Elevated IOP Research Articles

Aqueous inflammatory proteasome in open angle glaucoma in Caucasian patients

PurposePrimary open‐angle glaucoma is characterized by loss of retinal ganglion cells and their axons, resulting in optic nerve cupping and visual field loss. Until now, no specific cause was attributed to POAG development, but multiple pathogenic theories have been approached, beside IOP elevation and aging.The aim of this study was to assess the inflammatory and immune dysregulation theory in POAG.MethodsWe included in a cross‐sectional study 40 eyes, from 40 patients: 16 eyes with POAG and 24 eyes from healthy subjects. Aqueous was collected during conventional cataract surgery. 21 inflammatory markers were quantified and compared between groups using a Luminex® Performance Assay multiplex kit based on flowcytometric methods.ResultsMean age in POAG group was 75.69 ± 5.54 years vs 72.33 ± 11.26 years in controls (p = 0.23). Mean IOP in healthy controls was 14.21 ± 2.68 mmHg compared to 18.19 ± 4.3 mmHg in glaucoma patients, controlled by 3 ± 0.87 topical substances. Mean MD level in POAG group was ‐13.59+/‐9.35 dB, whereas PSD mean level was 4.25 ± 4.22dB. Cytokines expression in glaucoma patients compared to healthy controls was found significantly different for CXCL5 (p = 0.008), CXCL8 (p = 0.048), IL‐1α (p = 0.005), IL‐2 (p = 0.015) and TNFα (p = 0.041). Therefore, a prediction statistical model for these cytokines was created. All markers point out a common inflammatory pathway that triggeres TNFα release. A mathematical model proved that CXCL5, CXCL8, IL‐1α and IL‐2 can accurately predict TNFα level in this study (r square = 0.842, p = 0.000).ConclusionsOur results show that in POAG patients there is an increased production of inflammatory cytokines in aquoeous humor. Moreover our statistical predictions point out TNFα molecule and its signalling pathways as the determinant pathogenic pathway involved in the inflammatory compound of POAG caucasian patients.

To evaluate the effects of Nd:YAG laser posterior capsulotomy on best corrected visual acuity (bcva) and intraocular pressure

Background: Nd:YAG laser is non-invasive and effective means to deal with the posterior capsule opacification.However safe it may have some inherent complications. Rise of intraocular pressure is frequently encountered and incompletely understood complication of YAG laser capsulotomy and documented with conflicting results.Aims and Objective: To assess the efficacy of Nd: YAG laser capsulotomy in term of visual outcome(Best Corrected Visual Acuity) and also study the changes in IOP after the procedure.Materials and Methods: Study evaluated the changes in IOP and visual acuity after Nd-YAG laser capsulotomy in 100 eyes with significant PCO after uncomplicated cataract surgery with IOL implantation. Complete ocular examination including visual acuity, anterior segment examination with slit lamp, fundus and applanation tonometry were performed pre and post-laser in all cases. Posterior capsulotomy was done with VISULAS YAG III Q-switched Nd: YAG laser machine by ZEISS. IOP was recorded before and then at 1hour, 1 Day, 1 week and 1 month post-laser in order to determine the IOP changes.Results: Pre-laser visual acuity ranged from 1/60 to 6/12. Results showed statistically significant improvement in BCVA with 70% patients had BCVA 6/6, 21% had BCVA 6/9 and 8% having BCVA 6/12 post-laser at 1 month. It was observed that 36% of the patients showed no change in IOP while 64% patients showed elevated IOP. Among these 59% patients show rise in IOP that was ≤5 mm Hg while only 5% of the patients had a rise of more than IOP >5 mm Hg. Most of these patients achieved their baseline IOP within 1 day and only 7 % patient had rise in IOP compared to baseline IOP on day 1. None of the patients show elevated IOP after 1 week.Conclusion: Our study showed that Nd: YAG laser posterior capsulotomy provided excellent results in terms of visual improvement and most of the patients had a rise of <5mm Hg which was transient in nature and routine antiglaucoma medication may not be needed in all the patient undergoing Nd;Yag capsulotomy, however caution should be exercised in glaucomatous, aphakic, high myopic and other high risk patients.Asian Journal of Medical Sciences Vol.8(5) 2017 93-97

Magnetic Resonance Imaging of Optic Nerve Traction During Adduction in Primary Open-Angle Glaucoma With Normal Intraocular Pressure.

PurposeWe used magnetic resonance imaging (MRI) to ascertain effects of optic nerve (ON) traction in adduction, a phenomenon proposed as neuropathic in primary open-angle glaucoma (POAG).MethodsSeventeen patients with POAG and maximal IOP ≤ 20 mm Hg, and 31 controls underwent MRI in central gaze and 20° to 30° abduction and adduction. Optic nerve and sheath area centroids permitted computation of midorbital lengths versus minimum paths.ResultsAverage mean deviation (±SEM) was −8.2 ± 1.2 dB in the 15 patients with POAG having interpretable perimetry. In central gaze, ON path length in POAG was significantly more redundant (104.5 ± 0.4% of geometric minimum) than in controls (102.9 ± 0.4%, P = 2.96 × 10−4). In both groups the ON became significantly straighter in adduction (28.6 ± 0.8° in POAG, 26.8 ± 1.1° in controls) than central gaze and abduction. In adduction, the ON in POAG straightened to 102.0% ± 0.2% of minimum path length versus 104.5% ± 0.4% in central gaze (P = 5.7 × 10−7), compared with controls who straightened to 101.6% ± 0.1% from 102.9% ± 0.3% in central gaze (P = 8.7 × 10−6); and globes retracted 0.73 ± 0.09 mm in POAG, but only 0.07 ± 0.08 mm in controls (P = 8.8 × 10−7). Both effects were confirmed in age-matched controls, and remained significant after correction for significant effects of age and axial globe length (P = 0.005).ConclusionsAlthough tethering and elongation of ON and sheath are normal in adduction, adduction is associated with abnormally great globe retraction in POAG without elevated IOP. Traction in adduction may cause mechanical overloading of the ON head and peripapillary sclera, thus contributing to or resulting from the optic neuropathy of glaucoma independent of IOP.

Establishment and Characterization of an Acute Model of Ocular Hypertension by Laser-Induced Occlusion of Episcleral Veins.

PurposeThis study was designed to develop and characterize a laser-induced model of acute intraocular hypertension that permits the study of the anterior segment of the eye.MethodsCD1 mice aged 5 and 8 weeks were examined for elevation of IOP induced by laser photocoagulation. We compared between occlusion of episcleral veins alone and when combined with 270° limbal vessel occlusion. Anterior chamber angle, corneal thickness, and retinal nerve fiber layer (RNFL) thickness were evaluated by anterior- and posterior-segment optical coherence tomography (OCT). Additionally, at day 7 post-procedure, the anterior segment was evaluated for inflammatory cellular presentation by histologic analysis and OCT, and limbal vessels and whole-mount retina were immunostained for CD31 and Brn3a, respectively. Brn3a-positive retinal ganglion cells (RGCs) were quantified with ImageJ software.ResultsAfter single or combined laser treatment in mice aged 5 or 8 weeks, IOP was significantly elevated for 5 to 6 days before returning to the baseline by day 7 post-procedure. Anterior segment assessment indicated less synechiae in the anterior chamber angle and better preserved limbal vessels with single versus combined laser treatment. Corneal thickness was significantly increased after single or combined treatment. No inflammatory cells were detected in the anterior chamber. The thickness of the RNFL and the density of RGCs were both significantly reduced after single or combined treatment.ConclusionsLaser photocoagulation of episcleral veins alone in CD1 mice aged 5 to 8 weeks may be used to induce ocular hypertension resulting in RNFL thinning and ganglion cell loss. This model permits the study of the anterior as well as the posterior segment of the eye.

Non-steroidal anti-inflammatory drugs versus corticosteroids for controlling inflammation after uncomplicated cataract surgery.

Non-steroidal anti-inflammatory drugs versus corticosteroids for controlling inflammation after uncomplicated cataract surgery.

Near infra-red light attenuates corneal endothelial cell dysfunction in situ and in vitro

In the present study mechanical damage to the corneal endothelium was induced by elevation of intraocular pressure (IOP, 140 mmHg, 60 min) to one eye of rats, delivered either in complete darkness or in the presence of red light (16.5 W/m2, 3000 lx, 625–635 nm). IOP raised in the dark revealed the endothelium to be damaged as staining for the gap junction protein ZO-1 was irregular in appearance with some cells displaced in position or lost to leave gaps or holes. This damage was clearly attenuated when red light was focused through the pupil during the insult of raised IOP. Moreover, staining of endothelium with JC-1 dye showed mitochondria to be activated by both elevated IOP and red light but the activation of mitochondria persisted longer for red light. We interpret this finding to suggest that raised IOP causes apoptosis of endothelial cells and that their mitochondria are activated in the initial stages of the process. In contrast, red light activates mitochondria to induce a protective mechanism to counteract the negative influence of raised IOP on endothelial cells. Evidence is provided to support this notion by the finding that red light stimulates mitochondrial cytochrome oxidase IV (COX IV). Moreover, mitochondria in corneal endothelial cell cultures are activated by red light, revealed by staining with JC-1, that results in an increased rate of proliferation and are also able to counteract toxic insults (sodium azide or cobalt chloride) to the cultures.The present studies therefore show that a non-toxic level of red light attenuates damage to the corneal endothelium both in situ and in vitro through action on COX IV located in mitochondria that results in an enhancement of a cell's survival mechanisms. The study provides proof of principle for the non-invasive use of red-light therapy to attenuate any dysfunctions associated with the corneal endothelium and so preserve maximum visual acuity.

Interleukin-6 Deficiency Attenuates Retinal Ganglion Cell Axonopathy and Glaucoma-Related Vision Loss.

The pleotropic cytokine interleukin-6 (IL-6) is implicated in retinal ganglion cell (RGC) survival and degeneration, including that associated with glaucoma. IL-6 protects RGCs from pressure-induced apoptosis in vitro. However, it is unknown how IL-6 impacts glaucomatous degeneration in vivo. To study how IL-6 influences glaucomatous RGC axonopathy, accompanying glial reactivity, and resultant deficits in visual function, we performed neural tracing, histological, and neurobehavioral assessments in wildtype (B6;129SF2/J; WT) and IL-6 knock-out mice (B6;129S2-IL6tm1kopf/J; IL-6-/-) after 8 weeks of unilateral or bilateral microbead-induced glaucoma (microbead occlusion model). IOP increased by 20% following microbead injection in both genotypes (p < 0.05). However, deficits in wound healing at the site of corneal injection were noted. In WT mice, elevated IOP produced degenerating axon profiles and decreased axon density in the optic nerve by 15% (p < 0.01). In IL-6-/- mice, axon density in the optic nerve did not differ between microbead- and saline-injected mice (p > 0.05) and degenerating axon profiles were minimal. Preservation of RGC axons was reflected in visual function, where visual acuity decreased significantly in a time-dependent manner with microbead-induced IOP elevation in WT (p < 0.001), but not IL-6-/- mice (p > 0.05). Despite this preservation of RGC axons and visual acuity, both microbead-injected WT and IL-6-/- mice exhibited a 50% decrease in anterograde CTB transport to the superior colliculus, as compared to saline-injected controls (p < 0.01). Assessment of glial reactivity revealed no genotype- or IOP-dependent changes in retinal astrocytes. IOP elevation decreased microglia density and percent retinal area covered in WT mice (p < 0.05), while IL-6-/- mice exhibited only a decrease in density (p < 0.05). Together, our findings indicate that two defining features of RGC axonopathy—axon transport deficits and structural degeneration of axons—likely occur via independent mechanisms. Our data suggest that IL-6 is part of a mechanism that specifically leads to structural degeneration of axons. Furthermore, its absence is sufficient to prevent both structural degeneration of the optic nerve and vision loss. Overall, our work supports the proposition that functional deficits in axon transport represent a therapeutic window for RGC axonopathy and identify IL-6 signaling as a strong target for such a therapeutic.

Regional Retinal Ganglion Cell Axon Loss in a Murine Glaucoma Model.

PurposeTo determine if retinal ganglion cell (RGC) axon loss in experimental mouse glaucoma is uniform in the optic nerve.MethodsExperimental glaucoma was induced for 6 weeks with a microbead injection model in CD1 (n = 78) and C57BL/6 (B6, n = 68) mice. From epoxy-embedded sections of optic nerve 1 to 2 mm posterior to the globe, total nerve area and regional axon density (axons/1600 μm2) were measured in superior, inferior, nasal, and temporal zones.ResultsControl eyes of CD1 mice have higher axon density and more total RGCs than control B6 mice eyes. There were no significant differences in control regional axon density in all mice or by strain (all P > 0.2, mixed model). Exposure to elevated IOP caused loss of RGC in both strains. In CD1 mice, axon density declined without significant loss of nerve area, while B6 mice had less density loss, but greater decrease in nerve area. Axon density loss in glaucoma eyes was not significantly greater in any region in either mouse strain (both P > 0.2, mixed model). In moderately damaged CD1 glaucoma eyes, and CD1 eyes with the greatest IOP elevation exposure, density loss differed by region (P = 0.05, P = 0.03, mixed model) with the greatest loss in the temporal and superior regions, while in severely injured B6 nerves superior loss was greater than inferior loss (P = 0.01, mixed model, Bonferroni corrected).ConclusionsThere was selectively greater loss of superior and temporal optic nerve axons of RGCs in mouse glaucoma at certain stages of damage. Differences in nerve area change suggest non-RGC responses differ between mouse strains.

Secondary Sulcus-Fixed Foldable IOL Implantation with 25-G Infusion in Patients with Previous PPV after Open-Globe Injury.

PurposeTo evaluate the safety and efficacy of secondary sulcus-fixed foldable intraocular lens (IOL) implantation through a clear corneal incision with 25-G infusion in patients with previous pars plana vitrectomy (PPV) after open-globe injury, and to analyze postoperative outcomes and prognostic factors of treatment.MethodsClinical data of 89 eyes of 89 patients with open-globe injury who underwent secondary sulcus-fixed foldable IOL implantation through a clear corneal incision with 25-G infusion after vitrectomy in our hospital between January 2008 and June 2015 were retrospectively analyzed. The examinations before IOL implantation mainly included visual acuity, slit-lamp examination, direct and indirect ophthalmoscope, visual electrophysiology, corneal endothelium, B scan, ultrasound biomicroscope, and intraocular pressure. Five eyes underwent suturing of peripheral iris and 7 eyes underwent suturing of iris laceration simultaneously. The mean follow-up was 18 months with a range from 6 months to 8 years.ResultsThe mean interval between secondary sulcus-fixed foldable IOL implantation and vitrectomy was 2.8 months with a range from 2 to 6 months. The uncorrected visual acuity improved in all patients with a well-centered IOL ranging from 0.1 to 0.8 with the best-corrected visual acuity from 0.1 to 1.0 after secondary IOL implantation. The postoperative complications mainly included mild anterior chamber exudates in 10 eyes (11%), temporary IOP elevation in 12 eyes (13%), and recurrent retinal detachment in 5 eyes (6%), which were subsequently managed by surgery.ConclusionsThe interval of 2.8 months between vitrectomy and secondary IOL implantation is an appropriate and safe option to correct aphakia in patients receiving vitrectomy for open-globe injury.

Elevated Intraocular Pressure Induces Cellular Responses in the Retinal Capillaries

Background In the early diagnosis of clinical glaucoma, peripapillary bleedings were almost pathognomonic for a capillary insult. In the perfusion diagnostics, it is predominantly accepted that perfusion imbalances and IOP-induced changes occur and play a crucial role. Biomechanical peculiarities of the optic nerve head and cellular responses to astrocytes are also likely involved. Material and Methods We present in vivo and ex vivo models of IOP-elevation to enhance the resolution of examining cellular and molecular changes and to understand the mechanisms of capillary changes due to IOP-elevation. Results The in vivo model consists of cauterization-caused elevation of IOP in rat eyes. Two to 3 veins were cauterized to increase outflow resistance. The retinas were analyzed several weeks later and we found an abnormal expression of the neuron-specific molecule beta-III-tubulin in the capillary endothelium cells and in the vascular pericytes. Combined immunohistochemical stainings with different markers for various retinal cells confirmed the findings. The isolation of capillary endothelium cells and pericytes from rat brains (BMECs) and retinas (RMECs), and their cultivation under elevated IOP in vitro, confirmed the in vivo results. Conclusion The unexpected capillary response to elevation of IOP in vivo and in vitro could be seen as an early response of cells with expression of abnormal proteins. This result may explain clinical observations which dominate as peripapillary bleedings or microinfarctions and are likely associated with the glaucoma-induced opticopathy.

European Glaucoma Society Terminology and Guidelines for Glaucoma, 4th Edition - Chapter 2: Classification and terminologySupported by the EGS Foundation

### 2.1 - Primary Congenital Forms/Childhood Glaucomas Primary congenital glaucoma is a rare disease but has a major impact on the child’s development and quality of life over his/her whole...

Intravitreal injection of β-crystallin B2 improves retinal ganglion cell survival in an experimental animal model of glaucoma.

Purpose of this study was to investigate firstly specific proteomic changes within the retina in the course of an animal glaucoma model and to identify secondly new approaches for neuroprotective, therapeutic options in glaucoma by addressing those specific changes. Intraocular pressure was elevated through cauterization of episcleral veins in adult Sprague Dawley rats. Molecular and morphological changes were surveyed using mass spectrometry, optical coherence tomography as well as immunohistochemical cross section- and flat mount stainings. By quantifying more than 1500 retinal proteins, it was found that the HspB5 protein and numerous beta-crystallins showed a uniform and unique shifting expression pattern as a result of different periods of elevated IOP exposure. Crystallins showed a significant downregulation (p<0.05) after 3 weeks of elevated IOP and an upregulation after 7 weeks. Counteracting those typical changes, an intravitreal injection of β-crystallin B2 at the time of IOP elevation was found to reduce retinal ganglion cell loss (p<0.05), decrease of the retinal nerve fiber layer (p<0.05) and impairment of the optic nerve. Ultimately, proteomic data revealed that β-crystallin B2 might influence calcium-depended cell signaling pathways with severe effect on apoptosis and gene regulation. In this context especially annexin A5, calcium-transporting ATPase 1 and various histone proteins seem to play a major role.

Comparing three different modes of electroretinography in experimental glaucoma: diagnostic performance and correlation to structure.

To compare diagnostic performance and structure-function correlations of multifocal electroretinogram (mfERG), full-field flash ERG (ff-ERG) photopic negative response (PhNR) and transient pattern-reversal ERG (PERG) in a non-human primate (NHP) model of experimental glaucoma (EG). At baseline and after induction of chronic unilateral IOP elevation, 43 NHP had alternating weekly recordings of retinal nerve fiber layer thickness (RNFLT) by spectral domain OCT (Spectralis) and retinal function by mfERG (7F slow-sequence stimulus, VERIS), ff-ERG (red 0.42 log cd-s/m2 flashes on blue 30 scotopic cd/m2 background, LKC UTAS-E3000), and PERG (0.8° checks, 99% contrast, 100cd/m2 mean, 5reversals/s, VERIS). All NHP were followed at least until HRT-confirmed optic nerve head posterior deformation, most to later stages. mfERG responses were filtered into low- and high-frequency components (LFC, HFC, >75Hz). Peak-to-trough amplitudes of LFC features (N1, P1, N2) and HFC RMS amplitudes were measured and ratios calculated for HFC:P1 and N2:P1. ff-ERG parameters included A-wave (at 10ms), B-wave (trough-to-peak) and PhNR (baseline-to-trough) amplitudes as well as PhNR:B-wave ratio. PERG parameters included P50 and N95 amplitudes as well as N95:P50 ratio and N95 slope. Diagnostic performance of retinal function parameters was compared using the area under the receiver operating characteristic curve (A-ROC) to discriminate between EG and control eyes. Correlations to RNFLT were compared using Steiger's test. Study duration was 15±8months. At final follow-up, structural damage in EG eyes measured by RNFLT ranged from 9% above baseline (BL) to 58% below BL; 29/43 EG eyes (67%) and 0/43 of the fellow control eyes exhibited significant (>7%) loss of RNFLT from BL. Using raw parameter values, the largest A-ROC findings for mfERG were: HFC (0.82) and HFC:P1 (0.90); for ff-ERG: PhNR (0.90) and PhNR:B-wave (0.88) and for PERG: P50 (0.64) and N95 (0.61). A-ROC increased when data were expressed as % change from BL, but the pattern of results persisted. At 95% specificity, the diagnostic sensitivity of mfERG HFC:P1 ratio was best, followed by PhNR and PERG. The correlation to RNFLT was stronger for mfERG HFC (R=0.65) than for PhNR (R=0.59) or PERG N95 (R=0.36), (p=0.20, p=0.0006, respectively). The PhNR flagged a few EG eyes at the final time point that had not been flagged by mfERG HFC or PERG. Diagnostic performance and structure-function correlation were strongest for mfERG HFC as compared with ff-ERG PhNR or PERG in NHP EG.

Levels of cytokines in the aqueous humor of eyes with primary open angle glaucoma, pseudoexfoliation glaucoma and cataract.

ObjectiveThe focus of this study aimed at measuring multiple inflammatory cytokines levels in the aqueous humor of patients with primary open angle glaucoma (POAG), pseudoexfoliation glaucoma (PEXG) and senile cataract.MethodsThis case control study was conducted at the Research Institute of Ophthalmology, Giza, Egypt in 2016. Aqueous humor (AH) samples were withdrawn from 50 patients (30 POAG, and 20 PEXG) and from 15 patients with senile cataract serving as controls. The levels of IL6, IL8, transforming growth factor β1 (TGFβ1), tumor necrosis growth factor α (TNFα) and serum amyloid A (SAA) were analyzed by ELISA immune-assay. Data were analyzed by SPSS 10, using Pearson Product-Moment Correlation and independent-samples t-test.ResultsThe levels of IL8, TGFβ1, TNFα and SAA were significantly higher in POAG and PEXG patients, compared to senile cataract patients. While the levels of IL6, were significantly decreased in both groups of glaucoma patients compared to cataract patients. Significant positive correlations were detected between IL6, IL 8 & TGF β1, IL 8; SAA, IL8 & TGFβ1, SAA in the aqueous humor of different groups.ConclusionThus the assayed cytokines including TGFβ1, TNFα, IL8 and SAA in aqueous humor, play a vital role in IOP elevations in patients with POAG and PEXG.

Role of ID Proteins in BMP4 Inhibition of Profibrotic Effects of TGF-β2 in Human TM Cells

PurposeIncreased expression of TGF-β2 in primary open-angle glaucoma (POAG) aqueous humor (AH) and trabecular meshwork (TM) causes deposition of extracellular matrix (ECM) in the TM and elevated IOP. Bone morphogenetic proteins (BMPs) regulate TGF-β2–induced ECM production. The underlying mechanism for BMP4 inhibition of TGF-β2–induced fibrosis remains undetermined. Bone morphogenic protein 4 induces inhibitor of DNA binding proteins (ID1, ID3), which suppress transcription factor activities to regulate gene expression. Our study will determine whether ID1and ID3 proteins are downstream targets of BMP4, which attenuates TGF-β2 induction of ECM proteins in TM cells.MethodsPrimary human TM cells were treated with BMP4, and ID1 and ID3 mRNA, and protein expression was determined by quantitative PCR (Q-PCR) and Western immunoblotting. Intracellular ID1 and ID3 protein localization was studied by immunocytochemistry. Transformed human TM cells (GTM3 cells) were transfected with ID1 or ID3 expression vectors to determine their potential inhibitory effects on TGF-β2–induced fibronectin and plasminogen activator inhibitor-I (PAI-1) protein expression.ResultsBasal expression of ID1-3 was detected in primary human TM cells. Bone morphogenic protein 4 significantly induced early expression of ID1 and ID3 mRNA (P < 0.05) and protein in primary TM cells, and a BMP receptor inhibitor blocked this induction. Overexpression of ID1 and ID3 significantly inhibited TGF-β2–induced expression of fibronectin and PAI-1 in TM cells (P < 0.01).ConclusionsBone morphogenic protein 4 induced ID1 and ID3 expression suppresses TGF-β2 profibrotic activity in human TM cells. In the future, targeting specific regulators may control the TGF-β2 profibrotic effects on the TM, leading to disease modifying IOP lowering therapies.

Longitudinal Cohort Study on the Incidence of Primary Open-Angle Glaucoma in Bai Chinese

The prevalence of primary open-angle glaucoma (POAG) in China has been reported previously, and was lower than that in white and black populations. However, the incidence of POAG in China has not been reported. Therefore, a longitudinal study was conducted to determine the 5-year cumulative incidence and predictors of POAG in China. Population-based cohort study. A total of 1520 participants (71.3% of the subjects in the baseline survey) of Bai ethnicity were examined and followed for 5 years. Glaucoma was defined based on the International Society of Geographical and Epidemiological Ophthalmology Classification criteria. Multivariable logistic regression models were fitted to calculate oddsratios (ORs) and 95% confidence intervals (95%CIs). A total of 19 new cases of POAG were detected. The 5-year cumulative incidence of POAG was 1.3% (95% CI, 0.7-1.9). In multivariate analyses, incident POAG was associated with baseline variables including increased age (OR, 4.3; 95% CI, 1.4-13.8; P= .02; 70 years or older vs 50-59 years), elevated IOP (OR, 3.5; 95% CI, 2.0-5.9; P < .001; per 10mm Hg increase), lower education level (OR, 0.3; 95% CI, 0.1-0.8; P= .02; post-primary education vs no formal education), and the presence of myopia (OR, 3.4; 95% CI, 1.3-8.6; P < .01). The average annual incidence of POAG in Bai Chinese was lower than that in populations of African descent and white race. The results are important to elucidate the racial/ethnic difference in POAG incidence and for the clinical management and health resource allocation in China.

New Developments in Cataract Surgery

Recent technological innovations in cataract surgery have made the procedure even more precise and safe and the odds of having a highly satisfied patient even higher. These innovations include visualisation systems - such as intraoperative aberrometry - which are particularly helpful when it comes to implanting toric IOLs, where even a slight rotation or misalignment can significantly reduce the postoperative visual quality. Another way to ensure the exact positioning of a toric IOL is to create a mark by making an intrastromal incision using the femtosecond laser. The latter technology has increased the precision of capsulotomy and other steps of the operation and has been successfully employed in patients with a challenging clinical profile, including paediatric and hypermature cataracts. The femtosecond laser, however, induces an increase in intraocular prostaglandins, which can lead to miosis. Applying topical NSAIDs before starting surgery has proved to be effective in coping with the consequences of the increase in prostaglandins. Good vision without using glasses for near, intermediate and far distances remains a goal for many patients. IOLs with extended depths of focus (EDOF) technology can provide this comfort - to some but not all patients. An intraocular sensor, Eyemate, that is implanted during cataract surgery, enables the glaucoma patient to check his or her IOP at any time and improves the management of glaucoma and its main risk factor, elevated IOP. Several methods - drugs or nutritive agents - are said to prevent cataractogenesis. These studies have probably to be taken with the proverbial grain of salt.

Simultaneous dexamethasone intravitreal implant and anti-VEGF therapy for neovascular age-related macular degeneration resistant to anti-VEGF monotherapy.

To evaluate the efficacy of a dexamethasone intravitreal implant in combination with intravitreal anti-VEGF agents for treatment resistant neovascular age-related macular degeneration (nvAMD). This study was designed as a single-center, retrospective interventional case series. Consecutive patients with treatment-resistant nvAMD underwent simultaneous combined injection of anti-VEGF agent and dexamethasone intravitreal implant. Eighteen patients with mean age of 81.5 years were included. Patients received average of 26.3 anti-VEGF injections before dual therapy, with mean follow up of 8.2 months after dual therapy. Dual therapy produced a significant mean decrease in CFT (126.3 μm), compared to a mean increase of 29.9 μm when treated with anti-VEGF monotherapy (p=0.0017). Patients also had mean decrease in MCV of -0.85 mm3 with dual therapy compared with anti-VEGF monotherapy (p=0.0014). There was a moderate correlation between the number of prior anti-VEGF injections and the magnitude of anatomic response, suggesting that shorter disease duration may positively influence response to combined treatment. Although there was a slight trend towards improved mean visual acuity after dual therapy, these differences did not reach statistical significance. Nevertheless, with combination treatment, 33% of patients gained one or more lines of vision. Dual therapy resulted in a significantly lower number of required anti-VEGF injections (4.25 vs 5.33) and an increase of the anti-VEGF injection-free interval to 1.41 months from 1.12 months during the 6 months following dual therapy compared to the same interval before dual therapy. Dual therapy was well tolerated; two eyes developed mild IOP elevation effectively managed with topical therapy and one patient developed worsening cataract. Combined treatment of anti-VEGF with the dexamethasone intravitreal implant is a viable alternative for treatment-resistant nvAMD, and may reduce treatment burden. Earlier treatment with dual therapy may be beneficial to maximize anatomic and visual outcomes in these patients.

A Period of Controlled Elevation of IOP (CEI) Produces the Specific Gene Expression Responses and Focal Injury Pattern of Experimental Rat Glaucoma.

PurposeWe determine if several hours of controlled elevation of IOP (CEI) will produce the optic nerve head (ONH) gene expression changes and optic nerve (ON) damage pattern associated with early experimental glaucoma in rats.MethodsThe anterior chambers of anesthetized rats were cannulated and connected to a reservoir to elevate IOP. Physiologic parameters were monitored. Following CEI at various recovery times, ON cross-sections were graded for axonal injury. Anterior ONHs were collected at 0 hours to 10 days following CEI and RNA extracted for quantitative PCR measurement of selected messages. The functional impact of CEI was assessed by electroretinography (ERG).ResultsDuring CEI, mean arterial pressure (99 ± 6 mm Hg) and other physiologic parameters remained stable. An 8-hour CEI at 60 mm Hg produced significant focal axonal degeneration 10 days after exposure, with superior lesions in 83% of ON. Message analysis in CEI ONH demonstrated expression responses previously identified in minimally injured ONH following chronic IOP elevation, as well as their sequential patterns. Anesthesia with cannulation at 20 mm Hg did not alter these message levels. Electroretinographic A- and B-waves, following a significant reduction at 2 days after CEI, were fully recovered at 2 weeks, while peak scotopic threshold response (pSTR) remained mildly but significantly depressed.ConclusionsA single CEI reproduces ONH message changes and patterns of ON injury previously observed with chronic IOP elevation. Controlled elevation of IOP can allow detailed determination of ONH cellular and functional responses to an injurious IOP insult and provide a platform for developing future therapeutic interventions.

Expression of Mutant Myocilin Induces Abnormal Intracellular Accumulation of Selected Extracellular Matrix Proteins in the Trabecular Meshwork.

PurposeAbnormal accumulation of extracellular matrix (ECM) in the trabecular meshwork (TM) is associated with decreased aqueous humor outflow facility and IOP elevation in POAG. Previously, we have developed a transgenic mouse model of POAG (Tg-MYOCY437H) by expressing human mutant myocilin (MYOC), a known genetic cause of POAG. The purpose of this study is to examine whether expression of mutant myocilin leads to reduced outflow facility and abnormal ECM accumulation in Tg-MYOCY437H mice and in cultured human TM cells.MethodsConscious IOP was measured at various ages of Tg-MYOCY437H mice using a rebound tonometer. Outflow facility was measured in 10-month-old Tg-MYOCY437H mice. Selected ECM proteins were examined in human TM-3 cells stably expressing mutant myocilin and primary human TM cells (n = 4) as well as in the TM of Tg-MYOCY437H mice by real-time PCR, Western blotting, and immunostaining. Furthermore, TM cells expressing WT or mutant myocilin were treated with 5 mM sodium 4-phenylbutyrate (PBA), and ECM proteins were examined by Western blot and immunostaining.ResultsStarting from 3 months of age, Tg-MYOCY437H mice exhibited significant IOP elevation compared with wild-type (WT) littermates. Outflow facility was significantly reduced in Tg-MYOCY437H mice (0.0195 μl/min/mm Hg in Tg-MYOCY437H vs. 0.0332 μl/min/mm Hg in WT littermates). Increased accumulation of fibronectin, elastin, and collagen type IV and I was observed in the TM of Tg-MYOCY437H mice compared with WT littermates. Furthermore, increased ECM proteins were also associated with induction of endoplasmic reticulum (ER) stress markers, GRP78 and CHOP in the TM of Tg-MYOCY437H mice. Human TM-3 cells stably expressing DsRed-tagged Y437H mutant MYOC exhibited inhibition of myocilin secretion and its intracellular accumulation compared with TM cells expressing WT MYOC. Expression of mutant MYOC in TM-3 cells or human primary TM cells induced ER stress and also increased intracellular protein levels of fibronectin, elastin, laminin, and collagen IV and I. In addition, TM-3 cells expressing mutant myocilin exhibited reduced active forms of matrix metalloproteinase (MMP)-2 and MMP-9 in conditioned medium compared with TM-3 cells expressing WT myocilin. Interestingly, both intracellularly accumulated fibronectin and collagen I colocalized with mutant myocilin and also with ER marker KDEL further suggesting intracellular accumulation of these proteins in the ER of TM cells. Furthermore, reduction of ER stress via PBA decreased selected ECM proteins in primary TM cells.ConclusionsThese studies demonstrate that mutant myocilin induces abnormal ECM accumulation in the ER of TM cells, which may be responsible for reduced outflow facility and IOP elevation in myocilin-associated glaucoma.