Elevated Increased Intraocular Pressure Research Articles

Retinal Neurodegeneration in an Intraocular Pressure Fluctuation Rat Model.

Increased intraocular pressure (IOP) is the most important risk factor for glaucoma. The role of IOP fluctuation, independently from elevated IOP, has not yet been confirmed in glaucoma. We investigated the effects of IOP fluctuation itself on retinal neurodegeneration. Male rats were treated with IOP-lowering eyedrops (brinzolamide and latanoprost) on Mondays and Thursdays (in the irregular instillation group) or daily (in the regular instillation group), and saline was administered daily in the normal control group for 8 weeks. The IOP standard deviation was higher in the irregular instillation group than the regular instillation group or the control group. The degree of oxidative stress, which was analyzed by labeling superoxide, oxidative DNA damage, and nitrotyrosine, was increased in the irregular instillation group. Macroglial activation, expressed by glial fibrillary acidic protein in the optic nerve head and retina, was observed with the irregular instillation of IOP-lowering eyedrops. Microglial activation, as indicated by Iba-1, and the expression of TNF-α did not show a significant difference between the irregular instillation and control groups. Expression of cleaved caspase-3 was upregulated and the number of retinal ganglion cells (RGCs) was decreased in the irregular instillation group. Our findings indicate that IOP fluctuations could be induced by irregular instillation of IOP-lowering eyedrops and this could lead to the degeneration of RGCs, probably through increased oxidative stress and macrogliosis.

Viability of Transplanted De Novo Retinal Ganglion Cells in Human Donor Eyes Maintained Under Elevated Intraocular Pressure

Purpose: Glaucoma is a group of optic neuropathies characterized by visual field loss, classically due to increased intraocular pressure (IOP) and retinal ganglion cell (RGC) degeneration. Current treatment options reduce IOP, but RGC degeneration persists. De novoRGCs can be differentiated from reprogrammed human corneal fibroblasts and transplanted into the retina to potentially restore vision in patients with late-stage disease when most RGCs are irreversibly damaged. We investigate the survival of these human induced pluripotent stem cell (IPSC) derived RGCs after culturing them in human donor eyes under conditions of elevated and normal IOP using the ocular translaminar autonomous system (TAS) chamber.
 Methods: Human iPSCs were generated by reprogramming human donor corneal fibroblasts using Sendai viral vectors with Yamanaka factors. These iPSCs were then differentiated into retinal organoids from which RGCs were obtained. The RGCs were transduced with AAV2-GFP and transplanted into donor human eyes obtained from control individuals. They were pressurized for approximately 5 days, with the left eye maintained at normal IOP and right eye at elevated IOP. Viability was measured by expression levels of pro-survival pathways via qRTPCR, immunohistochemistry staining, and electroretinography for retinal function (ERG).
 Results: We successfully transplanted human RGCs into human donor eyes and visualized them after GFP transduction. We maintained a pressure differential between the two eyes for approximately 5 days using the TAS model. Differential expression of survival, inflammatory and apoptotic genes was identified between normal and high IOP. We identified retinal function changes under normal and high IOP after RGC transplantation.
 Conclusions: Human iPSC derived RGCs provide a potential strategy to overcome vision loss in patients with diseases that damage RGCs such as glaucoma, Parkinson’s, Alzheimer's, multiple sclerosis, and traumatic optic neuropathy. Future investigation would involve integration of transplanted RGCs and directing their axons towards visual centers in the brain.

Protective effects of neuropeptide Y treatment on retina in a mouse model of experimental glaucoma

Purpose: Neuropeptide Y (NPY) is an endogenous 36‐amino acid linear peptide with tyrosine residues on both ends of the molecule. Cumulative evidence suggests that NPY and its receptors in the CNS may be a potential neuroprotective targets in various degenerative conditions. This study aimed to investigate the protective effects of NPY in the retina in an experimentally induced glaucoma animal model.Methods: Weekly intracameral microbead injections were performed to induce sustainably increased intraocular pressure (IOP) and NPY was administered intravitreally for 2 months. Wild‐type C57BL/6J mice (n = 40) were categorized into four major groups i) control, ii) control + NPY, iii) high IOP model, & iv) high IOP + NPY. Inner retinal function was evaluated by using positive scotopic threshold response (pSTR) amplitudes. Eye and optic nerve sections were then immunostained with pNFH (phosphorylated neurofilament heavy chain), GFAP (glial fibrillary acidic protein) and Iba‐1(Ionized calcium‐binding adaptor molecule 1) antibodies to understand the protective effects of NPY treatment.Results: IOP elevation was observed in the microbead model (control, 10.5 ± 0.75; microbead, 27.35 ± 1.92 mmHg). Functional data revealed a significant decline in the pSTR amplitudes in high IOP conditions (p < 0.0001, n = 10) compared to the control group, and a significant increase in pSTR was observed in the high IOP + NPY group (p < 0.001, n = 10). Optic nerves stained with pNFH revealed a significant protective effect of NPY treatment against high IOP‐induced axonal damage (p < 0.01, n = 4). Increased GFAP expression observed in high IOP condition was significantly decreased with NPY treatment both in the retina (p < 0.001, n = 4) and optic nerves (p < 0.01, n = 4). Similarly, microglial activation evaluated by Iba‐1 expression was also significantly decreased by NPY treatment both in the retina (p < 0.01, n = 4) and optic nerves (p < 0.01, n = 4).Conclusions: NPY treatment significantly reduced inner retinal functional loss and optic nerve damage against high IOP‐induced glaucomatous injury. NPY also reduced the microglial activation and reactive gliosis in experimental glaucoma. Our ongoing investigation will reveal specific NPY receptors activation and biochemical mechanism underlying these protective effects in the retina.

Effect of suprachoroidal triamcinolone on intraocular pressure: a systematic review and meta-analysis.

Triamcinolone acetonide is a synthetic corticosteroid with multiple ocular uses. Like other corticosteroids, it too is associated with ocular side effects such as increased intraocular pressure (IOP), glaucoma and cataracts. Suprachoroidal administration of triamcinolone is hoped to reduce the ocular side effects of the drug, especially rises in IOP. Our systematic review and meta-analysis aims to study this phenomenon. The purpose of this study was to evaluate the effect of suprachoroidal triamcinolone injections on IOP. Systematic review and meta-analysis. We utilized the Medline, Scopus and Cochrane databases for this review. Studies published till June 2023, which fulfilled the eligibility criteria, were included. Studies in the English language with adult participants who were administered suprachoroidal triamcinolone without any concurrent intervention were included, whereas studies that did not report the mean and standard deviation for IOP were excluded. The outcome of interest was IOP at 1, 3 and 6 months post-suprachoroidal triamcinolone injection. IOP values from included studies were extracted onto Review Manager version 5.4 for analysis. Our search yielded 104 results, from which 22 papers were shortlisted for full-text screening. Finally, 12 studies were included in the analysis. Our analysis suggests a statistically significant increase in IOP in the first month after suprachoroidal triamcinolone injection but no significant differences at 3 and 6 months post-injection as compared to baseline. Elevated IOP at 1 month post-injection must be considered when using suprachoroidal triamcinolone and adequate safety measures must be taken. However, the absence of a significant rise at 3 and 6 months post-injection indicates that this modality is safer than other existing drug delivery methods. Registered with the Research Registry with the unique identifying number 'reviewregistry1656.' https://www.researchregistry.com/browse-the-registry#registryofsystematicreviewsmeta-analyses/registryofsystematicreviewsmeta-analysesdetails/648eefe65b6523002995eb21/.

OUTCOMES OF PRIMARY UNCOMPLICATED RHEGMATOGENOUS RETINAL DETACHMENT REPAIR USING SILICONE OIL TAMPONADE IN VITREORETINAL SURGERY

In a prospective observational study, we aimed to determine anatomical and functional outcomes, as well as possible complications, following pars plana vitrectomy (PPV) with silicone oil (SO) tamponade for primary, uncomplicated rhegmatogenous retinal detachments. This study was conducted from August 2023 to November 2023. During the study, 32 patients underwent surgical repair through PPV and SO injection. PPV over scleral buckling was chosen when cataracts or vitreous hemorrhages hindered proper fundus visualization. Patients received comprehensive ocular assessments, including best-corrected visual acuity, anterior segment examination, IOP measurements via applanation, and fundus examinations at different intervals: 1 day, one week, one month, and three months. Intraocular pressure exceeding 21 mmHg was defined as increased IOP. Our study included 32 patients (22 men and ten women) of Asian ethnicity who underwent retinal detachment repair by PPV and SO injection. The patients had an average age of 57.8 ± 10.1 years (34–76 years) at the time of intervention. The follow-up period was three months. An anatomical success rate, defined as retinal reattachment three months after SO removal, was achieved in 29 eyes (90.6%). Final best-corrected visual acuity (BCVA) improved 26 looks (81.2%), with a mean gain of 3 Snellen lines. BCVA remained unchanged in 4 eyes (12.5%) and deteriorated in 2 eyes (6.3%), with a mean loss of 2 Snellen lines. During the 3-month follow-up period, 17 eyes (53.1%) experienced increased intraocular pressure (IOP). Out of these, 15 patients had transient ocular hypertension, requiring topical treatment during the immediate postoperative period (within one month). Only one eye (5.9%) required filtrating drainage surgery for IOP control. Notably, no eyes developed optic neuropathy due to elevated IOP during this short-term follow-up. Pars plana vitrectomy (PPV) combined with silicone oil (SO) injection is a safe and effective surgical approach for treating primary uncomplicated rhegmatogenous retinal detachment. Our series indicates that PPV and SO injection lead to good anatomical and functional outcomes, with high reattachment rates and low rates of proliferative vitreoretinopathy. Although cataract formation and elevated intraocular pressure (IOP) are common complications, they can be successfully controlled.

New Evidence for Regulatory Role of Trigeminal Ganglion on the Intraocular Pressure Following Subarachnoid Hemorrhage.

Increased intraocular pressure (IOP) likely secondary to an activated oculo-trigeminal reflex network is an important issue following subarachnoid hemorrhage (SAH). The relationship between the IOP and trigeminal ganglion (TGG) following experimental SAH was investigated in this study. Twenty-three rabbits were used in this study. Five rabbits (n = 5) were used as the control group, another 5 as the sham group (n = 5), and the remaining 13 (n = 13) as the study group. The study group was further divided into two groups of animals with mild (n = 6) and severe (n = 7) TGG degeneration. The IOP values were recorded. After 2 weeks, the animals were decapitated. The mean degenerated neuron density of TGGs was estimated by stereological methods and analyzed statistically. The average IOP values were 11.85, 14.12, and 21.45 mm Hg in the control (n = 5), sham (n = 5), and study (n = 13) groups, respectively. The mean degenerated neuron density was 34, 237, and 3,165 mm3 in the control, sham, and study groups, respectively. According to the findings of this study, the experimental SAH leads to changes in IOP by affecting the TGG. By predicting and preventing IOP elevation in the setting of SAH, our findings will shed light on secondary sequelae such as glaucoma and irreversible blindness.

Glaucoma and Alzheimer: Neurodegenerative disorders show an adrenergic dysbalance.

Glaucoma disease is characterized by an increased intraocular pressure (IOP), glaucomatous alterations of the optic disc and corresponding visual field defects. Even lowering the main risk factor IOP until an individual target level does not prevent this neurodegenerative disorder from proceeding. Several autoimmune mechanisms were discovered, partly showing a functionality. One of these autoimmune phenomena targets the ß2-adrenergic receptor (ß2-AR; i.e. agonistic autoantibodies; ß2-agAAb) and is linked to an elevated IOP and an impaired retinal microcirculation. As neurodegenerative disorder, Alzheimer’s Disease (AD) is postulated to share a common molecular mechanism with glaucoma. In the present study we investigated autoimmune phenomena targeting the ß2-AR in patients with AD. Sera of the patients were analyzed in a rat cardiomyocyte bioassay for the presence of functional autoantibodies against ß2-AR. In addition, different species of amyloid beta (Aß) monomers were tested (Aß1-14, Aß10-25, Aβ10–37 Aß1-40, Aß1-42, Aβ28–40, and Aß-[Pyr]3–43). Our results demonstrate that none of the short-chain Aß (Aß1-14, Aß10-25, or Aβ28–40) showed any agonistic or inhibitory effect on ß2-AR. Contrary, long-chain Aß-[Pyr]3–43, representing a major neurogenic plaque component, exerted an activation that after blocking by the ß2-AR antagonist ICI118.551, could be identified as that the effect was realized via the ß2-AR. Moreover, the long chain Aß1-40, Aβ1–42, and Aβ10–37, yet not the short-chain Aß peptides prevented the clenbuterol induced desensitization of the ß2-AR. In addition, we identified functional autoantibodies in the sera of AD patients, activating the ß2-AR, like the ß2-agAAb found in patients with glaucoma. As autoimmune mechanisms were reportedly involved in the pathogenesis of glaucoma and Alzheimer’s Disease, we postulate that overstimulation of the ß2-AR pathway can induce an adrenergic overdrive, that may play an important role in the multifactorial interplay of neurodegenerative disorders.

Risk factors for intraocular pressure elevation following Descemet membrane endothelial keratoplasty in Asian patients.

To investigate risk factors for increased intraocular pressure (IOP) after Descemet membrane endothelial keratoplasty (DMEK) in Asian patients. Data from January 2015 to February 2021 were obtained from our prospective database. IOP elevation after DMEK was defined as IOP ≥ 22mmHg or an increase in IOP of ≥ 10mmHg from baseline. In addition, we examined maximum IOP. Using iCare, we measured IOP 1, 2, 3, and 6months after DMEK, and every 6months thereafter. Logistic regression and linear regression were performed to find factors predictive of IOP elevation and maximum IOP, respectively, based on the results of univariate analysis. We enrolled 90 eyes (mean patient age, 74.9 ± 7.5years; mean follow-up duration, 25.6 ± 9.9months) that underwent DMEK. IOP elevation was present in 19 eyes (21%). IOP increased from 12.6 ± 3.9mmHg preoperatively to a postoperative maximum of 17.0 ± 5.5mmHg up to 36months after DMEK (p < 0.0001). In univariate logistic regression analysis for IOP elevation, only one variable, pseudoexfoliation syndrome (PEX) and preexisting glaucoma, was significant (p < 0.05). Preexisting glaucoma without PEX (OR, 19.33; 95% CI, 4.75-93.46), PEX without glaucoma (OR, 7.25; 95% CI, 1.20-41.63), and PEX glaucoma (OR, 58.00; 95% CI, 6.78-1298.29) were associated with higher risk of IOP elevation. In this cohort, the eyes of patients with PEX and preexisting glaucoma were found to be prone to IOP elevation after DMEK.

A review of neovascular glaucoma. Etiopathogenesis and treatment.

Neovascular glaucoma (NVG) is a type of secondary glaucoma, refractory to treatment, often incurable, with very poor visual prognosis. It is characterized by the appearance of new vessels over the iris and iridocorneal angle and frequently associates the presence of a fibrovascular membrane which limits the aqueous humor outflow from the anterior chamber. The most common causes of NVG are: central retinal vein occlusion, proliferative diabetic retinopathy, and ocular ischemic syndrome. Once the gonioscopy developed as a part of clinical examination, it became possible to visualize the new vessels of the anterior segment of the eye in early stages and to understand the mechanisms of increased intraocular pressure (IOP), including narrowing and closing of the iridocorneal angle. Also, the modern imaging techniques, such as optical coherence tomography angiography and fluorescein angiography became indispensable for the clinician. Thus, an early diagnosis, followed by starting an appropriate therapy: panretinal photocoagulation or administration of anti-VEGF drugs, with or without hypotensive ocular therapy, allows the preservation of visual functions for patient’s better quality of life. However, one or more surgeries will often be required, especially in the advanced stages of the disease, which do not respond to drug therapy. Managing the NVG we should aim to: 1) reduce ocular ischemia and treat its underlying cause, 2) reduce elevated IOP, once installed and 3) control the inflammatory process. Anyway, the best treatment is prevention, so we must be very attentive at patients with risk factors for developing the NVG.Abbreviations: NVG = neovascular glaucoma, ICA = iridocorneal angle, IOP = intraocular pressure, TM = trabecular meshwork, AH = aqueous humor, AC = anterior chamber, PRP = panretinal photocoagulation, VEGF = vascular endothelial growing factor, Anti-VEGF = anti- vascular endothelial growing factor, PAS = peripheral anterior synechiae, CRVO = central retinal vein occlusion, PDR = proliferative diabetic retinopathy, DR = diabetic retinopathy, OIS = ocular ischemic syndrome, CRAO = central retinal artery occlusion, ROP = retinopathy of prematurity, FEVR = familial exudative vitreoretinopathy, PVR = proliferative vitreoretinopathy, MMPs = matrix metalloproteinases, VEGFR = vascular endothelial growing factor receptor, PDGF = platelet-derived growth factor, PIGF = placental growth factor, NRP = neuropilins, HIF = hypoxia-inducible factor, SDF1 = stromal cell-derived factor 1, DDL4 = delta like ligand 4, NICD = Notch intracellular domain, TIMMPs = tissue inhibitors of matrix metalloproteinases, ANGPT = angiopoietin, Tie 2 = tyrosine-protein kinase receptor for angiopoietins, IGF-1 = insulin-like growth factor 1, RPE = retinal pigment epithelium, IL = interleukin, TNF = tumor necrosis factor, bFGF = basic fibroblast growth factor, TGF = transforming growth factor, HGF = hepatocyte growth factor, TNFR 2 = tumor necrosis factor receptor 2, OIR = oxygen induced retinopathy, NVI = neovascularization of the iris, NVA = neovascularization of the iridocorneal angle, FA = fluorescein angiography, RAPD = relative afferent pupillary defect, CNP = capillary non-perfusion, NVE = neovascularization elsewhere in the retina, NVD = neovascularization of the optic disc, FFA = fundus fluorescein angiography, OCTA = optical coherence tomography angiography, B-scan US = B-scan ocular ultrasound, AS-OCT = anterior segment optical coherence tomography, ARC = anterior retinal cryotherapy, FDA = food and drug administration, United States of America, BVZ = bevacizumab, RBZ = ranibizumab, AFB = aflibercept, AMD/ ARMD = age related macular degeneration, DME = diabetic macular edema, GDDs = glaucoma drainage devices, MMC = mitomycin C, 5-FU = 5-fluorouracil, AGV = Ahmed glaucoma valve, AADI = Aurolab aqueous drainage implant, MIGS = minimally invasive glaucoma surgery, BCVA = best corrected visual acuity, TVT = Tube versus Trabeculectomy study, MPC = micro-pulse cyclophotocoagulation.

Rapid morphologic changes to microglial cells and upregulation of mixed microglial activation state markers induced by P2X7 receptor stimulation and increased intraocular pressure

BackgroundThe identification of endogenous signals that lead to microglial activation is a key step in understanding neuroinflammatory cascades. As ATP release accompanies mechanical strain to neural tissue, and as the P2X7 receptor for ATP is expressed on microglial cells, we examined the morphological and molecular consequences of P2X7 receptor stimulation in vivo and in vitro and investigated the contribution of the P2X7 receptor in a model of increased intraocular pressure (IOP).MethodsIn vivo experiments involved intravitreal injections and both transient and sustained elevation of IOP. In vitro experiments were performed on isolated mouse retinal and brain microglial cells. Morphological changes were quantified in vivo using Sholl analysis. Expression of mRNA for M1- and M2-like genes was determined with qPCR. The luciferin/luciferase assay quantified retinal ATP release while fura-2 indicated cytoplasmic calcium. Microglial migration was monitored with a Boyden chamber.ResultsSholl analysis of Iba1-stained cells showed retraction of microglial ramifications 1 day after injection of P2X7 receptor agonist BzATP into mouse retinae. Mean branch length of ramifications also decreased, while cell body size and expression of Nos2, Tnfa, Arg1, and Chil3 mRNA increased. BzATP induced similar morphological changes in ex vivo tissue isolated from Cx3CR1+/GFP mice, suggesting recruitment of external cells was unnecessary. Immunohistochemistry suggested primary microglial cultures expressed the P2X7 receptor, while functional expression was demonstrated with Ca2+ elevation by BzATP and block by specific antagonist A839977. BzATP induced process retraction and cell body enlargement within minutes in isolated microglial cells and increased Nos2 and Arg1. While ATP increased microglial migration, this required the P2Y12 receptor and not P2X7 receptor. Transient elevation of IOP led to microglial process retraction, cell body enlargement, and gene upregulation paralleling changes observed with BzATP injection, in addition to retinal ATP release. Pressure-dependent changes were reduced in P2X7−/− mice. Death of retinal ganglion cells accompanied increased IOP in C57Bl/6J, but not P2X7−/− mice, and neuronal loss showed some association with microglial activation.ConclusionsP2X7 receptor stimulation induced rapid morphological activation of microglial cells, including process retraction and cell body enlargement, and upregulation of markers linked to both M1- and M2-type activation. Parallel responses accompanied IOP elevation, suggesting ATP release and P2X7 receptor stimulation influence the early microglial response to increased pressure.

Cytokine profile and cytoskeletal changes after herpes simplex virus type 1 infection in human trabecular meshwork cells.

Uveitis caused by herpes simplex virus (HSV)‐1 is characterized by increased intraocular pressure (IOP) in the presence of anterior chamber inflammation. Despite their clinical significance, the pathogenic changes associated with HSV‐1 infection in trabecular meshwork (TM) cells, the key cell type regulating IOP, have not been completely elucidated. In this study, cytokine array analyses showed a significant stepwise increase in monocyte chemoattractant protein (MCP)‐1 expression upon HSV‐1 infection in TM cells (p < 0.05). HSV‐1 infection led to downregulation of fibrogenic molecules (fibronectin, α‐smooth muscle actin, connective tissue growth factor and TGF‐β1). Notably, HSV‐1 infection caused a significant increase in actin stress fibres, with a twofold increase in active RhoA, which was enhanced by treatment with TGF‐β1 and inhibited by treatment with the Rho‐kinase inhibitor, Y‐27632. TM cells treated with MCP‐1 exhibited a dose‐dependent increase in actin stress fibres compared to untreated TM cells. Our study suggests that HSV‐1 infection in TM cells increases cell contractile activity rather than fibrotic changes in the extracellular matrix (ECM) components. Taken together, these observations demonstrate the enhanced expression of MCP‐1 and TM cell contractile activity upon HSV‐1 infection and events with potential implications for the pathobiology of abrupt IOP elevation in HSV‐1 anterior uveitis.

Targeting the NLRP3 Inflammasome in Glaucoma.

Glaucoma is a group of optic neuropathies characterised by the degeneration of retinal ganglion cells, resulting in damage to the optic nerve head (ONH) and loss of vision in one or both eyes. Increased intraocular pressure (IOP) is one of the major aetiological risk factors in glaucoma, and is currently the only modifiable risk factor. However, 30–40% of glaucoma patients do not present with elevated IOP and still proceed to lose vision. The pathophysiology of glaucoma is therefore not completely understood, and there is a need for the development of IOP-independent neuroprotective therapies to preserve vision. Neuroinflammation has been shown to play a key role in glaucoma and, specifically, the NLRP3 inflammasome, a key driver of inflammation, has recently been implicated. The NLRP3 inflammasome is expressed in the eye and its activation is reported in pre-clinical studies of glaucoma. Activation of the NLRP3 inflammasome results in IL-1β processing. This pro inflammatory cytokine is elevated in the blood of glaucoma patients and is believed to drive neurotoxic inflammation, resulting in axon degeneration and the death of retinal ganglion cells (RGCs). This review discusses glaucoma as an inflammatory disease and evaluates targeting the NLRP3 inflammasome as a therapeutic strategy. A hypothetical mechanism for the action of the NLRP3 inflammasome in glaucoma is presented.

Early Functional Impairment in Experimental Glaucoma Is Accompanied by Disruption of the GABAergic System and Inceptive Neuroinflammation.

Glaucoma is a leading cause of irreversible blindness worldwide, and increased intraocular pressure (IOP) is a major risk factor. We aimed to determine if early functional and molecular differences in the glaucomatous retina manifest before significant retinal ganglion cell (RGC) loss is apparent. Adenoviral vectors expressing a pathogenic form of myocilin (Ad5.MYOC) were used to induce IOP elevation in C57BL/6 mice. IOP and pattern electroretinograms (pERG) were recorded, and retinas were prepared for RNA sequencing, immunohistochemistry, or to determine RGC loss. Ocular injection of Ad5.MYOC leads to reliable IOP elevation, resulting in significant loss of RGC after nine weeks. A significant decrease in the pERG amplitude was evident in eyes three weeks after IOP elevation. Retinal gene expression analysis revealed increased expression for 291 genes related to complement cascade, inflammation, and antigen presentation in hypertensive eyes. Decreased expression was found for 378 genes associated with the γ-aminobutyric acid (GABA)ergic and glutamatergic systems and axon guidance. These data suggest that early functional changes in RGC might be due to reduced GABAA receptor signaling and neuroinflammation that precedes RGC loss in this glaucoma model. These initial changes may offer new targets for early detection of glaucoma and the development of new interventions.

Clinical improvement in indirect carotid cavernous fistulas treated endovascularly: A patient based review

Patients with indirect carotid cavernous fistulas (CCF) were reviewed to emphasize the importance of diagnosing patients even with trivial findings and to raise awareness. Eighteen patients diagnosed as CCF were included. Neuro-ophthalmological findings before and after treatment, diagnostic investigations, treatment, clinical course was noted. Twelve patients were female (67%), 6 were males (33%) and the mean age at presentation was 54 years (range: 29–70 years). Conjunctival hyperemia was present in all patients. Seventeen (94%) patients had proptosis and diplopia, nine (50%) had orbital pain and/or headache, four (22%) had blurred vision, one (5.5%) had ptosis. On examination, 17 patients (94%) had restricted eye movements, four (22%) had low visual acuity and five patients had (28%) increased intraocular pressure (IOP). One patient had been diagnosed as myasthenia gravis and two as thyroid orbitopathy and had been on treatment accordingly before CCF was diagnosed. In two patients, bilateral findings were present despite unilateral CCF on angiography. Barrow Type B fistula was found in 7 (38%), Barrow Type D in 11 (62%) patients. In three bilateral CCF was detected. All were treated by endovascular intervention. Residual deficits at the sixth month control were, eye movement deficits in seven (39%), decrease in visual acuity in one (5.5%) and elevated IOP in one (5.5%) patient. Indirect CCF patients generally present with mild symptoms and the diagnosis may be overlooked. Mild progressive ophthalmoparesis with conjunctival hyperemia must be warning. Though rare bilateral CCF can be detected as well as unilateral CCF with bilateral findings.

Activation of ATF4 triggers trabecular meshwork cell dysfunction and apoptosis in POAG.

Primary open angle glaucoma (POAG) is the leading cause of irreversible blindness. Dysfunction of the trabecular meshwork (TM), resulting in decreased outflow of aqueous humor and increased intraocular pressure (IOP), plays an important role in the pathogenesis of POAG. However, the underlying mechanisms still remain unclear. In this study, we demonstrated that the eIF2-α/ATF4/CHOP branch of unfolded protein response (UPR) was activated in human trabecular meshwork cells (HTMCs) upon tert-butyl hydroperoxide (TBHP) exposure. Inhibition of ATF4 ameliorated TBHP-induced apoptosis and inflammatory cytokine production, while ectopic expression of ATF4 increased the expression of endothelial leukocyte adhesion molecule (ELAM)-1 and IL-8 in HTMCs. Furthermore, we found that ATF4 inhibition reduced tunicamycin-induced caspase-3 activation, ROS production, ELAM-1 expression, and HTMCs phagocytosis impairment. By an in vivo study in mice, we showed that overexpression of ATF4 in the TM induced C/EBP homologous protein (CHOP) expression and TM cells apoptosis, contributing to inflammatory cytokine production, and probably IOP elevation. More importantly, upregulation of ATF4 and CHOP, and colocalization of ATF4 with ELAM-1 were found in the TM of POAG patients. These results suggest that ATF4 is a critical mediator of oxidative stress and ER stress-induced TM cell dysfunction and apoptosis in POAG.

Intraocular Pressure Elevation Compromises Retinal Ganglion Cell Light Adaptation.

PurposeFunctional adaptation to ambient light is a key characteristic of retinal ganglion cells (RGCs), but little is known about how adaptation is affected by factors that are harmful to RGC health. We explored adaptation-induced changes to RGC physiology when exposed to increased intraocular pressure (IOP), a major risk factor for glaucoma.MethodsWild-type mice of both sexes were subjected to 2 weeks of IOP elevation using the bead model. Retinas were assessed using a multielectrode array to record RGC responses to checkerboard white noise stimulation under both scotopic and photopic light levels. This information was used to calculate a spike-triggered average (STA) for each RGC with which to compare between lighting levels.ResultsLow but not high IOP elevation resulted in several distinct RGC functional changes: (1) diminished adaptation-dependent receptive field (RF) center-surround interactions; (2) increased likelihood of a scotopic STA; and (3) increased spontaneous firing rate. Center RF size change with lighting level varied among RGCs, and both the center and surround STA peak times were consistently increased under scotopic illumination, although none of these properties were impacted by IOP level.ConclusionsThese findings provide novel evidence that RGCs exhibit reduced light-dependent adaptation and increased excitability when IOP is elevated to low but not high levels. These results may reveal functional changes that occur early in glaucoma, which can potentially be used to identify patients with glaucoma at earlier stages when intervention is most beneficial.

Drug-induced glaucoma

Glaucoma is seen as a heterogeneous group of diseases characterized by optical neuropathy with associated visual field loss; one of the main risk factors for its development is increased intraocular pressure (IOP). In the case of drug-induced glaucoma (DIG), patients develop elevated IOP, optic neuropathy and visual field defects associated with the use of certain drugs. Corticosteroids are one of the most well-known classes of drugs that can cause an increase in IOP through the open-angle mechanism. Drug-induced glaucoma, which develops similarly to open-angle glaucoma, can also be caused by some non-steroidal anti-inflammatory agents, antibodies to the endothelial growth factor, etc. Classes of drugs that can cause angle-closure glaucoma include topical anticholinergic or sympathomimetic drops, tricyclic antidepressants, monoamine oxidase inhibitors, antihistamines, antiparkinsonian drugs, antipsychotic drugs, antispasmodics. Products containing sulfa group drugs can cause DIG due to a different closing angle mechanism involving a forward rotation of the ciliary body. It is important for medical practitioners to be aware of this unwanted drug reaction in order to prevent, detect and treat DIG. In the case of drug-induced increase in IOP, if the underlying disease allows discontinuation of drugs, this measure usually leads to normalization of IOP. In cases when the patient's IOP does not normalize after discontinuation of steroids or when they must continue to take corticosteroids, the administration of topical drugs for the treatment of glaucoma should be considered.

Cannabis and glaucoma: A literature review

Introduction: Primary open-angle glaucoma (POAG) is characterized by the loss of retinal ganglion cells secondary to optic neuropathy; increased intraocular pressure (IOP) may or may not be present. Many treatment options focus on decreasing IOP measurements to attempt to prevent progression of glaucoma. Our literature review addressed a relatively common question; if cannabis is effective for treating elevated IOP in patients with glaucoma. Objective: To evaluate the current evidence for the use of cannabis for reducing IOP in glaucoma. Methods: PubMed, Embase, and the Cochrane Database were searched along with references drawn from full text articles published before January 2018 for the best available evidence that met the inclusion criteria.Three authors independently evaluated and selected the articles that represented the best available evidence.The selected articles were chosen based on study methodology and the type of cannabis used for the treatment of glaucoma. Randomized Control Trials were preferred, although lacking. No studies directly compared cannabis to the current standard of care medications for lowering IOP. Results: Five randomized controlled trials were included as best available evidence although they used different routes of administration. All studies included compared cannabis to placebo. The studies evaluated showed a range of IOP lowering effects and side effects.Topical administration has shown conflicting results for the treatment of glaucoma.Conclusion:The many forms of cannabinoid administration have demonstrated variable levels of effectiveness. The variability of the studies indicates the need for more research. Specifically, larger sample sizes, and comparison of standardized cannabis to current standards of care instead of placebo are strongly encouraged.

Meox2 Haploinsufficiency Accelerates Axonal Degeneration in DBA/2J Glaucoma.

PurposeGlaucoma is a complex disease with major risk factors including advancing age and increased intraocular pressure (IOP). Dissecting these earliest events will likely identify new avenues for therapeutics. Previously, we performed transcriptional profiling in DBA/2J (D2) mice, a widely used mouse model relevant to glaucoma. Here, we use these data to identify and test regulators of early gene expression changes in DBA/2J glaucoma.MethodsUpstream regulator analysis (URA) in Ingenuity Pathway Analysis was performed to identify potential master regulators of differentially expressed genes. The function of one putative regulator, mesenchyme homeobox 2 (Meox2), was tested using a combination of genetic, biochemical, and immunofluorescence approaches.ResultsURA identified Meox2 as a potential regulator of early gene expression changes in the optic nerve head (ONH) of DBA/2J mice. Meox2 haploinsufficiency did not affect the characteristic diseases of the iris or IOP elevation seen in DBA/2J mice but did cause a significant increase in the numbers of eyes with axon damage compared to controls. While young mice appeared normal, aged Meox2 haploinsufficient DBA/2J mice showed a 44% reduction in MEOX2 protein levels. This correlated with modulation of age- and disease-specific vascular and myeloid alterations.ConclusionsOur data support a model whereby Meox2 controls IOP-dependent vascular remodeling and neuroinflammation to promote axon survival. Promoting these earliest responses prior to IOP elevation may be a viable neuroprotective strategy to delay or prevent human glaucoma.

Suprachoroidally injected pharmacological agents for the treatment of chorio-retinal diseases: a targeted approach.

Delivery of pharmaceuticals to the posterior segment presents challenges that arise from the anatomy and clearance pharmacokinetics of the eye. Systemic and several local administration options [topical, periocular, intravitreal (IVT) and subretinal] are in clinical use, each with a unique benefit to risk profile shaped by factors including the administered agent, frequency of dosing, achievable pharmaceutical concentrations within posterior segment structures versus elsewhere in the eye or the body, invasiveness of the procedure and the inherent challenges with some administration methods. The use of thesuprachoroidal space (SCS), which is the region between the sclera and the choroid, is being explored as a potential approach to target pharmacotherapies to the posterior segment via a minimally invasive injection procedure. Preclinical data on agents such as vascular endothelial growth factor inhibitors and triamcinolone acetonide (TA) indicate that administration via suprachoroidal injection results in more posterior distribution of the pharmacologic agent, with higher exposure to the sclera, choroid, retinal pigment epithelium cells and retina, and lesser exposure to the anterior segment, than observed with IVT administration. Based in part on these findings, clinical trials have explored the efficacy and safety of suprachoroidal administration of pharmacologic therapies in conditions affecting the posterior segment. Data on a proprietary formulation of TA administered by suprachoroidal injection show improvement in anatomic and visual outcomes in subjects with noninfectious uveitis, with the potential to mitigate the known risks of cataract and increased intraocular pressure (IOP) associated with the use of intraocular corticosteroids. Suprachoroidal administration appears to be a promising treatment modality and is also in the early stages of investigation for other possible applications, such as injection of antiglaucoma agents into the anterior SCS for long-lasting control of elevated IOP, and as a mode of delivery for gene- or cell-based therapies for retinal disorders.