Association of the CYP39A1 G204E Genetic Variant with Increased Risk of Glaucoma and Blindness in Patients with Exfoliation Syndrome.

PURPOSE: Carriers of functionally deficient mutations in the CYP39A1 gene have been recently reported to have a 2-fold increased risk of exfoliation syndrome (XFS). The aim of this study was to evaluate the risk of blindness and related clinical phenotypes of XFS patients carrying the loss-of-function CYP39A1 G204E mutation in comparison with XFS patients without any CYP39A1 mutation. DESIGN: Retrospective case study. PARTICIPANTS: A total of 35 patients diagnosed with XFS carrying the CYP39A1 G204E mutation and 150 XFS patients without any CYP39A1 mutation who were randomly selected from the Japanese XFS cohort. METHODS: Two-sided Fisher exact test with an alpha level < 0.05 was used to estimate the significance of the calculated odds ratio (OR) for all categorical measures. Comparisons between groups of subjects were performed using linear mixed effect models with group as random effect and taking possible dependence between eyes within a subject into account. MAIN OUTCOME MEASURES: Primary analysis compared the incidence of blindness (defined as visual acuity [VA] < 0.05 decimal), prevalence of exfoliation glaucoma (XFG), history of glaucoma surgery, and indices of glaucoma severity such as visual field (VF) mean deviation (MD), intraocular pressure (IOP), and vertical cup-disc ratio (CDR) between CYP39A1 G204E carriers and those without any CYP39A1 mutation. RESULTS: The overall risk for blindness was significantly higher in XFS patients carrying the CYP39A1 G204E variant (10/35 [28.6%]) compared with XFS patients without any CYP39A1 mutations (8/150 [5.4%]; odds ratio [OR], 7.1; 95% confidence interval [CI], 2.7-20.2]; P < 0.001). A higher proportion of XFS patients with the CYP39A1 G204E mutation (23/35 [65.7%]) had evidence of XFG in at least 1 eye compared with the comparison group (41/150 [27.3%]; OR, 5.1; 95% CI, 2.4-11.4]; P < 0.0001). Significantly higher peak IOP, larger vertical CDR, and worse VF MD were also found in CYP39A1 G204E variant carriers (P < 0.001). Additionally, patients with the CYP39A1 G204E mutation (18/35 [51.4%]) required more laser or glaucoma surgical interventions compared with those without any CYP39A1 mutation (32/150 [21.3%], P < 0.001). CONCLUSIONS: Patients with XFS carrying the CYP39A1 G204E mutation had significantly increased risk of blindness, higher occurrence of XFG, and more severe glaucoma compared with patients with XFS without any CYP39A1 mutation.

Twelve-month efficacy and safety of glaucoma filtration device for surgery in patients with normal-tension glaucoma.

PURPOSE: To assess the efficacy and safety of filtration surgery using the EX-PRESS glaucoma filtration device in patients with normal-tension glaucoma (NTG). STUDY DESIGN: Prospective, single-arm, multicenter interventional case series. METHODS: Eyes with NTG underwent EX-PRESS implantation with or without cataract surgery. The efficacy and safety were assessed at 1 day; 1 and 2 weeks; and 1, 3, 6, and 12 months after surgery. The main outcome measure was reduction in intraocular pressure (IOP) from baseline at 3, 6, and 12 months after surgery. Safety assessments included adverse event incidence, postoperative inflammation, and corneal endothelial cell density. RESULTS: Thirty-two Japanese patients (37 eyes) with NTG were enrolled. The mean IOP decreased from 14.8 ± 2.3 mmHg at baseline to 10.0 ± 3.1 mmHg at 12 months after surgery (mean reduction 4.9 ± 4.2 mmHg [31.1%]; P < .0001). IOP-lowering medication use decreased from a mean of 3.3 medications per eye before surgery to 0.1 medications per eye at 12 months after surgery. IOP reductions > 20% were achieved by 61.5% of the eyes at 12 months. Adverse events were typical for filtration procedures, and none was deemed device-related. Postoperative inflammation was mild and self-limiting. The mean corneal endothelial cell density had decreased by 3.3% at 12 months after surgery. CONCLUSION: The EX-PRESS glaucoma filtration device is safe and effective for filtration surgery in patients with NTG, providing mean IOP reduction consistent with recommendations based on the Collaborative NTG Study.

High interleukin-8 level in aqueous humor is associated with poor prognosis in eyes with open angle glaucoma and neovascular glaucoma.

Glaucoma is a leading cause of blindness worldwide. Purpose of this study was to identify molecular markers that were significantly correlated with presence of glaucoma and outcome of glaucoma surgery. To accomplish this, we determined the profiles of pro-inflammatory cytokines in the aqueous humor of 101 glaucoma patients; 31 primary open angle glaucoma (POAG), 38 pseudoexfoliation glaucoma (PEG), and 32 neovascular glaucoma (NVG). We also studied 100 normal subjects as controls. In eyes with POAG or PEG, the level of interleukin (IL)-1α, IL-2, IL-4, IL-8, IL-23, and CCL2 were significantly elevated. In the NVG eyes, many inflammatory cytokines were also highly elevated. IL-8 had the highest odds ratio, and levels of IL-8 and CCL2 were significantly correlated with preoperative IOP or visual field defects in PEG eyes. Principal component analysis showed that IL-8 had the highest association to the IOP-cytokine component, and Cox proportional hazard model indicated that an elevation of IL-8 was a significant risk of filtering surgery failure. Together with modeling of their interactions and prognosis, IL-8 elevation is a significant risk factor both for detecting and managing glaucoma and may serve as a therapeutic target candidate to improve the prognosis of glaucoma surgery.

Treat-and-extend versus every-other-month regimens with aflibercept in age-related macular degeneration.

PURPOSE: To compare the 1-year outcomes of treat-and-extend (TAE) and every-other-month (2M) regimens with intravitreal aflibercept in Japanese wet age-related macular degeneration (AMD) patients. METHODS: Prospective, multicenter, randomized clinical trial. The primary outcome measure was the proportion of eyes in which the best-corrected visual acuity (BCVA) was maintained at week 52 [with a loss of <0.3 logarithm of minimum angular of resolution (logMAR) units]. The secondary outcome measures were the mean change from baseline in the central retinal thickness (CRT) and the number of injections. RESULTS: Forty-one patients were enrolled. The mean changes in the BCVA from baseline in the TAE and 2M were -0.32 ± 0.27 and -0.26 ± 0.30 logMAR units (p = 0.46). The TAE group was noninferior to the 2M group in BCVA maintenance. The mean CRT changes from baseline in the TAE and 2M were -161 ± 133 and -157 ± 90 µm (p = 0.73). The mean number of injections in the TAE and 2M were 7.5 ± 1.2 (range, 7-12) and 8.0 ± 0.0 (p < 0.0001). CONCLUSION: Treat-and-extend (TAE) regimen with aflibercept improved the BCVA and CRT to the same extent as 2M regimen, with a reduced number of injections.

A common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome.

Exfoliation syndrome (XFS) is the most common recognizable cause of open-angle glaucoma worldwide. To better understand the etiology of XFS, we conducted a genome-wide association study (GWAS) of 1,484 cases and 1,188 controls from Japan and followed up the most significant findings in a further 6,901 cases and 20,727 controls from 17 countries across 6 continents. We discovered a genome-wide significant association between a new locus (CACNA1A rs4926244) and increased susceptibility to XFS (odds ratio (OR) = 1.16, P = 3.36 × 10(-11)). Although we also confirmed overwhelming association at the LOXL1 locus, the key SNP marker (LOXL1 rs4886776) demonstrated allelic reversal depending on the ancestry group (Japanese: OR(A allele) = 9.87, P = 2.13 × 10(-217); non-Japanese: OR(A allele) = 0.49, P = 2.35 × 10(-31)). Our findings represent the first genetic locus outside of LOXL1 surpassing genome-wide significance for XFS and provide insight into the biology and pathogenesis of the disease.

Findings of secondary corneal amyloidosis with ultrahigh-resolution optical coherence tomography.

PURPOSE: To describe observations by ultrahigh-resolution optical coherence tomography (OCT) in a secondary corneal amyloidosis (SCA) patient with histological analysis of excised tissue. A unique finding under OCT of her fellow eye is also described. CASE: A 39-year-old female had suffered from trichiasis in both of her eyes for more than 30 years. Slit-lamp examination showed a milky-white soft mass on her left cornea and a linear opacity on the fellow cornea at the cilia-attached region. OCT demonstrated the presence of a mass region within a thin epithelial layer and no destruction of Bowman's layer in her left cornea. In the fellow cornea, which exhibited a linear opacity, a high-density spot in Bowman's layer was observed at the cilia-attached region covered by the epithelial layer, with normal thickness. Histological examination of the excised cornea showed that the mass was positive with both Congo red and antilactoferrin antibody. CONCLUSION: SCA, amyloid gradually accumulates above Bowman's layer, occupying the epithelial layer, with no destruction of Bowman's layer until the advanced stage. A high-density spot in Bowman's layer might be the first stage of SCA.

Robot-assisted vitreoretinal surgery: development of a prototype and feasibility studies in an animal model.

PURPOSE: To develop a prototype robotic system designed to assist vitreoretinal surgery and to evaluate its accuracy and maneuverability. DESIGN: Experimental study. PARTICIPANTS: This study used harvested porcine eyes. METHODS: After development of a prototype robotic system, pointing accuracy tests of the system were performed on graph paper and in harvested porcine eyes. The average maximal deviation from the aiming point to the actual position of the tip of the instrument was compared between manually conducted procedures and those conducted with robotic assistance. The feasibility of creating posterior vitreous detachment (PVD), retinal vessel sheathotomy (RVS), and retinal vessel microcannulation also were evaluated in porcine eye models, and the success rates of 4 consecutive attempts for each kind of procedure were evaluated. MAIN OUTCOME MEASURES: The average maximum deviation in pointing accuracy tests both on graph paper and in animal eye models was a main outcome measure. The success rate of making PVD, RVS, and retinal vessel microcannulation was the other primary outcome measure. RESULTS: The pointing accuracy was superior with robotic assistance both on graph paper (327.0 microm vs. 32.3 microm) and in animal eye models (140.8 microm vs. 33.5 microm). Creating PVD, RVS, and retinal vessel microcannulation was feasible in 4 of 4 attempts, 4 of 4 attempts, and 2 of 4 attempts, respectively. The 2 failures in microcannulation were considered to be the result of difficulty in visual differentiation between the retinal vessel and retina in harvested porcine eyes. CONCLUSIONS: Improved accuracy and desirable feasibility of a prototype robotic system to assist vitreoretinal surgery were shown in this study. Research for wider implementation of robot-assisted surgery should be continued; there are some hurdles to overcome.

Suture fixation of an intraocular lens combined with pars plana vitrectomy and gas tamponade.

We describe suturing an intraocular lens (IOL) after pars plana lensectomy and vitrectomy combined with gas tamponade in 4 patients with vitreoretinal disease and subluxated lenses that could not be managed with capsular tension rings. The IOL haptics were sutured before the fluid-gas exchange in a horizontal (case 1), oblique (cases 2 and 4), and vertical (case 3) manner. In a case of unavoidable horizontal fixation due to limited scleral space, the upper part of the IOL tilted anteriorly postoperatively because of the enhanced effect of the gas bubble. A peripheral anterior iris synechia also occurred. The IOL remained well positioned in cases with oblique and vertical fixations, and no other complications occurred. Careful preoperative planning of the surgical design can help avoid unnecessary horizontal fixation.