Open-Angle Glaucoma: Burden of Illness, Current Therapies, and the Management of Nocturnal IOP Variation.

Glaucoma is a chronic, debilitating disease and a leading cause of global blindness. Despite treatment efforts, 10% of patients demonstrate loss of vision. In the US, > 80% of glaucoma cases are classified as open-angle glaucoma (OAG), with primary open-angle (POAG) being the most common. Although there has been tremendous innovation in the surgical treatment of glaucoma as of late, two clinical variants of OAG, normal-tension glaucoma (NTG) and severe POAG, are especially challenging for providers because patients with access to care and excellent treatment options may progress despite achieving a "target" intraocular pressure value. Additionally, recent research has highlighted the importance of nocturnal IOP control in avoiding glaucomatous disease progression. There remains an unmet need for new treatment options that can effectively treat NTG and severe POAG patients, irrespective of baseline IOP, while overcoming adherence limitations of current pharmacotherapies, demonstrating a robust safety profile, and more effectively controlling nocturnal IOP.Funding The Rapid Service Fees were funded by the corresponding author, Tanner J. Ferguson, MD.

Glaucoma-associated corneal endothelial cell damage: A review.

The corneal endothelium is critical in maintaining a healthy and clear cornea. Corneal endothelial cells have a significant reserve function, but preservation of these cells is paramount as they have limited regenerative capacity. Glaucoma is a prevalent disease, and damage to the corneal endothelium may be caused by the disease process itself as well as by its treatment. The mechanisms involved in glaucoma-associated damage to the corneal endothelium need further investigation. Understanding how glaucoma and glaucoma surgery impact the endothelium is important for protecting corneal clarity and visual acuity in all glaucoma patients, including those undergoing corneal transplant. We will discuss a range of identified factors that may impact corneal endothelial cell health in glaucoma, including intraocular pressure, glaucoma medications, surgical glaucoma management, mechanical forces, and alterations in the aqueous environment.

Optical Coherence Tomography Analysis Based Prediction of Humphrey 24-2 Visual Field Thresholds in Patients With Glaucoma.

Purpose: A pilot study showed that prediction of individual Humphrey 24-2 visual field (HVF 24-2) sensitivity thresholds from optical coherence tomography (OCT) image analysis is possible. We evaluate performance of an improved approach as well as 3 other predictive algorithms on a new, fully independent set of glaucoma subjects. Methods: Subjects underwent HVF 24-2 and 9-field OCT (Heidelberg Spectralis) testing. Nerve fiber (NFL), and ganglion cell and inner plexiform (GCL+IPL) layers were cosegmented and partitioned into 52 sectors matching HVF 24-2 test locations. The Wilcoxon rank sum test was applied to test correlation R, root mean square error (RMSE), and limits of agreement (LoA) between actual and predicted thresholds for four prediction models. The training data consisted of the 9-field OCT and HVF 24-2 thresholds of 111 glaucoma patients from our pilot study. Results: We studied 112 subjects (112 eyes) with early, moderate, or advanced primary and secondary open angle glaucoma. Subjects with less than 9 scans (15/112) or insufficient quality segmentations (11/97) were excluded. Retinal ganglion cell axonal complex (RGC-AC) optimized had superior average R = 0.74 (95% confidence interval [CI], 0.67-0.76) and RMSE = 5.42 (95% CI, 5.1-5.7) dB, which was significantly better (P < 0.05/3) than the other three models: Naïve (R = 0.49; 95% CI, 0.44-0.54; RMSE = 7.24 dB; 95% CI, 6.6-7.8 dB), Garway-Heath (R = 0.66; 95% CI, 0.60-0.68; RMSE = 6.07 dB; 95% CI, 5.7-6.5 dB), and Donut (R = 0.67; 95% CI, 0.61-0.69; RMSE = 6.08 dB, 95% CI, 5.8-6.4 dB). Conclusions: The proposed RGC-AC optimized predictive algorithm based on 9-field OCT image analysis and the RGC-AC concept is superior to previous methods and its performance is close to the reproducibility of HVF 24-2.

Genetics and genetic testing for glaucoma.

PURPOSE OF REVIEW: In recent decades, investigators have identified numerous genes and genetic factors that cause or contribute risk for glaucoma. These findings have increased our understanding of disease mechanisms, provided us with new diagnostic tools, and may allow for development of improved therapies for glaucoma. However, genetic testing is most useful when it is reserved for appropriate patients. The purpose of this article is to review key points and recent developments regarding the genetics and genetic testing for glaucoma and to provide recommendations for when genetic testing may be warranted. RECENT FINDINGS: Large genome-wide association studies have identified multiple new susceptibility loci associated with primary open angle glaucoma and primary angle closure glaucoma. SUMMARY: Several glaucoma-causing genes and genetic risk factors for glaucoma have been discovered. As a result, there are specific clinical scenarios in which genetic testing is warranted. In select cases (i.e., familial juvenile open angle glaucoma), genetic testing can serve as a powerful tool to improve diagnostic accuracy, efficiency of disease surveillance, and selection of treatment, enabling physicians to better optimize care for their patients.

Intraocular Pressure Spike and Corneal Decompensation Following Selective Laser Trabeculoplasty in Patients With Exfoliation Glaucoma.

PURPOSE: To report 5 cases of intractable intraocular pressure (IOP) elevation and 2 cases of corneal failure in patients with exfoliation glaucoma after undergoing selective laser trabeculoplasty (SLT). METHODS: SLT was performed for the treatment of exfoliation glaucoma in 5 patients, all of whom subsequently developed significant IOP elevation within 1 to 5 weeks following treatment. Two patients went on to develop corneal endothelial failure requiring transplantation within 9 to 11 months. RESULTS: All 5 patients failed to respond adequately to topical antiglaucoma therapy and required trabeculectomy. Two patients required secondary implantation of a glaucoma drainage device. Two patients suffered significant endothelial injury requiring corneal transplantation (one receiving penetrating keratoplasty and another receiving Descemet stripping automated endothelial keratoplasty). CONCLUSIONS: Significant and persistent IOP spikes requiring surgical intervention following SLT are extremely rare, with only 1 other case series of 4 patients (all with heavily pigmented angles) reported in the literature. Exfoliation patients, and likely all patients with heavily pigmented angles, should be considered at higher risk for developing this complication. Corneal endothelial failure is similarly rare. Nine cases have been reported in the literature, none requiring corneal transplantation. Further clinical attention and research is needed to help elucidate what factors (both pressure-dependent and pressure-independent) may predispose patients to corneal changes following SLT.

Comparing consistency of clear corneal incisions using a traditional diamond keratome and a newly designed diamond keratome.

PURPOSE: To compare the consistency of incision architecture utilizing a traditional diamond keratome and a newly designed diamond keratome. METHODS: We used a traditional diamond keratome and newly designed diamond keratome to create clear corneal incisions in human cadaveric donor eyes. Three surgeons with varying levels of experience made 30 incisions with each keratome; and the wound architecture was measured including incision lengths, epithelial and endothelial widths, and the central epithelial incision's deviation from a straight line entrance. RESULTS: The mean absolute difference in right and left incision lengths (traditional: 0.182 ± 0.158 mm and new 0.088±0.077 mm [P<0.003]), mean absolute difference in epithelial and endothelial incision width (traditional: 0.181±0.144 mm and new 0.080±0.092 mm [P<0.002]), endothelial incision central deviation from a straight line (traditional: 0.128±0.242 mm and new -0.046±0.124 mm [P<0.001]) were all significantly more consistent with the newly designed diamond keratome than with the traditional diamond keratome. CONCLUSION: The newly designed diamond keratome creates a more consistent clear corneal incision than a traditional diamond keratome across a variety of surgical skill levels and does not require advanced levels of training to achieve this consistency.

Trabeculectomy With Mitomycin C or Ahmed Valve Implantation in Eyes With Uveitic Glaucoma.

PURPOSE: To report and compare the results of trabeculectomy with mitomycin C (MMC) and Ahmed valve implantation in the management of uveitic glaucoma. PATIENTS AND METHODS: The records of 41 eyes of 29 patients who underwent trabeculectomy with MMC or Ahmed valve implantation for uveitic glaucoma were retrospectively reviewed. Seventeen eyes underwent trabeculectomy with MMC, and 24 eyes underwent Ahmed valve implantation. Outcomes included postoperative intraocular pressure (IOP), percent reduction from preoperative IOP, postoperative number of medications, time to failure, and complications. RESULTS: Mean follow-up was 21.2 months in the trabeculectomy group and 23.8 months in the valve group (P=0.06). Mean IOP was reduced from 29.2 to 18.4 mm Hg in the trabeculectomy group (31.3%), compared with a reduction from 33.4 to 15.5 mm Hg in the Ahmed valve group (42.7%, P=0.53). Postoperatively, 1.76 medications were used in the trabeculectomy group, compared with 1.83 medications in the Ahmed valve group (P=0.89). Cumulative success at 1 year was 66.7% in the trabeculectomy group, compared with 100% in the Ahmed valve group (P=0.02). Mean time to failure was 8.36 months with trabeculectomy, and 21.8 months with Ahmed valve (P=0.02). Complications in both groups were typically rare and self-limited, with recurrent inflammation being most common. CONCLUSIONS: Although both trabeculectomy with MMC and Ahmed valve implantation are reasonable surgical options in the management of uncontrolled uveitic glaucoma, Ahmed valve implantation was associated with higher cumulative success rate at 1 year and a longer mean time to failure.

Bilateral acute iris transillumination following systemic moxifloxacin for respiratory illness: report of two cases and review of the literature.

PURPOSE: To describe two cases of bilateral acute iris transillumination following systemic administration of moxifloxacin and review the literature. METHODS: Review of clinical records, and review of the literature using the PubMed database. RESULTS: A 75 year-old man and 33 year-old woman presented with bilateral conjunctival injection, photophobia, and atonic, distorted pupils. The symptoms began acutely following a respiratory illness, for which both were treated with moxifloxacin. Both patients demonstrated profound iris transillumination, sectoral posterior bowing of the iris, corneal endothelial pigment dusting, and trabecular meshwork hyperpigmentation. One patient had a cotton-wool spot. A literature review identified 59 previous reports in 5 publications, including 17 patients with no antecedent fluoroquinolone use. CONCLUSIONS: Increased awareness of this recently described clinical entity should lead to a decrease in unnecessary diagnostic evaluations. It is currently unclear whether this disease represents an adverse effect of fluoroquinolone use or a sequela of a systemic illness.

Corneal collagen cross-linking for nonectatic disorders: a systematic review.

PURPOSE: To provide a background regarding the biochemical rationale for corneal collagen cross-linking (CXL) and outline its current use, critically evaluate the current literature for the use of CXL in nonectatic disorders, highlight limitations and areas for further research, and address additional novel applications of CXL. METHODS: A literature search was performed using the EMBASE and MEDLINE database from 1970 to November 2011. Keywords included "corneal collagen cross linking," "crosslinking," "cross-linking," "ultraviolet," "riboflavin," "corneal edema," and "keratitis" in various combinations. A search through the references of retrieved articles was also performed. RESULTS: Cross-linking for corneal edema showed a temporary improvement in objective measures of central corneal thickness, corrected distance visual acuity, and corneal clarity along with subjective measures such as pain and irritation. Cross-linking was also tolerated as an adjunctive therapy for infectious keratitis without complications. In all studies, the progression of corneal melting was halted after treatment, avoiding the need for emergency keratoplasty. CONCLUSIONS: Cross-linking with riboflavin and ultraviolet A light is a promising, minimally invasive treatment for corneal ectasia. A growing number of studies suggest additional application in corneal edema and infectious keratitis may be beneficial. However, further studies are needed to address long-term outcomes and safety concerns.

Localization of angiotensin converting enzyme in rabbit cornea and its role in controlling corneal angiogenesis in vivo.

PURPOSE: The renin angiotensin system (RAS) has been shown to modulate vascular endothelial growth factor and angiogenesis. In this study we investigated (i) the existence of the RAS components angiotensin converting enzyme (ACE) and angiotensin II receptors (AT(1) and AT(2)) in the rabbit cornea using in vitro and ex vivo models and (ii) the effect of enalapril, an ACE inhibitor, to inhibit angiogenesis in rabbit cornea in vivo. METHODS: New Zealand White rabbits were used. Cultured corneal fibroblasts and corneal epithelial cells were used for RNA isolation and cDNA preparation using standard molecular biology techniques. PCR was performed to detect the presence of ACE, AT(1), and AT(2) gene expression. A corneal micropocket assay to implant a vascular endothelial growth factor (VEGF) pellet in the rabbit cornea was used to induce corneal angiogenesis. Rabbits of the control group received sterile water, and the treated group received 3 mg/kg enalapril intramuscularly once daily for 14 days starting from day 1 of pellet implantation. The clinical eye examination was performed by slit-lamp biomicroscopy. We monitored the level of corneal angiogenesis in live animals by stereomicroscopy at days 4, 9, and 14 after VEGF pellet implantation. Collagen type IV and lectin immunohistochemistry and fluorescent microscopy were used to measure corneal angiogenesis in tissue sections of control and enalapril-treated corneas of the rabbits. Image J software was used to quantify corneal angiogenesis in the rabbit eye in situ. RESULTS: Our data demonstrated the presence of ACE, AT(1), and AT(2) expression in corneal fibroblasts. Cells of corneal epithelium expressed AT(1) and AT(2) but did not show ACE expression. Slit-lamp examination did not show any significant difference between the degree of edema or cellular infiltration between the corneas of control and enalapril-treated rabbits. VEGF pellet implantation caused corneal angiogenesis in the eyes of vehicle-treated control rabbits, and the mean area of corneal neovascularization was 1.8, 2.8, and 3.2 mm(2) on days 4, 9, and 14, respectively. Enalapril treatment caused a notable decrease in corneal neovascularization of 44% (1 mm(2)), 28% (2.1 mm(2)), and 31% (2.2 mm(2)) on the three tested time points, respectively. The immunostaining of corneal tissue sections with collagen type IV and lectin confirmed the presence of blood vessels, with enalapril-treated rabbit corneas showing a lesser degree of blood vessel staining. CONCLUSIONS: Corneal cells show expression of tissue RAS components, such as ACE, AT(1), and AT(2). Treatment with ACE inhibitor enalapril markedly decreased corneal angiogenesis in a rabbit model of VEGF-induced corneal neovascularization, suggesting that ACE inhibitors may represent a novel therapeutic strategy to treat corneal angiogenesis.