Interim Analysis of Clinical Outcomes with Open versus Closed Conjunctival Implantation of the XEN45 Gel Stent.

OBJECTIVE: To examine the longitudinal postoperative outcomes of open versus closed conjunctiva implantation of the XEN45 gel stent. DESIGN: Retrospective multicenter study. SUBJECTS: One hundred ninety-three patients with glaucoma underwent XEN45 implantation via an open or closed conjunctiva approach. METHODS: Data on patient demographics; diagnoses; preoperative and postoperative clinical data; outcome measures, including intraocular pressure (IOP); use of glaucoma medications; visual acuity; and complications were collected. Statistical analyses were performed with P < 0.05 as significant. MAIN OUTCOME MEASURES: Failure was defined as < 20% reduction in IOP from the medicated baseline or a IOP of > 21 mmHg at 2 consecutive visits at postoperative month 1 and beyond, the need for subsequent operative intervention or additional glaucoma surgery, or a catastrophic event, such as loss of light perception. Eyes that had not failed by these criteria and were not on glaucoma medications were considered complete successes. Overall success was defined as those who achieved success either with or without topical medications. RESULTS: Patients were followed for an average of 17 months. Complete success was achieved in 42.5% and 24.7% of the open and closed groups, respectively (P = 0.01). Overall success was achieved in 64.2% and 37.0% of the open and closed groups, respectively (P < 0.001) at the last follow-up. Bleb needling was performed in 12.4% of eyes in the open group compared with 40% of eyes in the closed group. An IOP spike of ≥ 10 mmHg was twice as likely to occur in the closed group compared with the open group during the postoperative period (40% vs. 18%; P = 0.001). CONCLUSIONS: Implantation of XEN45 with opening of the conjunctiva resulted in a lower IOP with greater success and lower needling rate compared with those achieved with the closed conjunctiva technique. Similar rates of postoperative complications and vision loss were noted in each group. Although both procedures provide substantial IOP reduction, the open technique appears to result in higher success rates and fewer postoperative interventions. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Netarsudil and latanoprost ophthalmic solution for the reduction of intraocular pressure in open-angle glaucoma or ocular hypertension.

Introduction: Netarsudil and latanoprost ophthalmic solution (0.02%/0.005%) is indicated for intraocular pressure (IOP) lowering in open-angle glaucoma (OAG) or ocular hypertension (OHTN). The once-daily agent combines the mechanism of action for each of the individual components and provides a new avenue for long-term intraocular pressure control. This review aims to cover the agent's current efficacy and safety data and opine as to its role in glaucoma management.Areas covered: This article will cover Phase II-III clinical efficacy and safety data as well as basic science literature pertaining to the agent's mechanism of action and pharmacodynamics. In selecting articles for inclusion in this review, a literature search using the PubMed database was carried out. Cross-referencing was carried out where applicable. We did not use any date or language restrictions in electronic searches.Expert opinion: Netarsudil and latanoprost ophthalmic solution plays a pivotal role in management of individuals with OAG and OHTN. The agent may be used as first-line therapy to provide substantial IOP-lowering or when additional lowering is indicated and prostaglandins have provided insufficient IOP lowering. The once-daily dosing regimen decreases the risk of inadequate treatment due to nonadherence.

Effects of Circumpapillary Retinal Nerve Fiber Layer Segmentation Error Correction on Glaucoma Diagnosis in Myopic Eyes.

PURPOSE: In a myopic population, we investigated the occurrence of circumpapillary retinal nerve fiber layer (RNFL) segmentation errors that required manual correction in optical coherence tomography (OCT) and its effect on glaucoma diagnostic capability of OCT. MATERIALS AND METHODS: Myopic subjects (spherical equivalent refractive error <-3 D) with and without primary open-angle glaucoma were recruited. Three circumpapillary RNFL scans with diameters of 3.45, 4.50, and 6.00 mm were obtained using spectral-domain OCT. RNFL segmentation errors were manually corrected. Receiver operating characteristic curves of retinal nerve fiber layer thickness (RNFLT) were obtained and area under the curves were calculated before and after manual correction. RESULTS: In total, 90 myopic eyes with glaucoma (90 patients; visual field mean deviation, -9.5±7.1 dB) and 58 myopic eyes without glaucoma (58 control subjects) were included. Glaucomatous eyes required manual correction more frequently than control eyes (56% vs. 32% of RNFL OCT scans; P<0.001). After manual correction in the glaucoma group, the global RNFLT decreased significantly from 61.8 to 57.5 µm (P=0.025), 50.8 to 47.2 µm (P=0.019), and 45.5 to 39.6 µm (P=0.006) for the 3.45-, 4.50-, and 6.00-mm scans, respectively. After manual correction of RNFL segmentation errors, the glaucoma diagnostic capability of the global RNFLT improved significantly; the area under the curves increased from 0.827 to 0.886 (P=0.017), 0.829 to 0.880 (P=0.033), and 0.762 to 0.846 (P=0.006) for the 3.45-, 4.50-, and 6.00-mm scans, respectively. CONCLUSIONS: A significant proportion of myopic eyes had RNFL segmentation errors in automated spectral-domain OCT analysis, decreasing glaucoma diagnostic capability of OCT RNFLT measurement.

Risk factors for multiple epinephrine doses in food-triggered anaphylaxis in children.

BACKGROUND: Food-related anaphylactic reactions may require treatment with more than 1 dose of epinephrine. Current guidelines advise patients at risk of anaphylaxis to carry 2 epinephrine autoinjectors. OBJECTIVE: The objective of this study was to determine risk factors of multiple-dose epinephrine treatment in pediatric food-related anaphylaxis. METHODS: Parents of children with physician-confirmed diagnosis of food allergy were administered a standardized questionnaire at the time of their clinic visit. These patients were then followed-up prospectively by phone. RESULTS: Six hundred forty-two subjects had allergic reactions. Twenty-six percent of patients reported at least 1 reaction treated with epinephrine, for a total of 221 reactions. Among reactions treated with epinephrine, 24 reactions (11%) received 2 or more doses of epinephrine. The most common triggers were milk (30%) and peanut (18%). Milk-triggered allergic reactions (odds ratio [OR] 3.2; 95% confidence interval [CI] 1.2-8.4) and treatment with oxygen (OR 5.0, 95% CI 2.0-12.4) were significant risk factors for requiring multiple doses of epinephrine to treat an allergic reaction. CONCLUSION: This study demonstrates that treatment of anaphylaxis may require more than 1 epinephrine injection. Reactions triggered by milk or requiring treatment with oxygen are at higher risk for needing more than 1 dose of epinephrine. Families of food-allergic children should be counseled on the importance of carrying 2 epinephrine auto-injectors.

A method for age-matched OCT angiography deviation mapping in the assessment of disease- related changes to the radial peripapillary capillaries.

PURPOSE: To present a method for age-matched deviation mapping in the assessment of disease-related changes to the radial peripapillary capillaries (RPCs). METHODS: We reviewed 4.5x4.5mm en face peripapillary OCT-A scans of 133 healthy control eyes (133 subjects, mean 41.5 yrs, range 11-82 yrs) and 4 eyes with distinct retinal pathologies, obtained using spectral-domain optical coherence tomography angiography. Statistical analysis was performed to evaluate the impact of age on RPC perfusion densities. RPC density group mean and standard deviation maps were generated for each decade of life. Deviation maps were created for the diseased eyes based on these maps. Large peripapillary vessel (LPV; noncapillary vessel) perfusion density was also studied for impact of age. RESULTS: Average healthy RPC density was 42.5±1.47%. ANOVA and pairwise Tukey-Kramer tests showed that RPC density in the ≥60yr group was significantly lower compared to RPC density in all younger decades of life (p<0.01). Average healthy LPV density was 21.5±3.07%. Linear regression models indicated that LPV density decreased with age, however ANOVA and pairwise Tukey-Kramer tests did not reach statistical significance. Deviation mapping enabled us to quantitatively and visually elucidate the significance of RPC density changes in disease. CONCLUSIONS: It is important to consider changes that occur with aging when analyzing RPC and LPV density changes in disease. RPC density, coupled with age-matched deviation mapping techniques, represents a potentially clinically useful method in detecting changes to peripapillary perfusion in disease.

Noninvasive Detection of Mitochondrial Dysfunction in Ocular Hypertension and Primary Open-angle Glaucoma.

PURPOSE: To assess mitochondrial dysfunction in vivo in ocular hypertension (OHT) and primary open-angle glaucoma (POAG) using retinal metabolic analysis. PATIENTS AND METHODS: This was an observational, cross-sectional study performed from November 2015 to October 2016 at the New York Eye and Ear Infirmary of Mount Sinai. Thirty-eight eyes with varying stages of POAG, 16 eyes with OHT, and 32 control eyes were imaged on a custom fundus camera modified to measure full retinal thickness fluorescence at a wavelength optimized to detect flavoprotein fluorescence (FPF). Optical coherence tomography was used to measure the retinal ganglion cell-plus layer (RGC+) thickness. Macular FPF and the ratio of macular FPF to RGC+ thickness were the primary outcome variables and were compared among the three groups using an age-adjusted linear regression model. A mixed-effects model was used to assess correlations between FPF variables and clinical characteristics. RESULTS: Both macular FPF and the macular FPF/RGC+ thickness ratio were significantly increased in OHT compared with control eyes (P<0.05 and <0.01, respectively). In POAG eyes, macular FPF was not significantly increased compared with controls (P=0.24). However, the macular FPF/RGC+ thickness ratio in POAG eyes was significantly increased compared with controls (P<0.001). FPF was significantly correlated to age in POAG eyes. CONCLUSIONS: Despite lacking clinical evidence of glaucomatous deterioration, OHT eyes displayed significantly elevated macular FPF, suggesting that mitochondrial dysfunction may be detected before structural changes visible on current clinical imaging. Our preliminary results suggest that macular FPF analysis may prove to be a useful tool in assessing and evaluating OHT and POAG eyes.

Association of Myopia With Peripapillary Perfused Capillary Density in Patients With Glaucoma: An Optical Coherence Tomography Angiography Study.

Importance: This study used optical coherence tomographic angiography to assess for impaired blood flow in myopic eyes with or without open-angle glaucoma. Objective: To compare the peripapillary perfused capillary density (PCD) between eyes with and without glaucoma. Design, Setting, and Participants: In this cross-sectional study at a tertiary glaucoma referral practice, we recruited patients with myopic eyes of spherical equivalent of more than -3.0 diopters with and without open-angle glaucoma, patients with nonmyopic eyes with glaucoma, and patients with no disease from February 2016 to October 2016. We obtained 4.5 × 4.5-mm optical coherence tomographic angiography images of the optic nerve head and calculated PCD as the ratio of pixels associated with capillaries to the number of pixels in the region of interest after large blood vessel removal. Both eyes of each patient were used in the analysis. Continuous variables were assessed by analysis of variance and Tukey tests. A marginal model of generalized estimating equations was performed to adjust for confounding factors and intraclass correlations. Main Outcomes and Measures: Mean PCD. Results: We matched 87 patients with myopic eyes with glaucoma (of whom 39 [45%] were women), 17 with myopic eyes without glaucoma (of whom 10 [59%] were women), and 93 with non-myopic eyes with glaucoma (of whom 55 [59%] were women) for visual field defects and included 51 control participants (or whom 38 [75%] were women). Mean (SD) ages were 67.5 (12.0) years for patients with myopia and glaucoma, 48.2 (19.0) years for those with myopia without glaucoma, 67.3 (11.0) years for those with glaucoma without myopia, and 64.7 (8.9) years in control participants. Global PCD demonstrated a progressive decrease from the control group (mean [SD], 41.0 [4.2]) to those with myopia without glaucoma (38.4 [5.8]) to those with glaucoma without myopia (31.9 [7.5]) to those with both (28.2 [6.0]; all P < .001). The mean difference in global PCD between the 3 groups and control group, adjusted for age and axial length, was greatest in those with myopia and glaucoma (-11.1; 95% CI, -14.0 to -8.1; P < .001), followed by those with glaucoma without myopia (-8.6; 95% CI, -10.9 to -6.3; P < .001) and those with myopia without glaucoma (-2.8; 95% CI, -6.9 to 1.2; P = .17). No interaction was found between glaucoma and myopia. Conclusions and Relevance: These findings demonstrate peripapillary microvascular attenuation to a greater extent in open-angle glaucoma than myopia. The cross-sectional design means we cannot determine if this association is a cause and/or is associated with other confounding factors.

Pattern of peripapillary capillary density loss in ischemic optic neuropathy compared to that in primary open-angle glaucoma.

PURPOSE: Both non-arteritic anterior ischemic optic neuropathy (NAION) and primary open-angle glaucoma (POAG) damage retinal ganglion cell axons, which are perfused by the radial peripapillary capillaries. To evaluate the pattern of ischemia, we compared peripapillary capillary density (PCD) in NAION eyes to POAG eyes matched for visual field mean deviation and retinal nerve fiber layer thickness. METHODS: 31 chronic NAION (>6 months after the acute event) and unaffected fellow eyes (31 subjects), 42 moderate and severe POAG eyes (27 subjects), and 77 control eyes (46 healthy subjects) were imaged with a commercial optical coherence tomography angiography system (AngioVue, Avanti RTVue-XR, Optovue, CA) at two academic institutions. Two concentric circles of diameters 1.95mm (inner) and 3.45mm (outer) were manually placed on images centered on the optic nerve head, producing an annular region-of-interest. Image analysis with major vessel removal was performed using a custom program. Whole-image, whole-annulus, and sectoral PCDs were measured. RESULTS: Whole-image and whole-annulus PCDs in NAION and moderate and severe POAG eyes were significantly decreased compared to unaffected fellow eyes and control eyes (all P<0.001). Superior and temporal PCD values were affected more than other sectors in both NAION and POAG groups compared to control group. Whole-image and whole-annulus PCDs were not statistically different between NAION and POAG eyes (both P = 0.99). However, of all peripapillary sectors, the inferior sector PCD value was less affected in POAG eyes compared to NAION eyes (P = 0.001). Univariate analysis results also revealed a significant positive correlation between superior and inferior PCDs and corresponding RNFL thicknesses. The inferior sector correlation was greater in POAG than NAION eyes. CONCLUSION: While the whole PCD values were not different in chronic NAION and POAG, the greater correlation of inferior PCD with corresponding RNFL sectors in POAG compared to NAION suggests greater susceptibility of the inferior radial peripapillary capillary in the pathogenesis of POAG.

Peripapillary Perfused Capillary Density in Exfoliation Syndrome and Exfoliation Glaucoma versus POAG and Healthy Controls: An OCTA Study.

PURPOSE: To compare the peripapillary perfused capillary density (PCD) among eyes with exfoliation syndrome (XFS), exfoliation glaucoma (XFG), primary open-angle glaucoma (POAG), and controls. DESIGN: Observational, cross-sectional study. METHODS: Optical coherence tomography angiography (OCTA) images (4.5×4.5 mm) of the optic nerve head were obtained using a commercial spectral domain OCTA system (AngioVue Avanti RTVue-XR, OptoVue, Fremont, CA). Two concentric circles with 1.95-mm (inner) and 3.45-mm (outer) diameters were placed manually, producing an annulus of width 0.75 mm centered at the optic disc. PCD was calculated as the ratio of pixels associated with capillaries to the pixels in the annulus after large blood vessel removal. Continuous variables were assessed by analysis of variance and Tukey honest significant difference (HSD) test. Multiple linear regression analysis was performed to adjust for confounding factors. RESULTS: Forty-three XFG eyes, 31 POAG eyes matched for visual field mean deviation, 33 XFS eyes, and 45 control eyes were analyzed. PCD demonstrated a progressive decrease from controls to XFS to POAG to XFG. Pairwise comparisons revealed significant differences in PCD between each pair of groups (all P<0.01) except for PCD between XFS and POAG (P = 0.08). A multivariable model adjusting for age and stage showed a more significant decrease in PCD in XFG compared with POAG (P = 0.001). CONCLUSIONS: PCD was more significantly decreased in XFG compared with POAG eyes and in XFS compared with control eyes. OCTA provides the first quantitative evidence of the microvascular disturbance that accompanies XFS.

Peripapillary perfused capillary density in primary open-angle glaucoma across disease stage: an optical coherence tomography angiography study.

AIMS: To assess peripapillary perfused capillary density (PCD) in primary open-angle glaucoma (POAG) across stage of disease. METHODS: In this observational, cross-sectional study, 60 eyes with varying stages of POAG and 24 control eyes were imaged on a spectral domain optical coherence tomography angiography system (AngioVue, Optovue, Fremont, California, USA) generating images centred on the optic nerve head. Major blood vessels were removed using custom automated software. PCD was calculated as a percentage as the ratio of pixels associated with perfused capillaries to the total number of pixels in the corresponding region-of-interest (ROI). Analysis of covariance was used to compare PCD among the subject groups and control for possible covariates. Area under the receiver operating characteristic curve (AROC) and sensitivity at 95% specificity were calculated to assess the capability of PCD to distinguish mild glaucoma from control. The Pearson's product-moment correlation coefficient was used to assess correlations between PCD and circumpapillary retinal nerve fibre layer thickness (cpRNFLT) and visual field mean deviation (MD). RESULTS: PCD demonstrated a progressive stepwise decrease from control eyes throughout worsening POAG stage at all ROIs. PCD demonstrated AROC and sensitivity values comparable to cpRNFLT and visual field parameters and exhibited significant correlations with cpRNFLT and MD at all corresponding ROIs. CONCLUSIONS: PCD displayed significant correlations with morphological and functional indices and exhibited diagnostic capabilities comparable to currently employed clinical variables. Our preliminary results suggest that PCD analysis may prove to be a useful tool in monitoring POAG across stage and identifying early POAG.

Acircularity index and axis ratio of the foveal avascular zone in diabetic eyes and healthy controls measured by optical coherence tomography angiography.

Given the complexity of the current system used to stage diabetic retinopathy (DR) and the risks and limitations associated with intravenous fluorescein angiography (IVFA), noninvasive quantification of DR severity is desirable. We examined the utility of acircularity index and axis ratio of the foveal avascular zone (FAZ), metrics that can noninvasively quantify the severity of diabetic retinopathy without the need for axial length to correct for individual retinal magnification. A retrospective review was performed of type 2 diabetics and age-matched controls imaged with optical coherence tomography angiography (OCTA). Diabetic eyes were divided into three groups according to clinical features: No clinically observable diabetic retinopathy (NoDR), nonproliferative diabetic retinopathy (NPDR), and proliferative diabetic retinopathy (PDR). OCTAs of the superficial and deep vascular layers centered at the fovea were superimposed to form a full vascular layer on which the FAZ was manually traced. Acircularity index and axis ratio were calculated for each FAZ. Significant differences in acircularity index were observed between all groups except for controls vs. NoDR. Similar results were found for axis ratio, although there was no significant difference observed between NPDR and PDR. We demonstrate that acircularity index and axis ratio can be used to help noninvasively stage DR using OCTA, and show promise as methods to monitor disease progression and detect response to treatment.

Visualization of Radial Peripapillary Capillaries Using Optical Coherence Tomography Angiography: The Effect of Image Averaging.

OBJECTIVES: To assess the effect of image registration and averaging on the visualization and quantification of the radial peripapillary capillary (RPC) network on optical coherence tomography angiography (OCTA). METHODS: Twenty-two healthy controls were imaged with a commercial OCTA system (AngioVue, Optovue, Inc.). Ten 10x10° scans of the optic disc were obtained, and the most superficial layer (50-µm slab extending from the inner limiting membrane) was extracted for analysis. Rigid registration was achieved using ImageJ, and averaging of each 2 to 10 frames was performed in five ~2x2° regions of interest (ROI) located 1° from the optic disc margin. The ROI were automatically skeletonized. Signal-to-noise ratio (SNR), number of endpoints and mean capillary length from the skeleton, capillary density, and mean intercapillary distance (ICD) were measured for the reference and each averaged ROI. Repeated measures analysis of variance was used to assess statistical significance. Three patients with primary open angle glaucoma were also imaged to compare RPC density to controls. RESULTS: Qualitatively, vessels appeared smoother and closer to histologic descriptions with increasing number of averaged frames. Quantitatively, number of endpoints decreased by 51%, and SNR, mean capillary length, capillary density, and ICD increased by 44%, 91%, 11%, and 4.5% from single frame to 10-frame averaged, respectively. The 10-frame averaged images from the glaucomatous eyes revealed decreased density correlating to visual field defects and retinal nerve fiber layer thinning. CONCLUSIONS: OCTA image registration and averaging is a viable and accessible method to enhance the visualization of RPCs, with significant improvements in image quality and RPC quantitative parameters. With this technique, we will be able to non-invasively and reliably study RPC involvement in diseases such as glaucoma.

Age-related homeostatic midchannel proteolysis of neuronal L-type voltage-gated Ca²âº channels.

Neural circuitry and brain activity depend critically on proper function of voltage-gated calcium channels (VGCCs), whose activity must be tightly controlled. We show that the main body of the pore-forming α1 subunit of neuronal L-type VGCCs, Cav1.2, is proteolytically cleaved, resulting in Cav1.2 fragment channels that separate but remain on the plasma membrane. This "midchannel" proteolysis is regulated by channel activity, involves the Ca(2+)-dependent protease calpain and the ubiquitin-proteasome system, and causes attenuation and biophysical alterations of VGCC currents. Recombinant Cav1.2 fragment channels mimicking the products of midchannel proteolysis do not form active channels on their own but, when properly paired, produce currents with distinct biophysical properties. Midchannel proteolysis increases dramatically with age and can be attenuated with an L-type VGCC blocker in vivo. Midchannel proteolysis represents a novel form of homeostatic negative-feedback processing of VGCCs that could profoundly affect neuronal excitability, neurotransmission, neuroprotection, and calcium signaling in physiological and disease states.