Low-fluence photodynamic therapy versus ranibizumab for chronic central serous chorioretinopathy: one-year results of a randomized trial.

PURPOSE: To compare the efficacy and safety between low-fluence photodynamic therapy (PDT) and the intravitreal ranibizumab in the treatment of chronic central serous chorioretinopathy (CSC). DESIGN: Prospective, randomized, single-center, parallel-arm, controlled trial. PARTICIPANTS: Thirty-four eyes of 32 patients with chronic CSC with >6 months' duration of symptoms or recurrent CSC were randomly placed into the low-fluence PDT group (n = 18) or the ranibizumab group (n = 16). INTERVENTION: The patients underwent a single session of low-fluence PDT or 3 consecutive monthly injections of ranibizumab. Rescue treatment was available from month 3 if the subretinal fluid (SRF) persisted or recurred after primary treatment; low-fluence PDT was given to the ranibizumab group and intravitreal ranibizumab to the low-fluence PDT group. MAIN OUTCOME MEASURES: The primary outcome was the proportion of eyes with complete resolution of SRF without rescue treatment. Secondary outcomes included the mean changes in logarithm of the minimum angle of resolution best-corrected visual acuity (BCVA), central retinal thickness (CRT), and angiographic findings from baseline to 12 months. RESULTS: At month 12, 16 eyes (88.9%) of the low-fluence PDT group maintained complete resolution of SRF without rescue treatment versus 2 eyes (12.5%) in the ranibizumab group (P <0.001). Two eyes (11.1%) in the low-fluence PDT group and 11 eyes (68.8%) in the ranibizumab group met the criteria for rescue treatment (P = 0.001). In the low-fluence PDT group, the mean decrease in CRT from baseline was significantly greater than that in the ranibizumab group until month 6 (P <0.05), but the differences became insignificant thereafter. The improvement in BCVA from baseline was superior in the low-fluence PDT group to that in the ranibizumab group, but the differences were not statistically significant except at month 3 (P = 0.025). On indocyanine green angiography, a significantly greater proportion of the low-fluence PDT group (16 eyes; 88.9%) showed a marked reduction in choroidal hyperpermeability after primary treatment than that of the ranibizumab group (0 eyes; P <0.001). No serious adverse events related to the drugs or procedures were observed. CONCLUSIONS: This study represents the overall superiority of low-fluence PDT compared with intravitreal ranibizumab in the treatment of chronic CSC.

Microarray-based mutation detection and phenotypic characterization in Korean patients with retinitis pigmentosa.

PURPOSE: To evaluate microarray-based genotyping technology for the detection of mutations responsible for retinitis pigmentosa (RP) and to perform phenotypic characterization of patients with pathogenic mutations. METHODS: DNA from 336 patients with RP and 360 controls was analyzed using the GoldenGate assay with microbeads containing 95 previously reported disease-associated mutations from 28 RP genes. Mutations identified by microarray-based genotyping were confirmed by direct sequencing. Segregation analysis and phenotypic characterization were performed in patients with mutations. The disease severity was assessed by visual acuity, electroretinography, optical coherence tomography, and kinetic perimetry. RESULTS: Ten RP-related mutations of five RP genes (PRP3 pre-mRNA processing factor 3 homolog [PRPF3], rhodopsin [RHO], phosphodiesterase 6B [PDE6B], peripherin 2 [PRPH2], and retinitis pigmentosa 1 [RP1]) were identified in 26 of the 336 patients (7.7%) and in six of the 360 controls (1.7%). The p.H557Y mutation in PDE6B, which was homozygous in four patients and heterozygous in nine patients, was the most frequent mutation (2.5%). Mutation segregation was assessed in four families. Among the patients with missense mutations, the most severe phenotype occurred in patients with p.D984G in RP1; less severe phenotypes occurred in patients with p.R135W in RHO; a relatively moderate phenotype occurred in patients with p.T494M in PRPF3, p.H557Y in PDE6B, or p.W316G in PRPH2; and a mild phenotype was seen in a patient with p.D190N in RHO. CONCLUSIONS: The results reveal that the GoldenGate assay may not be an efficient method for molecular diagnosis in RP patients with rare mutations, although it has proven to be reliable and efficient for high-throughput genotyping of single-nucleotide polymorphisms. The clinical features varied according to the mutations. Continuous effort to identify novel RP genes and mutations in a population is needed to improve the efficiency and accuracy of the genetic diagnosis of RP.

Changes in ciliary body thickness in patients with diabetic macular edema after vitrectomy.

PURPOSE: The purpose of the study to determine whether ciliary body thickness increased in the presence of diabetic macular edema (DME) and whether it changed after pars plana vitrectomy. METHODS: A DME group consisted of 26 diabetic patients who underwent pars plana vitrectomy for diffuse DME. An epiretinal membrane group, a surgical control group, consisted of 23 nondiabetic patients with epiretinal membrane who underwent pars plana vitrectomy. A healthy control was also included for the comparison of preoperative ciliary body thickness. Ciliary body thickness was measured using ultrasound biomicroscopy, and central macular thickness was determined using optical coherence tomography. The visual acuity, ciliary body thickness, and central macular thickness were compared between groups before and 1, 2, and 4 months after pars plana vitrectomy, and the correlations between the central macular thickness and ciliary body thickness and best-corrected visual acuity were determined. RESULTS: The preoperative ciliary body thickness was increased significantly in the DME group compared with the epiretinal membrane and healthy control groups (both P < 0.001). The ciliary body thickness decreased significantly 1 and 2 months after surgery in the DME group (both P < 0.001) but not in the epiretinal membrane group. In the DME group, the postvitrectomy changes in the ciliary body thickness and central macular thickness showed similar trends and persisted significantly, until 4 months postoperatively (P = 0.027 and P = 0.010, respectively). The correlations between the preoperative central macular thickness and ciliary body thickness and between changes in central macular thickness and ciliary body thickness before and 2 months after surgery were not significant. CONCLUSION: Ciliary body thickness was increased in patients with DME, and vitrectomy was effective in decreasing ciliary body edema as well as macular edema in those patients during the 4-month follow-up period.

Spectrum of rhodopsin mutations in Korean patients with retinitis pigmentosa.

PURPOSE: To determine the spectrum and frequency of rhodopsin gene (RHO) mutations in Korean patients with retinitis pigmentosa (RP) and to characterize genotype-phenotype correlations in patients with mutations. METHODS: The RHO mutations were screened by direct sequencing, and mutation prevalence was measured in patients and controls. The impact of missense mutations to RP was predicted by segregation analysis, peptide sequence alignment, and in silico analysis. The severity of disease in patients with the missense mutations was compared by visual acuity, electroretinography, optical coherence tomography, and kinetic visual field testing. RESULTS: Five heterozygous mutations were identified in six of 302 probands with RP, including a novel mutation (c.893C>A, p.A298D) and four known mutations (c.50C>T, p.T17M; c.533A>G, p.Y178C; c.888G>T, p.K296N; and c.1040C>T, p.P347L). The allele frequency of missense mutations was measured in 114 ethnically matched controls. p.A298D, newly identified in a sporadic patient, had never been found in controls and was predicted to be pathogenic. Among the patients with the missense mutations, we observed the most severe phenotype in patients with p.P347L, less severe phenotypes in patients with p.Y178C or p.A298D, and a relatively moderate phenotype in a patient with p.T17M. CONCLUSIONS: The results reveal the spectrum of RHO mutations in Korean RP patients and clinical features that vary according to mutations. Our findings will be useful for understanding these genetic spectra and the genotype-phenotype correlations and will therefore help with predicting disease prognosis and facilitating the development of gene therapy.

Absence of intravitreal bevacizumab-induced neuronal toxicity in the retina.

Bevacizumab is a complete humanized monoclonal antibody directed against all isoforms of vascular endothelial growth factor (VEGF). It was originally used as a first-line treatment for metastatic colorectal cancer. Recently, intravitreal bevacizumab has been effectively applied to vasoproliferative diseases, such as retinal and choroidal neovascularization. However, it is known that intravenous administration of bevacizumab in the treatment of cancer can lead to serious adverse events, such as congestive heart failure, thromboembolism, and neuropathy. In this study, we showed that very high concentrations of intravitreal bevacizumab, even up to 15 times the dose normally used in human clinical applications, (1microl, 25mg/ml), caused no definite histological abnormalities and no significant increase in apoptotic cell death in the mouse retina at 4 weeks after treatment. Moreover, intravitreal bevacizumab induced no neuronal toxicity in the retina. Even in high concentrations, bevacizumab caused no changes in the viability of retinal neurons or the expression of neurofilament, a marker of neuronal differentiation. Therefore, we believe that intravitreal bevacizumab has therapeutic potential for the treatment of retinal and choroidal neovascularization and has the added benefit of exhibiting no acute or chronic toxicity in retinal neurons.

Conjunctival epithelial changes induced by cilia in patients with epiblepharon or entropion.

PURPOSE: To evaluate the effect of mechanical trauma induced by cilia on the conjunctival epithelium in patients with epiblepharon or entropion and to evaluate changes in epithelium after surgical correction in patients with entropion. DESIGN: Case-control study. METHODS: One hundred and seven eyes of 61 patients were enrolled in this study and were divided into three groups: the epiblepharon group (n = 59), the entropion group (n = 17), and the age-matched control group for the epiblepharon group (n = 31). Impression cytologic specimens were obtained from nasal and temporal bulbar conjunctiva of the epiblepharon and control groups immediately after the induction of general anesthesia. In the entropion group, these were obtained before and one month after surgical correction. Conjunctival changes were graded using the Tseng method and goblet cell densities were compared. RESULTS: Cytologic scores were significantly higher in the epiblepharon group than in the control group (P < .001), and goblet cell densities of nasal and temporal conjunctiva were significantly lower in the epiblepharon group than in the control group (P = .044 and P = .018, respectively). In the entropion group, postoperative scores were significantly lower than preoperative scores in both conjunctival areas (P = .033 and P = .003, respectively). No statistically significant difference was found between nasal and temporal conjunctiva in the three groups. CONCLUSIONS: The persistent mechanical trauma by cilia in patients with epiblepharon or entropion can induce squamous metaplasia of the conjunctival epithelium. However, these conjunctival changes can be reversed by surgical correction.

Association of p.P347L in the rhodopsin gene with early-onset cystoid macular edema in patients with retinitis pigmentosa.

PURPOSE: To describe early-onset cystoid macular edema (CME) in a family with retinitis pigmentosa (RP) due to the p.P347L in the rhodopsin gene (RHO). METHODS: All affected family members, including a 44-year-old mother and four children in their teens (two daughters, 17 and 15 years old, and two sons, 13 and 11 years old), have a mutation of p.P347L in RHO. Funduscopy, Goldmann perimetry, spectral domain optical coherence tomography (SD-OCT) and electroretinogram (ERG) were performed in all affected members to assess the retinal anatomy and function. RESULTS: The mother had very poor visual acuity of light perception in both eyes, and marked foveal atrophy was observed via SD-OCT. Although the macular appearance in the funduscopy looked unremarkable in the four children, SD-OCT revealed bilateral CME in all the children. The rod response in ERG was extinguished and the cone response was decreased in all children. CONCLUSION: The results present the possibility that CME in RP patients may be associated with a specific genotype such as the p.P347L in RHO. We speculate that the severe visual prognosis of this mutation may be related to early-onset CME, as shown in this family. However, further investigation in more RP patients with this mutation and CME will be needed.

Presumed atypical HDR syndrome associated with Band Keratopathy and pigmentary retinopathy.

This report describes presumed atypical hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome associated with unexpected ocular findings. The patient had exotropia, bilateral band keratopathy, and pigmentary retinopathy, including attenuated retinal vessels and atrophy of the retinal pigment epithelium. Even though the calcific plaques were successfully removed, visual acuity in both eyes gradually decreased and electroretinography was extinguished.

Five-year results of corneal tattooing for cosmetic repair in disfigured eyes.

PURPOSE: To investigate the 5-year results of corneal tattooing for cosmetic repair in disfigured eyes and identify the risk factors associated with complications. METHODS: Corneal tattooing was performed in patients with stable corneal opacity and blind eyes. A total of 147 eyes of 147 patients who were followed up for at least 5 years after tattooing were enrolled in the study. The following valuables were included as potential risk factors for long-term complications: age, sex, duration of opacity before tattooing, and the presence of calcific plaque. Corneal tattooing was also performed in 6 rabbit eyes, and the stained eyes were enucleated at 6 months postoperatively for histological analysis. RESULTS: The average follow-up time after surgery was 65 ± 5 months. Long-term complications such as reopacification or increased opacity, fading of color, and epithelial growth developed in 12% of the tattooed eyes between 2 and 4 years after surgery and most required reoperation. Univariate analysis of risk factors affecting recurrence or complications revealed no statistically significant differences among candidate factors. Histological results of the tattooed rabbit eyes showed that clumps of blackish granules were present in the anterior half of the stroma without any infiltration of inflammatory cells to the adjacent layers. CONCLUSIONS: Corneal tattooing in disfigured eyes provided a good cosmetic outcome more than 5 years after surgery.

A randomized pilot study of low-fluence photodynamic therapy versus intravitreal ranibizumab for chronic central serous chorioretinopathy.

PURPOSE: To report 6-month outcomes of a prospective, randomized study comparing the efficacy and safety between low-fluence photodynamic therapy (PDT) and intravitreal injections of ranibizumab in the treatment of chronic central serous chorioretinopathy. DESIGN: Prospective, randomized, single-center pilot study. METHODS: Sixteen eyes with chronic central serous chorioretinopathy were randomized to receive either low-fluence PDT or intravitreal injections of ranibizumab: 8 eyes in the low-fluence PDT group and 8 in the ranibizumab group. Rescue treatment was considered if subretinal fluid was sustained after completion of primary treatment: low-fluence PDT for the ranibizumab group and ranibizumab injection for the low-fluence PDT group. Main outcome measures were excess foveal thickness, resolution of subretinal fluid, choroidal perfusion on indocyanine green angiography, and best-corrected visual acuity. RESULTS: At 3 months, the mean excess foveal thickness was reduced from 74.1 ± 56.0 µm to -35.4 ± 44.5 µm in the low-fluence PDT group (P = .017) and from 26.3 ± 50.6 µm to -23.1 ± 56.5 µm in the ranibizumab group (P = .058). After a single session of PDT, 6 eyes (75%) in the low-fluence PDT group achieved complete resolution of subretinal fluid and reduction of choroidal hyperpermeability, whereas 2 (25%) eyes in the ranibizumab group achieved this after consecutive ranibizumab injections. Four eyes (50%) in the ranibizumab group underwent additional low-fluence PDT and accomplished complete resolution. At 3 months, significant improvement of best-corrected visual acuity was not demonstrated in the low-fluence PDT group (P = .075), whereas it was observed in the ranibizumab group (P = .012). However, the tendency toward improvement of best-corrected visual acuity was not maintained. CONCLUSIONS: In terms of anatomic outcomes, the effect of ranibizumab injections was not promising compared with that of low-fluence PDT.

The anti-angiogenic effect of chlorogenic acid on choroidal neovascularization.

PURPOSE: To evaluate the inhibitory effect of chlorogenic acid on laser-induced choroidal neovascularization (CNV) in a rat model. METHODS: Intraperitoneal injection of chlorogenic acid (10 mg/kg) was initiated one day prior to laser photocoagulation and continued for eight days. Eyes were removed 14 days after laser photocoagulation. Fluorescein angiography was employed at seven and 14 days to assess the CNV lesions, and histological examination was performed. Quantification of CNV size and leakage were performed both in histological sections and fluorescein angiography in order to compare the inhibitory effects of chlorogenic acid on CNV with the results of the control. RESULTS: Histological analysis showed no significant difference in CNV size between the treated and control groups. However, CNV leakage on fluorescein angiography had significantly decreased in the chlorogenic acid-treated group at 14 days after laser photocoagulation compared with that of the control group. In addition, CNV size on fluorescein angiography had significantly decreased in the treated group at seven and 14 days. CONCLUSIONS: These results suggest that chlorogenic acid has anti-angiogenic effects on CNV and may be useful as an inhibitor in the treatment or prevention of neovascular age-related macular degeneration.

Comparison of risk factors for bilateral and unilateral eye involvement in normal-tension glaucoma.

PURPOSE: To compare the risk factors for bilateral and unilateral disease in normal-tension glaucoma (NTG). METHODS: The study analyzed data from consecutive NTG patients with either bilateral (n = 194) or unilateral (n = 193) disease. Multivariate regression models were used to evaluate the following potential risk factors for bilateral eye involvement: age, sex, central corneal thickness, mean deviation in standard automated perimetry, mean and fluctuation of diurnal intraocular pressure (IOP) without glaucoma medication, spherical equivalent, family history of glaucoma, and underlying systemic disease such as diabetes mellitus, hypertension, hypercholesterolemia, ischemic heart disease, previous cerebrovascular accident, migraine, and cold extremities. RESULTS: Multivariate analysis showed that worse mean deviation in the first affected eye (odds ratio [OR], 1.19/1 dB decrease; P < 0.001), diabetes mellitus (OR, 2.31; P = 0.004), previous cerebrovascular accident (OR, 4.27; P = 0.039), and mean IOP greater than 14 mm Hg in the less affected eye (OR, 1.66; P = 0.030) were significantly associated with bilateral eye involvement in NTG. CONCLUSIONS: Besides being an indicator of disease severity (worse mean deviation), diabetes mellitus, previous cerebrovascular accident, and IOP were associated with bilateral eye involvement. These data suggest that systemic vascular factors and IOP play significant roles in the pathogenesis of NTG. It appears that although systemic vascular factors increase the susceptibility of the optic nerve, a certain level of pressure-induced stress is also required to cause glaucomatous optic neuropathy.

Feasibility of microelectrode array (MEA) based on silicone-polyimide hybrid for retina prosthesis.

PURPOSE: To adopt micropatterning technology in manufacturing silicone elastomer-based microelectrode arrays for retinal stimulation, a silicone-polyimide hybrid microelectrode array was proposed and tested in vivo. METHODS: Gold microelectrodes were created by semiconductor manufacturing technology based on polyimide and were hybridized with silicone elastomer by spin coating. The stability of the hybrid between the two materials was flex and blister tested. The feasibility of the hybrid electrode was evaluated in the rabbit eye by reviewing optical coherence tomography (OCT) findings after suprachoroidal implantation. RESULTS: The flex test showed no dehiscence between the two materials for 24 hours of alternative flexion and extension from -45.0 degrees to +45.0 degrees . During the blister test, delamination was observed at 8.33 +/- 1.36 psi of pressure stress; however, this property was improved to 11.50 +/- 1.04 psi by oxygen plasma treatment before hybridization. OCT examination revealed that the implanted electrodes were safely located in the suprachoroidal space during the 4-week follow-up period. CONCLUSIONS: The silicone-polyimide hybrid microelectrode array showed moderate physical properties, which are suitable for in vivo application. Appropriate pretreatment before hybridization improved electrode stability. In vivo testing indicated that this electrode is suitable as a stimulation electrode in artificial retina.