Elevated IOP Research Articles

TGF-β2 Promotes Oxidative Stress in Human Trabecular Meshwork Cells by Selectively Enhancing NADPH Oxidase 4 Expression.

PurposeThe multifunctional profibrotic cytokine TGF-β2 is implicated in the pathophysiology of primary open angle glaucoma (POAG). While the underlying cause of POAG remains unclear, TGF-β2 dependent remodeling of the extracellular matrix (ECM) within the trabecular meshwork (TM) microenvironment is considered an early pathologic consequence associated with impaired aqueous humor (AH) outflow and elevated IOP. Mitochondrial-targeted antioxidants have been recently shown by our group to markedly attenuate TGF-β2 profibrotic responses, strongly implicating oxidative stress as a key facilitator of TGF-β2 signaling in human TM cells. In this study, we determined the mechanism by which oxidative stress facilitates TGF-β2 profibrotic responses in cultured primary human TM cells.MethodsSemiconfluent cultures of primary or transformed human TM cells were conditioned overnight in serum-free media and subsequently challenged without or with TGF-β2 (5 ng/mL). Relative changes in the mRNA content of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) isoforms, connective tissue growth factor (CTGF), collagen 1α1 and 4α1 isoforms or relative changes in the protein content of Nox4, phospho- and total-Smad2 and -Smad3, collagens I and IV were determined in the absence or presence of GKT137831, a Nox1-Nox4 dual enzyme inhibitor, and quantified by real-time qPCR or by immunoblot, respectively. Relative in situ changes in collagens I and IV and in alpha smooth muscle actin (αSMA) were semiquantified by immunocytochemistry, whereas relative changes in filamentous actin stress fiber formation was semiquantified by phalloidin staining.ResultsQuiescent primary human TM cells cultured in the presence of TGF-β2 exhibited a marked selective increase in endogenous Nox4 mRNA and Nox4 protein expression. Actinomycin D prevented TGF-β2 mediated increases in Nox4 mRNA expression. TM cells reverse transfected with siRNA against Smad3 prevented TGF-β2 mediated increases in Nox4 mRNA expression. Pre-incubating TM cells with GKT137831 attenuated TGF-β2 mediated increases in intracellular reactive oxygen species (ROS), in COL1A1, COL4A1, and CTGF mRNA expression, in Smad3 protein phosphorylation, in collagens I, collagens IV, and αSMA protein expression, and in filamentous actin stress fiber formation.ConclusionsTGF-β2 promotes oxidative stress in primary human TM cells by selectively increasing expression of NADPH oxidase 4. Dysregulation of redox equilibrium by induction of NADPH oxidase 4 expression appears to be a key early event involved in the pathologic profibrotic responses elicited by TGF-β2 canonical signaling, including ECM remodeling, filamentous actin stress fiber formation, and αSMA expression. Selective inhibition of Nox4 expression/activation, in combination with mitochondrial-targeted antioxidants, represents a novel strategy by which to slow the progression of TGF-β2 elicited profibrotic responses within the TM.

The role of aquaporin-4 in optic nerve head astrocytes in experimental glaucoma.

To study aquaporin channel expression in astrocytes of the mouse optic nerve (ON) and the response to IOP elevation in mice lacking aquaporin 4 (AQP4 null). C57BL/6 (B6) and AQP4 null mice were exposed to bead-induced IOP elevation for 3 days (3D-IOP), 1 and 6 weeks. Mouse ocular tissue sections were immunolabeled against aquaporins 1(AQP1), 4(AQP4), and 9(AQP9). Ocular tissue was imaged to identify normal AQP distribution, ON changes, and axon loss after IOP elevation. Ultrastructure examination, cell proliferation, gene expression, and transport block were also analyzed. B6 mice had abundant AQP4 expression in Müller cells, astrocytes of retina and myelinated ON (MON), but minimal AQP4in prelaminar and unmyelinated ON (UON). MON of AQP4 nulls had smaller ON area, smaller axon diameter, higher axon density, and larger proportionate axon area than B6 (all p≤0.05). Bead-injection led to comparable 3D-IOP elevation (p = 0.42) and axonal transport blockade in both strains. In B6, AQP4 distribution was unchanged after 3D-IOP. At baseline, AQP1 and AQP9 were present in retina, but not in UON and this was unaffected after IOP elevation in both strains. In 3D-IOP mice, ON astrocytes and microglia proliferated, more in B6 than AQP4 null. After 6 week IOP elevation, axon loss occurred equally in the two mouse types (24.6%, AQP4 null vs. 23.3%, B6). Lack of AQP4 was neither protective nor detrimental to the effects of IOP elevation. The minimal presence of AQP4 in UON may be a vital aspect of the regionally specific phenotype of astrocytes in the mouse optic nerve head.

C-FLIP regulates pyroptosis in retinal neurons following oxygen-glucose deprivation/recovery via a GSDMD-mediated pathway

Cellular FLICE-inhibitory protein (c-FLIP), an anti-apoptotic regulator, shows remarkable similarities to caspase-8, which plays a key role in the cleavage of gasdermin D (GSDMD). It has been reported that the oxygen-glucose deprivation/recovery (OGD/R) model and lipopolysaccharide (LPS)/adenosine triphosphate (ATP) treatment could induce inflammation and pyroptosis. However, the regulatory role of c-FLIP in the pyroptotic death of retinal neurons is unclear. In this study, we hypothesized that c-FLIP might regulate retinal neuronal pyroptosis by GSDMD cleavage. To investigate this hypothesis, we induced retinal neuronal damage in vitro (OGD/R and LPS/ATP) and in vivo (acute high intraocular pressure [aHIOP]). Our results demonstrated that the three injuries triggered the up-regulation of pyroptosis-related proteins, and c-FLIP could cleave GSDMD to generate a functional N-terminal (NT) domain of GSDMD, causing retinal neuronal pyroptosis. In addition, c-FLIP knockdown in vivo ameliorated the already established visual impairment mediated by acute IOP elevation. Taken together, these findings revealed that decreased c-FLIP expression protected against pyroptotic death of retinal neurons possibly by inhibiting GSDMD-NT generation. Therefore, c-FLIP might provide new insights into the pathogenesis of pyroptosis-related diseases and help to elucidate new therapeutic targets and potential treatment strategies.

27-gauge trocar-assisted sutureless intraocular lens fixation

BackgroundsHowever there have been numerous investigations of intrascleral intraocular lens (IOL) fixation techniques, there is room for improvement in terms of simplifying complicated techniques and reducing the high levels of skill required. This study aimed to report a novel technique for sutureless intrascleral fixation of the IOL using retinal forceps with a 27-gauge trocar.MethodsNineteen eyes of 18 patients underwent intrascleral fixation of the IOL from July 2018 to September 2019 were enrolled in this study. A 27-gauge trocar formed 3-mm scleral tunnels positioned at 4 and 10 o’clock, 2 mm from the corneal limbus. We used a 3-piece IOL haptic grasped by a 27-gauge retinal forceps and pulled from the 27-gauge trocar. The IOL was fixed by making a flange. Main outcome measures were visual acuity, corneal endothelial cell density, IOL tilt, decentration, predicted error of refraction and complications.ResultsThe 19 eyes were followed up for 1 month. The mean pre- and postoperative logMAR uncorrected visual acuity (UCVA) was 1.06 ± 0.63 and 0.40 ± 0.26, respectively (p < 0.01), while the mean pre- and postoperative logMAR best corrected visual acuity (BCVA) was 0.27 ± 0.51 and 0.06 ± 0.15, respectively (p = 0.09). The mean corneal endothelial cell density was 2406 ± 625 to 2004 ± 759 cells/mm2 at 1 month (p = 0.13). The mean IOL tilt was 3.52 ± 3.00°, and the mean IOL decentration was 0.39 ± 0.39 mm. There was no correlation among IOL tilt, decentration and BCVA (p > 0.05). The mean prediction error of the target refraction was − 0.03 ± 0.93 D. The complications were vitreous hemorrhage (3 eyes), hyphema (1 eye), IOP elevation (1 eye), iris capture of the IOL (1 eye) and hypotony (2 eyes). No IOL dislocation occurred.ConclusionsIOL intrascleral fixation with a flange achieved good IOL fixation and visual outcome in the scleral tunnels created with the 27-gauge trocar.

Current intravitreal therapy and ocular hypertension: A review.

To determine the effect of commonly used intravitreal agents on immediate and long-term IOP elevations and their association, if any, with glaucoma. Literature searches in PubMed and the Cochrane databased in January 2020 yielded 407 individual articles. Of these, 87 were selected for review based on our inclusion criteria. Based on the evidence provided, 20 were assigned level I, 27 level II, and 22 level III. Eight articles were rejected because of poor quality, insufficient clarity, or irrelevance based on standardized protocols set out by the American Academy of Ophthalmology. The studies that reported on short-term IOP elevation (i.e., between 0 and 60 min) showed that an immediate increase in IOP is seen in all patients who receive anti-VEGF agents or triamcinolone acetonide when measured between 0 and 30 min of intravitreal injection and that the IOP elevation decreases over time. The data on long-term IOP elevation were mixed; Pretreatment with glaucoma medications, anterior chamber tap, vitreous reflux, longer intervals between injections, and longer axial lengths were associated with lower IOP elevations after injection of anti-VEGF agents, while the position of the implant vis-à-vis, the anterior chamber was important for steroid therapy. Data were mixed on the relationship between IOP increase and the type of intravitreal injection, number of intravitreal injections, preexisting glaucoma, and globe decompression before injection. There were no data on the onset or progression of glaucoma in the studies reviewed in this assessment. However, some studies demonstrated RNFL thinning in patients receiving chronic anti-VEGF therapy. Most, if not all, intravitreal agents cause ocular hypertension, both in the short term and long term. The functional consequences of these observations are not very clear.

Clinical correlation of glaucoma with systemic hypertension and its effect on visual morbidity

Glaucoma and hypertension share a common pathophysiology of altered sodium transport in the renal and ciliary epithelium and can co exist. High blood pressure is a significant risk factor for glaucoma progression due to intraocular pressure spikes.This study was performed to evaluate the association of hypertension with glaucoma and to assess the extent of optic disc damage, the role of anti hypertensive medications and visual morbidity.This is a prospective, multidisciplinary study performed on a cohort of118 hypertensive patients over 1 year. Ophthalmic examination, ancillary ocular investigations, systemic tests and multi speciality referrals were obtained for all patients.Among 118 hypertensive patients, 64 (54.8%) had glaucoma. 65 patients (55.1%) were female and 53 patients (44.1%) male. Age group most frequently affected was between 60 and 70 years. There was increased incidence of ocular hypertension which was statistically significant (p value of 0.02). The range of IOP in those on anti hypertensive medications was 10-16 mmHg which was statistically significant (p value = 0. 03).Risk of glaucoma in hypertension was higher in women. An elevation of diastolic blood pressure is more significant than systolic BP in raising IOP. Decreased IOP was highest among patients taking calcium channel blockers.: Hypertension can cause both reduction and elevation in IOP. Treatment of hypertension does lower the IOP and prevent further progression of glaucoma and prevent any visual loss.

Modeling of the increased intraocular pressure effect on changes in the stress state of the eyeball’s internal structures

The aim of the study was creating a model and evaluating the effect of elevated IOP in the anterior chamber during phacoemulsification on the changes in the stress state of various ocular structures.&#x0D; Materials and methods.A simplified axial symmetrical anatomical model of the eyeball was created using the finite element method. Using the Deform software package, the deformation problem was worked out by calculating the redistribution of the excess pressure in the anterior chamber during phacoemulsification, on the changes in the stress state of different ocular structures.Results. At processing of modeling results, data were obtained on redistribution of the excess pressure delivered to the anterior chamber towards its decrease in the posterior pole area. The pressure level amounted to 0.85 % of excess pressure applied. The findings are supported by few animal experiments.&#x0D; Conclusions.Proposed model of the increased IOP level effect on changes in the stressed state of various ocular structures demonstrates that the autoregulation mechanism maintaining ocular blood flow at a constant level includes a compensating mechanism for a steep IOP increase due to elastic properties of the vitreous body. This model allows calculating the redistribution of pressure in different parts of the eyeball, depending on the state of resilient-elastic properties of the vitreous, as well as on avitreal eyes, and in patients with silicone oil tamponade.

A 3D Model of Human Trabecular Meshwork for the Research Study of Glaucoma.

Glaucoma is a multifactorial syndrome in which the development of pro-apoptotic signals are the causes for retinal ganglion cell (RGC) loss. Most of the research progress in the glaucoma field have been based on experimentally inducible glaucoma animal models, which provided results about RGC loss after either the crash of the optic nerve or IOP elevation. In addition, there are genetically modified mouse models (DBA/2J), which make the study of hereditary forms of glaucoma possible. However, these approaches have not been able to identify all the molecular mechanisms characterizing glaucoma, possibly due to the disadvantages and limits related to the use of animals. In fact, the results obtained with small animals (i.e., rodents), which are the most commonly used, are often not aligned with human conditions due to their low degree of similarity with the human eye anatomy. Although the results obtained from non-human primates are in line with human conditions, they are little used for the study of glaucoma and its outcomes at cellular level due to their costs and their poor ease of handling. In this regard, according to at least two of the 3Rs principles, there is a need for reliable human-based in vitro models to better clarify the mechanisms involved in disease progression, and possibly to broaden the scope of the results so far obtained with animal models. The proper selection of an in vitro model with a “closer to in vivo” microenvironment and structure, for instance, allows for the identification of the biomarkers involved in the early stages of glaucoma and contributes to the development of new therapeutic approaches. This review summarizes the most recent findings in the glaucoma field through the use of human two- and three-dimensional cultures. In particular, it focuses on the role of the scaffold and the use of bioreactors in preserving the physiological relevance of in vivo conditions of the human trabecular meshwork cells in three-dimensional cultures. Moreover, data from these studies also highlight the pivotal role of oxidative stress in promoting the production of trabecular meshwork-derived pro-apoptotic signals, which are one of the first marks of trabecular meshwork damage. The resulting loss of barrier function, increase of intraocular pressure, as well the promotion of neuroinflammation and neurodegeneration are listed as the main features of glaucoma. Therefore, a better understanding of the first molecular events, which trigger the glaucoma cascade, allows the identification of new targets for an early neuroprotective therapeutic approach.

Comparison of intravitreal injection of conbercept and triamcinolone acetonide for macular edema secondary to branch retinal vein occlusion.

To compare the safety and efficacy of the intravitreal injection of conbercept (IVC) and triamcinolone acetonide (IVTA) for macular edema (ME) secondary to branch retinal vein occlusion (BRVO). A prospective, randomized clinical study. Patients with ME secondary to BRVO were randomly assigned to either IVC group or IVTA group at a ratio of 2:1 and a 12-month follow-up was performed. The efficacy outcome measures included the mean changes and differences in best corrected visual acuity (BCVA) and the central retinal thickness (CRT). The safety profiles and the mean retreatment intervals were also compared. There was no statistically significant difference of baseline between the two groups (IVC group, n=36; IVTA group, n=17). At 12mo, the BCVA letters improved by 27.31±18.36 in the IVC group, and 13.53±11.37 in the IVTA group (P=0.0004). CRT reduction was 253.33±163.69 and 150.24±134.32 µm, respectively (P=0.0034). The mean BCVA in the IVC group was superior to that of the IVTA group for months 6-12 (P<0.01). The mean CRT at 9 and 12mo were thinner in the IVC group compared to the IVTA group (P<0.01). The mean retreatment interval in the IVC group was longer than that in the IVTA group (97.40±36.27d vs 68.71±36.38d, P=0.0030). One eye in the IVC group and seven eyes in the IVTA group developed elevated intraocular pressure (IOP; P=0.0012). The proportion of eyes with cataract new-onset or progression were 19.44% in the IVC group and 64.71% in the IVTA group (P=0.0012). IVC could maintain or improve BCVA and reduce CRT for a longer time and have longer retreatment interval than IVTA. In addition, patients treated with IVTA are more susceptible to IOP elevation and cataract progression.

The Variants of Technologies of Suture Fixation in Case of IOL-Capsular Bag Complex III–IV Degree Dislocation

Purpose . To present the results of several technologies for suture fixation in case of IOL-capsular bag complex III–IV-degree dislocation and to estimate their impact on IOP. Patients and Methods. We have analyzed 42 cases of IOL-capsular bag complex dislocation complicated by absence of capsular support which were divided into three groups. Group 1 included 4 cases of complex fixation to the sclera (presence of capsular ring, IOLs with closed loop haptics such as T-26, T-28, single-piece IOLs with massive haptics such as Asphina). Suture fixation was performed in the ciliary sulcus projection with capture of haptics or capsular ring and buried knots in capsular pockets. Group 2 included 27 cases with iris suture fixation with capture of haptics or fibrotic capsular bag on a 30G needle. Reposition and support of dislocated IOL-capsular bag complex was performed with a bent 30G needle inserted through pars plana. Group 3 included 11 cases with iris suture fixation with additional surgical manipulations (anterior vitrectomy, removal of fibrotic anterior and posterior capsules, complete removal of the capsular bag with cortex, surgical dissection of opacified posterior capsule). The specific feature was the use of vitreotome needle for IOL-capsular bag complex centration and fixation as well as for subsequent removal of capsular bag fibrosis, secondary cataract or cortex. Results . Intraoperative complications included 3 cases of slight bleeding during iris perforation. Postoperative complications included 4 cases of inflammatory reaction in the form of fibrin in the pupil. No cases of hemophthalmia associated with the insertion of 30 G needle or port in the eye cavity were marked. Two patients developed pseudoexfoliation glaucoma treated with hypotensive drops. In the early and late postoperative period in all patients of all the groups stable position of IOL-capsular bag complex was marked. Conclusion . Use of discussed techniques gives a possibility to obtain high visual prognosis, low probability of IOP elevation and stable position of IOL-capsular bag complex in all the three groups.

Assessment of the effectiveness of Intravitreal anti-vascular endothelial growth factor on lowering intraocular pressure in early Neovascular glaucoma

Neovascular glaucoma (NVG) is a serious refractory form of secondary glaucoma with poor prognosis characterized by iris and iridocorneal neovascularization and increase intraocular pressure. The underlying pathogenesis in most cases is posterior segment ischemia such as proliferative diabetic retinopathy, central retinal vein occlusion, ocular ischemic syndrome. Neovascularization in the eye occurs due to an imbalance between pro-angiogenic factors as vascular endothelial growth factor VEGF and other anti-angiogenic factors as pigment-epithelium- derived factor. Therefore, anti –VEGF antibody may serve as a useful adjunctive to the therapy of NVG via its antiangiogenic anti fibroblastic properties. It lead to regression of both iris and angle neovascularization, and controlling intraocular pressureThe management of NVG is approached by first treating the underlying condition responsible for the neovascular stimulus. This can be achieved by panretinal photocoagulation and intravitreal anti VEGF. Secondarily Controlling the elevated IOP which may lead to progressive optic neuropathy if untreated either medically or surgically

Using retinal function to define ischemic exclusion criteria for animal models of glaucoma

Most animal models of glaucoma rely on induction of ocular hypertension (OHT), yet such models can suffer from high IOPs leading to undesirable retinal ischemia. Thus, animals with IOPs exceeding a threshold (e.g. > 60 mmHg) are often excluded from studies. However, due to the intermittent nature of IOP measurements, this approach may fail to detect ischemia. Conversely, it may also inappropriately eliminate animals with IOP spikes that do not induce ischemic damage. It is known that acute ischemia selectively impairs inner retinal function, which results in a reduced b-wave amplitude. Here, we explore the potential of using electroretinography (ERG) to detect ischemic damage in OHT eyes. 74 Brown Norway rats received a unilateral injection of magnetic microbeads to induce OHT, while contralateral eyes served as controls. IOP was measured every 2–3 days for 14 days after microbead injection. Retinal function was evaluated using dark-adapted bright flash ERG (2.1 log cd•s/m2) prior to, and at 7 and 14 days after, injection. We investigated two criteria for excluding animals: (IOP Criterion) a single IOP measurement > 60 mmHg; or (ERG Criterion) a b-wave amplitude below the 99.5% confidence interval for naïve eyes. 49 of 74 rats passed both criteria, 7 of 74 failed both, and 18 passed one criterion but not the other. We suggest that ERG testing can detect unwelcome ischemic damage in animal models of OHT. Since brief IOP spikes do not necessarily lead to ischemic retinal damage, and because extended periods of elevated IOP can be missed, such ERG-based criteria may provide more objective and robust exclusion criteria in future glaucoma studies.

Clinical Outcomes of the Scleral Fixation of Posterior Chamber Intraocular Lens using the Modified Yamane's Technique: a Swept-source Optical Coherence Tomography Study

To observe the postoperative outcomes of the scleral fixation of posterior chamber intraocular lens (SF-PCIOL) using the modified Yamane's technique with the aid of swept-source optical coherence tomography (SS-OCT). Prospective observational case series. This study involved 20 patients who underwent SF-PCIOL with the modified Yamane's technique, from December 2017 to November 2019. All patients had routine preoperative examinations, including biometric measurement by IOL master, measurements of uncorrected distance visual acuity (UDVA) and best corrected distance visual acuity (BCDVA). The SRK/T formula was used to calculate the power of intraocular lens (IOL). After the surgery, UDVA and intraocular pressure were evaluated for 1 d, UDVA, BCDVA, spherical equivalent (SE) and corneal endothelial cell density were measured for 1 week, 1 month, 3 and 6 months, respectively. The IOL tilt and the symmetry of hepatitis in the scleral tunnel were measured by SS-OCT. The mean follow-up duration was (7.20±6.56) months (range, 3-26 months). The mean preoperative UDVA was (1.70±0.38) LogMAR, and it improved to (0.48±0.50) LogMAR ( P=0.001). There was no statistically significant difference between the pre- and post-operative BCDVA, i.e. (0.44±0.50) LogMAR and (0.32±0.48) LogMAR, respectively ( P=0.08). The mean spherical equivalent was (-0.53±0.86) diopter (D) and the postoperative refractive error was (0.27±0.82) D. Seventeen patients underwent SS-OCT examinations. The mean IOL tilt was (3.28±3.00)°. There was no significant difference between the horizontal and vertical tilt ( P=0.326). The IOL tilt did not show a significant correlation with spherical and cylindrical refractive error ( P=0.532, P=0.241). There was no statistically significant difference in the HL (the length of haptics fixed in the scleral tunnel) of nasal and temporal haptic, which were (2.24±0.20) mm and (2.17±0.23) mm, respectively ( P=0.193). And there were no statistically significant differences between the HD (the distance between the center of haptic flange and scleral spur) of nasal and temporal haptic, (1.58±0.07) mm and (1.66±0.08) mm, respectively ( P=0.338). The changes of IOL haptics in the scleral tunnel were tracked by 10 patients. The HL (nasal: HL-N; temporal: HL-T) and the HD (nasal: HD-N; temporal: HD-T) of haptics in the tunnel were measured and recorded at three time points, including 1 week, 1 and 3 months after surgery. There was no significant difference in HL-N, HL-T, HD-N and HD-T at the three time points ( P=0.931, P=0.091, P=0.175, and P=0.505, respectively). All patients underwent uneventful surgery. The postoperative complications included transient corneal edema in 6 eyes, transient IOP elevation in 3 eyes, vitreous hemorrhage in 1 eye, cystoid macular edema in 2 eyes, and macular hole in 1 eye. The SF-PCIOL using modified Yamane's technique, is capable of producing satisfactory and consistent postoperative outcomes for patients with few postoperative complications. SS-OCT is a powerful tool for measuring optic tilt and the IOL hepatic symmetry in scleral tunnel.

Case Report: Tapioca Iris Melanoma: An Uncommon Presentation of an Uncommon Tumor

Iris tumors are rare conditions, and there is a relative paucity of recent published data on its broad clinical spectrum. Tapioca iris melanoma is a rarer yet devastating form with wide and challenging differential diagnoses because of its amelanotic nodular appearance. This study aimed to report the challenging presentation of an uncommon iris melanoma, describing the clinical and histological findings and comparing them with the existing published data. An uncommon clinicopathological report on the tumor unusual localization, patient age, absence of elevated IOP and heterochromia, and negative S-100 stain that caused diagnostic uncertainty is presented. The patient remains free of metastatic disease 7 years after a complete tumor full-thickness excision. Tapioca iris melanomas are uncommon tumors with a presentation/surgical management that differs from other malignant tumors. Ophthalmologists should consider it among the vast differential diagnoses when observing amelanotic lesions, even without the hallmark signs being evident.

Analysis of the effects of finite element type within a 3D biomechanical model of a human optic nerve head and posterior pole

Background and objectiveBiomechanical stresses and strains can be simulated in the optic nerve head (ONH) using the finite element (FE) method, and various element types have been used. This study aims to investigate the effects of element type on the resulting ONH stresses and strains. MethodsA single eye-specific model was constructed using 3D delineations of anatomic surfaces in a high-resolution, fluorescent, 3D reconstruction of a human posterior eye, then meshed using our simple meshing algorithm at various densities using 4- and 10-noded tetrahedral elements, as well as 8- and 20-noded hexahedral elements. A mesh-free approach was used to assign heterogeneous, anisotropic, hyperelastic material properties to the lamina cribrosa, sclera and pia. The models were subjected to elevated IOP of 45 mmHg after pre-stressing from 0 to 10 mmHg, and solved in the open-source FE package Calculix; results were then interpreted in relation to computational time and simulation accuracy, using the quadratic hexahedral model as the reference standard. ResultsThe 10-noded tetrahedral and 20R-noded hexahedral elements exhibited similar scleral canal and laminar deformations, as well as laminar and scleral stress and strain distributions; the quadratic tetrahedral models ran significantly faster than the quadratic hexahedral models. The linear tetrahedral and hexahedral elements were stiffer compared to the quadratic element types, yielding much lower stresses and strains in the lamina cribrosa. ConclusionsPrior studies have shown that 20-noded hexahedral elements yield the most accurate results in complex models. Results show that 10-noded tetrahedral elements yield very similar results to 20-noded hexahedral elements and so they can be used interchangeably, with significantly lower computational time. Linear element types did not yield acceptable results.

Outcomes of sutureless secondary intraocular lens fixation with haptic flanging in a cohort of surgically complex eyes.

To describe clinical outcomes of secondary intraocular lens (IOL) implantation using sutureless trans-scleral techniques in surgically complex eyes. Retrospective surgical case series of 45 eyes that underwent secondary IOL implantation using a sutureless haptic flange technique. Demographic data of age, sex, primary diagnosis, best-corrected visual acuity (BCVA), refractive error, intraocular pressure, full ophthalmic exam findings, surgical approach, and any intraoperative complications were noted. The most common indication for secondary IOL implantation was aphakia, most commonly after ocular trauma. The primary outcome measures were pre-operative and post-operative BCVA, which revealed recovery of pre-operative vision levels by post-operative week 1 and improved vision by post-operative month 1 (p = 0.03). Secondary outcome measures of target refraction pre-operatively and post-operatively revealed significant reduction in post-operative spherical equivalent to achieve BCVA (p < 0.001). Targeting of the secondary IOLs using Barrett Universal II, Holladay 1, Holladay 2, and SRK/T all exhibited a hyperopic shift post-operatively in post-traumatic aphakic eyes and a myopic shift in the post complicated cataract extraction eyes. No intraoperative adverse events were noted. The most common post-operative complication was transient IOP elevation, with most patients completing 6 months of follow-up. There is rapid visual rehabilitation and reduction of spherical equivalent correction to attain BCVA in eyes with a history of ocular trauma that undergo secondary IOL implantation using a trans-scleral flange technique. Moreover, this study highlights that a specific IOL power formula can be more predictive of the desired refractive outcome depending on the indication for secondary IOL implantation.

Physiologic Consequences of Caveolin-1 Ablation in Conventional Outflow Endothelia.

PurposePolymorphisms at the caveolin-1/2 locus are associated with glaucoma and IOP risk and deletion of caveolin-1 (Cav1) in mice elevates IOP and reduces outflow facility. However, the specific location/cell type responsible for Cav1-dependent regulation of IOP is unclear. We hypothesized that endothelial Cav1 in the conventional outflow (CO) pathway regulate IOP via endothelial nitric oxide synthase (eNOS) signaling.MethodsWe created a mouse with targeted deletion of Cav1 in endothelial cells (Cav1ΔEC) and evaluated IOP, outflow facility, outflow pathway distal vascular morphology, eNOS phosphorylation, and tyrosine nitration of iridocorneal angle tissues by Western blotting.ResultsEndothelial deletion of Cav1 resulted in significantly elevated IOP versus wild-type mice but not a concomitant decrease in outflow facility. Endothelial Cav1 deficiency did not alter the trabecular meshwork or Schlemm's canal morphology, suggesting that the effects observed were not due to developmental deformities. Endothelial Cav1 deletion resulted in eNOS hyperactivity, modestly increased protein nitration, and significant enlargement of the drainage vessels distal to Schlemm's canal. L-Nitro-arginine methyl ester treatment reduced outflow in Cav1ΔEC but not wild-type mice and had no effect on the size of drainage vessels. Endothelin-1 treatment decrease the outflow and drainage vessel size in both wild-type and Cav1ΔEC mice.ConclusionsOur results suggest that hyperactive eNOS signaling in the CO pathway of both Cav1ΔEC and global Cav1 knockout mice results in chronic dilation of distal CO vessels and protein nitration, but that Cav1 expression in the trabecular meshwork is sufficient to rescue CO defects reported in global Cav1 knockout mice.

FOXC1 variant in a family with anterior segment dysgenesis and normal-tension glaucoma

Our study describes the glaucoma phenotype in a family with Axenfeld-Rieger syndrome (ARS) and a FOXC1 variant.Included were 20 subjects from a large three generation family of Jewish Indian ancestry. Subjects underwent a comprehensive ophthalmic examination including automated perimetry and optical coherence tomography. Eight subjects were available for molecular analysis which included whole genome sequencing on selected patients and Sanger sequencing for variant screening.Eleven patients demonstrated a wide spectrum of Axenfeld-Rieger anomaly signs and symptoms. These ranged from subtle angle abnormalities to remarkable anterior segment abnormalities such as corectopia, iris adhesions and strands. Among them, six had glaucoma and two were glaucoma suspects. Of the six subjects with glaucoma three had high-tension glaucoma and two had normal-tension glaucoma. Molecular analysis revealed a previously described pathogenic variant in the FOXC1 gene (c.378C > G p.I126M; rs104893958), in six affected patients which was not identified in two healthy siblings. Molecular analysis also revealed a PITX2 missense variant (c.28T > A p.L10M; rs755864040) which did not segregate with clinical findings and was considered likely benign.In conclusion, patients with ARS due to FOXC1 variants may present with glaucomatous optic nerve damage without apparent elevation in IOP. Normal-tension glaucoma is less commonly reported in individuals with ARS and a comprehensive glaucoma assessment may be warranted in these individuals even with normal IOP. These findings raise the possibility that glaucomatous damage associated with FOXC1 is not only due to high IOP.

Herpetic Uveitis – The Masquerader

Although a large proportion of anterior uveitis is noninfectious, viruses are regarded as an important cause of infectious anterior uveitis. Herpes viruses are common infectious causes of hypertensive anterior uveitis. PCR analysis of aqueous sample collected at the slit lamp under aseptic conditions for viral DNA is commonly used technique to confirm the diagnosis during the acute phase. Anterior uveitis may be shortened by the prompt use of therapeutic doses of antiviral therapy and maintenance therapy may be effective in decreasing disease recurrence. In eyes with raised IOP, topical antiglaucoma medications can be given. Eyes with severe elevation of IOP may require oral carbonic anhydrase inhibitors, and filtration surgery may be indicated in medically uncontrolled glaucoma with optic neuropathy.

Incidence, Risk Factors and Treatment Outcomes of Intraocular Hypertension and/or Glaucoma Post-Penetrating Keratoplasty: A 5-Year Lebanese Retrospective Descriptive Study.

PurposeGlaucoma is one of the most common complications post-penetrating keratoplasty (PK). In this study, we report the Incidence, risk factors and treatment outcomes of intraocular hypertension (IOH) or/and glaucoma post-penetrating keratoplasty (PKG).MethodsA 5-year descriptive retrospective study, Lebanese patients who underwent PK at Beirut Eye & ENT Specialist Hospital, between 2012 and 2017, were included. Patients with history of glaucoma were excluded. IOH/PKG cases that necessitate treatment were identified and analyzed for the incidence, risk factors and treatment outcomes.ResultsA total of 189 eyes of 159 patients were included, with male/female ratio 1.6 and the mean age 47.2±21.3 years. Bullous keratopathy (BK) presented with a high mean age: 70.3 years while ectasia patients were the youngest: 36.5 years. 34.9% of eyes developed high IOP within a mean of 25 months of follow-up distributed between sub-groups of patient with corneal ectasia (22.5%), redo-PK (51.2%), bullous keratopathy (BK) (50%), keratitis (24.9%), and others (dystrophy, trauma …) (21.4%). High IOP developed in 67.4% of the diabetic patients. Visual acuity was less likely to improve in cases developing elevated IOP while postoperative complications were significantly high. In those refractory to medical treatment, trabeculectomy as a glaucoma surgery was effective in lowering the IOP. Combining procedures with PK was not a risk factor for glaucoma. Interrupted sutures and higher number of suturing were associated with increased IOP levels.ConclusionIOH developed in one out of three patients who underwent penetrating keratoplasty. DM, bullous keratopathy, infectious keratitis and redo-PK were highly associated with PKG, whereas high IOP was less likely to develop in cases with keratoconus. Glaucoma is considered a poor prognostic factor in patients post-PK.