Sustained Intraocular Pressure Elevation Research Articles

Lycium ruthenicum water extract preserves retinal ganglion cells in chronic ocular hypertension mouse models.

Lycium ruthenicum Murray (LR), known as "black goji berry" or "black wolfberry", is widely utilized in chinese herbal medicine. LR fruit showed its antioxidant and/or anti-inflammation activity in treating cardiac injury, experimental colitis, nonalcoholic fatty liver disease, fatigue, and aging. Glaucoma is the leading cause of irreversible blindness. Besides elevated intraocular pressure (IOP), oxidative stress and neuroinflammation were recognized to contribute to the pathogenesis of glaucoma. This study investigated the treatment effects of LR water extract (LRE) on retinal ganglion cells (RGCs) threatened by sustained IOP elevation in a laser-induced chronic ocular hypertension (COH) mouse model and the DBA/2J mouse strain. The antioxidation and anti-inflammation effects of LRE were further tested in the H2O2-challenged immortalized microglial (IMG) cell line in vitro. LRE oral feeding (2g/kg) preserved the function of RGCs and promoted their survival in both models mimicking glaucoma. LRE decreased 8-hydroxyguanosine (oxidative stress marker) expression in the retina. LRE reduced the number of Iba-1+ microglia in the retina of COH mice, but not in the DBA/2J mice. At the mRNA level, LRE reversed the COH induced HO-1 and SOD-2 overexpressions in the retina of COH mice. Further in vitro study demonstrated that LRE pretreatment to IMG cells could significantly reduce H2O2 induced oxidative stress through upregulation of GPX-4, Prdx-5, HO-1, and SOD-2. Our work demonstrated that daily oral intake of LRE can be used as a preventative/treatment agent to protect RGCs under high IOP stress probably through reducing oxidative stress and inhibiting microglial activation in the retina.

Real-Time Imaging of Single Retinal Cell Apoptosis in a Non-Human Primate Ocular Hypertension Model.

To evaluate the feasibility of using DARC (detection of apoptosing retinal cells) technology as a biomarker for preclinical assessment of glaucomatous damage in a non-human primate (NHP) model of ocular hypertension (OHT). Elevated intraocular pressure (IOP) was induced by applying a laser to the trabecular meshwork in each eye of NHPs. Changes in DARC counts in the retina, identified as fluorescent-tagged annexin V (ANX776)-positive cells, were evaluated together with optic nerve damage, assessed using spectral domain-optical coherence tomography. The pharmacokinetic properties of ANX776 in both healthy and OHT model monkeys were also examined. Sustained elevation of IOP and subsequent thinning of the retinal nerve fiber layer thickness (RNFLT) around the optic nerve head were confirmed in the OHT model. Increases in DARC counts were also detected after IOP elevation. We identified a statistically significant relationship between cumulative DARC counts and reductions in RNFLT both globally and in each peripapillary sector. Intravenous administration of ANX776 increased blood annexin V in a dose-dependent manner, which was subsequently eliminated. This study revealed that DARC technology can effectively assess glaucomatous damage in an NHP OHT model. We obtained the fundamental data that could serve as a reference for developing preclinical models to evaluate the pharmacodynamics of neuroprotective agents using DARC technology in NHP OHT models. Our basic data in a monkey OHT model could be useful for future preclinical studies using DARC technology to estimate the pharmacodynamic response of neuroprotective agents.

Microglial involvement in ocular hypertension

Glaucoma, a chronic and multifactorial neurodegenerative disease, is the leading cause of irreversible blindness. It is characterized by the degeneration of retinal ganglion cells (RGCs), loss of their axons, and damage to the lamina cribrosa. To study glaucomatous optic neuropathy, experimental rodent models are commonly used due to their low cost, ease of handling, and similarities to the human retina. The ideal model must reproduce tissue changes observed in human glaucoma, such as alterations of the optic nerve head, thinning of the retinal nerve fibre layer, activation of glial cells, and progressive degeneration of RGCs.The DBA/2J transgenic mouse model is the most commonly used genetic model, characterized by a gradual increase in intraocular pressure (IOP) with age, leading to rapid and progressive loss of RGCs and optic nerve degeneration. However, limitations such as iris atrophy and peripheral anterior synechiae can alter the anterior segment and influence IOP measurement. Induced models of ocular hypertension (OHT) have a predictable IOP increase following experimental procedures, but this increase is usually rapid and sustained for a relatively short time, which may not represent the slow and sustained IOP elevation observed in primary open‐angle glaucoma. Nonetheless, induced models produce similar pathophysiological mechanisms to genetic models. Other models include the injection of hypertonic saline into episcleral veins to cause scarring of the trabecular meshwork and elevate IOP, and the intracameral injection of polystyrene or magnetic microbeads to obstruct normal drainage flow of aqueous humour, resulting in an IOP increase. A new model employs an intracameral injection of a cross‐linking polymer that produces a viscosity increase, impeding normal drainage of the aqueous humour and resulting in an IOP increase and loss of RGCs.In this SIS, we review the different glaucoma models, their methods, and the retinal tissue changes, with a focus on microglial cell changes.

Exploring the Relationship between Anti-VEGF Therapy and Glaucoma: Implications for Management Strategies.

A short-term increase in intraocular pressure (IOP) is a common side effect after intravitreal anti-VEGF therapy, but a sustained increase in IOP with the development of secondary glaucoma has also been reported in some studies after repeated intravitreal anti-VEGF injections. The aim of this review is to present and discuss the possible pathophysiological mechanisms and factors contributing to a sustained rise in IOP, as well as treatment strategies for patients at risk. Close monitoring and adjustable IOP-lowering treatment are recommended for high-risk patients, including those with glaucoma, angle-closure anomalies, ocular hypertension or family history of glaucoma; patients receiving a high number of injections or at shorter intervals; and patients with capsulotomy. Strategies are needed to identify patients at risk in a timely manner and to prevent sustained elevation of IOP.

Cell-Specific Expression of Human SIRT1 by Gene Therapy Reduces Retinal Ganglion Cell Loss Induced by Elevated Intraocular Pressure.

SIRT1 prevents retinal ganglion cell (RGC) loss in several acute and subacute optic neuropathy models following pharmacologic activation or genetic overexpression. We hypothesized that adeno-associated virus (AAV)-mediated overexpression of SIRT1 in RGCs in a chronic ocular hypertension model can reduce RGC loss, thereby preserving visual function by sustained therapeutic effect. A control vector AAV-eGFP and therapeutic vector AAV-SIRT1 were constructed and optimized for transduction efficiency. A magnetic microbead mouse model of ocular hypertension was optimized to induce a time-dependent and chronic loss of visual function and RGC degeneration. Mice received intravitreal injection of control or therapeutic AAV in which a codon-optimized human SIRT1 expression is driven by a RGC selective promoter. Intraocular pressure (IOP) was measured, and visual function was examined by optokinetic response (OKR) weekly for 49days following microbead injection. Visual function, RGC survival, and axon numbers were compared among control and therapeutic AAV-treated animals. AAV-eGFP and AAV-SIRT1 showed transduction efficiency of ~ 40%. AAV-SIRT1 maintains the transduction of SIRT1 over time and is selectively expressed in RGCs. Intravitreal injections of AAV-SIRT1 in a glaucoma model preserved visual function, increased RGC survival, and reduced axonal degeneration compared with the control construct. Over-expression of SIRT1 through AAV-mediated gene transduction indicates a RGC-selective component of neuroprotection in multiple models of acute optic nerve degeneration. Results here show a neuroprotective effect of RGC-selective gene therapy in a chronic glaucoma model characterized by sustained elevation of IOP and subsequent RGC loss. Results suggest that this strategy may be an effective therapeutic approach for treating glaucoma, and warrants evaluation for the treatment of other chronic neurodegenerative diseases.

Glaucoma de células fantasmas: Caso clínicio

Introduction: Ghost cell glaucoma (GCG) is a very rare secondary open angle glaucoma, in which there is a sustained increase in intraocular pressure (IOP) due to obstruction of the trabecular meshwork (TM) due to the passage of ghost cells (GC) from the vitreous into the anterior chamber, after a vitreous hemorrhage (VH). Clinical Case: We present the case of a male patient with a history of vitreous hemorrhage and sustained IOP elevation in the right eye (RE). Medical treatment was insufficient, for this reason surgical treatment was required. Postoperative evolution was favorable. Conclusion: This pathology should prefer the differential diagnosis of traumatic glaucomas, correlating high clinical suspicion and histological confirmation.

A Novel and Reversible Experimental Primate Ocular Hypertension Model: Blocking Schlemm’s Canal

Introduction: The purpose of this study was to establish a novel and reversible experimental ocular hypertension primate model by blocking Schlemm’s canal. Methods: A model was induced in adult cynomolgus monkeys (n = 4) by blocking Schlemm’s canal with an inserted microcatheter (200 μm diameter); it was removed 6 weeks later from one monkey to reverse the elevated intraocular hypertension. All animals were monitored for 11 months; weekly measurements of intraocular pressure and biweekly examinations with spectral domain optical coherence tomography and disc photography were performed. Histopathology of the eye and retinal ganglion cell counts were completed at the end of the study. Results: The intraocular pressure of the blocked eyes was significantly higher than that of the contralateral eyes at 1 month after the blockage (p < 0.001); the mean intraocular pressure was similar to the contralateral eye from 1 week to 11 months after the microcatheter was removed in monkey A (p = 0.170). The mean intraocular pressure of the blocked eyes of the remaining monkeys was significantly higher than that of the contralateral eyes throughout the follow-up period (p < 0.001). The fundus imaging showed decreases in the retinal nerve fibre layer thickness, and localized defects were observed in two blocked eyes. A histological examination demonstrated that the number of retinal ganglion cells in the blocked eyes of monkeys A, B, and C was significantly decreased compared with the control. Conclusion: Schlemm’s canal blockage alone in the monkey model produces sustained elevation of intraocular pressure, which presents a novel animal model for studying the pathogenesis of glaucoma.

A Novel Mouse Model of TGFβ2-Induced Ocular Hypertension Using Lentiviral Gene Delivery.

Glaucoma is a multifactorial disease leading to irreversible blindness. Primary open-angle glaucoma (POAG) is the most common form and is associated with the elevation of intraocular pressure (IOP). Reduced aqueous humor (AH) outflow due to trabecular meshwork (TM) dysfunction is responsible for IOP elevation in POAG. Extracellular matrix (ECM) accumulation, actin cytoskeletal reorganization, and stiffening of the TM are associated with increased outflow resistance. Transforming growth factor (TGF) β2, a profibrotic cytokine, is known to play an important role in the development of ocular hypertension (OHT) in POAG. An appropriate mouse model is critical in understanding the underlying molecular mechanism of TGFβ2-induced OHT. To achieve this, TM can be targeted with recombinant viral vectors to express a gene of interest. Lentiviruses (LV) are known for their tropism towards TM with stable transgene expression and low immunogenicity. We, therefore, developed a novel mouse model of IOP elevation using LV gene transfer of active human TGFβ2 in the TM. We developed an LV vector-encoding active hTGFβ2C226,228S under the control of a cytomegalovirus (CMV) promoter. Adult C57BL/6J mice were injected intravitreally with LV expressing null or hTGFβ2C226,228S. We observed a significant increase in IOP 3 weeks post-injection compared to control eyes with an average delta change of 3.3 mmHg. IOP stayed elevated up to 7 weeks post-injection, which correlated with a significant drop in the AH outflow facility (40.36%). Increased expression of active TGFβ2 was observed in both AH and anterior segment samples of injected mice. The morphological assessment of the mouse TM region via hematoxylin and eosin (H&E) staining and direct ophthalmoscopy examination revealed no visible signs of inflammation or other ocular abnormalities in the injected eyes. Furthermore, transduction of primary human TM cells with LV_hTGFβ2C226,228S exhibited alterations in actin cytoskeleton structures, including the formation of F-actin stress fibers and crossed-linked actin networks (CLANs), which are signature arrangements of actin cytoskeleton observed in the stiffer fibrotic-like TM. Our study demonstrated a mouse model of sustained IOP elevation via lentiviral gene delivery of active hTGFβ2C226,228S that induces TM dysfunction and outflow resistance.

Age and intraocular pressure in murine experimental glaucoma.

Age and intraocular pressure (IOP) are the two most important risk factors for the development and progression of open-angle glaucoma. While IOP is commonly considered in models of experimental glaucoma (EG), most studies use juvenile or adult animals and seldom older animals which are representative of the human disease. This paper provides a concise review of how retinal ganglion cell (RGC) loss, the hallmark of glaucoma, can be evaluated in EG with a special emphasis on serial in vivo imaging, a parallel approach used in clinical practice. It appraises the suitability of EG models for the purpose of in vivo imaging and argues for the use of models that provide a sustained elevation of IOP, without compromise of the ocular media. In a study with parallel cohorts of adult (3-month-old, equivalent to 20 human years) and old (2-year-old, equivalent to 70 human years) mice, we compare the effects of elevated IOP on serial ganglion cell complex thickness and individual RGC dendritic morphology changes obtained in vivo. We also evaluate how age modulates the impact of elevated IOP on RGC somal and axonal density in histological analysis as well the density of melanopsin RGCs. We discuss the challenges of using old animals and emphasize the potential of single RGC imaging for understanding the pathobiology of RGC loss and evaluating new therapeutic avenues.

A Robust Microbead Occlusion Model of Glaucoma for the Common Marmoset.

PurposeTo establish a robust experimental model of glaucoma in the common marmoset (Callithrix jacchus), a New World primate, using an intracameral microbead injection technique.MethodsElevated intraocular pressure (IOP) was induced by an injection of polystyrene microbeads. Morphologic changes in the retina and optic nerve of glaucomatous eyes were assessed and electroretinogram (ERG) recordings were performed to evaluate functional changes.ResultsMicrobead injections induced a sustained IOP elevation for at least 10 weeks in a reproducible manner. At the end of the 10-week experimental period, there was significant loss of retinal ganglion cells (RGCs) in all quadrants and eccentricities, although it was more prominent in the mid-peripheral and peripheral regions. This was consistent with a thinning of the Retinal nerve fiber layer (RNFL) seen in spectral domain optical coherence tomography scans. Surviving RGCs showed marked changes in morphology, including somatic shrinkage and dendritic atrophy. Retinas also showed significant gliosis. The amplitude of the ERG photopic negative response, with subsequent a- and b-wave changes, was reduced in glaucomatous eyes. The optic nerve of glaucomatous eyes showed expanded cupping, disorganization of the astrocytic matrix, axonal loss, and gliosis.ConclusionsWe developed a robust and reproducible model of glaucoma in the marmoset. The model exhibits both structural and functional alterations of retina and optic nerve characteristic of glaucoma in humans and animal models.Translational RelevanceThe glaucoma model in the marmoset described here forms a robust method to study the disease etiology, progression, and potential therapies in a nonhuman primate, allowing for more effective translation of animal data to humans.

Ocular hypertension and its predictor after a single Ozurdex implant: One-year follow-up in Asian Indian eyes.

To determine the incidence and risk factors for an increase in the intraocular pressure (IOP) after a single dexamethasone intravitreal implant (Ozurdex). Medical records of 41 consecutive eyes who had received a single 0.7 mg Ozurdex implant for the various vitreoretinal pathology, between March 2015 and April 2016 were reviewed retrospectively. Ocular hypertension (OHT) was defined as IOP of >22 mmHg or an increase in the IOP of >6 mmHg from the baseline. Univariate regression analysis was used to measure the predictor of OHT after the implant. Among the 41 eyes, who received a single Ozurdex intravitreal implant, 6/41 (14.6%) of the injected eyes had OHT, with the peak of IOP at 1 month after the injection when compared with the baseline IOP. Eight eyes (19.5%) had preexisting glaucoma or OHT, and 4/8 (50%) of them developed sustained elevation of IOP after the injection. Two eyes had transient OHT, a day after the implant, which did not require any treatment. All the eyes were managed with topical antiglaucoma medications and none required surgery to control the IOP. Preexisting OHT or glaucoma was found to be a significant risk factor for OHT after the Ozurdex injection (P < 0.0001). Patients with preexisting OHT or glaucoma have an increased risk of OHT following the Ozurdex implant and hence needs to be informed of the possible risk. Follow-up at a regular interval is mandatory to monitor and recognize OHT early and treat it appropriately.

Aflibercept clearance through the drainage system in a rat model

BackgroundAs intravitreal anti-VEGF injections became the mainstay of treatment for many retinal diseases, the cause of a secondary sustained elevated intraocular pressure is still unclear. The aim of our study was to study the clearance of Aflibercept from the anterior chamber angle, in a rat model, to test if an aggregation exists.MethodsChoroidal neovascular lesions (CNV) were induced in the right eye of 12 brown Norway rats, using indirect laser ophthalmoscope. Intravitreal Aflibercept injection (0.12 mg/3 µl) was performed 3 days after CNV induction. Rats were euthanized at predetermine time intervals of 3, 6, 24 and 48 h post injection, with immediate enucleation for histological analysis with H&E and immunofluorescence staining. Aflibercept molecules were stained with red fluorescence thanks to the formation of the immune complex Aflibercept-Rabbit anti human IgG-Anti rabbit antibodies-Cy3.ResultsImmediately after the injection, a strong fluorescence signal was detected, indicating the presence of Aflibercept in the iridocorneal angle. At 3- and 6-h interval a strong signal of Aflibercept was still seen. Six hours post injection, the signal was highly concentrated in Schlemm’s canal. In the 2 eyes harvested 24 h post Aflibercept injection, red fluorescence signal intensity was decreased in one eye, occupying mainly intra scleral venous plexuses, and absent in the other eye. At 48 h there was no fluorescence signal, confirming complete clearance of Aflibercept.ConclusionsIn our rat model, a complete clearance of Aflibercept from the anterior chamber angle, was seen 48 h after the injection. This finding refutes the theory of possible connection between IOP elevation and mechanical obstruction. Evacuation time of Aflibercept through the angle is of the same magnitude as that of Bevacizumab in the same rat model.

Long-term effects of intravitreal bevacizumab and aflibercept on intraocular pressure in wet age-related macular degeneration

BackgroundTo evaluate the incidence of sustained elevation of intraocular pressure (SE-IOP) associated with intravitreal injections of anti-vascular endothelial growth factors (anti-VEGF) bevacizumab and aflibercept in patients with wet age-related macular degeneration (wAMD).MethodsA retrospective cohort study consisting of 120 eyes from 120 patients with anti-VEGF treatment for wAMD. Three different anti-VEGF groups were considered: i) 71 cases receiving bevacizumab only, ii) 49 cases receiving bevacizumab before switch to aflibercept, iii) 49 cases after switch to aflibercept. 120 uninjected fellow eyes served as controls. SE-IOP was defined as an increase from baseline ≥5 mmHg on 2 consecutive follow-up visits. The incidence of SE-IOP was analysed using exact Poisson tests and survival analysis. The time course of IOP was evaluated with linear mixed effect modelling.ResultsIn total, 6 treated eyes (2.38% incidence per eye-year) and 9 fellow eyes (3.58% incidence per eye-year) developed SE-IOP, and survival analysis showed no statistically significant difference (p = 0.43). Furthermore, the incidence of SE-IOP did not differ between the three anti-VEGF groups. Comparing the injected eyes of patients under 70 years to those of patients over 70 years, there was a statistically significant difference in survival without SE-IOP (incidence of 16.7% vs 0.7%, respectively, p < 0.0001).ConclusionIntravitreal anti-VEGF injections were not associated with sustained elevation of IOP. These results do not support the claim that repeated anti-VEGF injections could elevate IOP.

Effects of acute stress, general anesthetics, tonometry, and temperature on intraocular pressure in rats

Intraocular pressure (IOP) is important for eye health as abnormal levels can led to ocular tissue damage. IOP is typically estimated by tonometry, which only provides snapshots of pressure history. Tonometry also requires subject cooperation and corneal contact that may influence IOP readings. The aim of this research was to investigate IOP dynamics of conscious animals in response to stressors, common anesthetics, tonometry, and temperature manipulations. An eye of male Brown-Norway rats was implanted with a fluid-filled cannula connected to a wireless telemetry system that records IOP continuously. Stress effects were examined by restricting animal movements. Anesthetic effects were examined by varying isoflurane concentration or injecting a bolus of ketamine. Tonometry effects were examined using applanation and rebound tonometers. Temperature effects were examined by exposing anesthetized and conscious animals to warm or cool surfaces. Telemetry recordings revealed that IOP fluctuates spontaneously by several mmHg, even in idle and anesthetized animals. Environmental disturbances also caused transient IOP fluctuations that were synchronous in recorded animals and could last over a half hour. Animal immobilization produced a rapid sustained elevation of IOP that was blocked by anesthetics, whereas little-to-no IOP change was detected in isoflurane- or ketamine-anesthetized animals if body temperature (BT) was maintained. IOP and BT decreased precipitously when heat support was not provided and were highly correlated during surface temperature manipulations. Surface temperature had no impact on IOP of conscious animals. IOP increased slightly during applanation tonometry but not rebound tonometry. The results show that IOP is dynamically modulated by internal and external factors that can activate rapidly and last long beyond the initiating event. Wireless telemetry indicates that animal interaction induces startle and stress responses that raise IOP. Anesthesia blocks these responses, which allows for better tonometry estimates of resting IOP provided that BT is controlled.

Intraocular Pressure Change and Sustained Intraocular Pressure Elevation After Pars Plana Vitrectomy.

Objectives:The aim of this study was to investigate the incidence and influential factors of changes in intraocular pressure (IOP) and sustained IOP elevation (SIOPE) after an uncomplicated pars plana vitrectomy (PPV).Methods:In all, 41 eyes of 41 patients who underwent PPV due to the presence of epiretinal membrane, macular hole, or vitreomacular traction syndrome were included in the study. In the vitrectomized eye, an elevated IOP of ≥21 mmHg or an increase of ≥6 mmHg from the preoperative IOP on 2 or more postprocedure visits or the addition of a new IOP-lowering medication during follow-up was defined as sustained IOP elevation. The results of procedures performed with a 20-G instrument and a 23-G instrument were compared.Results:The mean postoperative IOP was significantly higher than the preoperative IOP in vitrectomized eyes (preoperative IOP: 15.2±3.1 mmHg; postoperative 1st month: 17.4±5.8 mmHg, p=0.018; 6th month: 17.3±2.6 mmHg, p=0.02; 12th month: 16.7±2.6 mmHg, p=0.020). While no significant difference in IOP was detected between the vitrectomized and fellow eyes preoperatively, the IOP was significantly higher in the vitrectomized eyes in the 1st, 6th, and 12th months (p=0.040, p <0.001, p <0.001, respectively). SIOPE was detected in 15 vitrectomized eyes (37%) and 1 fellow eye (2%). The postoperative first day IOP was significantly lower in the vitrectomized eyes (11.1±6.1 vs 15.4±2mmHg; p<0.001) and significantly lower in the 23-G group than the 20-G group (9.3±5.2 vs 15.7±5.8; p=0.001).Conclusion:IOP may rise significantly in comparison with the fellow eye or the preoperative IOP, even after an uncomplicated PPV. SIOPE and preoperative IOP values should be taken into consideration in addition to cross-sectional IOP findings in the evaluation of PPV.

Tau hyperphosphorylation in the retinal ganglion cells is attenuated upon silencing of SHP2 phosphatase

AbstractBackgroundHuman and animal studies demonstrate that both amyloid precursor protein and phosphorylated Tau which are hallmark proteins associated with Alzheimer’s disease (AD) pathology are perturbed in the retinal tissues. The accumulation of pTau in the retina in addition to the brain tissue suggests eye as a valuable structure for disease diagnosis and to study the disease mechanisms in neurodegenerative disease. Recent studies in human tissues and animal models have established a molecular overlap of AD with glaucoma in the eyes and both the diseases demonstrate altered amyloid beta and Tau phosphorylation profile. We show that Shp2 interacts with Tau protein in retina and silencing this phosphatase in the retinal ganglion cells using AAV2 mediated gene therapy can protect the retina.MethodAnimal model of ocular hypertension was generated by repeat administration of polystyrene beads into the anterior chamber of rat eyes for 8 weeks resulting in sustained elevation of intraocular pressure (20.84±1.65 mmHg). Tau expression changes were investigated both in the animal model and human tissues obtained from the Sydney Eye bank (n=3) using immunohistochemical and WB. Silencing of Shp2 expression in the inner retina was achieved using intravitreal administration of AAV2 constructs under the control of CAG hybrid promoter. The animals were monitored for 2 months after Shp2 silencing and effects on Tau protein expression studied (n=48).ResultIncreased Tau Ser404 phosphorylation was observed in both human glaucoma retinas (p&lt;0.02; student t‐test) and in the animal model of glaucoma (p&lt;0.05) in the WB and immunohistochemical analysis. Shp2 silencing (82±4%) was achieved using AAV2 administration and transduction was monitored using GFP staining. A 7.5±3‐fold downregulation Shp2 expression was achieved using shRNAmir that resulted in significant reduction of pTau Ser404 levels in the inner retina (p&lt;0.028, Bornferroni post‐hoc test) indicating a regulatory effect of the phosphatase on the pTau levels.ConclusionThis study demonstrates that TauSer404 phosphorylation in the retina in vivo is regulated by Shp2 phosphatase. Targeted gene therapy approaches to modulate Shp2 expression can be used as a novel strategy to reduce Tau pathology in the neural tissues in various neurodegenerative disorders.

Autophagy in the Aging and Experimental Ocular Hypertensive Mouse Model.

PurposeTo investigate autophagy in the outflow pathway and ganglion cell layer in the aging and ocular hypertensive mouse.MethodsBoth 4-month-old and 18-month-old C57BL/6J and GFP-LC3 mice were subjected to unilateral injection of hypertonic saline into a limbal vein, causing sclerosis of the outflow pathway and subsequent elevation of intraocular pressure (IOP). IOP was measured on a weekly basis using a rebound tonometer. Protein expression levels of LC3B, Lamp1, and p62 were evaluated by western blot and/or immunofluorescence. Retinal ganglion cell (RGC) count was performed in whole retinal flat mounts using an anti-Brn3a antibody. Optic nerves were fixed with 4% paraformaldehyde and resin-embedded for axon counts and electron microscopy.ResultsIn contrast to 18-month-old mice, which developed sustained elevated IOP with a single injection, 4-month-old mice were refractory to high elevations of IOP. Interestingly, both the percentage of animals that developed elevated IOP and the mean ∆IOP were significantly higher in the transgenic mice compared to C57BL/6J. Immunofluorescence and western blot analysis showed dysregulated autophagy in the iridocorneal and retina tissues from 18-month-old mice compared to 4-month-old ones. Moreover, the LC3-II/LC3-I ratio correlated with IOP. As expected, injected hypertensive eyes displayed axonal degeneration and RGC death. RGC and axon loss were significantly exacerbated with aging, especially when combined with GFP-LC3 expression. Autophagic structures were observed in the degenerating axons.ConclusionsOur results indicate dysregulation of autophagy in the trabecular meshwork and retinal tissues with aging and suggest that such dysregulation of autophagy contributes to neurodegeneration in glaucoma.

Secondary open-angle glaucoma in presumed ocular histoplasmosis syndrome

Purpose: Secondary glaucoma refers to any form of glaucoma in which there is an identifiable cause of increased eye pressure, resulting in optic nerve damage and vision loss. Presumed ocular histoplasmosis syndrome (POHS) is an infection caused by the fungus Histoplasma capsulatum. There are diverse ocular and systemic manifestations of POHS, ranging from influenza-like illness, cavitary lung disease to life threatening dissemination affecting multiple major organ systems. Once considered to be a public health threat mainly to Ohio, Mississippi River valley areas of the United States and South America, this case represents a new epidemiological report. Results: Initial presentation of a young patient to our clinical service revealed several punched-out-chorioretinal lesions evident in the left eye. Secondary glaucoma was diagnosed in the left eye after Avastin injection to treat a choroidal neovascular membrane secondary to histoplasmosis. The patient was treated successfully with a topical simbrinza for the glaucoma. Conclusion: The clinical presentation of histo-spots, peripapillary atrophy, and choroidal neovascularization represents a confirmed triad for POHS. Choroidal neovascular membranes can be a complication of POHS and anti-VEGF is a standard treatment. Certain anti-VEGF injections have been linked to sustained elevated intraocular pressure. From a public health perspective, we can look for POHS in other areas of the world where it is not usually and customarily found as well as monitor patients for prolonged increase in eye pressure after Avastin injection.

Effect of different lens status on intraocular pressure elevation in patients treated with anti-vascular endothelial growth factor injections

To assess the effect of lens status on sustained intraocular pressure (IOP) elevation in patients treated intravitreally with anti-vascular endothelial growth factor (VEGF) agents. Data were retrospectively collected for all patients treated with intravitreal injections of anti-VEGF medication at a tertiary medical center in July 2015. Findings were analyzed by lens status during 6 months' follow-up. The main outcome measure was a sustained increase in IOP (≥21 mm Hg or change of ≥6 mm Hg from baseline on ≥2 consecutive visits, or addition of a new IOP-lowering medication during follow-up). A total of 119 eyes of 100 patients met the study criteria: 40 phakic, 40 pseudophakic, and 39 pseudophakic after Nd:YAG capsulotomy. The rate of sustained IOP elevation was significantly higher in the post-capsulotomy group (23.1%) than in the phakic/pseudophakic groups (8.1%; P=0.032), with no statistically significant differences among the 3 groups in mean number of injections, either total (P=0.82) or by type of anti-VEGF mediation (bevacizumab: P=0.19; ranibizumab: P=0.13), or mean follow-up time (P=0.70). Nd:YAG capsulotomy appears to be a risk factor for sustained IOP elevation in patients receiving intravitreal anti-VEGF injections. This finding has important implications given the growing use of anti-VEGF treatment and the irreversible effects of elevated IOP.

EFFECT OF SERIAL ANTERIOR CHAMBER PARACENTESIS ON SUSTAINED INTRAOCULAR PRESSURE ELEVATION IN PATIENTS RECEIVING INTRAVITREAL ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY.

To investigate the effect of serial anterior chamber (AC) paracenteses in eyes with sustained elevations of intraocular pressure (IOP) in the setting of repeated intravitreal injections (IVI) of anti-vascular endothelial growth factor medications. This is a retrospective records review of patients undergoing IVI of anti-vascular endothelial growth factor medication (bevacizumab, ranubizumab, or aflibercept), who demonstrated a sustained elevation of preinjection IOP and also received AC paracentesis immediately after IVI on at least three consecutive visits. Changes in preinjection IOP and cup-to-disk (C:D) ratio were compared before and after the initiation of IVI and before and after the introduction of AC paracenteses with each subsequent IVI. Twenty-three eyes of 17 patients receiving a median of 26 IVI experienced a rise in preinjection IOP from 16.3 mmHg to 21.1 mmHg (P = 0.004) and an increase in mean C:D ratio from 0.37 to 0.47 (P = 0.0002). After introduction of AC paracenteses (median of 12), mean IOP was returned to baseline 16.00 mmHg (P = 0.002), mean C:D ratio stabilized (0.50, P = 0.197), and maximum IOP decreased from 26.8 mmHg to 23.0 mmHg (P = 0.05). Nineteen (82.6%) eyes required an increase in topical glaucoma medications during the study period, and 13 (56.5%) still required additional therapies after initiation of AC paracenteses. Five eyes (38.5%) required laser or glaucoma drainage device procedures. Serial AC paracenteses reduced immediate postinjection IOP, and along with standard glaucoma care in most patients, reversed preinjection IOP elevation, and stabilized optic nerve changes associated with repeated intravitreal anti-vascular endothelial growth factor injections in a subset of patients with sustained elevation of preinjection IOP.