Aqueous microRNA profiling in age-related macular degeneration and polypoidal choroidal vasculopathy by next-generation sequencing.

Although many studies demonstrated the differences of clinical features, natural course, and response to treatment between typical age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV), differential microRNAs (miRNAs) expression in the aqueous humor (AH) between them has not been reported yet. We investigated the roles of miRNAs in the AH of patients with typical AMD and PCV using next-generation sequencing (NGS) and quantitative PCR (qPCR). Target genes and predicted pathways of miRNAs were investigated via pathway enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes database. A total of 161 miRNAs from eyes with typical AMD and 185 miRNAs from eyes with PCV were differentially expressed. 33 miRNAs were commonly upregulated, and 77 miRNAs were commonly downregulated in both typical AMD and PCV groups. Among them, hsa-miR-140-5p, hsa-miR-374c-3p, and hsa-miR-200a-5p were differentially expressed and were predicted to regulate proteoglycans in cancer, p53 signaling pathway, Hippo signaling pathway, and adherens junction. The differential expression profiles and target gene regulation networks of AH miRNAs may contribute to the development of different pathological phenotypes in typical AMD and PCV. The results of this study provide novel insights into the pathogenesis, associated prognostic biomarkers, and therapeutic targets in AMD and PCV.

Comparison of lamina cribrosa depth shallowing after trabeculectomy between primary open-angle glaucoma and exfoliation glaucoma.

The lamina cribrosa (LC) becomes shallower as intraocular pressure (IOP) decreases after trabeculectomy. The LC in eyes with exfoliation syndrome has distinctive properties in the connective tissue and extracellular matrix, but how these affect the changes in LC depth in response to IOP reduction after trabeculectomy is unknown. We analyzed pre- and postoperative spectral-domain optical coherence tomography of exfoliation glaucoma (XFG) and primary open-angle glaucoma (POAG) patients who underwent trabeculectomy and investigated whether LC depth differed between XFG and POAG eyes after trabeculectomy. In total, 30 XFG eyes and 30 visual field mean deviation-matched POAG eyes were included. LC depth was determined at an average of 3.9 months after trabeculectomy. Postoperatively, the LC depth became shallower and the BMO-MRW became thicker in both XFG and POAG eyes. XFG eyes showed lesser amount of LC depth shallowing than POAG eyes. Greater preoperative LC depth, lower postoperative IOP, and absence of XFG were all associated with a greater degree of postoperative LC depth shallowing. These findings suggest that the LC of XFG eyes may inherently possess the distinctive properties of the connective tissue and extracellular matrix contained within it, which could affect the LC response to the reduction in IOP after trabeculectomy.

Risk factors for early-onset exfoliation syndrome.

Although exfoliation syndrome (XFS) is an age-related, late-onset disease, early-onset XFS has been reported, and its associated factors remain unknown. In this study, we investigated the clinical features and risk factors of early-onset XFS. The participants were divided into two groups according to age at the time of XFS diagnosis: early-onset (< 60 years) or late-onset (≥ 70 years) group. Among the 302 eyes of 240 patients with XFS, the early-onset group included 41 eyes (14%) of 33 patients, and the late-onset group included 163 eyes (54%) of 126 patients; the mean age was 54.8 ± 5.0 and 76.6 ± 4.9 years, respectively (p < 0.001). All eight cases diagnosed with XFS at the earliest age, ranging from 36 to 52 years, underwent trabeculectomy before the diagnosis of XFS. Multivariable logistic regression analysis showed that a history of trabeculectomy (odds ratio [OR] = 11.435, p < 0.001), presence of iridectomy (OR = 11.113, p < 0.001), and longer axial length (OR = 2.311, p = 0.003) were significantly associated with the development of early-onset XFS. Collectively, patients with early-onset XFS were more likely to have undergone trabeculectomy and have more axial myopia compared with those with late-onset XFS. These findings suggest that surgical trauma compromising the blood-aqueous barrier may trigger early manifestation of XFS.

Cytokine and Growth Factor Analysis in Exfoliation Syndrome and Glaucoma.

Purpose: We compared cytokines, chemokines, and growth factors in the aqueous humor (AH) of patients with exfoliation syndrome (XFS), with exfoliation glaucoma (XFG), with primary open angle glaucoma (POAG), and healthy controls. Methods: AH samples were collected from 21 patients with XFS, 28 with XFG, 14 with POAG, and 17 healthy controls during routine cataract surgery. The protein levels of 21 cytokines and growth factors, together with TGF-ß1, 2, and 3, were quantified using the multiplex immunoassay. The levels of each protein in the four groups were compared using the Kruskal-Wallis test. Results: Among the 24 cytokines and growth factors, 16 were out of the detectable range in >50% of samples in at least one group; the remaining 8 cytokines and growth factors (IL-8, MIP-1α, fractalkine, Flt3 ligand, PDGF-AA, VEGF, TGF-ß1, and TGF-ß2) were included in the analysis. TGF-ß1 and TGF-ß2 levels were the highest in patients with XFG and those with POAG, respectively. Expression levels of the inflammatory chemokines IL-8, MIP-1α, and fractalkine, as well as levels of the immune cell growth factor Flt3 ligand, were significantly higher in the XFG group than in the other groups. The protein levels of PDGF-AA and VEGF were not significantly different among the 4 groups. Conclusions: Both TGF-ß1 and inflammatory cytokines were highly expressed in the AH of patients with XFG. Considering that the levels of these cytokines are increased by oxidative stress and that they regulate the extracellular matrix, they may also play a role in intraocular pressure elevation in XFG.

Factors Associated with Increased Neuroretinal Rim Thickness Measured Based on Bruch's Membrane Opening-Minimum Rim Width after Trabeculectomy.

PURPOSE: To investigate the factors associated with an increase in the neuroretinal rim (NRR) thickness measured based on Bruch's membrane opening-minimum rim width (BMO-MRW) after trabeculectomy in patients with primary open-angle glaucoma (POAG). METHODS: We analyzed the BMO-MRW using spectral-domain optical coherence tomography (SD-OCT) of patients with POAG who underwent a trabeculectomy for uncontrolled intraocular pressure (IOP) despite maximal IOP reduction treatment. The BMO-MRW was measured before and after trabeculectomy in patients with POAG. Demographic and systemic factors, ocular factors, pre- and post-operative IOP, and visual field parameters were collected, together with SD-OCT measurements. A regression analysis was performed to investigate the factors that affected the change in the BMO-MRW after the trabeculectomy. RESULTS: Forty-four eyes of 44 patients were included in the analysis. The IOP significantly decreased from a preoperative 27.0 mmHg to a postoperative 10.5 mmHg. The mean interval between the trabeculectomy and the date of post-operative SD-OCT measurement was 3.3 months. The global and sectoral BMO-MRW significantly increased after trabeculectomy, whereas the peripapillary retinal nerve fiber layer thickness did not show a difference between before and after the trabeculectomy. Younger age and a greater reduction in the IOP after the trabeculectomy were significantly associated with the increase in the BMO-MRW after trabeculectomy. CONCLUSIONS: The NRR thickness measured based on the BMO-MRW increased with decreasing IOP after trabeculectomy, and the increase in the BMO-MRW was associated with the young age of the patients and greater reduction in the IOP after trabeculectomy. Biomechanically, these suggest that the NRR comprises cells and substances that sensitively respond to changes in the IOP and age.

Open-angle Glaucoma and Sensorineural Hearing Impairment in the Korean Population.

PURPOSE: This study identifies the prevalence and risk factors of sensorineural hearing loss and primary open-angle glaucoma (POAG). MATERIALS AND METHODS: Patients aged 19 years or older who had undergone both ophthalmologic examination and audiometry as part of the Korea National Health and Nutrition Examination Survey V (2010-2012) were analyzed. Hearing loss was defined as the pure-tone average over 40 decibels based on the automatic hearing test to determine the threshold of airway hearing for each frequency. We investigated the prevalence of glaucoma and hearing loss when they occurred alone or simultaneously. The risk factors for concurrent glaucoma and hearing loss were examined. RESULT: Among the participants, 6.6% had hearing loss alone, 2.3% had glaucoma alone, and 0.5% had both glaucoma and hearing loss. The weighted prevalence of glaucoma in patients with hearing loss was 7.5%; however, the weighted prevalence of glaucoma was 3.2% among patients without hearing loss, with a significant difference (P < .001). Multivariable logistic regression analysis revealed that the risk factors associated with concurrent glaucoma and hearing loss were age (3.786 times per 10 years, P < .001) and triglyceride level (1.002 times per 1 mg/dL, P = .028). CONCLUSION: Sensorineural hearing loss and POAG are relevant. If hearing impairment and visual impairment occur together, the quality of life of the patient is worsened and the social burden is greater. Therefore, care should be taken when treating elderly patients with glaucoma.

Comparison of the retinal nerve fiber layer and ganglion cell complex thickness in Korean patients with unilateral exfoliation syndrome and healthy subjects.

PURPOSE: To compare retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) thickness in patients with unilateral exfoliation syndrome (XFS) and age-matched controls using spectral domain-optical coherence tomography (SD-OCT). MATERIALS AND METHODS: This prospective case-control study included 54 eyes (the XFS-affected and the fellow eyes) of 27 unilateral XFS patients and 27 eyes of 27 age-matched control subjects. The RNFL and GCC thicknesses were measured using SD-OCT (RT-Vue 100, Optovue, Fremont, CA) after pupillary dilation. RNFL and GCC thicknesses were compared between case and control groups. RESULTS: The mean age of XFS patients was 73.3 years and that of age-matched controls was 74.3 years. Both groups demonstrated a male preponderance. Superior RNFL thickness of XFS-affected eyes were significantly thinner than those of the healthy age-matched controls (P = 0.002 by ANOVA). There were no statistically significant differences in the RNFL thickness between both eyes of unilateral XFS patients. Moreover, superior GCC thickness of both eyes in unilateral XFS patients were thinner than those in controls (P = 0.002 by ANOVA). CONCLUSIONS: Thinner RNFL and GCC thicknesses were observed in unilateral XFS patients without visual field defects. These findings imply that XFS itself might be a risk factor for development of glaucomatous optic disc and RNFL damage.

A Path Analysis of Effects of Patients' Underlying Conditions, Treatment Satisfaction, and Adherence on Quality of Life Among Korea Glaucoma Patients.

PRéCIS:: This observed patient-specific features and treatment-driven conditions that were significantly associated with the impairment of health-related quality of life (HRQOL) among glaucoma patients. The results suggest that more systematic strategies should be implemented to improve an HRQOL. PURPOSE: To determine factors contributing to an HRQOL and assess total, direct and indirect, effects that may exist between the determinants using path analysis. MATERIALS AND METHODS: Data were derived from previous Korea glaucoma outcomes research. A total of 847 glaucoma outpatients with ≤2 years of eye-drop use were included in the present study. Including factors and their hypothetical pathways to an HRQOL were based on the literature review and consultation with specialists. Age, sex, comorbidities, and education levels were included as underlying conditions and treatment patterns were defined by the number of daily instillations of prescribed eye-drops. Treatment satisfaction and adherence were estimated using a Treatment Satisfaction Questionnaire for Medication, which assessed side-effects, effectiveness, convenience, global satisfaction, and pill count. An HRQOL was assessed by EQ-5D and EQ-visual analogue scale (EQ-VAS). RESULTS: In EQ-5D analysis, male individuals showed total effects (ß=0.102, P=0.0026), including both direct (ß=0.076, P=0.0095) and indirect effects (ß=0.0253, P=0.0020), which were mediated by treatment satisfaction in the side effects and global satisfaction categories. Higher education (ß=0.197, P=0.0020) and satisfaction in the side effect (ß=0.095, P=0.0076) and global satisfaction (ß=0.075, P=0.0414) categories were found to have direct effects on EQ-5D. For EQ-VAS, higher education levels had significant total effects (ß=0.153, P=0.0020) accounting for direct effects (ß=0.131, P=0.0030) and indirect effects (ß=0.0223, P=0.0531) through global satisfaction. In addition, male individuals had indirect effects (ß=0.274, P=0.0165), which was indirectly mediated by satisfaction in the global satisfaction category. Comorbidity (ß=-0.096, P=0.0090) and satisfaction in the effectiveness (ß=0.094, P=0.0302), convenience (ß=0.076, P=0.0390), and global satisfaction (ß =0.144, P=0.0020) categories showed indirect effect on EQ-VAS. CONCLUSION: Higher education and better treatment satisfaction had positive effects on HRQOL both in direct and indirect ways whereas comorbidities indirectly showed negative associations with HRQOL.

Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci.

Exfoliation syndrome (XFS) is the most common known risk factor for secondary glaucoma and a major cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A, have previously been associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results across populations, and to identify new variants associated with XFS. We identified a rare protective allele at LOXL1 (p.Phe407, odds ratio (OR) = 25, P = 2.9 × 10-14) through deep resequencing of XFS cases and controls from nine countries. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 × 10-8). We identified association signals at 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.

Treatment patterns and medication adherence of patients with glaucoma in South Korea.

BACKGROUND/AIMS: This study aimed to investigate treatment patterns and medication adherence of glaucoma. It also identified key factors associated with non-adherence. METHODS: It was a cross-sectional, observational study. Patients who use eye-drops for ≤2 years were recruited at 15 eye clinics from March to November 2013. Data were collected through self-administered questionnaires and medical chart review. Medication adherence was evaluated using patients' self-report on pill count and defined as patients' administering drug for ≥80% of prescribed days. Medication adherence rate was calculated by dividing actual number of administration from total prescribed number of administration for 7 days. Patients whose self-reported prescription was different from total daily doses of physicians' prescription were considered as non-adherent. RESULTS: A total of 1050 patients included, and medication adherence rate was evaluated in 1046 patients whose verification of adherence was available. Of the total, 27.4% were non-adherent, and the medication adherence rates of the total, the adherent, and the non-adherent were 90.6±17.8%, 96.8±5.5% and 56.6±24.7%, respectively. The most commonly used medication was prostaglandin (PGA) alone and the second was combination of two-class (ß-blocker and carbonic anhydrase inhibitor (CAI)) and three-class combination of PGA, ß-blocker and CAI followed. In multivariate analysis, the risk of non-adherence was 1.466 times greater in males than in females (95% CI 1.106 to 1.943) and 1.328-fold greater as the daily number of administration was increased (95% CI 1.186 to 1.487). CONCLUSION: Approximately, one-third of the patients were non-adherent, and males and increased daily number of administration were associated with non-adherence. It highlights that more systematic treatment strategies should be considered for better medication adherence, leading to effective glaucoma management.

Long-term Outcomes of Mitomycin-C Trabeculectomy in Exfoliative Glaucoma Versus Primary Open-Angle Glaucoma.

PURPOSE: To compare long-term surgical outcomes in exfoliative glaucoma (XFG) versus primary open-angle glaucoma (POAG) after primary trabeculectomy with mitomycin-C. METHODS: This retrospective, case-control study included 32 eyes of XFG and 64 eyes of POAG matched by propensity score analysis. Surgical success was defined according to 3 different criteria: (1) intraocular pressure (IOP)<18 mm Hg and IOP reduction ≥20% without medication; (2) IOP<15 mm Hg and IOP reduction ≥25% without medication; and (3) IOP<18 mm Hg and IOP reduction ≥20% with or without medication. Cumulative probabilities of success were compared using Kaplan-Meier survival analysis, and risk factors of surgical failure were analyzed. RESULTS: Cumulative success rates were 84.4% at 1 year and 19.9% at 5 years for XFG, and 82.3% and 64.7%, respectively, for POAG by criterion A. Complete success rates were significantly lower for XFG than for POAG by criteria A and B. However, qualified success, as determined by criterion C, did not show a statistically significant difference. Postoperative hyphema was more frequent for XFG. The risk factors associated with surgical failure were a young age (<60 y; hazard ratio=2.58, P=0.047, criterion A) and exfoliation syndrome (hazard ratio=3.01, 2.96, P=0.006, 0.005, criteria A and B). CONCLUSIONS: Although trabeculectomy for XFG had success rates similar to POAG at 1 year, XFG showed poorer long-term IOP control from 2 years postoperatively. This study indicates that it is more difficult to achieve long-term low target IOP control in eyes with XFG than in eyes with POAG after trabeculectomy with mitomycin-C.

Prevalence of Pseudoexfoliation Syndrome and Associated Factors in South Koreans: The Korean National Health and Nutrition Examination Survey.

PURPOSE: To investigate the prevalence of pseudoexfoliation syndrome (PXS) and factors associated with PXS in South Koreans by analyzing data from the Korean National Health and Nutrition Examination Survey (KNHANES). METHODS: Using the KNHANES database of 2009-2012, 13,223 participants aged 50 years or older were included. Participants underwent standardized interviews and systemic and ocular examinations. Systemic factors analyzed included age, sex, daily length of sun exposure, presence of Raynaud phenomenon or migraine, hypertension, diabetes mellitus, body mass index, serum lipid profile, duration and frequency of smoking, and alcohol consumption. Evaluated ocular factors were refractive error, presence of cataract and glaucoma, intraocular pressure, and peripheral anterior chamber depth. Logistic regression analysis was performed to identify factors associated with the presence of PXS. RESULTS: PXS was found in 16 participants (0.12%). When compared with the non-PXS group, eyes with PXS showed a higher prevalence of cataract (p = 0.020). In logistic regression analysis, age (odds ratio, OR, 1.04, 95% confidence interval, CI, 0.99-1.09; p = 0.016) and the presence of cataract (OR 8.17, 95% CI 1.06-62.84; p = 0.044) were associated with the presence of PXS. Sun exposure for ≥5 hours/day was marginally associated with the presence of PXS (OR 2.76, 95% CI 0.96-7.95; p = 0.060). CONCLUSION: The prevalence of PXS per 1000 persons was 1.10 in South Koreans aged ≥50 years. Participants with PXS had a higher prevalence of cataract, were older, and were more likely to be exposed to the sun for ≥5 hours/day than participants without PXS.

Acute angle-closure glaucoma in a highly myopic patient secondary to Weill-Marchesani syndrome: histopathologic lens features.

The authors describe a case of acute angle-closure glaucoma in a highly myopic patient secondary to Weill-Marchesani syndrome (WMS) and histopathologic features of his lens. A 37-year-old male patient visited our clinic for ocular pain with elevated intraocular pressure (19/57 mmHg). The slit-lamp examination showed an inferiorly subluxated lens in the right eye, and anterior dislocated microspherophakia with corneolenticular contact in the left eye. The physical examination showed brachydactyly and relatively short stature. To control the IOP and to improve visual acuity, lens extraction, anterior vitrectomy, and scleral-sutured IOL implantation surgery were performed. To the best of our knowledge, this is the first histopathologic report of bilateral lens in a Korean patient with WMS. The pathologic specimens showed epithelial cell changes, hyaloid degeneration, and subcapsular cortical fiber changes. The authors attributed these changes to physical and mechanical factors because the lens is highly mobile and often comes in contact with the iris.

Recurrent symptomatic intraocular pressure spikes during hemodialysis in a patient with unilateral anterior uveitis.

BACKGROUND: The relationship between intraocular pressure (IOP) changes and hemodialysis has been evaluated for several decades. However, no report on an IOP rise in uveitis patients during hemodialysis has been previously documented. This report describes the case of an uveitis patient with repetitive IOP spikes associated with severe ocular pain during hemodialysis sessions, which resolved after glaucoma filtering surgery. CASE PRESENTATION: A 47-year-old male with diabetes and hypertension had complained of recurrent ocular pain in the left eye during hemodialysis sessions. A slit-lamp examination showed diffuse corneal epithelial edema with several white keratic precipitates and inflammatory cells (Grade 3+) in the anterior chamber of the left eye. No visible neovascularization or synechiae were visible on the iris or angle. Topical glaucoma eye-drops and intravenous mannitol before hemodialysis did not prevent subsequent painful IOP spikes in the left eye. At the end of hemodialysis, IOP averaged ~40 mmHg. After trabeculectomy with mitomycin C in the left eye, his IOP stabilized in the low-teens (range, 10-14 mmHg) and no painful IOP spikes occurred during hemodialysis over the first postoperative year. CONCLUSION: We present a case of recurrent painful IOP spikes during hemodialysis in a patient with unilateral anterior uveitis unresponsive to conventional medical treatment prior to hemodialysis. To our knowledge, this is the first case report of repetitive symptomatic IOP rise during hemodialysis in an uveitic glaucoma patient. This case highlights the importance of the awareness of the possibility that IOP may rise intolerably during hemodialysis in uveitis patients with a compromised outflow facility.

Association of lysyl oxidase-like 1 gene polymorphisms with exfoliation syndrome in Koreans.

PURPOSE: To evaluate the association of the lysyl oxidase-like 1 (LOXL1) single nucleotide polymorphisms (SNPs) in the Korean population with exfoliation syndrome (XFS) and to investigate the association between the SNPs and phenotypes of XFS. METHODS: Eighty-nine unrelated patients with XFS and 146 unrelated control subjects were recruited. LOXL1 SNPs, rs1048661, rs3825942, and rs2165241, were genotyped by direct DNA sequencing. Association between cases and controls was analyzed and phenotypic features of XFS were compared in terms of the SNPs. RESULTS: The three SNPs were found to be significantly associated with XFS. After adjusting for rs3825942, rs2165241, and other factors influencing the prevalence of XFS, only rs1048661 among three SNPs remained significant (95% confidence interval=4.11-35.78, p=6.11×10(-6)). T allele and TT genotype of rs1048661 and C allele and CC genotype of rs2165241 were associated with XFS, showing risk alleles and genotypes opposite to those reported in Caucasians. In the haplotype analysis, T-G-C was the only risk haplotype (p=3.35×10(-12)), which was not associated with XFS in Caucasians. No significant differences were noted in the allele and genotype frequencies depending on phenotypic features of XFS. CONCLUSIONS: Three LOXL1 SNPs are associated with XFS in the Korean population. Risk alleles and genotypes of rs1048661 and rs2165241 in Korean have a similar pattern with those of East Asians, including Japanese and Northern Chinese, while they have a different pattern from those of Caucasians.