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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.

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.

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.

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.

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.

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.

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.

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.

Nitric oxide (NO) is cytoprotective to certain types of neuronal cells. The neuroprotective ability of NO in the retina was reportedly mediated by the cyclic GMP (cGMP) to protein kinase G (PKG) pathway. Cyclic AMP-responsive element binding protein (CREB) plays an essential role in the NO/cGMP/PKG-mediated survival of rat cerebellar granule cells. We tested whether CREB transduces the NO/cGMP/PKG anti-apoptotic cascade in R28 neuro-glial progenitor cells. Apoptosis was induced in R28 cells by serum deprivation for 24 h. Varying concentrations of two NO donors, sodium nitroprusside (SNP) and nipradilol, were added to medium with or without an NO scavenger, a soluble guanylyl cyclase inhibitor, or a PKG inhibitor. The cells were immunostained against activated caspase-3 and counterstained with Hoechst 33258. Apoptosis was quantified by counting activated caspase-3 positive or pyknotic cells. SNP and nipradilol rescued R28 cells from apoptosis in a dose-dependent manner, at an optimal concentration of 1.0 microM and 10 microM, respectively. Higher concentrations were cytotoxic. The NO scavenger and the inhibitors decreased the anti-apoptotic effect of the NO donors. Intracellular cGMP levels were increased after exposure to SNP and nipradilol. Western blotting showed that both NO donors increased CREB phosphorylation, which was blocked when pre-exposed to the inhibitors. Transfection with a dominant negative CREB construct defective of phosphorylation at Ser-133 interfered with the anti-apoptotic activity of SNP. These results indicate that CREB at least in part mediates the cGMP/PKG-dependent anti-apoptotic signal induced by NO in R28 cells.

A relative afferent pupillary defect (RAPD) is known to develop only when more than 25% of retinal ganglion cells are ablated in monkeys' eyes. However, there was no prior study to estimate biometrically the degree of retinal nerve fiber layer (RNFL) thickness reduction leading to the development of RAPD in live human eyes. The purpose of this study was to examine the correlation between the amount of RNFL thickness reduction and the depth of a clinically detectable RAPD in patients with unilateral optic atrophy.Enrolled were 20 patients with optic atrophy of various etiologies. We quantified RAPD by performing the swinging flashlight test with log-scaled neutral density filters placed over the unaffected eye. Average RNFL thickness was measured by OCT3000 with the average RNFL thickness program. Linear regression analysis was used in assessing the relationship between RAPD and the ratio of affected to unaffected average RNFL thickness.The mean of average RNFL thickness was 95.6+/-17.3 microm in the unaffected eyes and 50.7+/-19.3 microm in the affected eyes (P0.001). Regression analysis between RAPD and the ratio of affected to unaffected average RNFL thickness revealed a correlation coefficient R2=0.48 (P=0.0007). The regression line intersected the y-axis at 0.77.RAPD was not clinically detected until at least approximately 25% of the retinal nerve fibers were lost when compared with the unaffected eyes. Substantial retinal ganglion cell damage is required for the development of RAPD.

Aim: To compare and evaluate the transitions in retinal function after photodynamic therapy (PDT) between age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) using multifocal electroretinograms (mfERGs). Methods: 10 eyes with choroidal neovascularisation (CNV) secondary to AMD and 11 eyes with CNV secondary to PCV were included in the study. mfERGs were recorded before PDT, and 1 week and 3 months after PDT. mfERG recordings were acquired by a Veris system (V.3.1.3) using a 103 hexagon stimulus. The first-order kernel was used to calculate amplitudes and latencies. Mean amplitudes and latencies from two central rings rated 0–4° of visual angle were analysed and compared with each disease. Results: In AMD, the mean first negative peak (N1) amplitudes tended to decrease, and the mean first positive peak (N1P1) amplitudes reduced to significant levels (p = 0.047) 1 week after PDT. 3 months after PDT, there were no significant differences in the mean N1 and N1P1 amplitudes compared with pre-PDT values. In PCV, there were no significant changes in the mean N1 and N1P1 amplitudes 1 week after treatment. However, 3 months after PDT, mean amplitudes showed significant increases in N1 (p = 0.008) and N1P1 (p = 0.006) amplitudes compared with pre-PDT values. Conclusions: mfERG recording transitions are different between patients with AMD and those with PCV. In patients with AMD, these results may show transient impairments in retinal function 1 week after PDT, but in those with PCV, the efficacy of PDT is superior to the impairment after PDT.

Diabetes mellitus (DM) is a risk factor for open-angle glaucoma, although the mechanistic interrelationship of the two is debatable. The purpose of this study is to test whether DM augments neural apoptosis in rat retina with chronically elevated intraocular pressure (IOP).Sprague-Dawley rats were made diabetic by intraperitoneal injection of streptozotocin (STZ). At one month after STZ injection, three episcleral veins in one eye were cauterized to elevate IOP. Rats without STZ injection were treated likewise as diabetic controls. At 2 weeks, 1 month, and 2 months after cauterization, the retina was dissected, flat-mounted, and subjected to terminal dUTP nick end labeling (TUNEL) staining. TUNEL positive cells per unit area of the whole retina were measured.DM did not affect base line IOP or augment IOP elevation due to episcleral vein cauterization. TUNEL positive cells, which primarily consisted of the neurons and glial cells in the inner retina including retinal ganglion cell (RGC), were counted consistently eight times more in the diabetic retina without IOP elevation than diabetic controls (n = 9, p0.001). The cauterization significantly elevated IOP up to 28.9 mmHg (p0.001), which was reduced over time, and substantially induced apoptosis in a IOP-dependent fashion (p0.001). Ocular hypertensive retinas with DM had significantly more TUNEL positive cells than those without DM despite of the similar time course of IOP changes (p0.001).DM has an additive effect on apoptosis induction by chronic elevation of IOP. Diabetes may act as a risk factor of open-angle glaucoma by increasing susceptibility of retinal cells including retinal ganglion cells to apoptosis triggered by additional stresses such as elevated IOP.

間歇性外斜視における内田ブルーカラーレンズの装用効果をみるために、装用前後の斜視角、病態の変化、立体視、片眼つぶりや羞明について比較検討を行なった。対象は手術既往のない間歇性外斜視19例、間歇性外斜視術後残余斜視23例。斜視角は間歇性外斜視では近見58.0%、遠見73.7%、術後残余斜視では近見47.8%、遠見21.8%に減少傾向を示した。病態は斜位斜視が正位または斜位に移行しやすかった。立体視は間歇性外斜視の近見にて改善効果が高かった。片眼つぶりや羞明は間歇性外斜視は全症例で、術後残余斜視は50%に改善がみられた。内田ブルーカラーレンズは間歇性外斜視の治療に有用であると考える。

我々は、2歳から間歇的に出現した内斜視が6歳時には外斜位に移行し、その後近見障害、その結果内よせ調節緊張症を生じた非定型的内斜視の経過をたどった症例を経験したので報告する。初診時(2歳4か月)に内斜視を主訴に来院したが、受診時に内斜視はなく軽度の遠視を認めたのみであった。再受診時(4歳)再び内斜視が出現したとのことで来院したが、病院内での眼位は正位であった。しかし、家庭での写真判定で内斜視が出現した時としない時が確認された。それ以降は外来経過観察を行った。6歳時にはわずかな外斜位に移行し7歳時には近見障害を伴う内よせ調節緊張症を生じた。9歳時、その内よせ調節緊張症は両眼に3プリズム基底内方の眼鏡装用にて遠見、近見ともに裸眼視力は良好となり、さらに遠見、近見ともに良好な立体視が得られた。

BRADDICK RANDOM-DOT GRADED STEREO SLIDES®(以下,RANDOM-DOT SLIDESと略す)を用いて,間歇性外斜視の遠見立体視機能について検討した。結果はRANDOM-DOT SLIDESでは720″の視標での正答率は70.4%,360″までは72.6%,180″までは58.1%,90″までは46.8%であった。

Purpose To evaluate the agreement of iCare rebound tonometer in measuring intraocular pressure (IOP) with Goldmann applanation tonometer (GAT), Tonopen XL, and noncontact tonometer, and the influence of the central corneal thickness (CCT) on IOP measurements made with these four tonometers in 45 (12 control and 33 glaucomatous or ocular hypertensive) eyes. Design Clinically relevant experimental study. Methods Tonometer intermethod agreement was assessed by the Bland-Altman method. The relations of CCT with absolute IOP values and intertonometer differences were analyzed by linear regression. Results The mean differences (95% limits of agreement) in IOP readings between iCare and GAT, Tonopen XL, and noncontact tonometer were 1.40 ± 4.29, 0.00 ± 4.78, and 2.22 ± 4.19 mm Hg, respectively. All tonometries had a marked association with CCT. As the CCT got thicker, iCare considerably overestimated GAT and Tonopen XL. Conclusions Although influenced by CCT, iCare agrees well with applanation tonometers.

To compare the healing process of the retinal pigment epithelium (RPE) with and without the overlying sensory retina.A dome-shaped retinal detachment was created in the pigmented rabbit eye by injecting balanced salt solution into the subretinal space. The detached retina was partially removed with a vitrector; in some eyes, the detached retina was removed completely. RPE about 1.5 mm in diameter was removed from Bruch's membrane and aspirated through the retinal break. All eyes were examined morphologically.Independent of the sensory retina, 4 days postoperatively the RPE wound was covered by immature RPE cells that gradually formed an epithelial-like sheet by 2 weeks postoperatively. In eyes with overlying sensory retina, regenerated RPE cells similar to normal RPE cells formed a monolayer in most areas. The RPE-photoreceptor outer segment interface gradually organized. In eyes with no sensory retina, the regenerated RPE cells were longer, mounded, and their microvilli were shorter and disorganized. The RPE cells were multilayered in some areas and often had a tubuloacinar structure.The RPE wounds healed rapidly, independent of the presence of the overlying sensory retina, up to 2 weeks after RPE removal. Reconstruction of the RPE monolayer and the apical morphology of regenerated RPE cells were influenced by the sensory retina.

私達は正常な両眼視を持つ77例に,大型弱視鏡を用いてBRADDICK RANDOM・DOT GRADED STEREO SLIDES®(イギリスClement Clarke社製)にて遠見の立体視の正常値を定量的に検討した。結果は70%に90″以上の立体視が得られ,80%に180″以上の立体視が得られた。また全例において360″以上の立体視が得られた。年齢毎の正答率に差は見られなかった。

Purpose To compare the ability of circumpapillary retinal nerve fiber layer (cpRNFL) thickness and macular parameters obtained by three spectral-domain optical coherence tomography (SD-OCT) instruments to detect highly myopic glaucoma. Methods In this study, 84 glaucomatous eyes, 53 normal eyes with high myopia, and 86 normal eyes (not highly myopic) were enrolled. Each participant was imaged using Cirrus, RTVue, and 3D OCT to evaluate the average and quadrant cpRNFL thicknesses. The macular retinal nerve fiber layer (mRNFL), ganglion cell layer + inner plexiform layer (GCL/IPL), and mRNFL + GCL/IPL (GCC) thicknesses were analyzed. The areas under the receiver operating characteristic curves (AUCs) were compared between the instruments. In addition, the best parameters for the AUC were compared between the cpRNFL parameters and macular parameters in each instrument. Results These analyses revealed similar AUCs for the average cpRNFL and GCC thicknesses between the instruments. RTVue displayed a significantly higher AUC in the nasal cpRNFL thickness than both Cirrus (P = 0.0004) and 3D OCT (P = 0.0006). 3D OCT showed higher AUCs than Cirrus in the mRNFL parameters. There were no significant differences between the best cpRNFL parameters and macular parameters in each instrument. Conclusions The average cpRNFL and GCC thicknesses that were measured using these OCT instruments exhibited similar abilities for diagnosing highly myopic glaucoma, and RTVue exhibited better diagnostic abilities than Cirrus and 3D OCT for nasal cpRNFL. 3D OCT had better ability than Cirrus in the mRNFL. Both cpRNFL and GCC in each instrument were comparable, and their measurements offered good ability for diagnosing glaucoma with high myopia. (http://www.umin.ac.jp/ctr/index/htm9, UMIN000006900.).

Purpose We compared the ability of circumpapillary retinal nerve fiber layer (cpRNFL) thickness and macular parameters obtained by three spectral-domain optical coherence tomography (SD-OCT) instruments to detect glaucoma. Methods We enrolled 87 normal eyes and 145 glaucomatous eyes (75 early glaucomatous eyes (EGs), mean deviation > -6 dB). Each participant was imaged using Cirrus, RTVue, and 3D-OCT to evaluate the average and quadrant cpRNFL thicknesses. The macular retinal nerve fiber layer (mRNFL), ganglion cell layer plus inner plexiform layer (GCL/IPL), and mRNFL + GCL/IPL (ganglion cell complex [GCC]) thicknesses were analyzed. The areas under the receiver operating characteristic curves (AUCs) were compared among the instruments. Results These instruments revealed similar AUCs for the average cpRNFL and GCC thicknesses in EGs, and total all-stage glaucomatous eyes (TGs). RTVue showed better performance in the nasal cpRNFL thickness than Cirrus and 3D-OCT, and better performance in the temporal cpRNFL thickness than 3D-OCT in TGs. RTVue had a higher AUC for the superior GCC thickness compared to Cirrus and 3D-OCT in EGs, and TGs. Cirrus had higher AUCs for GCL/IPL parameters in TGs, and lower AUCs for the mRNFL parameters in EGs and TGs compared to 3D-OCT. Conclusions The average cpRNFL and GCC thicknesses measured using these OCT instruments exhibited similar abilities in the diagnosis of glaucoma, and RTVue exhibited better diagnostic abilities than Cirrus and 3D-OCT for nasal cpRNFL, and superior GCC thicknesses. The diagnostic performance of Cirrus and 3D-OCT was different for GCL/IPL and mRNFL parameters. (http://www.umin.ac.jp/ctr number, UMIN000006900.)

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).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.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.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.

Multidrug resistance protein 4 (MRP4) effluxes a wide variety of endogenous compounds, including cyclic adenosine monophosphate (cAMP), and is exclusively expressed in vascular endothelial cells (ECs) of the retina. This study aimed to investigate the role of MRP4 in retinal vascular development.The retinal vascular phenotype of Mrp4(-/-) mice was examined by whole-mount immunohistochemistry at P3, P6, and P14. The retinas from P6 pups that received an intraperitoneal injection of either solvent control or forskolin, an inducer of intracellular cAMP formation, at P4 and P5 were analyzed in terms of their vascular formation (vascular length, vascular branching, vascular density, and the number of tip cells), cell proliferation and apoptosis, and vessel stability.The Mrp4(-/-) mice exhibited no overt abnormalities in the development of the retinal vasculature, but retinal vascular development in the Mrp4(-/-) mice was suppressed in response to forskolin administration. There was a significant decrease in the vascular length, vascular branching, and vascular density, and inhibited tip cell formation at the vascular front. The forskolin-treated Mrp4(-/-) mice showed an increased number of Ki67-positive and cleaved caspase 3-positive ECs, a significant decrease in the amount of pericyte coverage, and a reduced number of empty sleeves. In pups exposed to hyperoxia (75% oxygen) from P7 to P12, the Mrp4(-/-) mice showed a significant increase in the unvascularized retinal area.Mrp4(-/-) mice exhibited suppressed retinal vascular development in response to forskolin treatment. Thus, Mrp4 might have protective roles in retinal vascular development by regulating the intracellular cAMP level.

Background The effects of intravitreal ranibizumab (IVR) against exudative age-related macular degeneration (AMD) may be different associated with the lesion phenotype. This study was conducted to compare the outcomes of IVR between two different phenotypes of exudative AMD: typical neovascular AMD (tAMD) and polypoidal choroidal vasculopathy (PCV). Methods This is a retrospective cohort study of 54 eyes from 54 subfoveal exudative AMD patients (tAMD 24, PCV 30 eyes). Three consecutive IVR treatments (0.5 mg) were performed every month, followed by re-injections as needed. Change in the best-corrected visual acuity (BCVA) and central retinal thickness (CRT) were then compared between the tAMD and PCV groups over 12 months of follow-up. Results The mean BCVA was significantly improved (-0.11 logMAR units) at month 3 after the initial IVR (p Conclusions IVR is an effective therapy for tAMD and PCV in the BCVA improvement in Japanese patients over 12 months of follow-up. The phenotype of tAMD showed a significantly better outcome with IVR than PCV in terms of BCVA improvement.

Saya Nakano1, Shigeru Honda1, Hideyasu Oh2, Mihori Kita2, Akira Negi11Department of Surgery, Division of Ophthalmology, Kobe University Graduate School of Medicine, Kobe, 2Department of Ophthalmology, Hyogo Prefectural Amagasaki Hospital, Amagasaki, JapanBackground: The purpose of this work was to compare the efficacy of photodynamic therapy (PDT) with or without posterior subtenon injections of triamcinolone acetonide (STA) or intravitreal injections of ranibizumab (IVR) for retinal angiomatous proliferation (RAP).Methods: Thirty-seven eyes from 33 consecutive patients with RAP were treated by PDT monotherapy (Group 1), PDT combined with STA (Group 2), or PDT combined with IVR (Group 3). The best-corrected visual acuity, greatest linear dimension, central retinal thickness, and number of treatments were compared among the three groups.Results: The change in mean best-corrected visual acuity (logMAR) at month 3, 6, and 12 after the initial treatment was better in Group 2 (-0.13, -0.23, and -0.21, respectively) and Group 3 (-0.018, 0.0028, and -0.0067, respectively) than in Group 1 (0.13, 0.19, and 0.23, respectively); Group 1 versus Group 2 was statistically significant (P = 0.018). The mean central retinal thickness was reduced from baseline in all groups, but the reduction amplitude was significantly greater in Group 2 than in Group 1 and Group 3. The mean number of treatments was significantly lower in Group 2 (1.1 ± 0.4) and Group 3 (1.5 ± 0.5) than in Group 1 (2.9 ± 0.9) in the 12 months after the initial treatment.Conclusion: Treatment with STA + PDT may be an effective therapy for RAP lesions over 12 months of follow-up.Keywords: retinal angiomatous proliferation, photodynamic therapy, triamcinolone acetonide, ranibizumab, combined therapy

Michiaki Kubo and colleagues report a genome-wide association study for age-related macular degeneration in individuals of Japanese ancestry. They identify two genetic loci newly associated with this disease. Age-related macular degeneration (AMD), the leading cause of irreversible blindness in the world, is a complex disease caused by multiple environmental and genetic risk factors. To identify genetic factors that modify the risk of exudative AMD in the Japanese population, we conducted a genome-wide association study and a replication study using a total of 1,536 individuals with exudative AMD and 18,894 controls. In addition to CFH (rs800292, P = 4.23 × 10−15) and ARMS2 (rs3750847, P = 8.67 × 10−29) loci, we identified two new susceptibility loci for exudative AMD: TNFRSF10A-LOC389641 on chromosome 8p21 (rs13278062, combined P = 1.03 × 10−12, odds ratio = 0.73) and REST-C4orf14-POLR2B-IGFBP7 on chromosome 4q12 (rs1713985, combined P = 2.34 × 10−8, odds ratio = 1.30). Fine mapping revealed that rs13278062, which is known to alter TNFRSF10A transcriptional activity, had the most significant association in 8p21 region. Our results provide new insights into the pathophysiology of exudative AMD.

Mariko Yagi1, Motohiro Yamamori4, Ichiro Morioka2, Naoki Yokoyama2, Shigeru Honda3, Akira Negi3, Tsutomu Nakamura1, Noboru Okamura4, Katsuhiko Okumura1, Toshiyuki Sakaeda5, Masafumi Matsuo21Department of Clinical Evaluation of Pharmacotherapy, 2Department of Pediatrics, 3Department of Surgery, Division of Ophthalmology, Kobe University Graduate School of Medicine, Kobe, Japan; 4Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Mukogawa Women's University, Nishinomiya, Japan; 5Center for Integrative Education of Pharmacy Frontier, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, JapanAbstract: Vascular endothelial growth factor (VEGF) contributes to the development of retinopathy of prematurity (ROP). We investigated the association of ROP with VEGF genetic polymorphisms and its clinical parameters in Japanese people. Sixty-seven infants with a gestational age of 30 weeks or less were enrolled and classified into the threshold ROP group (infants with Stage 3 ROP in zone I or II, five continuous or eight total clock hours of the retina and the presence of plus disease, n = 30) and the nonthreshold ROP group (n = 37). The VEGF genotypes of −1498T>C, −1154G>A, −634C>G, −7C>T, 936C>T, and 1612G>A were determined. VEGF 936C>T polymorphism and 11 clinical parameters were significantly different between the two ROP groups by univariate analysis. A logistic regression analysis with adjustments for gestational age and birth weight showed that the heterozygous or homozygous carrier state of the T alleles of VEGF 936C>T polymorphism (odds ratio 5.12; 95% confidence interval: 1.25–20.92; P = 0.023) and duration of oxygen administration (odds ratio 1.05; 95% confidence interval: 1.00–1.10; P = 0.042) were independent risk factors of threshold ROP. VEGF 936C>T polymorphism may predict threshold ROP in Japanese infants with a gestational age of 30 weeks or less.Keywords: retinopathy of prematurity, vascular endothelial growth factor, gene polymorphism, premature infant&nbsp

Purpose To investigate whether the solute carrier family 1, member 3 (SLC1A3) gene, which encodes the glutamate aspartate transporter, is associated with normal tension glaucoma (NTG) in Japanese patients. Methods Two hundred and ninety-five Japanese patients with NTG and 518 Japanese healthy controls were recruited. Patients exhibiting comparatively early NTG onset were selected because early onset suggests that genetic factors may show stronger involvement. We genotyped 5 single-nucleotide polymorphisms (SNPs) in SLC1A3 and assessed the allelic and genotypic diversity among cases and controls. Results There were no statistically significant differences in the frequency of SLC1A3 alleles and genotypes between cases and controls. Conclusions Our study showed no association between SLC1A3 and NTG, suggesting that the SLC1A3 gene may not be an associated factor in NTG pathogenesis.

PURPOSE To investigate the effect of chronically elevated intraocular pressure (IOP) on the expression of water channel aquaporins (AQPs) 1, 4, and 9 in the optic nerve and retina in rats. METHODS Three episcleral veins were cauterized to elevate IOP in the left eyes of Sprague-Dawley rats. IOPs were monitored with a rebound tonometer. At 2 and 4 weeks after surgery, eyeballs with the attached optic nerve were enucleated for cryosectioning with immunohistochemistry, or dissected retinas and desheathed optic nerves were subjected to gene expression analyses. RESULTS IOP was significantly increased after surgery up to 4 weeks (P=0.0008). In the control optic nerve, the unmyelinated portion showed only AQP9 immunoreactivity, whereas the myelinated portion expressed both AQP4 and AQP9 immunoreactivities colabeled for glial fibrillary acidic protein but not for neurofilament. In the control retina, AQP1 was expressed in the outer nuclear layer and photoreceptors, AQP4 was expressed in Muller cell endfeet, and AQP9 was expressed primarily in NeuN-positive cells in the ganglion cell layer (GCL). Elevated IOPs substantially reduced AQP9 expression in the optic nerve head (ONH) and the GCL and decreased the retinal gene expression, but not immunoreactivity, of AQP1. CONCLUSIONS AQP9 was the only water channel expressed in the unmyelinated portion of the ONH and in the GCL whose expression was reduced after IOP elevation. Given that AQP9 presumably acts as a channel for metabolites to pass from astrocytes to neurons, the reduced expression of AQP9 at these specific sites may be implicated in the pathogenesis of glaucomatous optic neuropathy.

Purpose A nonsynonymous coding variant in the manganese superoxide dismutase (SOD2) gene (V16A, rs4880) has been implicated in neovascular age-related macular degeneration (AMD). However, the findings have been inconsistent. Two studies in Japanese populations reported an opposite direction of association of the same allele at the V16A variant, whereas one study in a Northern Irish population found no effect of the variant on the risk of developing neovascular AMD. To address these apparently contradictory reports, we validated the association in a Japanese population. Methods In a Japanese population, we genotyped the V16A variant in 116 neovascular AMD patients, 140 polypoidal choroidal vasculopathy (PCV) patients, and 189 control participants. This association was also tested in a population of PCV participants to avoid variable findings across studies due to underlying sample heterogeneity and because disease phenotype was not well described in previous studies. We analyzed a tagging single nucleotide polymorphism (SNP) in addition to the V16A variant to capture all common SOD2 variations verified by the HapMap project. Genotyping was conducted using TaqMan technology. Associations were tested using single-SNP and haplotype analyses as well as a meta-analysis of the published literature. Population stratification was also evaluated in our study population. Results We found no detectable association of the V16A variant or any other common SOD2 variation with either neovascular AMD or PCV, as demonstrated by both single-SNP and haplotype analyses. Population structure analyses precluded stratification artifacts in our study cohort. A meta-analysis of the association between the V16A variant and neovascular AMD also failed to detect a significant association. Conclusions We found no evidence to support the role of any common SOD2 variations including the V16A variant in the susceptibility to neovascular AMD or PCV. Our study highlights the importance and difficulty in replicating genetic association studies of complex human diseases.

Purpose Using a candidate-gene approach, a recent case-control study identified a previously unknown association between neovascular age-related macular degeneration (AMD) and the coding Met72Thr variant in the pigment epithelium-derived factor (PEDF) gene in a Taiwan Chinese population. However, a subsequent replication study failed to see this association in a white European population. We noted an important difference in the sample ascertainment scheme between these two studies. The original study did not consider findings of indocyanine green (ICG) angiography for disease classification, which is the only way to obtain a clear image of polypoidal choroidal vasculopathy (PCV) lesions. This suggests that their cohort might include a considerable amount of PCV, given its high prevalence in the Chinese population. In contrast, the replication study intentionally excluded PCV from the case cohort on the basis of ICG angiograms. Therefore, the inconsistent finding might be caused by potential sample heterogeneity between these two studies. In this respect, this association needed to be examined in a case series of clearly defined individuals with neovascular AMD and PCV. The aim of this study was to validate the previously reported association of the PEDF Met72Thr variant in a well characterized Japanese population with neovascular AMD and PCV. Methods We genotyped the Met72Thr variant (rs1136287) in 116 patients with neovascular AMD, 140 patients with PCV, and 189 control participants in a Japanese population. Genotyping was performed using TaqMan technology. We tested for an association of this variant with neovascular AMD and PCV separately. We also evaluated population stratification in our study cohort. Results We found no statistically significant evidence for association between rs1136287 and either neovascular AMD or PCV under any genetic models (trend, genotypic, dominant, and recessive genetic models; p>0.05). Population structure analyses excluded stratification artifact in our study population. Conclusions We report a lack of association between the PEDF Met72Thr variant and either neovascular AMD or PCV in a Japanese population. We conclude that the Met72Thr variant does not play a significant role in the risk of developing neovascular AMD or PCV.