An Intraocular Pressure Polygenic Risk Score Stratifies Multiple Primary Open-Angle Glaucoma Parameters Including Treatment Intensity.

PURPOSE: To examine the combined effects of common genetic variants associated with intraocular pressure (IOP) on primary open-angle glaucoma (POAG) phenotype using a polygenic risk score (PRS) stratification. DESIGN: Cross-sectional study. PARTICIPANTS: For the primary analysis, we examined the glaucoma phenotype of 2154 POAG patients enrolled in the Australian and New Zealand Registry of Advanced Glaucoma, including patients recruited from the United Kingdom. For replication, we examined an independent cohort of 624 early POAG patients. METHODS: Using IOP genome-wide association study summary statistics, we developed a PRS derived solely from IOP-associated variants and stratified POAG patients into 3 risk tiers. The lowest and highest quintiles of the score were set as the low- and high-risk groups, respectively, and the other quintiles were set as the intermediate risk group. MAIN OUTCOME MEASURES: Clinical glaucoma phenotype including maximum recorded IOP, age at diagnosis, number of family members affected by glaucoma, cup-to-disc ratio, visual field mean deviation, and treatment intensity. RESULTS: A dose-response relationship was found between the IOP PRS and the maximum recorded IOP, with the high genetic risk group having a higher maximum IOP by 1.7 mmHg (standard deviation [SD], 0.62 mmHg) than the low genetic risk group (P = 0.006). Compared with the low genetic risk group, the high genetic risk group had a younger age of diagnosis by 3.7 years (SD, 1.0 years; P < 0.001), more family members affected by 0.46 members (SD, 0.11 members; P < 0.001), and higher rates of incisional surgery (odds ratio, 1.5; 95% confidence interval, 1.1-2.0; P = 0.007). No statistically significant difference was found in mean deviation. We further replicated the maximum IOP, number of family members affected by glaucoma, and treatment intensity (number of medications) results in the early POAG cohort (P ≤ 0.01). CONCLUSIONS: The IOP PRS was correlated positively with maximum IOP, disease severity, need for surgery, and number of affected family members. Genes acting via IOP-mediated pathways, when considered in aggregate, have clinically important and reproducible implications for glaucoma patients and their close family members.

Efficacy of Multiple Dexamethasone Intravitreal Implants for Refractory Retinal Vein Occlusion-Related Macular Edema and Effect of Prior Vitrectomy.

Purpose: To evaluate the efficacy of dexamethasone intravitreal implants (DEX implant) in patients with treatment-resistant macular edema (ME) owing to branch and central retinal vein occlusion (BRVO/CRVO), and the influence of prior vitrectomy on this treatment. Methods: Multicenter retrospective chart review was performed on 40 CRVO and 32 BRVO eyes with persistent ME despite intravitreal anti-vascular endothelial growth factor agents and/or intravitreal triamcinolone, and/or laser therapy. Each patient received ≥1 dexamethasone 700 µg implant between March 2011 and December 2015. Thirteen patients underwent prior vitrectomy. Data were collected on best-corrected visual acuity (BCVA), central macular thickness (CMT), time to relapse, and adverse events. Results: At the end of follow-up, BRVO eyes had a lesser CMT reduction from baseline compared to CRVO eyes (-122.50 ± 152.47 µm and -202.26 ± 194.09 µm, respectively). Neither BRVO nor CRVO eyes had a sustained BCVA benefit (P = 0.7041 and P = 0.7027, respectively). Vitrectomized and nonvitrectomized eyes overall had a sustained significant CMT reduction throughout the study with -192.46 ± 172.62 µm and -164.02 ± 180.36 µm, respectively, at final follow-up. Similar time to relapse of 24.4 ± 6.5 and 23.3 ± 13.5 weeks, respectively, was observed. By the end of follow-up, BCVA had only improved in vitrectomized eyes. However, multivariable regression analyses showed no significant association between vitrectomy status and CMT or BCVA change after the first and last injection. Cataract formation and ocular hypertension occurred in 25% and 17%, respectively. Conclusions: Multiple DEX implant are effective in reducing CMT in patients resistant to previous treatments and appear to be similarly effective in vitrectomized and nonvitrectomized eyes.

Validity of using vision-related quality of life as a treatment end point in intermediate and posterior uveitis.

AIM: To evaluate the responsiveness of the Vision core module 1 (VCM1) vision-related quality of life (VR-QOL) questionnaire to changes in visual acuity in patients with posterior and intermediate uveitis and to validate its use as a clinical end point in uveitis. METHODS: Logarithm of the minimum angle of resolution visual acuity and VR-QOL using the VCM1 questionnaire were prospectively recorded in 37 patients with active posterior segment intraocular inflammation before starting systemic immunosuppression with ciclosporin, tacrolimus or the anti-tumour necrosis factor (TNF) agent, p55TNFr-Ig, and again 3 months later. Spearman analysis was used to correlate improvements in visual acuity and VR-QOL between baseline and 3 months. RESULTS: The correlation between changes in visual acuity and VR-QOL was moderate to good for the worse eye (r = 0.47, p = 0.003), but poor for the better eye (r = -0.05, p = 0.91). The responsiveness indices effect size and standardised response mean were 0.57 and 0.59, respectively, showing that the VCM1 questionnaire is moderately responsive to immunsosuppressive therapy for active uveitis. CONCLUSION: Changes in VR-QOL measured with the VCM1 questionnaire correlated moderately well with changes in the worse eye visual acuity, suggesting that the VCM1 is a valid instrument for monitoring response to treatment in uveitis.

A review of randomized controlled trials of penetrating keratoplasty techniques.

PURPOSE: To assess the effects of variations in operative technique on the outcomes of penetrating keratoplasty (PK). METHOD: Systematic literature review of published randomized controlled trials of operative techniques in PK. MAIN OUTCOME MEASURES: Visual acuity, refractive error, endothelial cell density, graft rejection, intraocular pressure (IOP), and other surgical complications. RESULTS: Twenty-seven trials were identified. Many involved small numbers, some of which were probably compromised by inadequate statistical power. There was some limited evidence from a small number of studies (usually 1 or 2) for preoperative cauterization of the cone in keratoconus, excimer laser trephination, taking into account the effect of trephine sizing on postoperative IOP, taking into account the effect of trephine sizing on postoperative spherical equivalent, using sodium hyaluronate, avoiding vitrectomy if possible, using an iris-fixated posterior chamber lens implant in the absence of capsular support, and adjusting a single continuous suture intraoperatively if used. However, there was little convincing evidence for choosing interrupted suturing versus continuous suturing or for an effect of suturing on final sutures-out astigmatism. Likewise, there was no convincing evidence for the superiority of any lamellar alternative to PK for deep stromal disease. Overall, most of the effects of changing technique were small, and there was no evidence for the superiority of any specific technique in terms of improved quality of life or cost-effectiveness. CONCLUSIONS: There is a need for further studies with which to refine decision-making as regards the choice of operative techniques in PK.

Cyclosporine vs tacrolimus therapy for posterior and intermediate uveitis.

OBJECTIVES: To compare the efficacy and tolerability of tacrolimus and cyclosporine therapy for noninfectious posterior segment intraocular inflammation and to evaluate their effect on peripheral blood CD4(+) T-cell phenotype and activation status. METHODS: Thirty-seven patients who required second-line immunosuppression for posterior segment intraocular inflammation were enrolled in this prospective randomized trial of tacrolimus vs cyclosporine therapy. The main outcome measures were visual acuity, binocular indirect ophthalmoscopy score, adverse effects, and quality of life. In addition, peripheral blood CD4(+) T-cell phenotype and activation status were evaluated by flow cytometry before treatment and at 2, 4, and 12 weeks using CD69, chemokine receptor (CCR4, CCR5, and CXCR3), and intracellular cytokine (tumor necrosis factor alpha, interferon-gamma, and interleukin 10) expression. RESULTS: Thirteen patients (68%) taking tacrolimus and 12 patients (67%) taking cyclosporine responded to treatment. Cyclosporine therapy was associated with a higher incidence of reported adverse effects. Mean arterial pressure and serum cholesterol level were significantly higher at 3 months in the cyclosporine group than the tacrolimus group. No significant difference was detected with regard to effect on quality of life or CD4(+) T-cell phenotype. CONCLUSIONS: Tacrolimus and cyclosporine were similar with regard to efficacy for posterior segment intraocular inflammation, but the results suggested a more favorable safety profile for tacrolimus therapy.

Associations of human crystalline lens retrodots and waterclefts with visual impairment: an observational study.

PURPOSE: To investigate the relationships between visual acuity, contrast sensitivity, and 11 clinicopathologic classes of opacity in the human crystalline lens. METHODS: The Somerset and Avon Eye Study is an observational population study of age-related sight-threatening eye disease, based in Bristol, UK. After excluding eyes with other visually relevant disease, data from 902 individuals aged 55 years or older were analyzed. The associations of lens features (posterior subcapsular cataract, nuclear color, nuclear white scatter, cortical spokes, anterior subcapsular cataract, vacuoles, waterclefts, coronary flakes, focal dots, retrodots, fiber folds), with refracted log minimum angle of resolution (MAR) distance acuity and Pelli-Robson contrast sensitivity, were investigated. Multivariable linear regression models using data from both eyes and taking account of the intraclass correlation between eyes were used for analysis, with the lens features and age included as potential explanatory variables. RESULTS: As anticipated from earlier studies, posterior subcapsular, nuclear, and cortical cataracts were associated with visual impairment. In addition, retrodots were strongly and independently associated in the multivariable models with both impaired visual acuity (P < 0.001) and contrast sensitivity (P < 0.001). Waterclefts were strongly associated with impaired visual acuity (P < 0.001). CONCLUSIONS: Retrodots and waterclefts are associated with visual impairment. A causal relationship between these lens features and retinal image degradation is plausible.

Estimation of the effects of rounding visual acuity data.

AIMS: To examine the effect of rounding of visual acuity data on estimates of surgical performance. METHOD: In this observational study, the distribution of 1-year Snellen visual acuity data from 606 endothelial keratoplasties from the NHSBT UK transplant database was analysed. A curve was fitted to the data and used to estimate the frequencies of partly read Snellen lines. The estimates were used to create a virtual database of grafts with Snellen acuities that included individual letter scores. The virtual database was then sampled to produce datasets for 10 virtual surgeons. Various acuity analysis methods were then applied to simulate possible effects of surgeons rounding their data. RESULTS: Rounding of acuity data was found to have a notable effect on estimates of surgeons' success rates. When a criterion of 6/12 or better was applied, the success rates ranged from 62% to 80% using a conservative method of estimation but ranged from 80% to 94% using a less conservative method. CONCLUSIONS: Rounding of visual acuity scores is an important potential bias in outcome data and should be avoided. If rounding is required we recommend that it is carried out conservatively, giving credit only for lines read completely.