Prospective, Randomized Controlled Trial of Cataract Surgery vs Combined Cataract Surgery With Insertion of iStent Inject.

PURPOSE: To evaluate the efficacy and safety of combined cataract surgery with insertion of an ab interno trabecular microbypass device (iStent Inject, Glaukos Corporation) compared to cataract surgery alone in patients with mild-to-moderate glaucoma. DESIGN: Prospective, randomized, assessor-masked controlled trial at a single centre. PARTICIPANTS: Eyes with visually-significant cataract and mild-to-moderate glaucoma with preoperative intraocular pressure (IOP) of 12 to 30 mmHg on 0 to 3 ocular hypotensive medications. METHODS: Participants eyes were randomized (2017-2020) 1:1 to combined cataract surgery with iStent Inject (treatment group, n = 56) or cataract surgery alone (control group, n = 48), and followed up for 2 years. MAIN OUTCOME MEASURES: The co-primary effectiveness endpoints were the number of ocular hypotensive medications and IOP at 24-months post-surgery. The secondary effectiveness endpoints were ocular comfort as measured by the Ocular Surface Disease Index (OSDI) and vision-related quality of life as measured by the Glaucoma Activity Limitation Questionnaire (GAL-9) at 24-months. Safety measures included postoperative visual acuity, any unplanned return to the operating theatre, adverse events, and complications. RESULTS: Participants (67.3% male) were aged 53 to 85 years, and treatment groups were similar in terms of mean medicated IOP (treatment group 17.7 mmHg ± 4.0; control group 17.1 mmHg ± 3.1), and number of ocular hypotensive medications (treatment group 1.69 ± 1.05; control group 1.80 ± 1.22) at baseline. At 24 months, the number of ocular hypotensive medications were 0.7 ± 0.9 in the treatment groups compared to 1.5 ± 1.9 in the control group, with an adjusted difference of 0.6 fewer medications per eye in the treatment group (95% CI 0.2-1.1, P = 0.008). In the treatment group, 57% of eyes were on no glaucoma medications compared to 36% in the control group. There was no significant difference in IOP between the 2 groups beyond the 4-weeks. There were no differences in patient-reported outcomes between the 2 groups. The visual outcomes and safety profiles were similar between the 2 groups. CONCLUSIONS: Combined cataract surgery with iStent Inject achieved a clinically- and statistically-significantly greater reduction in ocular hypotensive medication usage at 24-months compared to cataract surgery alone, with no significant difference in IOP. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Inhibitory Effects of 3',4'-Dihydroxyflavonol in a Mouse Model of Glaucoma Filtration Surgery and TGFß1-Induced Responses in Human Tenon's Fibroblasts.

Purpose: Cytotoxic agents such as mitomycin C (MMC) are part of the mainstay treatment for limiting subconjunctival scarring following glaucoma filtration surgery (GFS). However, a safer antifibrotic therapy is clinically needed. The anti-scarring properties of 3',4'-dihydroxyflavonol (DiOHF) were evaluated in a mouse model of GFS and in cultured human Tenon's fibroblasts (HTFs). Methods: GFS was performed in C57BL/6 mice receiving daily intraperitoneal injections of DiOHF or vehicle or a single intraoperative injection of MMC. Eyes were harvested on day 14 for assessment of collagen deposition, expression of alpha-smooth muscle actin (α-SMA), cluster of differentiation 31 (CD31), and 4-hydroxy-2-nonenal (4HNE) in the conjunctiva/Tenon's layer. The inhibitory effects of DiOHF on transforming growth factor ß (TGFß)-induced responses were also assessed in HTFs. Results: Treatment with DiOHF demonstrated a reduction in collagen deposition at the GFS site compared to vehicle-treated mice. The degree of 4HNE-positive fluorescence was significantly reduced in DiOHF-treated eyes compared to the other groups, indicating a decrease in oxidative stress. A reduction in expression of α-SMA and CD31 was seen in DiOHF-treated conjunctiva compared to those treated with vehicle. Concordant results were demonstrated in cultured HTFs in vitro. Furthermore, treatment of cultured HTFs with DiOHF also displayed a reduction in the proliferation, migration, and contractility of HTFs. Conclusions: Treatment with DiOHF reduces scarring and angiogenesis in the conjunctiva of mice with GFS at a level comparable to MMC. The reduction in oxidative stress suggests that DiOHF may suppress scarring via different mechanisms from MMC. Translational Relevance: DiOHF may be a safer and superior wound modulating agent than conventional antifibrotic therapy in GFS.

Oxidative Stress and the Role of NADPH Oxidase in Glaucoma.

Glaucoma is characterised by loss of retinal ganglion cells, and their axons and many pathophysiological processes are postulated to be involved. It is increasingly understood that not one pathway underlies glaucoma aetiology, but rather they occur as a continuum that ultimately results in the apoptosis of retinal ganglion cells. Oxidative stress is recognised as an important mechanism of cell death in many neurodegenerative diseases, including glaucoma. NADPH oxidase (NOX) are enzymes that are widely expressed in vascular and non-vascular cells, and they are unique in that they primarily produce reactive oxygen species (ROS). There is mounting evidence that NOX are an important source of ROS and oxidative stress in glaucoma and other retinal diseases. This review aims to provide a perspective on the complex role of oxidative stress in glaucoma, in particular how NOX expression may influence glaucoma pathogenesis as illustrated by different experimental models of glaucoma and highlights potential therapeutic targets that may offer a novel treatment option to glaucoma patients.

Prevalence of glaucoma in the Australian National Eye Health Survey.

AIM: To estimate the prevalence of glaucoma in Australia. METHODS: This was a population-based study of 3098 non-Indigenous Australians (50-98 years) and 1738 Indigenous Australians (40-92 years) stratified by remoteness. Each participant underwent a standard examination that included visual field assessment, tonometry and non-mydriatic fundus photography. Two fellowship-trained glaucoma specialists independently assessed relevant case notes (past ocular history, best-corrected visual acuity, frequency doubling technology visual fields, Van Herick grade, intraocular pressure and optic disc-centred photographs) and assigned a diagnosis ranked on a scale of certainty: none, possible, probable or definite glaucoma. RESULTS: A total of 4792 (99.1%, 3062 non-Indigenous and 1730 Indigenous) participants had retinal photographs in at least one eye that were gradable for glaucoma. The weighted prevalence of glaucoma (definite) in non-Indigenous Australians and Indigenous Australians was 1.5% (95% CI 1.0 to 2.2) and 0.6% (95% CI 0.4 to 1.1), respectively. When definite and probable cases of glaucoma were combined, rates were 3.4% (95% CI 2.7 to 4.3) among non-Indigenous and 1.6% (95% CI 1.1 to 2.3) in Indigenous Australians. Only 52.4% of non-Indigenous Australians and 28.0% of Indigenous Australians with glaucoma self-reported a known history of glaucoma. CONCLUSION: We estimate that 198 923 non-Indigenous Australians aged 50 years and over and 2139 Indigenous Australians aged 40 years and over have glaucoma. Given the high rates of undiagnosed glaucoma coupled with a significant ageing of the Australian population, improvements in case detection and access to low vision rehabilitation services may be required to cope with the growing burden of glaucoma.

Extreme Descemet's membrane rupture with hydrops in keratoconus: Clinical and histological manifestations.

PURPOSE: To study the clinical and histological manifestations of an extreme Descemet's membrane rupture as a result of keratoconus. OBSERVATIONS: Using Periodic acid-Schiff assay to study a keratoconic cornea with an extreme rupture showed that the ruptured Descemet's membrane had retracted and folded into scrolls and ridges. The dimensions of the rupture were estimated to be 3.7mm2, and the central cornea was extremely thinned with a thickness of only 260µm. Stromal scarring and loosely packed lamellae were present anterior to the scrolls and ridges. Antibodies targetting the major components of Descemet's membrane, Laminin and type IV collagen, displayed intense labelling adjacent to the scrolls where the stroma was denuded and differential expression patterns lined the ridges. Environmental scanning electron microscopy showed possible collagen deposition at the site of rupture. CONCLUSIONS AND IMPORTANCE: The specific staining patterns of laminin and type IV collagen suggest these components have an important role in re-endothelisation of the cornea. This is the first known report of spatial resolution of the topography of the Descemet's membrane rupture established by environmental scanning electron microscopic image montage.

Victorian trabeculectomy audit.

IMPORTANCE: This study highlights the efficacy and safety of trabeculectomy in Victoria, Australia. BACKGROUND: Trabeculectomy is currently the gold standard in glaucoma surgery. However, its role has been increasingly questioned because of its associated risks and complications. This audit aimed to assess the efficacy and safety of trabeculectomy surgery in the state of Victoria, Australia. DESIGN: A cross-sectional, retrospective and voluntary statewide audit of trabeculectomy surgery by individual surgeons in 2012 with 24 months follow-up. PARTICIPANTS: Twenty-four surgeons in the state of Victoria submitted data on 227 trabeculectomies. METHODS: Basic preoperative and perioperative data were collected. Post-operative data collected included intra-ocular pressure measurements, glaucoma medications, associated complications and subsequent surgery up to 24 months post-trabeculectomy. MAIN OUTCOME MEASURES: The main outcome measures were post-operative intra-ocular pressure and surgical complications. RESULTS: At 12 months, the mean intra-ocular pressure was 12.6 ± 4.1 mmHg (range 3-28 mmHg). A total of 91% of eyes had an intra-ocular pressure ≤18 mmHg with or without ocular hypotensive medications. One-third of eyes that were phakic at the time of trabeculectomy underwent cataract extraction within the 24 months of follow-up. Eyes that underwent combined cataract extraction and trabeculectomy (23% of trabeculectomies) had a significantly higher mean 12-month intra-ocular pressure than eyes that underwent trabeculectomy alone (13.9 vs. 12.2 mmHg, P = 0.01). At 24 months, there were no cases of blebitis/endophthalmitis. CONCLUSIONS AND RELEVANCE: The Victorian Trabeculectomy Audit demonstrates excellent efficacy and safety results that are comparable with international standards. Combined cataract extraction and trabeculectomy tended to result in a higher mean post-operative intra-ocular pressure than trabeculectomy alone.

Measuring the Photopic Negative Response: Viability of Skin Electrodes and Variability Across Disease Severities in Glaucoma.

PURPOSE: The purpose of this study was to determine the feasibility of measuring the photopic negative response (PhNR) of the full-field electroretinogram (ERG) using skin electrodes compared to conjunctival electrodes and its test-retest variability over a range of disease severities in open-angle glaucoma. METHODS: Recordings were performed twice (100 sweeps each) within the same session in 43 eyes of 23 participants with glaucoma to determine its intrinsic variability. The ratio between the PhNR and B-wave amplitude (PhNR/B ratio) was determined for each trace and computed across 5 to 100 sweeps of each recording. Spectral-domain optical coherence tomography was used to measure the average peripapillary retinal nerve fiber layer (RNFL) thickness. RESULTS: The PhNR/B ratio and its magnitude of variability were not significantly different between skin and conjunctival electrodes (P ≤ 0.197), and the degree of variability decreased substantially with increasing number of sweeps. For skin electrodes, the intraclass correlation coefficient was 0.89 and 0.91 for right and left eyes, respectively. The variability of the PhNR/B ratio decreased with lower RNFL thickness values and larger B-wave amplitudes (P ≤ 0.002). CONCLUSIONS: Skin electrodes are a viable alternative to conjunctival electrodes when measuring the PhNR in open angle glaucoma, and increasing the number of sweeps substantially reduced its intrinsic variability; the extent of variability was also lower with worsening disease severity. TRANSLATIONAL RELEVANCE: The feasibility of performing ERG recordings widely across a range of disease severities in glaucoma can be achieved through using skin electrodes and increasing the number of sweeps performed to improve measurement repeatability.

An Immunohistochemical Study of Inflammatory Cell Changes and Matrix Remodeling With and Without Acute Hydrops in Keratoconus.

PURPOSE: To determine the inflammatory cell and matrix changes in advanced keratoconus, including acute hydrops, using immunohistochemical analysis. METHODS: The corneal tissue from eight subjects with keratoconus undergoing corneal transplantation (three keratoconic buttons, five buttons post acute hydrops­one of them with extensive neovascularization following hydrops) was compared with tissue from two normal corneoscleral rims (n = 10). The corneas were sectioned and analyzed with specific markers for macrophages, lymphocytes, dendritic cells, and scar associated matrix molecules laminin, fibronectin, tenascin-C, and type III collagen. RESULTS: Populations of cells using markers for macrophages, leucocytes and antigen presenting cells were found to be associated with the epithelium and stroma of keratoconic tissue. Populations of these cells appeared decreased in hydrops-associated keratoconus except for a large increase in leucocytes in the stroma and endothelium associated with neovascularization. Extracellular matrix deposition was found to be uniquely demonstrated in localized areas of the stroma, corresponding to the site of hydrops involvement. CONCLUSIONS: Immunohistochemical analysis revealed a chronic, inflammatory process with recruitment of immunoinflammatory cells and deposition of scar tissue in keratoconus. The inflammatory markers were somewhat attenuated in hydrops-associated keratoconus corneas and thus inflammation was not considered to be a major factor in the development of acute corneal hydrops.

An unusual complication of crawford tube insertion.

The authors describe an unusual and challenging complication of bicanalicular (Crawford) stent insertion that has previously never been reported. A 27-year-old man sustained multiple lacerations to the left (L) periocular and facial areas with a glass bottle. He was admitted under the care of the Plastic Surgical team at another institution and underwent repair of the facial, eyelid, and canalicular lacerations in the operating room. During the surgery, a Crawford stylet was guided in the L inferior canaliculus but was not retrieved nasally. Neuroimaging revealed that the metallic stylet of the Crawford tube was within the orbit, extending via the superior orbital fissure into the middle cranial fossa. The patient was then transferred under the care of the neurosurgical team and underwent a combined orbital/neurosurgical procedure to retrieve the stylet.

A prospective study of acute corneal hydrops by in vivo confocal microscopy in a New Zealand population with keratoconus.

BACKGROUND/AIMS: To analyse the clinical and microstructural changes during the course of acute corneal hydrops in keratoconus. METHODS: A prospective study of consecutive patients presenting with acute corneal hydrops over 12 months was performed. Patients were examined with slit-lamp biomicroscopy and in vivo confocal microscopy (IVCM) at 2-weekly intervals until resolution of hydrops. RESULTS: 10 consecutive patients (mean age 23.6±7.5 years) were recruited. All were of Maori or Pacific Island Nations origin. All affected eyes exhibited extensive grade 3 acute corneal hydrops. Mean best corrected vision in hydrops eyes was 2/60 at presentation and 6/48 at resolution. Mean time to resolution of hydrops was 9.9±4.3 weeks. On IVCM, four corneas exhibited hyper-reflective round cells in the epithelium and stroma. Elongated branching cells with small cell bodies were noted in the anterior stroma in two cases at 6 and 12 weeks, respectively. Three months after presentation, both cases also exhibited unusual stromal cells with large speckled cell bodies and elongated branching cell processes. Both cases subsequently developed corneal neovascularisation. CONCLUSIONS: Corneal neovascularisation occurred in 20% of eyes in this pilot study and prolonged presence of presumed inflammatory cells was observed in these eyes. Further study of this potential association may enable identification of patients at risk of neovascularisation.

Acute corneal hydrops in keratoconus - new perspectives.

PURPOSE: To summarize the current concepts and recent literature regarding the epidemiology, pathogenesis, imaging modalities, and treatment of acute hydrops in keratoconus. DESIGN: Perspective. METHODS: Review and synthesis of selected literature, with interpretation and perspective. RESULTS: Acute corneal hydrops is an incompletely understood complication of keratoconus, characterized by marked corneal edema caused by a break in Descemet membrane, allowing aqueous to enter the corneal stroma and epithelium. Although usually self-limiting, with clinical signs of edema typically resolving after 3 months, it often leaves a vision-impairing scar, necessitating and expediting the need for corneal transplantation. Studies have identified risk factors for developing acute hydrops. Modern imaging modalities such as ultrasound biomicroscopy, anterior segment optical coherence tomography, and in vivo confocal microscopy have enlightened us to the microstructural changes that take place during acute hydrops, the factors that influence its duration, and sequelae. Newer treatment regimens have seen a reduction in the duration of corneal edema during acute hydrops, and have improved the survival of corneal grafts after transplantation for resolved hydrops. CONCLUSIONS: Effective management of acute corneal hydrops in keratoconus is based on recognizing and addressing the risk factors, treating the acute event effectively and promptly to reduce the duration of edema and its complications, and, ultimately, successful corneal transplantation with acceptable long-term graft survival rates. Improved in vivo imaging of the cornea during acute hydrops has led to an enhanced understanding of the pathogenesis and ultrastructural changes of the condition, and in turn has resulted in improved management of the disease.

Wound Healing Modulation in Glaucoma Filtration Surgery- Conventional Practices and New Perspectives: Antivascular Endothelial Growth Factor and Novel Agents (Part II).

Glaucoma filtration surgery is regularly performed for the treatment of glaucoma and trabeculectomy is often regarded as the 'gold standard' glaucoma operation. The biggest risk of failure of the operation is bleb scarring. The advent of antifibrotic agents, such as mitomycin C (MMC) and 5-fluorouracil (5FU) has vastly prolonged the longevity of the bleb, but concerns remain regarding the potential increase in postoperative complications. More selective therapeutic targets have therefore been explored. One of these is vascular endothelial growth factor (VEGF) inhibition. VEGF inhibition has a role not only in subconjunctival angiogenesis inhibition but also it has direct anti-fibrotic properties. Newer pharmacological compounds and materials have also been developed in recent years in attempt to modulate the wound healing in different ways after glaucoma surgery. These include physical barriers to scarring and vehicles for sustained release of pharmacological agents, and early promising results have been demonstrated. This two-part review will provide a discussion of the application of anti-fibrotic agents in glaucoma filtration surgery and evaluate the newer agents that have been developed. How to cite this article: Fan Gaskin JC, Nguyen DQ, Ang GS, O'Connor J, Crowston JG. Wound Healing Modulation in Glau coma Filtration Surgery-Conventional Practices and New Pers pectives: Antivascular Endothelial Growth Factor and Novel Agents (Part II). J Curr Glaucoma Pract 2014;8(2):46-53.

Wound Healing Modulation in Glaucoma Filtration Surgery-Conventional Practices and New Perspectives: The Role of Antifibrotic Agents (Part I).

Glaucoma filtration surgery is regularly performed for the treatment of glaucoma and trabeculectomy is often regarded as the 'gold standard' glaucoma operation. The biggest risk of failure of the operation is bleb scarring. The advent of anti-fibrotic agents, such as mitomycin C (MMC) and 5-fluorouracil (5FU) has vastly prolonged the longevity of the bleb, but concerns remain regarding the potential increase in postoperative complications. More selective therapeutic targets have therefore been explored. One of these is vascular endothelial growth factor (VEGF) inhibition. Vascular endothelial growth factor inhi bition has a role not only in sub conjunctival angiogenesis inhi bition but also it has direct anti-fibrotic properties. Newer phar macological compounds and materials have also been developed in recent years in attempt to modulate the wound healing in different ways after glaucoma surgery. These include physical barriers to scarring and vehicles for sustained release of pharmacological agents, and early promising results have been demonstrated. This two-part review will provide a discussion of the application of anti-fibrotic agents in glaucoma filtration surgery and evaluate the newer agents that have been developed. How to cite this article: Fan Gaskin JC, Nguyen DQ, Ang GS, O'Connor J, Crowston JG. Wound Healing Modulation in Glaucoma Filtration Surgery-Conventional Practices and New Pers pectives: The Role of Antifibrotic Agents (Part I). J Curr Glaucoma Pract 2014;8(2):37-45.

The Auckland keratoconus study: identifying predictors of acute corneal hydrops in keratoconus.

BACKGROUND: The aim was to identify potential factors associated with acute corneal hydrops in a New Zealand population with keratoconus referred to a hospital eye service. METHODS: In a single hospital centre, in a retrospective review, demographic and clinical features of subjects with keratoconus and corneal hydrops over a 17-year period were compared with an age- and gender-matched control group of subjects with keratoconus but no history of corneal hydrops. RESULTS: One hundred and one eyes of 101 subjects (mean age 24.6 ± 8.4 years) were identified with keratoconus-related corneal hydrops. Subjects were more likely to be of Pacific but less likely to be of New Zealand European ethnicity than control subjects (n = 101). In comparison, Maori ethnicity was not found to have a significantly positive or negative association with hydrops. The pre-hydrops visual acuity (VA) of affected eyes was poorer than that of controls (p < 0.001) at first presentation to our tertiary referral corneal and contact lens service. Hydrops typically developed approximately four years after diagnosis of keratoconus. Subjects with hydrops were more likely to have a history of eye-rubbing (p = 0.011) but less likely to have a family history of keratoconus (p = 0.05). In 31 cases, the acute hydrops event was their first optometric/ophthalmologic contact. There were no statistically significant differences in the prevalence of atopic disease, contact lens wear or overall corneal transplantation rate between the two groups. CONCLUSIONS: Pacific ethnicity, history of eye-rubbing, poor VA at first hospital presentation and lack of family history were statistically associated with developing acute corneal hydrops in keratoconus in a New Zealand population. Greater understanding of such predisposing risk factors may help develop early management strategies to delay or prevent progression of this disease.