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Although ocular circulation at the retina and optic disc is known to be associated with the pathology of glaucoma, direct measurement of blood flow velocity has been difficult to obtain. This prospective observational study enrolled 11 consecutive patients with treatment-naïve primary open-angle glaucoma (POAG) and 11 healthy subjects, and the effects of topical tafluprost treatment on ocular circulation were examined at baseline and at 1, 4, and 12 weeks after initiating treatment with topical tafluprost on POAG patients using multiple modalities, which include adaptive optics scanning laser ophthalmoscopy (AOSLO). Baseline mean intraocular pressure (IOP) was significantly higher and mean parafoveal blood flow velocity (pBFV) was significantly lower in POAG eyes than in healthy eyes. Mean IOP was significantly decreased (1 week, −19.1%; 4 weeks, −17.7%; and 12 weeks, −23.5%; all P P = 0.007; 4 weeks, 21.3%, P P = 0.002). These results reveal that tafluprost may not only lower IOP but may also improve retinal circulation in POAG eyes and AOSLO may be useful to evaluate retinal circulatory change after treatment.

To investigate the association between the characteristics of foveal cystoid spaces and short-term responsiveness to ranibizumab treatment for diabetic macular edema (DME) at 3 months from the initial injection. We retrospectively reviewed 66 eyes of 61 patients with center-involved DME who received three consecutive ranibizumab injections and following as-needed administrations. We evaluated the relationship between visual improvement at 3 months and the preoperative optical coherence tomography (OCT) parameters including hyperreflective foci, heterogeneous OCT reflectivity, mean levels of OCT reflectivity and height of foveal cystoid spaces. Twenty-three eyes without preoperative hyperreflective foci in the foveal cystoid spaces had significantly greater improvement in the logarithm of the minimum angle of resolution visual acuity (logMAR VA) at 3 months than 43 eyes with foci (P = 0.006). That was similar to the greater reduction in CSF thickness in eyes without lesions after treatment at the same time point (P

To investigate the incidence rate and risk factors for development of retinal pigment epithelial (RPE) atrophy during anti-vascular endothelial growth factor (anti-VEGF) treatment for retinal angiomatous proliferation.This study included 46 eyes with treatment-naive retinal angiomatous proliferation. All patients were treated with ranibizumab or aflibercept injections. Color fundus photography, spectral-domain optical coherence tomography, and fundus autofluorescence were evaluated for RPE atrophy diagnosis. Baseline characteristics and gene polymorphisms of ARMS2 A69S, and CFH I62V were analyzed for association with development and progression of RPE atrophy.Among 21 eyes treated with ranibizumab without preexisting RPE atrophy at baseline, 5 eyes (23.8%) developed RPE atrophy at 12 months. Among 20 eyes treated with aflibercept without preexisting RPE atrophy at baseline, 10 eyes (50.0%) developed RPE atrophy at 12 months. Refractile drusen at baseline was associated with RPE atrophy development at 12 months (P = 0.014), and the progression rate of RPE atrophy area was negatively correlated with subfoveal choroidal thickness at baseline (R = -0.595, P = 0.019). Gene polymorphisms were not associated with RPE atrophy.Retinal pigment epithelial atrophy developed in 36.6% during 12 months after anti-VEGF treatment for retinal angiomatous proliferation. The presence of refractile drusen at baseline was identified as a novel significant risk factor for RPE atrophy development.

Screening for causative genes in heterogeneous groups of diseases such as retinitis pigmentosa (RP) has been challenging, until recently. These days, even whole genomes can be sequenced using next-generation sequencers. This technology has enabled comprehensive screening of gene mutations in RP patients. However, whole-genome/exome sequencing is still expensive and takes considerable time and labor. In contrast, targeted exome sequencing focuses on selected genes and thereby enables faster and deeper analysis of the regions of interest at a lower cost. In this chapter, we review the data from our previous study on targeted exome sequencing in Japanese RP patients and discuss the utility and limitations of this technique. We also discuss the mutation spectrum in Japanese RP patients compared to previously reported spectra in other ethnicities.

To study the circumpapillary retinal nerve fiber layer thickness (cpRNFLT) in a 10°-wide sector using spectral-domain optical coherence tomography for diagnostic ability in early stage open-angle glaucoma (OAG).cpRNFLT measurements (3.4-mm diameter centered on the disc) were obtained from 89 eyes with early stage OAG (mean deviation, -2.5 ± 1.8 decibels) and 89 age-matched normal eyes. The ability of 180°-, 90°-, 30°-, and 10°-wide cpRNFLT sectors in discriminating early stage OAG eyes was evaluated by calculating the area under the receiver-operating characteristic curves (AUCs) and sensitivity/specificity per diagnostic criteria with varying sector widths, normative data-based cpRNFLT cutoff levels and numbers of abnormal sectors. The intra- and inter-visit reproducibilities of the cpRNFLT 10°-sector measurements were studied in a separate group of eyes with normal and early stage OAG.The greatest AUC obtained using the cpRNFLT 10° sector, 0.924 (confidence interval, 0.875-0.958), did not differ significantly from those obtained with the 180°, 90°, and 30° sectors. Only calculations using the 10° sectors had sensitivities and specificities of 0.90 or higher with the best performance of the sensitivity/specificity of 0.92/0.94. These values tended to be better (P = 0.070) than with the 30° sectors, 0.85/0.94, which were also selected with several combinations of various cutoff levels and the number of abnormal sectors. The coefficients of variation for the intra- and inter-visit reproducibility of the 10°-sector measurements were 10 % or less in 32 and 24 of the 36 sectors.The cpRNFLT 10°-sector measurements showed reasonable reproducibility and identified eyes with early stage OAG with a sensitivity and specificity of 0.92/0.94.

PURPOSE To compare therapeutic responses to intravitreal aflibercept and ranibizumab in neovascular age-related macular degeneration (AMD)-affected eyes with and without choroidal vascular hyperpermeability (CVH). METHODS Medical records of 216 consecutive patients (216 eyes) with treatment-naive exudative AMD who had received three monthly intravitreal injections of aflibercept (2 mg) and ranibizumab (0.5 mg) at a single institution were analyzed. The associations of CVH with functional and morphologic changes were compared between the treatment groups. RESULTS Although foveal thickness (P = 0.85) and visual acuity (P = 0.13) changes were not significantly different between the treatment groups, subfoveal choroidal thickness (CT) (P = 0.001) and pigment epithelial detachment (PED) height (P = 0.043) decreased more profoundly in the aflibercept-treated group. The incidence of dry macula after treatments was lower in the ranibizumab-treated eyes with CVH than in those without CVH (P = 0.043), but it showed no significant difference between the aflibercept-treated eyes with and without CVH (P = 0.74). The aflibercept-treated eyes with CVH showed a higher incidence of dry macula (P = 0.04) and greater decrease in subfoveal CT (P = 0.002) than the ranibizumab-treated eyes with CVH. CONCLUSIONS Intravitreal aflibercept can achieve remission of exudative retinal changes in eyes with AMD even in the presence of CVH. In addition, it showed greater effects on the choroid and PED than intravitreal ranibizumab. The possible relationship between CVH suppression and decrease in CT warrants further study.

A 22-year-old woman presented with double vision that she had experienced since an infection 2 weeks previously. A neurological examination showed limited bilateral eye abduction, mimicking Miller Fisher syndrome. However, T2-weighted magnetic resonance imaging of her brain revealed hyperintense areas in the tegmentum of the pons, including the abducens nucleus, and her serum anti-aquaporin-4 antibody test was positive. She was finally diagnosed with neuromyelitis optica. Intravenous high-dose steroid therapy immediately improved the patient's abduction palsy, but bilateral optic neuritis manifested during the treatment. Subsequent treatment with plasma exchange improved her optic neuritis symptoms.

PURPOSE Adaptive optics scanning laser ophthalmoscopy (AO-SLO) is a noninvasive technique that allows for the direct monitoring of erythrocyte aggregates in retinal capillaries. We analyzed the retinal hemorheologic characteristics in normal subjects, diabetic patients without diabetic retinopathy (NDR), and diabetic patients with nonproliferative diabetic retinopathy (NPDR), using spatiotemporal (ST) blood flow images to visualize blood corpuscle trajectory. METHODS AO-SLO images of the parafoveal capillary network were acquired for three groups: 20 healthy volunteers, 17 diabetic patients with NDR (8 type 1 and 9 type 2 patients), and 10 diabetic patients with NPDR (4 type 1 and 6 type 2). The erythrocyte aggregate velocity assigned to a relative cardiac cycle and the elongation rate of the erythrocyte aggregate were calculated. RESULTS Careful observation revealed that flow velocity fluctuations were found with higher frequency in diabetic patients than in normal subjects. The total average velocities were 1.26 ± 0.22 mm/s in the normal group, 1.31 ± 0.21 mm/s in the NDR group, and 1.63 ± 0.35 mm/s in the NPDR group. The average velocities of the NPDR group were higher than those in the normal (P = 0.001) and NDR (P = 0.009) groups. The average elongation rates of the 3 groups were 0.67 ± 0.20, 0.39 ± 0.19, and 0.33 ± 0.11, respectively. Elongation rate differed significantly between the normal and NDR (P = 0.003) groups as well as the normal and NPDR (P = 0.001) groups. CONCLUSIONS AO-SLO can be used to detect retinal hemorheologic changes in the early stages of diabetic retinopathy.

Masahiro Fujimoto,1 Ken Ogino,1 Chika Miyazaki,1,2 Miou Hirose,1,3 Hiroko Matsuyama,1,4 Takeshi Moritera,1,5 Nagahisa Yoshimura1 1Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan; 2Department of Ophthalmology, Hyogo Prefectural Tsukaguchi Hospital, Hyogo, Japan; 3Department of Ophthalmology, Hyogo Prefectural Amagasaki Hospital, Hyogo, Japan; 4Department of Ophthalmology, National Hospital Organization Himeji Medical Center, Hyogo, Japan; 5Moritera Eye Clinic, Shiga, Japan Purpose: To evaluate the surgical outcome of dacryocystorhinostomy (DCR) by measuring the tear meniscus, using optical coherence tomography and rebamipide ophthalmic suspension. Methods: Patients with nasolacrimal obstruction and chronic dacryocystitis who were scheduled for an endonasal DCR underwent tear meniscus examinations before and 2months after surgery. Vertical scans of the inferior menisci were performed before and at 1, 3, 5, 7, and 10minutes after the instillation of rebamipide ophthalmic suspension. The tear menisci areas were measured with imaging software. Ten young adults without epiphora formed the control group.Results: Anatomical success was achieved on 22sides of 21patients. The patients’ postoperative tear menisci were significantly smaller than the preoperative menisci at all points during the test, and the response to volume loading in the postoperative patients was corrected to nearly that of the young, healthy adults. Nevertheless, the postoperative meniscus area tended to be larger than that of the young adults at all points.Conclusion: The reduced tear meniscus area after DCR reflected the success of the surgical procedure. However, incomplete recovery of the meniscus after the test might suggest a residual disorder of the lacrimal drainage system after DCR. Keywords: dacryocystorhinostomy, tear meniscus, rebamipide, optical coherence tomography

To investigate the 2-year outcomes of intravitreal injections of ranibizumab in typical neovascular age-related macular degeneration (tAMD) and polypoidal choroidal vasculopathy (PCV). Factors associated with visual outcomes are examined. We retrospectively reviewed medical records of 128 consecutive eyes with treatment-naive subfoveal AMD treated with ranibizumab and followed for ≥24 months. The association between visual outcomes and single nucleotide polymorphisms (SNPs) in ARMS2 A69S and CFH I62V genes were examined. Fifty-eight eyes were diagnosed with tAMD and 70 eyes with PCV. In tAMD eyes, visual acuity (VA) improved at 3 months (P = 0.020) but returned to the baseline level at 6 months. Thereafter, VA was maintained until 24 months. In PCV eyes, VA significantly improved at 3 months (P = 0.015) and persisted at 12 months (P = 0.025), but the VA improvement dissipated by 24 months. With regard to genetic associations with VA and VA change, neither VA nor VA change showed significant associations with these SNPs at all time points in tAMD. In the PCV eyes, there were significant associations between ARMS2 A69S and VA at baseline and 1 year (P = 0.017 and P = 0.025, respectively). However, VA change showed no significant difference among these genotypes in PCV. Intravitreal ranibizumab significantly improved the VA initially, but this improvement did not persist at 2 years post-treatment. In PCV, ARMS2 A69S polymorphism is associated with the baseline and 12-month VA, but is not associated with the visual prognosis at 24 months.

Corneal curvature (CC) measures the steepness of the cornea and is an important parameter for clinically diseases such as astigmatism and myopia. Despite the high heritability of CC, only two associated genes have been discovered to date. We performed a three-stage genome-wide association study meta-analysis in 12 660 Asian individuals. Our Stage 1 was done in multiethnic cohorts comprising 7440 individuals, followed by a Stage 2 replication in 2473 Chinese and Stage 3 in 2747 Japanese. The SNP array genotype data were imputed up to the 1000 Genomes Project Phase 1 cosmopolitan panel. The SNP association with the radii of CC was investigated in the linear regression model with the adjustment of age, gender and principal components. In addition to the known genes, MTOR (also known as FRAP1) and PDGFRA, we discovered two novel genes associated with CC: CMPK1 (rs17103186, P = 3.3 × 10(-12)) and RBP3 (rs11204213 [Val884Met], P = 1.1 × 10(-13)). The missense RBP3 SNP, rs11204213, was also associated with axial length (AL) (P = 4.2 × 10(-6)) and had larger effects on both CC and AL compared with other SNPs. The index SNPs at the four indicated loci explained 1.9% of CC variance across the Stages 1 and 2 cohorts, while 33.8% of CC variance was explained by the genome-wide imputation data. We identified two novel genes influencing CC, which are related to either corneal shape or eye size. This study provides additional insights into genetic architecture of corneal shape.

[Purpose]: To investigate the prevalence and spatial distribution of cystoid spaces (CS) in retinitis pigmentosa patients with spectral domain optical coherence tomography. [Methods]: A total of 529 eyes of 275 patients with retinitis pigmentosa were examined with spectral domain optical coherence tomography. The presence or absence of CS was judged for each eye. Retinal layer and outer retinal status where the CS existed were also investigated. Statistical analysis was performed using 1 eye per 1 patient. [Results]: Cystoid spaces were present in 119 of 529 eyes (22.5%) of 74 of 275 patients (26.9%). There were no significant differences between the cases with and without CS except for central foveal thickness (P < 0.001). Cystoid spaces were noted in the inner nuclear layer in almost all eyes (98.6%), and outer nuclear layer/outer plexiform layer was also involved in many eyes (27.8%). Cystoid spaces were sometimes seen in ganglion cell layer (6.9%). Cystoid spaces were predominantly (78.9%) distributed in the relatively preserved retina where external limiting membrane was retained. The presence of epiretinal membrane or posterior vitreous adhesion was associated with the presence of CS (P < 0.001) but showed no relationship with the spatial location of CS (P = 1.000). [Conclusion]: The prevalence of CS in patients with retinitis pigmentosa was 26.9% and contrary to previous reports, most CS were present in inner nuclear layer. In addition, most CS were observed in relatively retained retina, which is compatible to the prevailing notion. Epiretinal membrane or posterior vitreous adhesion was also associated with the development of CS. The distribution of CS in inner and preserved retina may provide insight for the pathogenesis of CS in retinitis pigmentosa.

To characterize preperimetric retinal nerve fiber layer (RNFL) defects on speckle noise-reduced spectral-domain optical coherence tomography (SD-OCT), and to determine whether detection of preperimetric RNFL defects can be improved by speckle noise reduction.Thirty-two eyes of 32 patients with preperimetric glaucoma and 30 normal eyes of 30 volunteers underwent complete ophthalmic examinations and scanning by speckle noise-reduced SD-OCT (Spectralis), single-scan SD-OCT (RTVue-100), and single-scan time-domain (Stratus) OCT.All 40 RNFL defects identified by photography had angular widths30 degrees and no disruption of RNFL reflectivity on Spectralis. Circumpapillary RNFL (cpRNFL) boundaries were accurately determined by Spectralis for 38 (95.0%) of the 40 defects, by RTVue-100 for 25 (62.5%), and by Stratus OCT for 23 (57.5%). Sensitivity for the detection of RNFL defects (cpRNFL thinning to1% of normal for an age-matched database) was 15% for Stratus, 42.5% for RTVue, and 47.5% for Spectralis on sector maps and significantly higher for SD-OCT on temporal-superior-nasal-inferior-temporal (TSNIT) thickness graphs: RTVue-100 (57.5%; P=0.031) and Spectralis (90.0%; P=0.0001). On the basis of TSNIT thickness graphs, sensitivity for the detection of RNFL defects was significantly higher for Spectralis compared with RTVue-100 (P=0.001) and Stratus (P=0.0005). Spectralis TSNIT graphs were more sensitive (P=0.001) for glaucoma detection without significant reduction (P=0.125) in specificity compared with Spectralis sector maps.Our results suggest that accurate measurement of cpRNFL thickness by speckle noise-reduced SD-OCT and a comparison of the results with normative database using TSNIT graphs are required to improve the sensitivity for detecting preperimetric RNFL defects.

Although the cause of multiple evanescent white dot syndrome (MEWDS) has not been elucidated, 2 reports have described cases of MEWDS after vaccination. A 16-year-old girl presented with throat pain, headache, and photopsia in the left eye 2 weeks after receiving a human papillomavirus (HPV) vaccination. The clinical examination revealed numerous white dots on the fundus, visual field loss, and abnormal electroretinography results, which are concordant with a diagnosis of MEWDS. Although the white dots on the fundus disappeared within a few months, her visual field continued to deteriorate progressively over 1.5 years of follow-up. Images obtained by fundus autofluorescence and optical coherence tomography revealed longitudinal changes consistent with the observed functional losses. Immunosuppressive therapy (betamethasone 200 mg/day) resulted in the complete resolution of all fluorescein leakage from the retinal vasculature. Maintenance betamethasone treatment (0.5 mg/day) led to visual field results over a period of 6 months. In this case of MEWDS, subsequent to HPV vaccination, the results of fluorescein angiography showed a marked response to immunosuppressive therapy. These findings support the hypothesis that MEWDS is associated with an impaired immune function.

To describe, in glaucomatous patients, spectral-domain optical coherence tomography (SD-OCT) results predictive of paracentral visual field (VF) defects present on standard automated perimetry (SAP) 10-2, but not on SAP 24-2.The SAP 10-2 test was repeated 3 times to determine whether paracentral VF defects were present. Spectralis™ HRA + OCT was used to obtain speckle-noise-reduced macular B-scans. The macular scan protocol consisted of 19 vertical cross-sectional scan lines centered on the fovea (30° × 15° volume scan), each of which was the average of 50 scans. A 3D OCT-2000 was also used to determine macular layer thicknesses and to detect abnormally thin regions (below the 1 % confidence interval of the normative data).We identified 3 cases in which paracentral VF defects were detected on SAP 10-2, but not on SAP 24-2. Paracentral VF defects were detected on all of the SAP 10-2 tests repeated 3 times, and included absolute scotoma in 2 of the 3 SAP 10-2 results. Retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL) damage was diminished on SD-OCT macular images; 2 patients had RNFL and GCL thinning within and central to the parafoveal region, where the GCL is generally thickest in healthy eyes, and 1 patient had evident RNFL and GCL thinning in the papillomacular bundle.Macular SD-OCT scans may be useful in deciding whether SAP 10-2 should be performed.

[Purpose]To investigate the relationship between impairment of cone/rod photoreceptors and changes in optical coherence tomography (OCT) findings. [Methods]We retrospectively reviewed the clinical records of 35 patients with cone-rod dystrophy (CRD) and 35 visual acuity-matched patients with retinitis pigmentosa (RP). The presence or absence of the external limiting membrane (ELM), inner segment ellipsoid (ISe), interdigitation zone (IZ), and foveal cavitation (hyporeflective space in the outer retina) were determined using OCT image evaluation.[Results]There were no statistical differences in the number of CRD and RP patients with an intact ELM and ISe. None of the CRD patients had an intact IZ, but 20 % of RP patients did (P = 0.011). In addition, foveal cavitation tended to be observed more frequently in CRD patients than (25.7 %) in RP patients (5.7 %) despite the difference not being significant after the correction of multiple comparison. [Conclusions]Eyes with CRD and RP had significant differences in foveal morphology, even when visual acuity was matched. This result supports the notion that absence of an IZ and the presence of foveal cavitation is related to cone-dominant photoreceptor impairment.

Primary open angle glaucoma (POAG) is the most common form of glaucoma. High intraocular pressure (IOP), age, family history, race, and myopia are known risk factors for glaucoma.1–4 POAG eyes with...

[Purpose]To study the pathomorphology of subretinal hemorrhage (SRH) seen in eyes with branch retinal vein occlusion (BRVO) and its association with visual prognosis. [Methods]We retrospectively reviewed 42 consecutive patients (42 eyes) with BRVO that affected the fovea. Retinal structural changes were examined by spectral domain optical coherence tomography (SD-OCT). [Results]On SD-OCT sections, serous retinal detachment was seen at the fovea in 35 eyes, 18 of which accompanied foveal SRH. While initial detection of foveal SRH had no correlation with initial visual acuity (VA), it was correlated with poorer final VA (r = 0.361, P = 0.019). Our patients were classified into two groups by the initial detection of foveal SRH, and initial VA was not different between these two groups. At the final examination, damaged lengths in the foveal photoreceptor layer were significantly longer in the SRH-positive group than those in the SRH-negative group (P = 0.004), and final VA in the SRH-positive group was significantly worse than that in the SRH-negative group (P = 0.019). [Conclusion]Foveal SRH is not an uncommon feature in BRVO and may cause subsequent damage to the foveal photoreceptor layer, resulting in poor visual function.

The purpose of this study was to estimate the optimal size of visual field test for detecting longitudinal changes in retinitis pigmentosa (RP) by dividing the visual field.We reviewed the results of 10° static visual field tests in 19 eyes of 19 RP patients. Sixty-eight numeric value points were divided into two area types: concentric areas (A1, A1-2, A1-3, A1-4, A1-5, A1-6) and circular areas (A1, A2, A3, A4, A5, A6). Serial values of mean sensitivity in each area of each patient were analyzed by linear regression.Analysis of the concentric areas showed that 10 of 19 eyes had the best R (2) value in the most central area, A1. Analysis of circular areas showed that 7 of 19 eyes had the steepest slope of decline in A1. The inner-segment/outer-segment (IS/OS) line was significantly shorter in eyes with low variability and evident disease progression in the inner areas than the ones in the outer areas.The optimal size of monitoring RP progression was different in each case and may depend on the remaining morphology of the outer retina.

[Purpose]To compare the 2-year results after photodynamic therapy (PDT) alone and PDT combined with intravitreal injections of bevacizumab and triamcinolone acetonide (triple therapy) for polypoidal choroidal vasculopathy (PCV). [Methods]We retrospectively reviewed the medical records of 40 consecutive patients (40 eyes) with subfoveal PCV. Of these 40 eyes, 16 were treated with PDT alone and 24 were treated with triple therapy. [Results]The change in visual acuity in the triple therapy group was significantly better than that in the PDT group (P

[Purpose]To investigate longitudinal changes in peripapillary retinal nerve fiber layer (RNFL) thickness in patients with retinitis pigmentosa (RP). [Methods]We re-examined 103 RP patients whose RNFL thickness was previously examined and reported. RNFL thickness was measured using Stratus optical coherence tomography and was compared with the previous measurements. The results were also compared with that of previously reported normal subjects. Association between the decrease rate and visual acuity, and visual field was also investigated. [Results]The mean follow-up period was 56.9 months. After excluding the patients in whom RNFL images were of poor quality, 88 patients were eventually analyzed. The average RNFL thickness decreased from 105.8 to 98.2 μm during the period, with the average rate of decrease being 1.6 μm/year. The decrease in RNFL was more evident in superior and inferior sectors. Cross-sectional linear regression analysis also revealed an age-dependent decrease in RNFL, with the slower rate of decrease being 0.94 μm/year. The decrease in RNFL thickness was significantly faster than that reported in normal subjects. The decrease rate was not associated with visual functions. [Conclusion]Age-dependent RNFL thinning occurs at a faster rate in RP patients as compared with that in normal subjects. The result supports the notion that pathologic changes involve inner retina as well as outer retina in eyes with RP. Considering the discrepancy in the rate of RNFL thinning estimated from trend analysis and longitudinal measurement, care should be taken when interpreting the result of cross-sectional analysis.

Toru Ota, Akitaka Tsujikawa, Tomoaki Murakami, Ken Ogino, Yuki Muraoka, Kyoko Kumagai, Yumiko Akagi-Kurashige, Kazuaki Miyamoto, Nagahisa YoshimuraDepartment of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, JapanPurpose: To study the pathophysiology of subfoveal serous retinal detachment (SRD) observed in eyes with extramacular branch retinal vein occlusion (BRVO).Methods: We retrospectively reviewed the medical records of nine patients (nine eyes) with extramacular BRVO with macular complications that were examined using optical coherence tomography (OCT).Results: Extramacular BRVO was observed in the inferior area in three eyes, in the superior area in five eyes, and in the nasal area in one eye. Visual acuity was moderately disturbed (median, 0.6; range, 0.2–0.9, measured using the Landolt chart). One eye showed extensive SRD that was connected to the area affected by BRVO through the subretinal space. In eight of the eyes, focal SRD was observed beneath the fovea without subretinal connections to the area affected by BRVO. However, all these eyes showed marked retinal swelling in the outer retina, particularly in the outer plexiform layer. In two of the eyes, detailed OCT examinations showed a small break on the external surface of the retina connecting the swollen outer retina with the underlying SRD. All eyes showed hyperreflective foci in the outer retina, most frequently along the inner boundary of the outer plexiform layer and external limiting membrane.Conclusion: Extramacular BRVO is often accompanied by focal SRD beneath the fovea. Leakage from the retinal capillaries affected by BRVO travelled via the outer plexiform layer and caused SRD under the fovea.Keywords: branch retinal vein occlusion, extramacular, macular edema, optical coherence tomography, retinal detachment

Optical coherence tomography (OCT) has enabled objective measurement of the total retinal thickness in diabetic macular edema (DME). The central retinal thickness is correlated modestly with visual impairment and changes paradoxically after treatments compared to the visual acuity. This suggests the clinical relevance of the central retinal thickness in DME and the presence of other factors that affect visual disturbance. Recent advances in spectral-domain (SD) OCT have provided better delineation of the structural changes and fine lesions in the individual retinal layers. Cystoid spaces in the inner nuclear layer and outer plexiform layer are related to quantitative and qualitative parameters in fluorescein angiography. OCT often shows vitreoretinal interface abnormalities in eyes with sponge-like retinal swelling. Serous retinal detachment is sometimes accompanied by hyperreflective foci in the subretinal fluid, which exacerbates the pathogenesis at the interface of the photoreceptors and retinal pigment epithelium. Photoreceptor damage at the fovea is thought to be represented by disruption of the external limiting membrane or the junction between the inner and outer segment lines and is correlated with visual impairment. Hyperreflective foci in the outer retinal layers on SD-OCT images, another marker of visual disturbance, are associated with foveal photoreceptor damage.

Purpose In this study, the authors aimed to investigate structural abnormalities in the retinal nerve fiber layer (RNFL) using spectral-domain optical coherence tomography (SD-OCT) and study the surgical outcomes in eyes with such alterations by comparing ultrastructure findings of the surgically excised epiretinal membrane (ERM) and inner limiting membrane (ILM) in patients with idiopathic ERM. Methods and patients Vitreous surgery was performed on four eyes with idiopathic ERM, of which three had columnar alterations of the nerve fiber layer. The ERM and ILM were dissected and removed, and ultrathin sections were analyzed and imaged completely by using electron microscopy. All the patients underwent a comprehensive ophthalmologic examination, including SD-OCT, fundus-monitoring microperimetry, and red-free scanning laser ophthalmoscopic imaging. Results Preoperatively, SD-OCT revealed the presence of columnar structures only in the RNFL. Transmission electron microscopy showed that all samples contained retinal cell debris on the outer surface of the ILM. However, adhesion of retinal nerve fibers on the outer surface of the ILM was not observed in any specimen. The columnar alterations in the RNFL observed via SD-OCT resolved completely within 1 month in all eyes. At 6 months after surgery, no eyes showed scotoma on microperimetry. Further, no dissociated nerve fiber layer appearance was identified. Conclusion Vitrectomy with ILM peeling can be safely performed for ERMs with RNFL alterations, detected preoperatively by SD-OCT, without any structural or functional disturbances. The columnar alterations of the RNFL on SD-OCT may be inner retinoschisis.

Objective To study the morphologic and functional changes in retinal veins of eyes affected with branch retinal vein occlusion (BRVO) by thin sectioning with optical coherence tomography (OCT). Design Prospective, observational, cross-sectional study. Participants Twenty-five consecutive patients (25 eyes) with acute BRVO. Methods Major retinal veins, arteries, and arteriovenous (A/V) crossing were examined by sequential thin sectioning by Spectralis HRA+OCT (Heidelberg Engineering, Heidelberg, Germany). The retinal blood flow was mimicked in vitro and scanned with Spectralis HRA+OCT. Main Outcome Measures Morphologic characteristics of normal and BRVO-affected retinal vessels seen in OCT sections. Results Cross-sectional OCT images revealed physiologic retinal vessels as oval configurations with 4 distinctive hyperreflectivities in a line. The vessel walls showed the innermost and outermost hyperreflectivity, and the blood flow showed internal paired hyperreflectivities with an hourglass shape. No eye with disturbed blood flow due to BRVO showed this internal hyperreflectivity pattern. In vitro, OCT sections of the blood within the glass tube without flow showed homogeneous reflectivities. Increased blood flow velocity resulted in the development of heterogeneous internal reflectivity and hourglass-shaped hyperreflectivities. In all eyes with acute BRVO, sequential sectioning with OCT visualized 3-dimensional vascular architecture and the intravascular conditions at the A/V crossing. At the affected A/V crossing, arterial overcrossing was seen in 17 eyes and venous overcrossing was seen in 8 eyes. In eyes with arterial overcrossing, the retinal vein seemed to run deep under the artery at the A/V crossing, and the venous lumen often appeared to be preserved even at the A/V crossing. In all eyes with venous overcrossing, the retinal vein appeared to be compressed and choked between the internal limiting membrane and the arterial wall at the A/V crossing. Optical coherence tomography sectioning showed intravenous thrombi in 21 eyes, and the thrombi were detected downstream of the A/V crossing in all the cases. The detection of thrombus was significantly associated with ischemic pattern in BRVO ( P = 0.036). Conclusions In eyes with BRVO, sequential thin sections with OCT visualized 3-dimensional retinal vasculature. The present OCT findings suggest that BRVO may occur by 2 different mechanisms, depending on the relative anatomic positions of the crossing vessels. Financial Disclosure(s) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

To investigate the incidence rate, risk factors, and final outcomes of patients with age-related macular degeneration (AMD) who have experienced vision loss despite periodic aflibercept treatment. Subjects with treatment-naive AMD were prospectively recruited and treated with three monthly injections followed by two monthly injections of aflibercept. The incidence rate and risk factors of more than two lines of vision loss at any visit were investigated. We included 196 eyes of 196 patients. Vision loss was observed in 16 patients (8.2%). Eleven of 16 patients developed vision loss during the initial 3 months (68.8%). Vision loss remained in 11 eyes (68.8%) at the final visit. The maximum pigment epithelium detachment (PED) height (odds ratio = 1.46 for a 100-μm increase in the PED height) and disruption of the external limiting membrane (odds ratio = 4.45) were identified as risk factors for developing vision loss on logistic regression analysis. The incidence rate of vision loss during aflibercept treatment was relatively low. Identifying high-risk patients, those with a high PED height and disruption of the external limiting membrane, would be helpful in ensuring appropriate informed consent before treatment. Further studies are needed to establish optimal treatment for these patients.

PURPOSE:: To compare atrophy of the choroid and retina between Bietti crystalline dystrophy (BCD) patients and EYS-related retinitis pigmentosa (RP) patients with a similar degree of central visual field defects, age, and axial length (AL). METHODS:: Nine eyes of nine BCD patients with CYP4V2 mutations (BCD group) were examined. Moreover, we selected 10 eyes of 10 RP patients with EYS mutations matched for age, axial length, and mean deviation (measured with the 10-2 SITA standard program; EYS-RP group), and 10 eyes of 10 normal volunteers matched for age and axial length (control group). Macular thicknesses of the choroid and retina were measured via swept-source optical coherence tomography. RESULTS:: The macular choroid was significantly thinner in the BCD group than in the EYS-RP and control groups, although the thickness did not significantly differ between the EYS-RP and control groups. The macular retina was significantly thinner in the BCD and EYS-RP groups than in the control group, although the thickness did not significantly differ between the BCD and EYS-RP groups at most sites. CONCLUSION:: Bietti crystalline dystrophy patients with CYP4V2 mutations showed more severe macular choroid atrophy as compared to EYS-related RP patients. These different damage patterns suggest differences in choroidal expression between CYP4V2 and EYS.

Retinitis pigmentosa (RP) is one of the leading causes of adult blindness and has no established therapy. We have shown that valosin-containing protein (VCP) modulators, Kyoto University Substances (KUSs), ameliorated abnormally low ATP levels by inhibiting the ATPase of VCP, thereby protected several types of cells, including retinal neurons, from cell death-inducing insults. In this study, we found that KUS121, one of the VCP modulators, effectively protects photoreceptors both morphologically and functionally, in two animal models of retinal degeneration, rd12 mice and RP rabbits with a rhodopsin (Pro347Leu) mutation. In rd12 mice, KUS121 suppressed the loss of photoreceptors, not only rods but also cones, as well as the visual function deterioration. Significant protective effects existed even when the medication was started in later stages of the disease. In RP rabbits, KUS121 suppressed thinning of the outer nuclear layer and maintained visual function. In the retinas treated with KUS121, suppression of endoplasmic reticulum stress, activation of mammalian target of rapamycin and suppression of disease-associated apoptosis were evident. The ability of KUS121 to protect photoreceptors, especially cones, even in later stages of the disease may contribute to the preservation of central vision in RP patients, which is important for quality of vision.

Diabetes induces microvascular diseases including diabetic retinopathy and choroidopathy which reciprocally promote the pathogenesis, although optical coherence tomography images of diabetic choroidopathy remains to be documented. Here we evaluated the qualitative characteristics of choroidal vascular lesions in patients with diabetes and their association with diabetic retinopathy on swept-source optical coherence tomography (SS-OCT) images. We retrospectively reviewed 110 consecutive eyes of 110 patients with diabetes and 35 eyes of 35 healthy subjects for whom SS-OCT images (6x6-mm scans centered on the fovea) of sufficient quality were acquired. The curve of chorioretinal sections was flattened using Bruch's membrane as a reference surface, followed by generation of en-face images. We characterized choroidal vascular lesions and evaluated their association with the logarithm of the minimum angle of resolution visual acuity (logMAR VA), retinal and choroidal thicknesses, and diabetic retinopathy severity. En-face SS-OCT images showed unvisualized vessels in Sattler's layer in 33 eyes (30.0%). Focal narrowing was seen in choroidal vessels in Haller's layer in 56 eyes (50.9%). The choroidal vessels ended in the superficial or middle portion of Haller's layer, referred to as vascular stumps, in 20 eyes (18.2%). Diabetic eyes had these findings more frequently than nondiabetic eyes. The subfoveal choroid was thicker in eyes with focal vascular narrowing and vascular stumps than in eyes without such lesions. Vascular stumps in Haller's layer were significantly related to diabetic retinopathy severity, logMAR VA, and central retinal and choroidal thicknesses. These novel findings on SS-OCT images would promote the better understanding of complicated pathogenesis in diabetic retinopathy and choroidopathy.

To compare the 12-month-efficacy of 1 initial intravitreal ranibizumab injection (IVR) followed by pro re nata (PRN) dosing with that of three initial monthly IVR followed by PRN dosing in patients with macular edema (ME) after branch retinal vein occlusion.Prospective, interventional study.Of 81 eyes, 42 received 1 initial IVR injection (1+PRN group) and 39 eyes received 3 monthly IVRs (3+PRN). Pro re nata injections were performed when fovea exudative changes were evident.At Month 12, the visual acuity (VA) changes from baseline were -0.245 ± 0.227 and -0.287 ± 0.222, in the 1+PRN and 3+PRN groups, respectively; there were no significant difference between groups (P = 0.728). The stratified analysis showed that patients with better VA (baseline VA20/40) had similar significant improvement in VA at Month 12 (P0.001) to that of those with poorer VA (≤20/40). Better VA at Month 12 was significantly associated with younger age, better baseline VA, and thinner baseline central foveal thickness (P = 0.003,0.001, and0.001, respectively). Mean total number of IVR injections in the 1+PRN and 3+PRN groups were 3.8 ± 1.8 and 4.6 ± 1.4, respectively (P = 0.060). In both groups, shorter durations to the first PRN injection were associated with greater total PRN injection number (1+PRN, P = 0.006; 3+PRN; group, P0.001).In IVR treatment for ME after branch retinal vein occlusion, 1+PRN and 3+PRN regimens achieved similar 12-month functional outcomes. Patients with shorter durations to initial PRN injection may require more PRN treatments.

The decorrelation signals in optical coherence tomography angiography (OCTA) are derived from the flow of erythrocytes and concomitantly delineate the retinal vasculature. We compared the structural and functional characteristics of vascular lesions visualized in fluorescein angiography (FA), OCTA and en-face OCT images in 53 eyes (28 patients) with diabetic retinopathy (DR). The foveal avascular zone (FAZ) areas in OCTA images in the superficial layer almost corresponded to those in FA images. The FAZ areas in the en-face OCT images in the superficial layer were smaller than those in the FA images and correlated with each other, which agreed with the finding that en-face OCT images often delineated the vascular structure in the nonperfused areas in FA images. Microaneurysms appeared as fusiform, saccular, or coiled capillaries in OCTA images and ringed, round, or oval hyperreflective lesions in en-face OCT images. OCTA and en-face OCT images detected 41.0 ± 16.1% and 40.1 ± 18.6%, respectively, of microaneurysms in FA images, although both depicted only 13.9 ± 16.4%. The number of microaneurysms in FA images was correlated with that in OCTA and en-face OCT images. Comparisons of these modalities showed the associations and dissociations between blood flow and vascular structures, which improves the understanding of the pathogenesis of DR.

PURPOSE The purpose of this study was to cluster the test points of the combined 24-2 and 10-2 visual fields (VFs) and circumpapillary retinal nerve fiber layer thickness (cpRNFLT) sectors using explanatory factor analyses (EFAs). The correlations between the VF clusters and cpRNFLT clusters were determined, and a new function-structure relationship map was determined. METHODS Two hundred fifty-four eyes of 166 subjects (13 normal eyes and 241 eyes with glaucoma) were studied retrospectively. All eyes had an axial length

This prospective study included 63 eyes with acute branch retinal vein occlusion (BRVO) to evaluate the retinal hemorrhagic patterns at the posterior poles and explore their clinical relevance in macular perfusion differentiation. Retinal hemorrhagic patterns and macular perfusion status were evaluated via fundus photography and fluorescein angiography, respectively. Macular perfusion was judged as nonischemic in 30, ischemic in 28 and undeterminable in 5 among the 63 eyes. Predominant hemorrhagic patterns were flame-shaped in 39 (67.2%) and non-flame-shaped in 19 (32.8%) eyes. All 39 eyes with a flame-shaped hemorrhage showed a nonischemic macula. Of the 19 eyes classified as having a non-flame-shaped hemorrhage, 13 (68.4%) had an ischemic macula and 6 (31.6%) had a nonischemic macula (P P P P

Age-related macular degeneration (AMD) in the Japanese often shows different clinical features from those described in Caucasians. For example, we often observe choroidal neovascularization (CNV) in elderly patients without drusen in the fundus. The high incidence of polypoidal choroidal vasculopathy (PCV) in AMD among Japanese is well-known. The reason why such differences occur in clinical manifestations of AMD has been one of my main interests. In this review article, I will discuss the characteristics of AMD in the Japanese population, as found in our recent study. I. Prevalence and clinical characteristics of AMD in the Japanese population. Cohort studies are important to determine the prevalence and incidence of diseases. In Japan, cohort studies began to be carried out rather late compared with Western countries. Although good cohort studies from Japan are reported in the literature, the size of the cohorts was not sufficiently large to determine the prevalence of AMD. However, a recent meta-analysis of Asian cohorts has shown that the prevalence of late AMD in Asians is not different from that reported in Caucasians. On the other hand, the prevalence of early AMD appears lower in the Japanese than in Caucasians. Recently, we have published the results of the Nagahama Cohort study. In this cohort study, we found a high prevalence of drusen. It seems that the incidence of dry AMD is likely to increase among Japanese. In Japan, most retina specialists classify AMD into three categories : typical AMD, PCV, and retinal angiomatous proliferation (RAP). However, there are no definite diagnostic criteria to distinguish between the three conditions. To compare the clinical features of Japanese and Western cases of AMD, and to determine the incidence of the three types of AMD, we exchanged data about 100 consecutive cases between Kyoto University and Centre d'Ophtalmologie de Paris, France. Interestingly, the diagnoses made by the two institutes were not always in agreement. We also found more cases of PCV among the Japanese than among the French. II. PCV. About 50% of exudative AMD cases in the Japanese population are PCV. Because of its peculiar angiographic findings, PCV has long been considered to be a distinct clinical entity different from the usual exudative AMD. Also, there have been serious discussions on the nature of PCV. In our analyses, about 20% of PCV cases show rather large lesion sizes that exceed the vascular arcade. Scar formation in the macula and compromised vision are frequent findings in such cases. The occurrence of PCV in the inferior staphyloma or in angioid streaks shows heterogeneity in PCV. These findings suggest that PCV may be a finding on indocyanine green angiography rather than a distinct clinical entity. Spectral domain OCT examination shows that the branching vascular network of PCV is located between the retinal pigment epithelium and Bruch's membrane. In cases with retinal pigment epithelial detachment, CNV from the branching vascular network was found to extend along the roof of the detached retinal pigment epithelium. Such findings show that the branching vascular network of PCV is type 1 CNV. Complement factor H (CFH) and age-related maculopathy 2 (ARMS2)/High temperature requirement 1 (HTRA1) located on chromosome 10 (10q26) are well-established disease susceptible genes of AMD. In the Japanese, the prevalence of CFH Y402H gene polymorphism is low and ARMS2/HITRA1 plays a more important role in the development of AMD. In ARMS2 A69S polymorphism, a large deletion/insertion (443de1/54ins) that is reported in Caucasians was also found in Japanese. Thus, the genetic background of Caucasian and Japanese AMD is quite similar, as is also the case with exudative AMD and PCV. Our findings show that PCV is not a distinct clinical entity but is a subtype of exudative AMD. III. Exudative AMD with choroidal vascular hyperpermeability. Choroidal vascular hyperpermeability observed in central serous chorioretinopathy can be found in about 20% to 30% of exudative AMD cases in Japanese. Such cases often show a thick choroid, lack of drusen, and rather good visual prognosis with slow progression of the disease. Recently, "pachychoroid neovasculopathy" has been described by a group from New York. Such cases of AMD with choroidal vascular hyperpermeability, a thick choroid, and lack of drusen appears to belong to pachychoroid neovasculopathy. We studied the risk allele frequencies of CFH I62V and ARMS2 A69S gene polymorphisms in three groups : usual exudative AMD, pachychoroid neovasculopathy, and normal controls. Interestingly, cases of pachychoroid neovasculopathy show different gene polymorphisms of CFH I62V and ARMS2 A69S from the usual cases of exudative AMD and a more similar pattern to normal controls. Therefore, the possible mechanisms of the CNV development in such cases may differ from the classic well-documented drusen-dependent pathways. IV. Atrophic AMD in Japanese. Data from the Nagahama Cohort study show an increasing prevalence of drusen in Japanese. Recently, more extensive information on drusen has become available and the redefinition of drusen is currently in progress. In particular, the importance of reticular pseudodrusen (RPD) is more widely appreciated. This type of drusen is often found in Japanese AMD. Although the nature and location of RPD are still debatable, many investigators believe that this type of drusen is located under the sensory retina rather than under Bruch's membrane. In our analyses, RPD was found in 18.4% of late AMD cases in Japanese. It was more common in eyes with RAP or atrophic AMD and was seldom found in PCV. ARMS2 A69S gene polymorphism was found more frequently in cases of exudative AMD with RPD, than in cases of exudative AMD without RPD. Eyes with RPD show a thin choroid and diminished vascular densities of choroidal vessels.

To investigate longitudinal changes in intraocular pressure (IOP), axial length (AL), and choroidal thickness (ChT) in primary open-angle glaucoma (POAG) eyes after trabeculectomy and to evaluate the parameters that might influence those changes. In this prospective observational study, we recruited 28 patients with POAG (28 eyes) scheduled for trabeculectomy. The average macular ChTs and foveal retinal thicknesses along 6-mm segments centered on the fovea were examined preoperatively and postoperatively (at 1, 3, and 6 months) using swept-source optical coherence tomography. The IOP, AL, and mean deviation (MD) of standard automated perimetry (SAP) were also analyzed as independent variables. Results from 16 patients were included in the final analysis. A significant increase in ChT with respect to the preoperative value was observed at every postoperative stage (1 month, P

Purpose The purpose of this study was to characterize inner retinal spots with inverted reflectivity on en face images of swept-source optical coherence tomography (SS-OCT) in diabetic retinopathy (DR). Methods We retrospectively reviewed seventy-five eyes of 75 patients with DR (15 eyes with individual grades of DR severity). We obtained three-dimensional images (6 × 6 mm) centered on the fovea, followed by the generation of en face images. We investigated the morphologic characteristics of spots with inverted reflectivity, which had lower reflectivity than the surrounding areas in the nerve fiber layer (NFL) and higher reflectivity in the ganglion cell layer (GCL). Results Thirty-seven of 45 eyes (82.2%) with moderate nonproliferative diabetic retinopathy (NPDR) or more severe grades were accompanied with well-defined spots with inverted reflectivity, whereas 30 eyes with no apparent retinopathy or mild NPDR had no such lesions. These spots had various shapes in the NFL and GCL on en face OCT images; the mean area was 0.126 ± 0.052 mm2 at the NFL level. In all 75 eyes, 153 of 184 spots (83.2%) were localized in the NFL and GCL, whereas 31 spots (16.8%) extended to retinal layers deeper than the GCL. One-hundred sixty-nine spots (91.8%) were not visible on color fundus photographs, and 15 spots (8.2%) were accompanied by whitish-yellow lesions in the corresponding areas. In 45 eyes for which fluorescein angiography images were obtained, mild hypofluorescence was seen in 156 spots (84.8%) and focal nonperfused areas in 17 spots (9.2%). Conclusions En face images of SS-OCT showed spots with inverted reflectivity in the NFL and GCL in DR.

To quantify the area of photoreceptor damage surrounding geographic atrophy (GA) and evaluate the relationship between structural abnormalities and retinal function in eyes with GA.Prospective cross-sectional study.Twenty-five eyes of 25 patients with GA associated with age-related macular degeneration underwent a full ophthalmologic examination, including spectral-domain optical coherence tomography (SDOCT), fundus autofluorescence (FAF), and microperimetry. ImageJ software was used to quantify the disruption of the ellipsoid zone on SDOCT images. Hypofluorescent areas of the FAF images indicated areas of retinal pigment epithelium (RPE) loss. Areas of interest graded by SDOCT (photoreceptor damage) and FAF (RPE loss) were registered with microperimetry within a 6-mm circle centered on the fovea.The mean area of photoreceptor damage was 7.69 ± 5.36 mm(2), which was significantly greater than the mean area of RPE loss (4.57 ± 4.07 mm(2), P.001). The average retinal sensitivity of the area with photoreceptor damage outside the area of RPE loss was lower than that of the area without photoreceptor damage (6.57 ± 4.13 dB vs 11.27 ± 3.78 dB, P.001). The area of photoreceptor damage surrounding the area of RPE loss was larger in eyes with pseudodrusen than in eyes without pseudodrusen (4.96 mm(2) vs 1.91 mm(2), P = .008). The only significant predictor of decreased retinal sensitivity was the area of the photoreceptor damage (P.001).Widespread photoreceptor damage surrounding sites of RPE loss occurred in eyes with GA, and it correlated with visual function. Evaluation of photoreceptor damage surrounding sites of RPE loss using OCT is important in patients with GA associated with AMD.

Purpose To investigate photoreceptor changes in eyes with glaucoma. Design Cross-sectional study. Methods The study included 35 eyes of 35 patients with primary open-angle glaucoma who had suffered parafoveal visual field loss at least 3 years previously, as well as 21 eyes of 21 normal subjects. Eyes with an axial length ≥26.0 mm were excluded. All subjects underwent a full ophthalmologic examination, including spectral-domain optical coherence tomography (SDOCT) and prototype adaptive-optics scanning laser ophthalmoscopy (AO-SLO) imaging. Results As determined using AO-SLO, eyes with glaucoma did not differ significantly from normal eyes in terms of either cone density (26 468 ± 3392 cones/m 2 vs 26 147 ± 2700 cones/m 2 , respectively; P = .77; measured 0.5 mm from the foveal center) or cone spatial organization (ratio of hexagonal Voronoi domain: 43.7% ± 4.4% vs 44.3% ± 4.9%; P = .76; measured 0.5 mm from the foveal center). Furthermore, SDOCT showed that the 2 groups did not differ significantly in terms of the photoreceptor-related layer thickness, and that the photoreceptor ellipsoid zone band was continuous in all normal and glaucoma eyes. In glaucoma eyes with vertically asymmetric severity, the more affected side did not significantly differ from the less affected side in terms of cone density, cone spatial organization, or photoreceptor-related layer thickness. In 8 eyes (22.9%) with glaucoma, dark, partition-like areas surrounded the cones on the AO-SLO. Conclusions Both AO-SLO and SDOCT showed cone integrity in eyes with glaucoma, even in areas with visual field and nerve fiber loss. In AO-SLO, microcystic lesions in the inner nuclear layer may influence images of the cone mosaic.

To determine the clinical characteristics and surgical outcomes of highly myopic (HM) eyes with an axial length (AL) of ≥26.0 mm that underwent trabeculectomy with mitomycin C (MMC). This was a retrospective study of 63 eyes of 54 patients with primary open-angle glaucoma that underwent trabeculectomy with MMC. The characteristics and surgical outcomes of 19 HM eyes were compared with those of 44 non-HM eyes. Surgical success was defined as an high intraocular pressure (IOP) of ≤21 mmHg (criterion A), ≤18 mmHg (criterion B), or ≤15 mmHg (criterion C), with a lower IOP cutoff of 6 mmHg and a >20 % reduction regardless of the use of antiglaucoma medication. Cox regression analyses were performed to evaluate the effect of each pretreatment and surgical factor on the success rate. Patients with HM eyes were significantly younger than those with non-HM eyes (mean age 64.1 ± 9.9 vs. 69.1 ± 9.5 years; P

Importance Although trabeculotomy is a glaucoma surgical procedure for modest intraocular pressure (IOP) reduction, some eyes exhibit very low IOP during the early postoperative period. To our knowledge, the reason and its effect have not been investigated. Objectives To investigate ciliochoroidal detachment (CCD) immediately after ab interno trabeculotomy and evaluate its effect on IOP immediately after surgery. Design, Setting, and Participants This prospective, observational, case series was conducted at Kyoto University Hospital, Kyoto, Japan. Patients with open-angle glaucoma who underwent ab interno trabeculotomy using a microsurgical device by a single surgeon between July 1, 2014, and May 31, 2015, were included. Thirty-seven consecutive patients were enrolled, 33 of whom were included in the analysis. The dates of the analysis were August 1 to August 15, 2015. Intervention Imaging of CCD using anterior-segment optical coherence tomography (AS-OCT). Main Outcomes and Measures The incidence of CCD immediately after ab interno trabeculotomy and its effect on IOP in the early postoperative period. Results The study cohort comprised 33 patients. Their mean (SD) age was 69.4 (13.2) years, and 19 (58%) were male. At postoperative day 3, CCD was detected in 14 of 33 eyes (42%) (CCD group) using AS-OCT. The CCD group had shorter axial length (mean [SD], 23.66 [1.67] vs 25.16 [1.59] mm) and thinner central corneal thickness (mean [SD], 505.9 [35.8] vs 533.9 [39.1] μm) than the non-CCD group. Only 5 eyes had CCD at postoperative day 10, and 4 of these eyes had CCD at 1 month after surgery. The postoperative IOPs at all follow-up periods were lower in the CCD group than in the non-CCD group, but the difference in the postoperative IOPs between the groups decreased as time passed. The mean (SD) IOPs for the CCD group vs the non-CCD group were 9.1 (3.0) vs 14.2 (5.8) mm Hg at day 1, 8.4 (2.4) vs 13.4 (5.0) mm Hg at day 3, 11.0 (3.0) vs 15.5 (6.3) mm Hg at day 10, 13.4 (2.4) vs 15.5 (3.3) mm Hg at 1 month, and 13.9 (3.4) vs 15.5 (4.0) mm Hg at 3 months. In several eyes in the CCD group, the AS-OCT images revealed a connection between the CCD and the anterior chamber via the trabeculotomy site. Conclusions and Relevance Ciliochoroidal detachment after ab interno trabeculotomy was not rare and was associated with low IOP immediately after surgery. Postoperative CCD may be partially attributed to the transient increase in uveoscleral aqueous outflow via the trabeculotomy site.

Purpose: To characterize white dots in diabetic retinopathy (DR) and their association with disease severity using ultra-wide-field scanning laser ophthalmoscopy. Methods: We randomly selected 125 eyes of 77 patients (25 eyes from individual categories of the international classification of DR severity) for which ultrawide field photographs were obtained. We characterized white dots, which were delineated by higher signal levels on green but not red laser images, and evaluated the relationship between the number of white dots and the international severity scale of DR. Results: Most white dots were located in nonperfused areas, and the number of total white dots was significantly correlated to that of dots in nonperfused areas. White dots corresponded to microaneurysms around the boundary between nonperfused areas and perfused areas or unknown lesions in nonperfused areas. Eyes with DR had significantly more white dots than those with no apparent retinopathy. The numbers of white dots in moderate nonproliferative diabetic retinopathy (NPDR) or more severe grades were significantly higher than in mild NPDR. The area under the receiver operating characteristics curve (AROC) analyses demonstrated that the number of white dots had the significance in the diagnosis of DR (0.908-0.986) and moderate NPDR or more severe grades (0.888-0.974). Conclusions: These data suggest the clinical relevance of white dots seen on ultrawide field images in the diagnosis of the severity of DR.

PURPOSE Axonal damage precedes retinal ganglion cell (RGC) apoptosis in glaucomatous optic neuropathy. Because mitochondria in RGC axons are damaged before cell death, we examined axonal mitochondrial transport dynamics after axonal injury. METHODS Mitochondria in rat-cultivated RGCs were stained with rhodamine 123. After axonal injury induced using a laser microdissection system, axonal transport was evaluated by time-lapse imaging. The RGC apoptosis was detected using ethidium homodimer-1 on day 3 after axonal injury. RESULTS The rate of stationary mitochondria in RGC axons significantly increased from 37.6% before axonal injury to 70.6% at 5 minutes (P < 0.001) and 63.6% at 18 hours (P < 0.001) after axonal injury. The mean axonal mitochondrial transport velocity in RGCs transiently deteriorated from 0.48 ± 0.01 μm/s before axonal injury to 0.37 ± 0.02 μm/s at 5 minutes after axonal injury (P < 0.001). However, 23.5% of RGCs showed recovered axonal transport velocity at 18 hours after injury. On day 3 after axonal injury, RGCs with the recovery of axonal transport did not undergo apoptosis, whereas 69.2% of RGCs without the recovery of axonal transport underwent apoptosis (P = 0.029). CONCLUSIONS Axonal injury disrupts mitochondrial transport in RGC axons. Irreversible decreased axonal mitochondrial transport velocity may be useful to predict RGC apoptosis after axonal injury.

PurposeTo define a minimum set of outcome measures for tracking, comparing, and improving macular degeneration care.DesignRecommendations from a working group of international experts in macular degeneration outcomes registry development and patient advocates, facilitated by the International Consortium for Health Outcomes Measurement (ICHOM).MethodsModified Delphi technique, supported by structured teleconferences, followed by online surveys to drive consensus decisions. Potential outcomes were identified through literature review of outcomes collected in existing registries and reported in major clinical trials. Outcomes were refined by the working group and selected based on impact on patients, relationship to good clinical care, and feasibility of measurement in routine clinical practice.ResultsStandardized measurement of the following outcomes is recommended: visual functioning and quality of life (distance visual acuity, mobility and independence, emotional well-being, reading and accessing information); number of treatments; complications of treatment; and disease control. Proposed data collection sources include administrative data, clinical data during routine clinical visits, and patient-reported sources annually. Recording the following clinical characteristics is recommended to enable risk adjustment: age; sex; ethnicity; smoking status; baseline visual acuity in both eyes; type of macular degeneration; presence of geographic atrophy, subretinal fibrosis, or pigment epithelial detachment; previous macular degeneration treatment; ocular comorbidities.ConclusionsThe recommended minimum outcomes and pragmatic reporting standards should enable standardized, meaningful assessments and comparisons of macular degeneration treatment outcomes. Adoption could accelerate global improvements in standardized data gathering and reporting of patient-centered outcomes. This can facilitate informed decisions by patients and health care providers, plus allow long-term monitoring of aggregate data, ultimately improving understanding of disease progression and treatment responses.

[Purpose]To study the retinal structural changes associated with submacular hemorrhage due to exudative age-related macular degeneration (AMD) and their relationships with visual prognosis. [Methods]We retrospectively reviewed the medical records of 31 consecutive patients (31 eyes) with visual impairment due to an acute submacular hemorrhage associated with typical AMD (10 eyes) or polypoidal choroidal vasculopathy (21 eyes). [Results]Optical coherence tomography (OCT) revealed that submacular hemorrhage exhibited intense hyperreflectivity beneath the neurosensory retina and often seemed to infiltrate it. In the OCT sections, mild to moderate amorphous hyperreflectivity and/or hyperreflective dots were observed within the neurosensory retina, resulting in the loss of the junctions between the inner (IS) and outer (OS) segments of the photoreceptors. Of the 31 eyes, the foveal IS/OS line could be seen incompletely in 12 eyes and was totally absent in 16 eyes. The initial integrity of the foveal photoreceptor layer was correlated with the final visual acuity; the initial detection of the IS/OS just beneath the fovea was correlated with good final visual acuity (r = 0.375, p = 0.038). [Conclusion]As a hallmark of integrity of the foveal photoreceptor layer, the initial detection of the IS/OS just beneath the fovea may predict good visual outcomes.

Neuroinflammation involving CC chemokines such as monocyte chemoattractant protein-1 (MCP-1) has been demonstrated in the pathological process of retinitis pigmentosa (RP), an inherited degenerative retinal disease. However, the mechanism of MCP-1 and its receptor CCR2 involvement in the disease remains unclear. To investigate the role of MCP1/CCR2 in RP pathogenesis, ccr2 mutant RP mice (ccr2(-/-) rd10) were created and analyzed. The expression of MCP-1, RANTES, stromal cell-derived factor (SDF-1), and tumor necrosis factor-α (TNF-α) in the retinas of wild-type, rd10, and ccr2(-/-) rd10 mice was analyzed using quantitative RT-PCR. Photoreceptor apoptosis (TUNEL staining) and the number of microglia (positive for the F4/80 antibody) in the retina were examined. Retinal function was assessed using electroretinograms, and the structure of the whole retina was analyzed from images obtained using optical coherence tomography (OCT) and by histological examination. The expression levels of MCP-1, RANTES, and SDF-1 increased with time in the rd10 mice but not in the wild-type mice. Rearing the mice in the dark prevented degeneration and resulted in thicker photoreceptor layers at each time point. In those mice, the peaks of chemokine expression shifted to a later time with degeneration, suggesting that the expression of these chemokines was induced during the progression of degeneration. Although the difference was not so obvious, the retina in the ccr2(-/-) rd10 mice was consistently and significantly thicker than that in the rd10 (ccr2(+/+) rd10) mice at all time points. Rhodopsin gene expression was also higher in the ccr2(-/-) rd10 mice than in rd10 (ccr2(+/+) rd10) mice, suggesting photoreceptor survival in the former. Retinal function was also better preserved in the ccr2(-/-) rd10 mice than in the rd10 mice. The number of microglia in the retinas of the ccr2(-/-) rd10 mice was significantly lower than that in the retinas of the rd10 mice. Interestingly, the MCP-1 induction that was observed in the retinas of the rd10 mice was diminished in the retinas of the ccr2(-/-) rd10 mice. Our results suggest that the MCP-1/CCR2 system plays a role in retinal degeneration in rd mouse retinas. Retinal MCP-1 expression in the rd mouse retina may be partially controlled by ccr2-positive circulating cells.

Purpose: To investigate how combined cystoid spaces and serous retinal detachment affect photoreceptor status and visual acuity at final visit in macular edema associated with branch retinal vein occlusion. Methods: Forty-seven consecutive eyes from 47 patients with macular edema associated with branch retinal vein occlusion treated with intravitreal bevacizumab injection were retrospectively reviewed. Foveal pathomorphology on optical coherence tomography images were divided into two groups: those in which combined foveal cystoid spaces and serous retinal detachment were observed at least once (C+S(+)) and those in which they were not observed (C+S(−)). The relationship between foveal pathomorphology and photoreceptor status and logarithm of the minimum angle of resolution at final visit was investigated. Results: Sixteen eyes were categorized as C+S(+), and the final visual acuity of C+S(+) group was significantly worse than that of C+S(−) group compared with no difference at baseline. Intriguingly, combined foveal pathomorphologies during the course were significantly associated with the absence of external limiting membrane and the junction of inner and outer segments at last visit. Using multivariable analysis, final logarithm of the minimum angle of resolution was significantly related to baseline logarithm of the minimum angle of resolution, diabetes, and C+S(+). Conclusion: Combined foveal cystoid spaces and retinal detachment during follow-up predict the disrupted foveal photoreceptors and concomitant poor final visual acuity in branch retinal vein occlusion treated with intravitreal bevacizumab injection.