reduced at every time point postoperatively significantly compared with baseline. TOF improved significantly after cataract extraction at all time points (baseline of 0.14±0.06 vs 0.18±0.09 at 3 months, P=0.02 and 0.20±0.09 at 6 months, P=0.003, 0.17±0.07 µL/min mmHg at 12 months, P=0.04). Five contralateral eyes of patients with cataracts only who did not have any intraocular surgery during the follow-up period were used as comparison. Their IOP and TOF did not change significantly at any postoperative visits.ConclusionThis is the first study using electronic Schiotz tonography with documented anterior chamber depth and gonioscopy after modern cataract surgery (CS) with phacoemulsification and IOL implantation. We demonstrated that phacoemulsification increases TOF and this fully accounts for the IOP reduction following CS.ISTCRN registration numberISRCTN04247738.

Aqueous humor flows out of the eye primarily through the conventional outflow pathway that includes the trabecular meshwork and Schlemm's canal. However, a fraction of aqueous humor passes through an alternative or 'unconventional' route that includes the ciliary muscle, supraciliary and suprachoroidal spaces. From there, unconventional outflow may drain through two pathways: a uveoscleral pathway where aqueous drains across the sclera to be resorbed by orbital vessels, and a uveovortex pathway where aqueous humor enters the choroid to drain through the vortex veins. We review the anatomy, physiology and pharmacology of these pathways. We also discuss methods to determine unconventional outflow rate, including direct techniques that use radioactive or fluorescent tracers recovered from tissues in the unconventional pathway and indirect methods that estimate unconventional outflow based on total outflow over a range of pressures. Indirect methods are subject to a number of assumptions and generally give poor agreement with tracer measurements. We review the variety of animal models that have been used to study conventional and unconventional outflow. The mouse appears to be a promising model because it captures several aspects of conventional and unconventional outflow dynamics common to humans, although questions remain regarding the magnitude of unconventional outflow in mice. Finally, we review future directions. There is a clear need to develop improved methods for measuring unconventional outflow in both animals and humans.

See Herms and Schön (doi:10.1093/brain/awx100) for a scientific commentary on this article. Glaucoma is often diagnosed late when vision loss has already occurred. Cordeiro et al. report a new fluorescent marker for retinal imaging that can safely visualise real-time in vivo neuronal apoptosis in patients. Increased labelling is observed in patients with progressive neurodegenerative disease compared to healthy controls., See Herms and Schön (doi:10.1093/brain/awx100) for a scientific commentary on this article. Retinal cell apoptosis occurs in many ocular neurodegenerative conditions including glaucoma—the major cause of irreversible blindness worldwide. Using a new imaging technique that we have called DARC (detection of apoptosing retinal cells), which until now has only been demonstrated in animal models, we assessed if annexin 5 labelled with fluorescent dye DY-776 (ANX776) could be used safely in humans to identify retinal cell apoptosis. Eight patients with glaucomatous neurodegeneration and evidence of progressive disease, and eight healthy subjects were randomly assigned to intravenous ANX776 doses of 0.1, 0.2, 0.4 and 0.5 mg in an open-label, phase 1 clinical trial. In addition to assessing the safety, tolerability and pharmacokinetics of ANX776, the study aimed to explore whether DARC could successfully visualize individual retinal cell apoptosis in vivo in humans, with the DARC count defined as the total number of unique ANX776-labelled spots. DARC enabled retinal cell apoptosis to be identified in the human retina using ANX776. Single ANX776-labelled cells were visualized in a dose-dependent pattern (P < 0.001) up to 6 h after injection. The DARC count was significantly higher (2.37-fold, 95% confidence interval: 1.4–4.03, P = 0.003) in glaucoma patients compared to healthy controls, and was significantly (P = 0.045) greater in patients who later showed increasing rates of disease progression, based on either optic disc, retinal nerve fibre layer or visual field parameters. Additionally, the DARC count significantly correlated with decreased central corneal thickness (Spearman’s R = −0.68, P = 0.006) and increased cup-disc ratios (Spearman’s R = 0.47, P = 0.038) in glaucoma patients and with increased age (Spearman’s R = 0.77, P = 0.001) in healthy controls. Finally, ANX776 was found to be safe and well-tolerated with no serious adverse events, and a short half-life (10–36 min). This proof-of-concept study demonstrates that retinal cell apoptosis can be identified in the human retina with increased levels of activity in glaucomatous neurodegenerative disease. To our knowledge, this is the first time individual neuronal apoptosis has been visualized in vivo in humans and is the first demonstration of detection of individual apoptotic cells in a neurodegenerative disease. Furthermore, our results suggest the level of apoptosis (‘DARC count’) is predictive of disease activity, indicating the potential of DARC as a surrogate marker. Although further trials are clearly needed, this study validates experimental findings supporting the use of DARC as a method of detection and monitoring of patients with glaucomatous neurodegeneration, where retinal ganglion cell apoptosis is an established process and where there is a real need for tools to non-invasively assess treatment efficacy.

Intraocular pressure (IOP) is maintained as a result of the balance between production of aqueous humour (AH) by the ciliary processes and hydrodynamic resistance to its outflow through the conventional outflow pathway comprising the trabecular meshwork (TM) and Schlemm’s canal (SC). Elevated IOP, which can be caused by increased resistance to AH outflow, is a major risk factor for open-angle glaucoma. Matrix metalloproteinases (MMPs) contribute to conventional aqueous outflow homeostasis in their capacity to remodel extracellular matrices, which has a direct impact on aqueous outflow resistance and IOP. We observed decreased MMP-3 activity in human glaucomatous AH compared to age-matched normotensive control AH. Treatment with glaucomatous AH resulted in significantly increased transendothelial resistance of SC endothelial and TM cell monolayers and reduced monolayer permeability when compared to control AH, or supplemented treatment with exogenous MMP-3. Intracameral inoculation of AAV-2/9 containing a CMV-driven MMP-3 gene (AAV-MMP-3) into wild type mice resulted in efficient transduction of corneal endothelium and an increase in aqueous concentration and activity of MMP-3. Most importantly, AAV-mediated expression of MMP-3 increased outflow facility and decreased IOP, and controlled expression using an inducible promoter activated by topical administration of doxycycline achieved the same effect. Ultrastructural analysis of MMP-3 treated matrices by transmission electron microscopy revealed remodelling and degradation of core extracellular matrix components. These results indicate that periodic induction, via use of an eye drop, of AAV-mediated secretion of MMP-3 into AH could have therapeutic potential for those cases of glaucoma that are sub-optimally responsive to conventional pressure-reducing medications.

Purpose: Cerebrospinal fluid pressure (CSFp) changes are involved or implicated in various ocular conditions including glaucoma, idiopathic intracranial hypertension, and visual impairment and intracranial pressure syndrome. However, little is known about the effects of CSFp on lamina cribrosa and retrolaminar neural tissue (RLNT) biomechanics, potentially important in these conditions. Our goal was to use an experimental approach to visualize and quantify the deformation of these tissues as CSFp increased.\ud\udMethods: The posterior eye and RLNT of porcine eyes (n = 3) were imaged using synchrotron radiation phase-contrast micro-computed tomography (PC μCT) at an intraocular pressure of 15 mm Hg and CSFps of 4, 10, 20, and 30 mm Hg. Scans of each tissue region were acquired at each CSFp step and analyzed using digital volume correlation to determine 3-dimensional tissue deformations.\ud\udResults: Elevating CSFp increased the strain in the lamina cribrosa and RLNT of all three specimens, with the largest strains occurring in the RLNT. Relative to the baseline CSFp of 4 mm Hg, at 30 mm Hg, the lamina cribrosa experienced a mean first and third principal strain of 4.4% and −3.5%, respectively. The corresponding values for the RLNT were 9.5% and −9.1%.\ud\udConclusions: CSFp has a significant impact on the strain distributions within the lamina cribrosa and, more prominently, within the RLNT. Elevations in CSFp were positively correlated with increasing deformations in each region and may play a role in ocular pathologies linked to changes in CSFp.

Purpose: To present an overview of animal models of retinal artery occlusion (RAO).Methods: Through a systematic literature search in PubMed and Embase, papers describing methods of inducing RAO in animal models were included. The identified methodologic approaches were presented in a narrative synthesis and compared with RAO in humans.Results: In total, 83 papers reporting on 88 experiments were included. Six different species were used with rodents and monkeys being the most common, and a minority were performed using cats, dogs, rabbits, or pigs. The anatomy of pigs and monkeys resemble that of humans most closely. The two most frequently used methods were laser-induced occlusion or ligation of the arteries. Other methods included raised intraocular pressure, arterial clamping, administration of vasoconstricting agents, the use of an occluder, embolization, and endovascular approaches to induce occlusion. In general, occlusions lasted for only 30 to 90 minutes, often followed by reperfusion.Conclusions: Although a broad range of methods have previously been used, they all have limitations. Preferably, the methods should imitate the human disease as closely as possible and avoid damaging other structures. Therefore, monkeys followed by pigs are to be preferred and ligation or clamping may be a suitable model in larger animals as there is a potential to isolate and occlude the retinal artery only. Being less invasive, laser-induced occlusion is another suitable approach.Translational Relevance: This review aims at assisting researchers in deciding on the most ideal experimental setting, and thereby increase the translational value to human disease.

PURPOSE. To determine the association of statins, five classes of antihypertensive medications, and proton pump inhibitors with (1) primary open-angle glaucoma (POAG) progression and (2) conversion of POAG suspects to POAG.METHODS. We retrospectively investigated the records of a cohort with POAG cases and suspects from the Groningen Longitudinal Glaucoma Study. To quantify visual field (VF) deterioration in cases, we used the rate of progression of the mean deviation (MD). Suspects were considered to have converted at the time point after which two consecutive VF tests for at least one eye were abnormal (glaucoma hernifield test outside normal limits). Progression and conversion were analyzed with quantile and logistic regression, respectively, with the systemic medications as predictors, controlling for age, sex, body mass index, pretreatment IOP, corneal thickness, and baseline MD. The multivariable models were built with and without IOP intervention.RESULTS. No systemic medications were associated with POAG progression in the final IOP/treatment-adjusted or unadjusted model. However, angiotensin II receptor blockers (ARBs) appeared to slow progression in older patients (b = 0.014, P = 0.0001). Angiotensin-converting enzyme inhibitors (ACM) were significantly associated with a decrease in POAG suspect conversion in both the IOP/treatment-adjusted and -unadjusted model (odds ratio [OR] 0.23, 95% confidence interval [CI] 0.07-0.79, P = 0.012; OR=0.24, 95% CI 0.07-0.78, P = 0.021, respectively), as were ARBs (OR 0.12, 95% CI 0.01-0.98, P = 0.014; OR 0.11, 95% CI 0.01-0.87, P = 0.005, respectively).CONCLUSIONS. No overall association of VF progression with systemic medication was found; ARBs delayed progression in older patients. ACEIs and ARBs were associated with lower risk of suspect conversion. The pathophysiology of this relationship is to be disentangled.

PURPOSE. To determine genetic correlations between common myopia and primary open-angle glaucoma (POAG).METHODS. We tested the association of myopia polygenic risk scores (PRSs) with POAG and POAG endophenotypes using two studies: the Australian & New Zealand Registry of Advanced Glaucoma (ANZRAG) study comprising 798 POAG cases with 1992 controls, and the Rotterdam Study (RS), a population-based study with 11,097 participants, in which intraocular pressure (IOP) and optic disc parameter measurements were catalogued. PRSs were derived from genome-wide association study meta-analyses conducted by the Consortium for Refractive Error and Myopia (CREAM) and 23andMe. In total, 12 PRSs were constructed and tested. Further, we explored the genetic correlation between myopia, POAG, and POAG endophenotypes by using the linkage disequilibrium score regression (LDSC) method.RESULTS. We did not find significant evidence for an association between PRS of myopia with POAG (P = 0.81), IOP (P = 0.07), vertical cup-disc ratio (P = 0.42), or cup area (P = 0.25). We observed a nominal association with retinal nerve fiber layer (P = 7.7 3 x 10(-3)) and a significant association between PRS for myopia and disc area (P = 1.59 3 x 10(-9)). Using the LDSC method, we found a genetic correlation only between myopia and disc area (genetic correlation [RhoG] = -0.12, P = 1.8 x 10(-3)), supporting the findings of the PRS approach.CONCLUSIONS. Using two complementary approaches we found no evidence to support a genetic overlap between myopia and POAG; our results suggest that the comorbidity of these diseases is not influenced by common variants. The association between myopia and optic disc size is well known and validates this methodology.

Significance Glaucoma is the leading cause of irreversible blindness worldwide. The primary and only modifiable risk factor for the development of glaucoma is elevated intraocular pressure (IOP), and lowering IOP effectively slows glaucomatous disease progression. Unfortunately, the majority of available treatments do not target, or intentionally bypass, the diseased and stiffened glaucomatous outflow tissues responsible for IOP elevation. We recently established that conventional outflow tissue stiffness reflects tissue function. Therefore, detection of outflow tissue stiffness using noncontact, noninvasive optical coherence tomography, as we here demonstrate in an animal model of glaucoma, represents a valuable tool for assessing outflow tissue functional status. Such technology has the potential to monitor recently approved treatments targeting the outflow tissues, and to inform glaucoma surgery decisions., Ocular corticosteroids are commonly used clinically. Unfortunately, their administration frequently leads to ocular hypertension, i.e., elevated intraocular pressure (IOP), which, in turn, can progress to a form of glaucoma known as steroid-induced glaucoma. The pathophysiology of this condition is poorly understood yet shares similarities with the most common form of glaucoma. Using nanotechnology, we created a mouse model of corticosteroid-induced ocular hypertension. This model functionally and morphologically resembles human ocular hypertension, having titratable, robust, and sustained IOPs caused by increased resistance to aqueous humor outflow. Using this model, we then interrogated the biomechanical properties of the trabecular meshwork (TM), including the inner wall of Schlemm’s canal (SC), tissues known to strongly influence IOP and to be altered in other forms of glaucoma. Specifically, using spectral domain optical coherence tomography, we observed that SC in corticosteroid-treated mice was more resistant to collapse at elevated IOPs, reflecting increased TM stiffness determined by inverse finite element modeling. Our noninvasive approach to monitoring TM stiffness in vivo is applicable to other forms of glaucoma and has significant potential to monitor TM function and thus positively affect the clinical care of glaucoma, the leading cause of irreversible blindness worldwide.

As ocular hypertension refers to a condition in which the intraocular pressure is consistently elevated but without development of glaucoma, study of it may provide important clues to factors that may play a protective role in glaucoma. β-amyloid, one of the key histopathological findings in Alzheimer's disease, has been reported to increase by chronic elevation of intraocular pressure in animals with experimentally induced ocular hypertension and to cause retinal ganglion cell death, pointing to similarities in molecular cell death mechanisms between glaucoma and Alzheimer's disease. On the other hand, recent studies have reported that intracranial pressure is higher in patients with ocular hypertension compared with controls, giving rise to the idea that elevated intracranial pressure may provide a protective effect for the optic nerve by decreasing the trans-lamina cribrosa pressure difference. The speculation that the higher intracranial pressure reported in ocular hypertension patients may protect against glaucoma mainly through a lower trans-lamina cribrosa pressure difference remains at least questionable. Here, we present an alternative viewpoint, according to which the protective effect of higher intracranial pressure could be due, at least in part, to a pressure-independent mechanism, namely faster cerebrospinal fluid production leading to increased cerebrospinal fluid turnover with enhanced removal of potentially neurotoxic waste products that accumulate in the optic nerve. This suggests a new hypothesis for glaucoma, which, just like Alzheimer's disease, may be considered then as an imbalance between production and clearance of neurotoxins, including β-amyloid. If confirmed, then strategies to improve cerebrospinal fluid flow are reasonable and could provide a new therapeutic approach for stopping the neurotoxic β-amyloid pathway in glaucoma.

As ocular hypertension refers to a condition in which the intraocular pressure is consistently elevated but without development of glaucoma, study of it may provide important clues to factors thatmay play a protective role in glaucoma. beta-amyloid, one of the key histopathological findings in Alzheimer's disease, has been reported to increase by chronic elevation of intraocular pressure in animals with experimentally induced ocular hypertension and to cause retinal ganglion cell death, pointing to similarities in molecular cell death mechanisms between glaucoma and Alzheimer's disease. On the other hand, recent studies have reported that intracranial pressure is higher in patients with ocular hypertension compared with controls, giving rise to the idea that elevated intracranial pressure may provide a protective effect for the optic nerve by decreasing the trans-lamina cribrosa pressure difference. The speculation that the higher intracranial pressure reported in ocular hypertension patients may protect against glaucomamainly through a lower trans-lamina cribrosa pressure difference remains at least questionable. Here, we present an alternative viewpoint, according to which the protective effect of higher intracranial pressure could be due, at least in part, to a pressure-independent mechanism, namely faster cerebrospinal fluid production leading to increased cerebrospinal fluid turnover with enhanced removal of potentially neurotoxic waste products that accumulate in the optic nerve. This suggests a new hypothesis for glaucoma, which, just like Alzheimer's disease, may be considered then as an imbalance between production and clearance of neurotoxins, including beta-amyloid. If confirmed, then strategies to improve cerebrospinal fluid flow are reasonable and could provide a new therapeutic approach for stopping the neurotoxic beta-amyloid pathway in glaucoma.

Purpose: Glaucoma is the most common age-related neurodegenerative eye disease in western society. It is an insidious disease that, when untreated or detected too late, leads inevitably to blindness. An outstanding issue is whether glaucoma should be considered exclusively an eye disease or also a brain disease. To further examine it, we used Diffusion Tensor Imaging (DTI) to study white matter integrity in a Japanese glaucoma population. This population has a very high incidence of normal-pressure glaucoma, in which optic nerve damage occurs in the absence of the elevated eye pressure that characterises the more common form of glaucoma.Methods: We performed DTI in 30 participants with normal-pressure glaucoma and 21 age-matched healthy controls. We used voxel-wise tract-based spatial statistics to compare fractional anisotropy and mean diffusivity of the white matter of the brain between patients and control group. Whole-brain and region of interest-based analyses served to find associations between diffusion indices and clinical measures of glaucomatous damage.Results: Fractional Anisotropy was significantly lower in glaucoma patients in a cluster in the right occipital lobe (p Conclusions: In this specific population, glaucoma is associated with lower Fractional Anisotropy in the optic radiations, forceps major and corpus callosum. We interpret these reductions as evidence for white matter degeneration in these loci. In particular, the degeneration of the corpus callosum suggests the presence of neurodegeneration of the brain beyond what can be explained on the basis of propagated retinal and pre-geniculate damage. We discuss how this finding links to the emerging view that a brain component that is independent from the eye damage plays a role in the aetiology of glaucoma.

Purpose: To develop a prediction model for glaucomatous visual field progression using easily accessible baseline clinical data.Patients and Methods: We collected baseline data of 613 consecutive patients with open-angle glaucoma from 2001 to 2003. The rate of visual field progression was calculated using the Visual Field Index (VFI) of routine follow-up examinations until 2010. Baseline data of 333 patients from 3 hospitals were used to develop a model to predict the rate of VFI progression using a linear regression analysis and univariate preselection (P Results: After a mean follow-up period of 5.8 years of all 613 eyes, the mean rate of VFI progression was -1.6% per year. The final model contained the following predictors: age, baseline intraocular pressure, and baseline visual field status. During model development, 10.3% of the observed variation in VFI rates was explained by the model. The area under the receiver-operating characteristic curve was 0.76 when the prediction model was used to detect a VFI rate of -3% per year or worse, which decreased to 0.71 at external validation.Conclusions: Although our prediction model could explain only a small amount of the variance in visual field progression, it may offer the possibility to identify subgroups of treated patients with high rates of visual field progression, thereby providing an opportunity to select those patients for more intensive treatment.

Purpose. To investigate the relationship between corneal biomechanical parameters, anterior segment parameters, and geometric corneal parameters in a healthy Caucasian group. Methods. This retrospective study included the healthy eyes with best corrected visual acuity of at least 20/40 of 122 Caucasian subjects. The anterior segment parameters and geometric corneal parameters such as corneal volume, central corneal thickness, horizontal and vertical corneal radii, anterior and posterior steep, and flat keratometric values were measured with a Scheimpflug camera. The biomechanical properties were measured with Ocular Response Analyzer. Results. One hundred and twenty-two healthy Caucasian subjects (67 males, 55 females) with a mean age of 45.32±20.23 were enrolled. Both corneal hysteresis and corneal resistance factor were positively correlated with CCT (r=0.529, p<0.001; r=0.638, p<0.001) and CV (r=0.635, p<0.001; r=0.579, p<0.001) and negatively correlated with age (r=-0.373, p<0.001; r=-0.249, p<0.001). Both in age-gender and multivariate models, CH and CRF had statistically significant negative association with the posterior steep K value. Conclusions. CH and CRF are negatively correlated with posterior steep and average posterior K values.

Glucocorticoid (GC) therapy is widely used to treat a variety of inflammatory diseases and conditions. While unmatched in their anti-inflammatory and immunosuppressive activities, GC therapy is often associated with the significant ocular side effect of GC-induced ocular hypertension (OHT) and iatrogenic open-angle glaucoma. Investigators have generated GC-induced OHT and glaucoma in at least 8 different species besides man. These models mimic many features of this condition in man and provide morphologic and molecular insights into the pathogenesis of GC-OHT. In addition, there are many clinical, morphological, and molecular similarities between GC-induced glaucoma and primary open-angle glaucoma (POAG), making animals models of GC-induced OHT and glaucoma attractive models in which to study specific aspects of POAG.

Kailin Tian,1,2 Shannon Shibata-Germanos,1 Milena Pahlitzsch,1 M Francesca Cordeiro1,3 1Glaucoma and Retinal Neurodegeneration Research Group, UCL Institute of Ophthalmology, London, UK; 2Eye Centre, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China; 3Western Eye Hospital, ICORG, Imperial College NHS Trust, London, UK Abstract: Glaucoma is the second leading cause of blindness worldwide and is most notably characterized by progressive optic nerve atrophy and advancing loss of retinal ganglion cells (RGCs). The main concomitant factor is the elevated intraocular pressure (IOP). Existing treatments are focused generally on lowering IOP. However, both RGC loss and optic nerve atrophy can independently occur with IOP at normal levels. In recent years, there has been substantial progress in the development of neuroprotective therapies for glaucoma in order to restore vital visual function. The present review intends to offer a brief insight into conventional glaucoma treatments and discuss exciting current developments of mostly preclinical data in novel neuroprotective strategies for glaucoma that include recent advances in noninvasive diagnostics going beyond IOP maintenance for an enhanced global view. Such strategies now target RGC loss and optic nerve damage, opening a critical therapeutic window for preventative monitoring and treatment. Keywords: glaucoma, retinal ganglion cell, neuroprotection

Purpose The large-conductance calcium-activated potassium channel KCa1.1 (BKCa, maxi-K) influences aqueous humor outflow facility, but the contribution of auxiliary β-subunits to KCa1.1 activity in the outflow pathway is unknown. Methods Using quantitative polymerase chain reaction, we measured expression of β-subunit genes in anterior segments of C57BL/6J mice (Kcnmb1-4) and in cultured human trabecular meshwork (TM) and Schlemm's canal (SC) cells (KCNMB1-4). We also measured expression of Kcnma1/KCNMA1 that encodes the pore-forming α-subunit. Using confocal immunofluorescence, we visualized the distribution of β4 in the conventional outflow pathway of mice. Using iPerfusion, we measured outflow facility in enucleated mouse eyes in response to 100 or 500 nM iberiotoxin (IbTX; N = 9) or 100 nM martentoxin (MarTX; N = 12). MarTX selectively blocks β4-containing KCa1.1 channels, whereas IbTX blocks KCa1.1 channels that lack β4. Results Kcnmb4 was the most highly expressed β-subunit in mouse conventional outflow tissues, expressed at a level comparable to Kcnma1. β4 was present within the juxtacanalicular TM, appearing to label cellular processes connecting to SC cells. Accordingly, KCNMB4 was the most highly expressed β-subunit in human TM cells, and the sole β-subunit in human SC cells. To dissect functional contribution, MarTX decreased outflow facility by 35% (27%, 42%; mean, 95% confidence interval) relative to vehicle-treated contralateral eyes, whereas IbTX reduced outflow facility by 16% (6%, 25%). Conclusions The β4-subunit regulates KCa1.1 activity in the conventional outflow pathway, significantly influencing outflow function. Targeting β4-containing KCa1.1 channels may be a promising approach to lower intraocular pressure to treat glaucoma.

PURPOSE: To evaluate the effectiveness of an ab interno subconjunctival gelatin implant as primary surgical intervention in reducing intraocular pressure (IOP) and IOP-lowering medication count in medically uncontrolled moderate primary open-angle glaucoma (POAG). METHODS: In this prospective, non-randomized, open-label, multicenter, 2-year study, eyes with medicated baseline IOP 18-33 mmHg on 1-4 topical medications were implanted with (phaco + implant) or without (implant alone) phacoemulsification. Changes in mean IOP and medication count at months 12 (primary outcomes) and 24, clinical success rate (eyes [%] achieving ≥ 20% IOP reduction from baseline on the same or fewer medications without glaucoma-related secondary surgical intervention), intraoperative complications, and postoperative adverse events were assessed. RESULTS: The modified intent-to-treat population included 202 eyes (of 218 implanted). Changes (standard deviation) in mean IOP and medication count from baseline were - 6.5 (5.3) mmHg and - 1.7 (1.3) at month 12 and - 6.2 (4.9) mmHg and - 1.5 (1.4) at month 24, respectively (all P