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To investigate the relationships between sensitivity loss in various subfields of the central 10° of the binocular integrated visual field (IVF) and vision-related quality of life (VRQoL) in 172 patients with advanced glaucoma. Using the Random Forest algorithm, which controls for inter-correlations among various subfields of the IVF, we analysed the relationships among the Rasch analysis-derived person ability index (RADPAI), age, best-corrected visual acuity (BCVA), mean total deviations (mTDs) of eight quadrant subfields in the IVF measured with the Humphrey Field Analyzer (HFA) 10-2 program (10-2 IVF), and mTDs of the upper/lower hemifields in the IVF measured with the HFA 24-2 program (24-2 IVF). Significant contributors to RADPAIs were as follows: the inner and outer lower-right quadrants of the 10-2 IVF contributed to the dining and total tasks; the lower-left quadrant of the 10-2 IVF contributed to the walking, going out and total tasks; the lower hemifield of the 24-2 IVF contributed to the walking, going out, dining, miscellaneous and total tasks; and BCVA contributed more to the letter, sentence, dressing and miscellaneous tasks than to others. The impact of damage in different 10-2 IVF subfields differed significantly across daily tasks in patients with advanced glaucoma.

Purpose To report the occurrence probability of disc haemorrhage (DH) and risk factors for it in otherwise healthy Japanese normal-tension glaucoma (NTG) patients who had lower normal intraocular pressure (IOP) and were followed without treatment for 5 years. Methods A prospective observational study. Normal-tension glaucoma (NTG) patients with IOP consistently ≤15 mmHg without treatment were enrolled. The presence or absence of DH was checked semi-annually on the fundus photographs by three independent observers, while patients were followed without treatment. Cox proportional hazards model taking inter-eye correlation into consideration was adopted to identify risk factors for DH occurrence. The main outcomes were DH occurrence probability during 5-year period and its risk factors. Results One hundred seventeen eyes of 90 patients with mean age of 54.1 years, mean deviation value of -3.6 decibels and mean IOP during follow-up of 12.4 mmHg were included. Disc haemorrhage (DH) was observed at least once in 34 eyes and more than twice in 15 eyes during the follow-up. The DH occurrence probability at 5 years was 31% (95% confidence interval: 21-40%), and lower myopic refraction (HR = 1.18; p = 0.018), higher IOP during follow-up (HR = 1.35; p = 0.047) and presence of DH at baseline (HR = 4.19; p = 0.002) were its risk factors. Conclusion Disc haemorrhage (DH) occurrence probability of Japanese healthy NTG patients with mean IOP of 12.4 mmHg and no systemic and/or topical treatment was 31% at 5 years. Lower myopic refraction, higher IOP and its existence at baseline were its risk factors.

The impairment of mitochondrial function is an important pathogenic factor in glaucoma and other optic neuropathies in which retinal ganglion cell (RGC) death is the fundamental pathology. Syntaphilin was recently discovered as a docking protein that affects mitochondrial mobility. However, no reports have investigated the involvement of syntaphilin in the visual system. We investigated the expression of syntaphilin in the rat retina, optic nerve and brain. The expression of syntaphilin exhibited varying patterns in the visual system. Syntaphilin was expressed in retinal ganglion cells in the retina, in the cell bodies of neurons in the superior colliculus and was abundant in the astrocytes of rat optic nerves (similar to the findings that syntaphilin is expressed in human optic nerves). After optic nerve transection, which caused RGC death and axonal degeneration, quantitative real-time RT-PCR was used to assess changes in gene expression in the rat retina and optic nerve. Syntaphilin gene and protein expression in the optic nerve was downregulated 3 and 7 days after optic nerve transection. Our study suggests that syntaphilin expression in astrocytes at the optic nerve might be involved in axonal injury.

We conducted a genome-wide association study (GWAS) on the outcome of anti-VEGF treatment for exudative age-related macular degeneration (AMD) in a prospective cohort. Four hundred and sixty-one treatment-naïve AMD patients were recruited at 13 clinical centers and all patients were treated with 3 monthly injections of ranibizumab followed by pro re nata regimen treatment for one year. Genomic DNA was collected from all patients for a 2-stage GWAS on achieving dry macula after the initial treatment, the requirement for an additional treatment, and visual acuity changes during the 12-month observation period. In addition, we evaluated 9 single-nucleotide polymorphisms (SNPs) in 8 previously reported AMD-related genes for their associations with treatment outcome. The discovery stage with 256 patients evaluated 8,480,849 SNPs, but no SNPs showed genome-wide level significance in association with treatment outcomes. Although SNPs with P-values of −6 were evaluated in replication samples of 205 patients, no SNP was significantly associated with treatment outcomes. Among AMD-susceptibility genes, rs10490924 in ARMS2/HTRA1 was significantly associated with additional treatment requirement in the discovery stage (P = 0.0023), and pooled analysis with the replication stage further confirmed this association (P = 0.0013). ARMS2/HTRA1 polymorphism might be able to predict the frequency of injection after initial ranibizumab treatment.

Purpose To investigate whether complement factor H ( CFH ) gene DNA variants are associated with central serous chorioretinopathy (CSCR). Design Cross-sectional study. Participants A case-control group of 140 CSCR subjects and 2 different control groups: 934 population-based controls and 335 hospital-based controls. Methods Five single-nucleotide polymorphisms (SNPs) in CFH (rs3753394, rs800292, rs2284664, rs1329428, and rs106548) were evaluated for association with CSCR in 2 separate association analyses comparing CSCR subjects with 2 different control groups. Genotyping was performed using TaqMan technology (Applied Biosystems, Foster City, CA). Main Outcome Measures Allele and haplotype frequencies of the 5 variants in the CFH region. Results Highly statistically significant associations with CSCR were found for the 5 SNPs. The strongest association was observed with rs1329428 (allelic P = 6.44×10 −6 ; odds ratio, 1.79; 95% confidence interval [CI], 1.39–2.31, cases vs. population-based controls), which accounted for 35.5% of the population-attributable fraction for CSCR. Consistent with the analysis, rs1329428 showed the strongest disease association (allelic P = 1.00×10 −5 ; odds ratio, 1.89; 95% CI, 1.42–2.50) in comparing cases with hospital-based controls. The second most strongly associated SNP, rs1065489, was correlated highly with the most strongly associated SNP, rs1329428 ( r 2 = 0.77), and their effects could not be distinguished statistically from each other. A conditional logistic regression analysis revealed that the 2 highly correlated SNPs, rs1329428 and rs1065489, account for the association signals detected at the CFH locus. Conclusions We identified a novel association between CSCR and common CFH polymorphisms. Our findings support the involvement of CFH in the pathogenesis of CSCR; exploration of the role of CFH could yield important insights into the biological mechanisms underlying CSCR. Our identification of common CFH variants as susceptibility elements for CSCR will open new avenues for research, leading to a better understanding of CSCR pathogenesis and ultimately to the development of improved therapeutic approaches.

Neuromyelitis optica (NMO) is an autoimmune inflammatory, neurodestructive disease primarily targeting the optic nerve and spinal cord. An autoantibody against water channel protein aquaporin-4 (AQP4), which is expressed at endofeet of astrocytes has been implicated in the pathogenesis of NMO. We evaluated the impact of sera of seropositive patients with NMO spectrum disorders (NMOSDs) on the rodent optic nerve and retina. Serum was obtained either from patients with seropositive NMOSD (AQP4+), seronegative patient with idiopathic optic neuritis (AQP4-), and healthy volunteers (control). Anti-AQP4 antibody in a serum was measured by a previously established cell-based assay. The patients' sera were applied on the optic nerve after de-sheathed. Immunohistochemistry showed that at 7 days after the treatment, the area of the optic nerve exposed to the AQP4+ sera lost expression of both AQP4 and glial fibrillary acidic protein. Also, Human-IgG immunoreactivity and marked invasion of inflammation cells were observed in the optic nerve treated with AQP4+ serum. Immnoreactivity of neurofilament was reduced at 14 days after the treatment, not 7 days. Real-time polymerase chain reaction revealed the reduced gene expression of neurofilament in retina from the eye that was exposed to the AQP4+ sera at 14 days. Retrograde fluorogold-labeling on the retinal flatmount disclosed the significantly reduced number of retinal ganglion cells when the AQP4+ sera were applied. The present model has demonstrated that the sera from patients with seropositive NMOSDs led to the regional astrocytic degeneration and inflammatory cell invasion in the optic nerve, resulting in the ultimate loss of RGCs and their axons at areas beyond the injury site.

Aim: To report a case of choroidal neovascularization secondary to unilateral retinal pigment epithelium dysgenesis (URPED), which was resistant to posterior subtenon injection of triamcinolone acetonide (STTA) and intravitreal bevacizumab injection (IVB). Case Report: An 8-year-old boy was referred to us because of a unilateral unique clinical appearance on funduscopic examination in his left eye (OS). A geometric lesion at the retinal pigment epithelium level of the interpapillomacular area was disclosed OS. The optic nerve was slightly hyperemic OS. Findings from the right fundus examination were normal. Based on these characteristic findings, he was diagnosed as having URPED. Best corrected Landolt ring chart visual acuity (BCVA) was 1.0 in both eyes. Twenty-three months after the first visit, the patient presented with visual disturbance OS. Funduscopic examination showed an expansion of the geometric lesion and the development of a subfoveal choroidal neovascularization (CNV). BCVA was 0.4 OS. Two-time STTA (40 mg/1 ml) was performed at the onset of CNV and 6 months later, and additional IVB (1.25 mg/0.05 ml) was done 10 months later for the treatment of CNV, but the geometric lesion and CNV were resistant to the treatment and continued to expand. Seven years after the first visit, the geometric lesion and the CNV kept expanding steadily. Conclusion: URPED is a rare clinical entity, and the prognosis of this disease is still unclear. The visual prognosis may depend on whether CNV fully develops.

Since Kelly and Wendel [Arch Ophthalmol 1991;109:654-659] first reported successfully treating macular holes (MHs) using pars plana vitrectomy in 1991, MH surgery has been constantly improved. For example, introducing the removal of the internal limiting membrane considerably increased the closure rate of MHs, and the advent of microincision vitrectomy surgery reduced surgical trauma and decreased patient discomfort after surgery. As modern MH surgery can achieve a higher anatomical success rate and alleviate patients' postoperative distress, postoperative visual outcomes have lately become the primary concern. Informing patients of the expected visual acuity and visual improvement before surgery is ideal, but predicting postoperative visual outcomes is difficult because a large number of factors are associated with them. In this paper, we review previous studies and provide accumulating evidence for the relationship between individual prognostic factors and visual outcomes after MH surgery.

Polypoidal choroidal vasculopathy (PCV) is currently recognized as a phenotype of age-related macular degeneration (AMD). PCV is believed to be a type of choroidal neovascularization, although some cases of PCV show a distinct vascular abnormality of the choroidal vessels. PCV often shows several unique clinical manifestations which are apparently different from typical neovascular AMD (tAMD). In addition, the natural course and response to treatment are often different between tAMD and PCV. Moreover, recent genetic studies suggested a possible difference in the genetic susceptibility to disease between tAMD and PCV, as well as the existence of heterogeneity among PCV cases. In viewing the accumulation of knowledge about PCV, we have summarized the recent literature regarding PCV in this review article to improve the understanding of this clinical entity including possible susceptibility genes. We will also discuss the optimal treatment strategies for PCV in accordance with the results of recent clinical and genetic studies.

Aquaporin 9 (AQP9), an aquaglyceroporin belonging to the AQP water channel family, is permeable not only to water but also to noncharged solutes such as lactate. In neurons, lactate presumably acts as an energy substrate and as a source of NADH (the reduced form of nicotinamide adenine dinucleotide), a scavenger of reactive oxygen species (ROS). We previously reported that retinal ganglion cells (RGCs) express AQP9 and that elevated intraocular pressure reduces AQP9 expression and increases death of neurons in the retinal ganglion cell layer of rodents. In the present study, we investigated the association of AQP9 expression with serum deprivation-induced death of RGC-5 cells and with death of neurons in the rat retinal ganglion cell layer after optic nerve transection (ONT). The effect of AQP9 RNA interference on serum deprivation-induced apoptosis, ROS accumulation, and the NAD(+)/NADH ratio in RGC-5 cells was examined. Both serum deprivation and ONT significantly reduced AQP9 protein expression in RGCs and increased the rate of RGC death. Retinal AQP9 gene expression also declined after ONT. Down-regulation of AQP9 significantly increased apoptosis, ROS accumulation, and the NAD(+)/NADH ratio in the RGC-5 cells. These findings suggest that AQP9 loss adversely affects survival of RGCs, at least partly because of decreased transport of lactate as a substrate for energy and/or ROS scavenger.

Background Choroidal neovascularisation is often associated with pathological myopia. Bisphosphonates (BP), the preferred drug for treatment of osteoporosis, are known to have anti-angiogenic effects. Objective To compare the therapeutic effects of oral BP with anti-vascular endothelial growth factor therapy (anti-VEGF) and photodynamic therapy (PDT) for myopic choroidal neovascularisation (mCNV) over 2 years of follow-up. Methods One hundred eyes of 96 consecutive patients with mCNV who underwent oral BP treatment (alendronate 5 mg/day or 35 mg/week), anti-VEGF therapy, PDT or observation only were followed up for 2 years. The best-corrected visual acuity (BCVA) and the central retinal thickness (CRT) in optical coherence tomography were compared among the treatment groups. Results The mean BCVA of the patients was maintained for up to 2 years in the BP and PDT groups. In the anti-VEGF group, the mean BCVA was significantly improved but was significantly worse in the no-treatment group. The visual outcomes were significantly better in the BP, PDT and anti-VEGF groups than the no-treatment group over 2 years of follow-up (−0.28, −0.26 and −0.39 logMAR units, p=0.032, 0.021 and 0.0004, respectively). The mean CRT was significantly decreased in all treatment groups (−84, −121 and −122 mm, p=0.0025, 0.017 and 0.000025, respectively). Conclusions Oral BP should be investigated further as possible therapeutic and preventive drugs for mCNV.

Purpose: To compare the relationships of parapapillary retinal nerve fibre layer (RNFL) thickness among three spectral-domain optical coherence tomography (SD-OCT) instruments with visual field sensitivity (VFS). Methods: One hundred and thirteen eyes of 113 Japanese subjects with glaucoma (mean deviation in standard automated perimetry = −8.9 ± 6.7 dB) were imaged by Cirrus, RTVue and 3D OCT. The average hemi-superior and hemi-inferior RNFL thicknesses were obtained. In addition, the structure–function relationship using two retinotopic maps that consisted of six or nine sectors was also evaluated. Decibel (dB) scale and 1/Lamert (1/L) were used to express VFS. RNFL thickness correlation with corresponding VFS in visual field sectors was compared among the three instruments. Background RNFL thickness (non-neuronal tissue) for each instrument was estimated using a linear regression model at 1/L = 0. Results: The correlation between the average hemi-superior and hemi-inferior RNFL thickness in the three SD-OCT instruments with corresponding VFS was similar. In the analysis of retinotopic maps, 3D OCT showed a higher correlation in superotemporal sectors than RTVue, whereas RTVue had a stronger relationship in the nasal sector than Cirrus. The background RNFL thickness extrapolated was approximately 60% that of normal eyes in all the instruments. Conclusions: The three SD-OCT showed similar overall correspondence with VFS with a partially discordant retinotopic relationship. RNFL measured with any SD-OCT devices likely contains non-neuronal tissue, comprising 60% of its thickness.

To evaluate the long-term effects of photodynamic therapy (PDT) on typical neovascular age-related macular degeneration (tAMD) and polypoidal choroidal vasculopathy (PCV). This was a multicenter prospective study of 139 eyes from 136 patients (tAMD: 74 eyes; PCV: 65 eyes) who underwent PDT as the initial treatment. The change in best-corrected visual acuity (BCVA), predictive factors for the BCVA at 60 months, frequency of recurrence, and mean recurrence period were analyzed. The pre-PDT BCVA and greatest linear dimension (GLD) did not differ between the two groups. The mean BCVA (logMAR) was significantly improved at 6 months post-initial PDT (post-PDT) in the PCV group (−0.11, P = 0.0091). However, at 60 months post-PDT, the mean BCVA was significantly worse than baseline in the tAMD (+0.21, P = 0.0035) and PCV (+0.21, P = 0.0076) groups. Pre-PDT BCVA, age, and GLD were the factors significantly associated with the BCVA at 60 months post-PDT. Although the frequency of recurrence did not significantly differ between the two phenotype groups, the mean recurrence period was significantly longer in the PCV group than in the tAMD group (15.7 vs. 8.6 months, P = 0.0020). PDT may not have benefits for visual acuity in cases of tAMD and PCV over 5 years of follow-up.

We describe two cases of IgG4-related disease associated with skin manifestations with IgG4-positive plasma cells. The first patient was a 52-year-old woman with a 3-year history of IgG4-related sialadenitis who presented with pruritic, indurated erythematous lesions on the auricle, postauricular and submandibular regions and neck. A skin biopsy showed infiltration of IgG4-positive plasma cells in the subcutaneous tissue. The second patient was a 53-year-old woman with IgG4-related lesions in the ocular adnexal tissues and nasal cavity who presented with pruritic, indurated erythema on the cheek and submandibular region. Histopathological examination of a skin biopsy revealed a dense, patchy infiltrate comprised of lymphocytes, IgG4-positive plasma cells and eosinophils around blood vessels and sweat glands in the entire dermis and subcutis. The skin lesions in these cases were considered to be skin manifestations of IgG4-related disease. The findings of these two cases together with the three reported cases of IgG4-related disease with skin manifestations in the literature suggest that IgG4-related skin lesions may appear on the scalp, face, neck, auricle and postauricular regions during the course of IgG4-related disease.

To compare the association of age-related maculopathy susceptibility 2 (ARMS2) and complement factor H (CFH) variants between two different angiographic phenotypes of polypoidal choroidal vasculopathy (PCV).We included 175 Japanese patients with PCV and 150 age- and sex-matched controls. PCV was classified into two phenotypes (Type 1 and Type 2) according to the presence or absence of the feeding vessels found in indocyanine-green angiography. The single nucleotide polymorphism (SNP) at rs10490924 (A69S) in ARMS2 and rs800292 (I62V), rs1061170 (Y402H) in the CFH region were genotyped using the TaqMan assay.The minor allele frequency (MAF) of rs10490924 was significantly different between Type 1 PCV (n = 81) and control (p0.0001), while no difference was found between Type 2 PCV (n = 94) and control (p = 0.20). The MAF of rs800292 was significantly different between each type of PCV and control (p0.0001 and 0.0001 for Type 1 versus control and Type 2 versus control, respectively). The MAF of rs1061170 was not significantly different between either type of PCV and control (p = 0.084 and 0.15, respectively).There may be significantly different associations in the genetic variants of ARMS2 between two angiographic phenotypes of PCV.

It has been hypothesized that dysfunction of the solute carrier family 1, member1 gene (SLC1A1), which encodes the glutamate aspartate transporter, may play a role in normal tension glaucoma. In this study we investigate whether SLC1A1 is associated with normal tension glaucoma in Japanese patients.A total of 292 Japanese patients with normal tension glaucoma and 500 healthy control subjects were recruited. We genotyped 12 single-nucleotide polymorphisms in SLC1A1. We also performed an imputation analysis to evaluate the potential association of un-genotyped SLC1A1 single-nucleotide polymorphisms, and 165 single-nucleotide polymorphisms were imputed.We observed an increased frequency of the G allele of rs10739062 in patients compared to controls (p = 0.043, OR = 1.25). The rs10739062 polymorphism exhibited a dominant effect: individuals with genotype GG and GC showed a 1.91-fold increase in risk compared to genotype CC (p = 0.0082). However, the statistical significance disappeared after Bonferroni correction for multiple testing (pc 0.05). We did not find any significant association between any of the remaining 176 single-nucleotide polymorphisms and disease risk.Our study showed a lack of association between SLC1A1 variants and normal tension glaucoma in Japanese patients, suggesting that the SLC1A1 gene does not play a critical role in the development of the disorder in this patient population. However, further genetic studies with larger sample sizes are needed to clarify whether SLC1A1 may make some contribution that affects the risk of developing normal tension glaucoma.

To evaluate the effects of ocular rotation on parapapillary retinal nerve fiber layer (RNFL) thickness measured by spectral-domain optical coherence tomography (SD-OCT).Eighty-eight normal and 205 glaucomatous eyes were studied. RNFL thickness was measured by 3D OCT. Ocular rotation angle was measured from a fundus image obtained by a non-mydriatic fundus camera equipped with 3D OCT. The average, hemi-superior, and hemi-inferior RNFL thicknesses as well as those in the 4 quadrants and the 16-segmented superotemporal (ST-1) and inferotemporal (IT-4) sectors were compared both before and after correcting for ocular rotation. Receiver operating characteristic curves and the areas under the curve (AUC) for the RNFL thicknesses were calculated on the basis of the data from glaucomatous and control eyes. The relationships between RNFL thickness and retinal sensitivity in the corresponding visual field were analyzed using a Humphrey field analyzer.Correction for ocular rotation did not affect the AUCs of the hemi-superior and hemi-inferior RNFL thicknesses. RNFL thicknesses in all of the quadrants and in ST-1 and IT-4 were significantly changed by correcting for ocular rotation. The correlations between all RNFL sectors and retinal sensitivity were not changed by correcting for the ocular rotation angle.Ocular rotation compensation affected RNFL thickness measurement with 3D OCT. However, the effect was clinically negligible in the diagnosis of glaucoma.

To determine whether amniotic membrane transplantation (AMT) at trabeculectomy affects intrableb structures and which intrableb parameters are significantly correlated with the long-term intraocular pressure (IOP) control.Enrolled were 64 eyes of 56 glaucoma patients who underwent trabeculectomy without (36 eyes) or with (28 eyes) AMT. Bleb structure was evaluated by ultrasound biomicroscopy (UBM) at least one year after surgery. IOP control was defined as good when the eyes had a more than 30% decrease in the preoperative IOP and an IOP value18 mmHg if the preoperative IOP was higher than 21 mmHg. Logistic regression analyses were conducted to identify factors significantly associated with IOP control.Intervals between surgery and the timing of the UBM examinations (median; 2.5 years) and the overall frequency of good IOP control (28/36 in the eyes without AMT and 17/28 in those with AMT; chi-square test, P = 0.2276) were similar in the two groups. The eyes with AMT had a significantly lower number of type H (high reflective) or L (low reflective) blebs and a higher number of type E (encapsulated) blebs compared to those without AMT (P 0.0001). Among independent variables, which included age, sex, glaucoma type, lens status, the number of ocular hypotensives, and previous intraocular surgeries, only type F (flattened) bleb in eyes without AMT (P = 0.0008, odds ratio [OR] = 0.0256) and no or limited intrableb fluid-filled space in eyes with AMT were significantly associated with poor IOP control (P = 0.0026, OR = 0.0111, and 0.0071, 0.0167, respectively).Intrableb structures after trabeculectomy alone versus AMT-assisted trabeculectomy were distinct. The bleb wall reflectivity in the former and the extent of the subconjunctival fluid-filled space in the latter were factors associated with long-term IOP control.

To investigate whether retinal surface imaging by Cirrus high-definition optical coherence tomography (HD-OCT) clearly depicts the development process of a dissociated optic nerve fiber layer (DONFL) appearance after macular hole (MH) surgery. We reviewed the medical records of the patients who underwent MH surgery with internal limiting membrane peeling. The cases were then selected using three principal criteria: (1) surgeries performed by the same surgeon (S. K.), (2) pre- and postoperative Cirrus HD-OCT imaging, and (3) minimal follow-up of 3 months. All cases received a complete ophthalmologic examination. The presence/absence of a DONFL appearance was determined using a retinal surface image provided by Cirrus HD-OCT. Color fundus photographs were also used for determination if available. Fifteen cases met the criteria. A DONFL appearance was identified in 11 (73%) cases during the postoperative course by retinal surface imaging. A DONFL appearance was not detected in any OCT retinal surface image within the first postoperative month, gradually became distinct between 1 and 3 months after surgery, and remained detectable thereafter in all cases but one whose DONFL appearance became less detectable at 12 months. Indentations of the innermost retinal layer became apparent on cross-sectional OCT images as a DONFL appearance developed on OCT retinal surface images. There were two cases in which the DONFL appearance was not observed on color fundus photographs but detected on OCT retinal surface images. Retinal surface imaging provided by Cirrus HD-OCT appeared to be a promising option in evaluating a DONFL appearance after MH surgery.

Purpose: To report a case of proliferative diabetic retinopathy (PDR) showing transient macular edema (ME) and deteriorated retinal function after intravitreal bevacizumab injection (IVB). Methods and Results: A 53-year-old man received IVB (1.25 mg/0.05 ml) in both eyes for the treatment of PDR. There was no treatment-related complication. However, he complained of photopsia in both eyes 6 h after the injection. Slit-lamp examination revealed mild cellular infiltrations (1+) in the anterior chamber in both eyes. Optical coherence tomography showed ME formation in the left eye. Both full-field and multifocal electroretinography (ERG) revealed the deterioration of all parameters in both eyes compared with pretreatment. The inflammation in the anterior segment and ME disappeared 1 day after the injection. ERG parameters were improved 9 days after the injection, except for the N1 and P1 amplitude of multifocal ERG in the left eye. Conclusion: We propose that patients who undergo IVB should be carefully informed and followed up for possible complications including temporal ME formation and retinal function deterioration.

Diabetes redistributes the expression of glial aquaporin (AQP) water channels in the retina. However, it is not known whether diabetes also affects retinal AQP-0 expression. This study examined the effects of the development of diabetes on the expression of retinal AQP-0 in spontaneously diabetic Torii (SDT) rats. Male SDT rats at 10 and 40 weeks of age and age-matched male Sprague-Dawley (SD) rats were used. The localization of AQP-0 was assessed immunohistochemically using sagittal cryosections of the rats’ retinas and optic nerves. Fold changes in AQP-0 gene expression relative to controls were assessed by real-time RT-PCR. All SDT rats spontaneously developed diabetes by 40 weeks of age (the mean hemoglobin (Hb) A1c levels were 2.8 ± 0.2% and 11.2 ± 1.0% at 10 and 40 weeks, respectively). SD rats did not develop diabetes (the HbA1c levels were 2.7 ± 0.2% and 2.6 ± 0.3% at 10 and 40 weeks, respectively). In the retinas of SD rats and in those of SDT rats at 10 weeks of age, immunoreactivity for AQP-0 was confined predominantly to the inner nuclear layer and to the border between the inner plexiform layer and the ganglion cell layer (GCL), where AQP-0 colocalized with protein kinase C-α. AQP-0 immunoreactivity was also observed in the GCL to a lesser degree, which colocalized with the neuronal nuclei. In the 40-week-old SDT rat retinas, additional AQP-0 immunoreactivity was observed in the GCL and colocalized with neurofilaments, indicating expression of AQP-0 in ganglion cell axons. However, the axonal AQP-0 immunoreactivity was restricted to the retinal nerve fibers, whereas the optic nerve axons were devoid of AQP-0. Retinal blood vessels did not express AQP-0. AQP-0 gene expression was 3.4-fold higher in SDT rat retinas than in SD rat retinas at 40 weeks of age. AQP-0 was predominantly expressed in the bipolar cells of the non-diabetic rat retinas, whereas it was also expressed in the retinal nerve fibers of diabetic rat retinas. The disrupted water transport between astrocytes and retinal nerve fibers may be associated with the known accelerated apoptosis of retinal ganglion cells induced by diabetes.

Purpose: To evaluate the retinal toxicity of intravitreal tissue plasminogen activator (tPA) injection for branch and central retinal vein occlusion (BRVO and CRVO) using the electroretinogram (ERG). Procedures: Ten BRVO patients and 5 CRVO patients were enrolled. A complete examination including full-field ERG, visual acuity, central retinal thickness (CRT), and evaluation of systemic and ocular complications was performed before and after intravitreal tPA injection. Results: No significant differences were found in the amplitude or implicit time of any ERG component after tPA injection, and no systemic or ocular complication was observed. The improvement of visual acuity was significant at month 3 in the BRVO group (p < 0.05) but not in the CRVO group. CRT significantly decreased over the course of 3 months in both groups (p < 0.01). Conclusion: Intravitreal tPA injection seems to be a safe and effective treatment option for macular oedema caused by retinal vein occlusions.

Purpose: To describe the ophthalmic findings in the fundus of a Japanese infant with Potter sequence having a mutation in the PAX2 gene. Methods: A 1-month-old infant diagnosed with Potter sequence who had bilateral renal hypoplasia and a mutation in the PAX2 gene was subjected to detailed ophthalmic examination. Results: Funduscopy revealed a megalopapilla with marked excavation in the right eye. The left optic disc showed a similar abnormality, but to a lesser extent. B-mode ultrasonography and magnetic resonance imaging detected giant cystic lesions occupying the optic nerve head in both eyes. According to these results, we diagnosed this patient as having papillorenal syndrome (PRS) associated with a PAX2 mutation. Conclusions: This report shows ophthalmic findings in the youngest patient with PRS and PAX2-associated Potter sequence. Optic disc anomalies may be involved in some infants with Potter sequence. We anticipate an increase in opportunities for ophthalmic examinations in infants with diseases such as Potter sequence with previously high mortality rates.

Evidence is mounting that not only microangiopathy, but also neurodegenerative events occur in the retinas of humans and rodents with early diabetes. Diverse pathologies are known to alter the amount and/or location of glial expression of the water-selective channels aquaporins (AQPs) 1 and 4. However, the temporal relationships among glial activation, the altered expression of the AQP proteins and neuronal death in the retinas of diabetic animals remains to be investigated. Male spontaneously diabetic Torii (SDT) rats reportedly develop diabetes by 40 weeks of age at the latest and manifest proliferative diabetic retinopathy at 50 weeks or later. This study compared temporal changes in neuroretinal apoptosis, glial fibrillary acidic protein (GFAP) expression and the expression of AQPs 1 and 4 between SDT rat retinas and age-matched Sprague-Dawley (SD) rat retinas. Cell death was detected by terminal deoxynucleotidyl transferase-mediated deoxy-uridine triphosphate nick end-labeling on retinal flatmounts and activated caspase 3 immunofluorescence of retinal cryosections. The expression of GFAP and AQPs 1 and 4 was assessed by immunohistochemistry of cryosections and retinal flatmounts. Diabetes started to develop around 15 weeks in SDT rats. Apoptotic cells in the ganglion cell layer and the inner nuclear layer were significantly more numerous in 40-week-old SDT rat retinas than in either age-matched SD rat retinas or 10-week-old SDT rats. GFAP immunoreactivity was confined to the nerve fiber layer both in SD and SDT rats at 10 weeks, whereas it spanned the whole retina in SDT rats, but not in SD rats, at 40 weeks. AQP1 was expressed in the outer retina, whereas AQP4 was expressed in the perivascular and end feet of Muller cells and astrocytes in the inner retina in the control SD rats and the SDT rats at 10 weeks. The perivascular AQPs shifted from AQP4 to AQP1 in 40-week-old SDT rats that exhibited marked hyperglycemia. Thus, the development of diabetes increases neuroretinal apoptosis, and this coincides with an altered expression pattern of GFAP and water-selective channels AQPs 1 and 4 in SDT rats.

In this study, the effects of maternal smoking along with other clinical risk factors in developing severe retinopathy of prematurity (ROP) were evaluated.A case-control study.Records of newborn infants with an estimated postmenstrual age of 32 weeks or less (n=86) were reviewed. ROP grading was evaluated in accordance with the International Classification of Retinopathy of Prematurity. Severe ROP was diagnosed when it progressed to stage 3 with plus disease. The factors were first evaluated using a univariate logistic regression analysis between the groups of severe and non-severe ROP, followed by a multivariate logistic regression analysis using STATA version 10 and R version 2.71.A low birth weight, a long duration of artificial ventilation and oxygen supplementation, presence of chronic lung disease, and absence of maternal smoking were found to be significantly associated with severe ROP in the univariate logistic regression analysis. In the multivariate logistic regression analysis, maternal smoking was revealed as a significant factor independently associated with the incidence of severe ROP.An inhibitory effect of maternal smoking against developing severe ROP is suggested. The mechanism by which smoking may reduce the incidence of severe ROP needs to be further investigated.

Purpose To investigate whether polymorphisms in 4 tightly linked genes of the major histocompatibility complex class III—complement component 2 ( C2 ), complement factor B ( CFB ), RD RNA-binding protein ( RDBP ), and superkiller viralicidic activity 2-like ( SKIV2L )—are associated with polypoidal choroidal vasculopathy (PCV). Design Cross-sectional study. Participants A case-control group of 136 PCV subjects and 183 unrelated controls. Methods We performed an association analysis between PCV and polymorphisms across the C2 - CFB - RDBP - SKIV2L region in a Japanese population, genotyping 13 single nucleotide polymorphisms (SNPs) spanning this region, including rs9332739 (E318D), rs547154, rs4151667 (L9H), and rs641153 (R32Q) that are known to be associated with age-related macular degeneration (AMD). Genotyping was conducted using TaqMan technology (Applied Biosystems, Foster City, CA). We also examined population stratification in our study cohort. Main Outcome Measures Allele and haplotype frequencies of the variants across the C2 - CFB - RDBP - SKIV2L region. Results We initially scanned the C2 - CFB locus using 11 SNPs that capture the majority of common variations in this locus. We found a significant omnibus haplotype association and a single disease-protective haplotype, but individually, none of the 11 SNPs were associated with PCV. Further studies led to the identification of 2 untested allelic variants in RDBP (rs3880457) and SKIV2L (rs2075702) that were located on the protective haplotype. We also analyzed these 2 SNPs, detecting a significant association with a decreased risk of developing PCV (for both SNPs, allelic P = 0.0038 and per allele odds ratio=0.31 [95% confidence interval, 0.13–0.71]). The 2 SNPs were correlated (r 2 = 1) in our dataset. Haplotype analysis and conditional testing demonstrated that either rs3880457 or rs2075702 could fully account for the omnibus haplotype association detected across the C2 - CFB - RDBP - SKIV2L region. Population stratification analyses excluded stratification artifacts in our study cohort. Conclusions Our results do not support any major role of the 4 AMD-associated variants in the risk of developing PCV, but favor a predominant association with the RDBP - SKIV2L variants, which has some potential implications for pathobiological differences between PCV and neovascular AMD. Further genetic characterization of this locus will provide additional insights into the genetic basis of PCV susceptibility. Financial Disclosure(s) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

To investigate whether tafluprost, which is a prostaglandin-related compound and an anti-glaucoma drug, has a direct anti-apoptotic effect in cultured retinal ganglion cells (RGCs) and rat RGCs in retinas with optic nerve crush (ONC).RGC-5 cells were induced to undergo apoptosis by a serum deprivation and by exogenous glutamate. The level of cell death with or without tafluprost was monitored by an XTT assay and by immunocytochemistry with activated caspase-3. Changes in intracellular calcium ([Ca(2+)]i) levels were measured with fluo-4 fluorescence. Rat RGCs were degenerated by ONC. After topical instillation of tafluprost for 7 and 14 days, the numbers of retrograde-labeled RGCs were counted. Retinal flatmounts were subjected to terminal dUTP nick end labeling (TUNEL) staining to detect apoptotic cells.Tafluprost dose-dependently promoted RGC-5 cell viability with an optimum concentration of 3 microM (p = 0.006). Tafluprost significantly reduced caspase-3-positive cells and suppressed [Ca(+2)]i evoked by exogenous glutamate. The cGMP-dependent protein kinase inhibitor and KT-5823 partially blocked the rescue effect of tafluprost (p = 0.002). The survival rate of RGCs significantly increased in eyes treated with tafluprost (p = 0.01), and the prevalence of TUNEL-positive cells was significantly decreased 14 days after ONC (p0.001).These data suggest that tafluprost has an anti-apoptotic effect in RGCs.

OBJECTIVE To evaluate which of the 3 clinically used visual field indices including mean deviation (MD), Advanced Glaucoma Intervention Study (AGIS) score, and Collaborative Initial Glaucoma Treatment Study (CIGTS) score are best in evaluating functional damage of glaucomatous optic neuropathy. METHODS In 213 glaucomatous eyes, peripapillary retinal nerve fiber layer thickness (RNFLT) and optic disc configuration were measured with Stratus optical coherence tomography and Heidelberg Retina Tomograph-2, respectively. Visual field was measured with standard automated perimetry 30-2. Correlations of the structural parameters compared with the 3 VF indices using second polynomial regression were calculated. In addition, these correlations were analyzed among eyes of 3 different stages of glaucoma, as defined by MD score (early, MD> or =-6 dB; moderate, -12 dB< or =MD

Kayo Nakamura1*, Masao Ota2*, Akira Meguro1, et al1Department of Ophthalmology, Yokohama City University School of Medicine, Yokohama, Kanagawa, Japan; 2Departmentof Legal Medicine, Shinshu University School of Medicine, Matsumoto, Nagano, JapanBackground: To investigate whether the GPDS1 locus, a potential causative locus of pigment-dispersion syndrome, is associated with normal-tension glaucoma (NTG) in Japanese patients. Materials and methods: We used polymerase chain reaction amplification with sequencespecific primers to analyze 20 polymorphic microsatellite markers in and around the GPDS1 locus with an automated DNA analyzer and automated fragment detection by fluorescent-based technology. The DNA samples used for these analyses were obtained from ethnicity- and gendermatched patients, including 141 Japanese patients with NTG and 101 healthy controls. Patients exhibiting a comparatively early onset were selected as this suggests that genetic factors may show stronger involvement.Results: One allele of D7S2462 exhibited a frequency that was significantly decreased in NTG cases compared to controls (P = 0.0013, Pc = 0.019, OR = 0.48, 95% CI = 0.30–0.75). Alleles at another six microsatellite loci were positively or negatively associated with NTG, but these associations did not retain statistical significance after Bonferroni correction (P< 0.05, Pc> 0.05).Conclusion: Our study showed a significant association between the GPDS1 locus and NTG, suggesting that there may be some genetic risk factor(s) in the development of NTG.Keywords: microsatellite, normal tension glaucoma, glaucoma-related pigment dispersion syndrome, GPDS1, DPP6

Changes in the physical properties of the vitreous induced by various biological stimuli were investigated with Cannon-Fenske kinematic and cone-plate rotary viscometers. Heating greatly decreased the viscosity of the human vitreous, the critical temperature being between 50 degrees C and 60 degrees C. Freezing also affected the viscosity, but less so than heating. Viscosity of hyaluronic acid was also decreased by heating to approximately 60 degrees C. Preliminary incubation with hyaluronidase made the viscosity of both the vitreous and hyaluronic acid heat-stable. Lens extraction decreased vitreous viscosity markedly, suggesting a decrease of hyaluronic acid concentration and/or a lowering of hyaluronic acid molecular weight. Vitreous haemorrhage resulted in decreased vitreous viscosity. Cryoretinopexy at the level employed in this study induced little change in vitreous viscosity, while retinal diathermy caused a moderate decrease. In the course of vitreous haemorrhage and retinal diathermy, a return towards normal of the viscosity was observed, suggesting the presence of local hyaluronic acid production.

We observed the influence of panretinal photocoagulation on the ERG c-wave in rabbit eyes. DC-registered ERGs were recorded from rabbit eyes before and after photocoagulation, and compared with those of the fellow eyes. The rabbits were subdivided into 3 groups according to application numbers: 500, 1000, and 1500 spots. The ERG c-waves were found to have totally disappeared in all rabbits 3 days after panretinal photocoagulation, then reappeared with various intervals. In the 500 spot group, the c-wave reappeared after one week, and almost reached control levels in one and a half months. In the 1000 spot group, a 10 day delay was noted, and 90% of control levels were regained after 6 months. In the 1500 spot group, the c-wave didn't reappear until 2 weeks later, and regained 70% (of the control level) after 6 months. The recovery rates were related to the number of laser applications. These results indicate that the ultimate degree of recovery in c-wave amplitude and the time required for the reestablishment of retinal pigment epithelium function both depend on the size of the coagulated area.

Purpose To investigate whether variants in the complement factor H ( CFH ) gene are associated with polypoidal choroidal vasculopathy (PCV). Design Cross-sectional study. Participants A case-control group of 130 PCV subjects and 173 unrelated controls. Methods We conducted an association analysis between CFH variants and PCV in a Japanese population, genotyping 12 tag single nucleotide polymorphisms (SNPs)—including rs3753394, rs800292 (I62V), and rs1061170 (Y402H)—that are highly representative of the common genetic variation in the CFH region. Genotyping was performed using TaqMan technology. Main Outcome Measures Allele and haplotype frequencies of the CFH variants. Results A highly significant association with PCV was observed across the CFH region. The strongest association was observed at I62V ( P = 1.7 × 10 −7 ). Six other SNPs (rs3753394, rs6680396, rs1410996, rs2284664, rs1329428, and rs1065489) also showed significant association (10 −3 P −6 ). These associations became nonsignificant after accounting for rs800292 in a conditional logistic regression analysis. A significant omnibus haplotype association was detected in the entire CFH region (omnibus P = 1.6 × 10 −5 at 7 degrees of freedom). Conditional haplotype-based likelihood ratio tests revealed that the significant omnibus haplotype association disappeared when it was estimated conditional on I62V (omnibus P = 0.20, 6 degrees of freedom, post-I62V dependency), whereas the omnibus haplotype association remained significant when it was estimated conditional on any SNP other than I62V. These findings indicate that multiple observed effects were caused by linkage disequilibrium with I62V, and that this variant fully accounts for the association signals observed at the set of SNPs examined at this locus. Conclusions The present study provides evidence that the complement pathway plays a substantial role in the pathogenesis of PCV. The nonsynonymous variant I62V is a plausible candidate for a causal polymorphism leading to the development of PCV, given its potential for functional consequences on the CFH protein and our own statistical evidence. Financial Disclosure(s) The authors have to proprietary or commercial interest in any materials discussed in this article.

To compare the morphologic alterations between upper and lower sectors of the optic nerve head (ONH) in eyes with primary open-angle glaucoma (POAG) that have hemifield visual field defects and to evaluate the correlation between this sectoral ONH damage and visual field sensitivity loss within the corresponding clustered test points of standard automated perimetry.Visual field testing with Humphrey Field Analyzer and imaging with Heidelberg Retina Tomograph (HRT) were performed in 87 eyes from 87 Japanese patients with POAG and 150 eyes from 150 normal subjects. Global and segmental HRT topographic parameters were compared among POAG patients with superior hemifield defects, those with inferior hemifield defects, and controls. The correlation between the sectoral HRT measurements and the sum of total deviation values in the corresponding clustered visual field test points was analyzed in the 2 POAG groups.The HRT measurements in both POAG groups were significantly different from those of controls, not only in the sectors corresponding to abnormal hemifield, but also in the sectors corresponding to the normal visual hemifield. There was a linear correlation between the sectoral HRT parameters and clustered visual field sensitivities in the affected hemifield areas.The present study indirectly supports the notion that the relationship between structural and functional damage of glaucomatous optic neuropathy is not linear when evaluated with the currently available techniques and instruments.

To evaluate the anti-angiogenic effects of integrin alphavbeta3 specific antagonist BS-1417 on laser-induced choroidal neovascularization (CNV) in mice.Male C57BL/6 mice were treated with daily intraperitoneal injections of BS-1417 or saline starting at the onset (day 0) of experiments. CNV was induced by laser photocoagulation the next day. Fluorescein angiograms (FA) and choroidal flatmount FITC-dextran perfusion were performed on experimental day 8. Histological and immunohistochemical examinations were performed with consecutive cryosections. Sub-confluent human vascular endothelial cells (HUVEC) were grown in vitro under various concentrations (0-10 microg/ml) of BS-1417 and the numbers of cell were measured at 48 hours of incubation. After fixation, immunocytochemistry was performed.BS-1417 significantly decreased the area of dye leakage determined by FA (40% of control, p = 0.0008) and reduced the CNV size found on choroidal flatmount (18% of control, p = 0.007). In histological findings, BS-1417 apparently suppressed the size of laser-induced CNV. Immunoreactivities for VEGF and integrin alphav were remarkably attenuated with BS-1417 compared to control. BS-1417 inhibited the growth and VEGF expression of HUVEC in vitro.The integrin alphavbeta3 may play a key role in the induction of laser-induced CNV. The antagonists for integrin alphavbeta3 may have therapeutic effects in CNV associated diseases such as age-related macular degenerations.

Aims: The aim of this study was to investigate the association between normal tension glaucoma and the candidate disease locus glaucoma 1, open angle, B (GLC1B) on chromosome 2. There are many reports describing the results of association or linkage studies for primary open angle glaucoma (POAG), with GLC1B as one of the loci associated with normal or moderately elevated intraocular pressure. However, there are few reports about the association of genes or defined genomic regions with normal tension glaucoma, which is the leading type of glaucoma in Japan. The GLC1B locus is hypothesized to be a causative region for normal tension glaucoma. Methods: Genomic DNA was extracted from whole blood of normal tension glaucoma (n = 143) and healthy controls (n = 103) of Japanese origin. Results: Fifteen microsatellite markers within and/or near to the GLC1B locus were genotyped, and their association with normal tension glaucoma was analysed. Two markers D2S2264 and D2S176 had significant positive associations. Conclusion: The D2S176 marker had the strongest significant association and it is located 24 kb from the nearest gene NCK2, which now becomes an important new candidate gene for future studies of its association with normal tension glaucoma.

PURPOSE To report a case of ocular toxoplasmosis with the direct evidence of intraocular infection of Toxoplasma gondii. METHODS Diagnostic vitrectomy was performed to collect vitreous and retinal samples on a 67-year-old female patient who had been suffering from recalcitrant intraocular inflammation with retinal lesions for a year. RESULTS Histopathological examinations of the retinal sample revealed numerous terminal colonies and extracellular tachyzoites that were confirmed to be Toxoplasma gondii by genetic analysis of vitreous and retinal sample using polymerase chain reaction (PCR). The intraocular disease was successfully treated with combination of anti-toxoplasma agents. CONCLUSION Recent evolution of vitrectomy technique and genetic analysis can help ophthalmologists to reach more accurate diagnosis in a complicated case of ocular toxoplasmosis.

Purpose: To investigate if nipradilol has an anti-apoptotic effect in serum-deprived RGC-5 cells and in the streptozotocin-induced diabetic rat retina. Methods: Apoptosis was quantified by activated caspase-3 immunohistochemistry or terminal dUTP nick end-labeling assay. Results: Nipradilol dose-dependently suppressed apoptosis in a protein kinase A- and G-dependent manner and counteracted glutamate-induced calcium entry in the RGC-5 cells and reduced apoptotic cells in the retinal ganglion cell layer of 4- and 12-week diabetic retinas compared to controls when instilled for 5 days. Removal of the nitric oxide moiety from nipradilol blocked these effects. Conclusions: Nipradilol protects RGCs from apoptosis induced by serum-deprivation in vitro and by diabetes in vivo. The NO-related signaling pathway mediates the anti-apoptotic ability of nipradilol.

To evaluate the safety and efficacy of intravitreal injection of bevacizumab advanced to vitrectomy for severe proliferative diabetic retinopathy. Eight eyes of six patients (33–64 years old, all male patients) with severe proliferative diabetic retinopathy were investigated. An intravitreal injection of 1.25 mg bevacizumab was performed 3–30 days prior to planned vitrectomy. All cases showed minimum bleeding during surgical dissection of fibrovascular membrane. Two cases receiving bevacizumab 7 days before the surgery showed strong fibrosis and adhesion of fibrovascular membrane, resulted in some surgical complications. The cases having intravitreal bevacizumab for shorter time did not show extensive fibrosis. The pretreatment of bevacizumab is likely effective in the vitrectomy for severe PDR. The appropriate timing of vitrectomy after bevacizumab injection should be further evaluated.