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To elucidate the current clinical practice patterns of branch retinal vein occlusion (BRVO) management by retina specialists in Japan in the era of anti-vascular endothelial growth factor (VEGF) therapy. A voting survey using an answer pad system. On May 28, 2017, forty-one retina specialists were surveyed on the pathology and clinical practice of BRVO management. Most specialists (77.5%) use fundus examination and optical coherence tomography (OCT) for diagnosis of macular edema (ME) secondary to BRVO. All assess the condition of the ellipsoid zone (EZ) and external limiting membrane (ELM) and consider this a visual prognostic factor. For ME secondary to BRVO, anti-VEGF therapy is the first choice, and most specialists (82.4%) select initial injection followed by a pro re nata (PRN) regimen. For switching to other treatment options for persistent cases, combination therapy of anti-VEGF injections and laser therapy is the most common choice (35.9%), whereas 25.6% select vitreous surgery and 15.4% select adding steroid injections. Our survey presents the current opinions on the diagnosis and treatment of BRVO by retina specialists in Japan, and reveals the common views about damage to the EZ/ELM as a factor of poor prognosis and anti-VEGF therapy as the first line treatment, highlighting various opinions on initiation and switching of therapy.

Long living animal models of retinitis pigmentosa (RP) can provide important information on the retinal changes that occur at the late stages of photoreceptor degeneration. The rhodopsin Pro347Leu transgenic rabbit (P347L Tg) is a model of RP, and it has been used to analyze the functional and morphological changes in the retina following the degeneration of the photoreceptors. They have also been used to test newly-developed therapies to treat eyes with photoreceptor degeneration. However, assessments of the retinal changes in P347L Tg rabbits older than 1-year have not been reported even though the data are important for research on developing new therapies to restore vision at the end stages of RP. The purpose of this study was to determine the time course of the loss of photoreceptor function and the changes in the morphology of the retina of P347L Tg rabbits. The experiments were performed on 26 older P347L Tg rabbits. The results showed that the amplitudes of the ERGs of the P347L Tg rabbits gradually decreased and reached10 μV between 30- and 54-months-of-age. Histological analysis at these later stages showed a loss of the photoreceptor layer, and OCT analysis showed absence of the layering of the retina. However, the thickness between the inner limiting membrane and the outer plexiform layer was about 1.7 times thicker than the corresponding thickness of WT rabbits in the OCT images. This thickening was caused by a marked gliosis of the entire retina which was confirmed by light and transmission electron microscopy. In addition, immunohistochemical analysis showed there was excessive staining of the glial fibrillary acid protein in the older P347L Tg rabbits although the rod ON bipolar cells and horizontal cells were still present in the inner nuclear layer. Our results indicate that the P347L Tg rabbit progressed to complete photoreceptor loss within 30- and 54-months-of-age and severe gliosis altered the morphology of the retina.

Eye fatigue is a common health problem across all age groups. Herein, we explored the correlation between eye fatigue and thickness of the retinal nerve fiber layer (NFL). Included in the NFL are intrinsically photosensitive retinal ganglion cells (ipRGCs), which are associated with trigeminal pain. This retrospective cross-sectional study included outpatients with best-corrected visual acuity above 20/30 in both eyes and without dry eye, glaucoma, or retinal disease. A total of 1981 patients were initially enrolled and 377 patients were declared as eligible for the study analysis. We tested subjects for the presence of major ocular symptoms and measured thickness of ganglion cell complex (GCC) using optical coherence tomography. A total of 377 outpatients (46.4% men, mean age of 57.1 years) were enrolled for analysis, based on the interview-reported prevalence of six eye symptom, as follows: 31.5% for eye fatigue, 19.2% for blurring, 18.6% for dryness, 15.7% for photophobia, 13.5% for irritation, and 4.6% for pain. The macular GCC was significantly thicker in subjects with eye fatigue compared to the group not reporting eye fatigue (103.8 μm versus 100.3 μm, P = 0.014). Regression analysis identified eye fatigue (P = 0.026, β=0.122, adjusted for age and sex) and dryness (P =0.024, β=0.130) as significantly correlated with the macular GCC thickness, while the full macular thickness showed no significant correlation. In conclusions, eye fatigue and dryness were positively associated with thickness of the macular GCC. Nonvisual symptoms might therefore play a role in the development of eye fatigue.

In the original publication [...]

A new clinical ultrahigh-resolution spectral domain optical coherence tomography (UHR-SD-OCT) system using an original averaging technique named “A-scan matching algorithm” was developed. The aim of this study was to determine whether our new UHR-SD-OCT system can obtain clearer sectional images of the retina than conventional standard resolution SD-OCT systems (SR-SD-OCT). We recorded horizontal B-scan images of 42 normal eyes using our new UHR-SD-OCT device (Bi-μ, Kowa) and a conventional SR-SD-OCT (Spectralis, Heidelberg). To evaluate the clarity of the interdigitation zone (IZ) subjectively, the integrity of IZ was divided into three types by two raters. To evaluate the clarity of the IZ objectively, a peak height score (PHS) was calculated at five different points of the macula using the longitudinal reflectivity profile. The mean (± SD) of the subjective visibility score of the IZ in the UHR-SD-OCT images was 2.64 ± 0.54 which was significantly higher than the 2.46 ± 0.46 in the SR-SD-OCT images (P = 0.02). The PHS was also significantly higher for the UHR-SD-OCT than for the SR-SD-OCT images at all five locations (all P

To report abnormal full-field electroretinograms (ERGs) in a patient with cystoid macular edema (CME) induced by systemic paclitaxel. This is an observational case report. Full-field ERGs were recorded to evaluate the retinal function using the RETeval system and conventional ERGs using contact lens electrodes with built-in white light-emitting diodes. Optical coherence tomography (OCT) was also used to assess the retinal morphology. A 70-year-old man, who was diagnosed with gastric cancer, had undergone gastrectomy. Subsequently, systemic paclitaxel was administered once a week as an adjuvant therapy. After the tenth course of paclitaxel, he experienced blurred vision in both eyes and visited our department of ophthalmology. OCT revealed the presence of CME in both eyes, and the RETeval flicker ERGs showed a marked reduction in the amplitudes and a prolongation of the implicit times in both eyes. Conventional ERGs showed that the amplitudes of the oscillatory potentials (OPs) were also severely attenuated. The abnormal OCT findings and reduced visual acuity recovered to normal at 1 and 2 months, respectively, after the discontinuation of paclitaxel. However, the flicker ERGs did not recover to normal values until 4 months after the discontinuation of paclitaxel. These results suggest that the ERGs can be used to monitor the changes in the overall retinal function in patients receiving paclitaxel.

We evaluated the pupil reaction to blue and white light stimulation in 70 eyes with cataract and in 38 eyes with a selective blue-light filtering intra-ocular lens. The diameter of the pupil before stimulation was set as baseline (BPD) and, after a stimulus duration of 1 s, the post-illumination pupillary response (PIPR) was measured using an electronic pupillometer. The BPD showed no significant difference among three grades of nuclear sclerosis (NS). In contrast, the PIPRs differed significantly among the NS grades eyes including with and without subcapsular cataract (SC) and IOL eyes for white light (p p p > 0.05 for blue light). Our study demonstrates retention of the PIPR for blue light, but not for white light in cataract eyes. We also confirmed that the pupillary response in pseudohakic eyes with a selective blue light-filtering intra ocular lens was greater than that in cataractous eyes for white light.

The multifocal electroretinogram (mfERG) is an electrophysiological test that allows the function of multiple discrete areas of the retina to be tested simultaneously. This document, from the International Society for Clinical Electrophysiology of Vision (ISCEV), presents an updated and revised ISCEV standard for clinical mfERG and defines minimum protocols for basic clinical mfERG recording and reporting so that responses can be recognized and compared from different laboratories worldwide. The major changes compared with the previous mfERG standard relate to the minimum length of m-sequences used for recording, reporting of results and a change in document format, to be more consistent with other ISCEV standards.

The ZIPANGU study assessed the efficacy and safety of ranibizumab as a one loading dose + pro re nata (one + PRN) regimen with/without focal/grid laser among treatment-naïve patients suffering from macular edema (ME) following branch retinal vein occlusion (BRVO). ZIPANGU was a phase IV, prospective, randomized, open-label, active-controlled, 12-month, two-arm, multicenter study. Treatment-naïve patients with visual impairment (19–73 letters) caused by ME, defined as central subfield thickness (CSFT) > 300 µm, due to BRVO were randomly assigned to ranibizumab monotherapy (n = 29) or combination therapy (ranibizumab + focal/grid short-pulse laser, n = 30). The primary endpoint was the number of ranibizumab injections. Secondary endpoints were mean changes in best-corrected visual acuity (BCVA) and CSFT, and safety. There were no statistically significant differences in the mean number of ranibizumab injections between monotherapy (4.3 injections) vs. combination (4.1 injections) therapy, or in CSFT. BCVA improvement in the monotherapy arm (22.0 letters) was better than the combination therapy arm (15.0 letters) (p = 0.035). Overall, both regimens appeared to be safe and well tolerated. One + PRN ranibizumab is safe and efficacious in treatment-naïve patients with ME secondary to BRVO. A conjunctive laser treatment did not lead to better functional outcomes or fewer ranibizumab injections.

The ZIPANGU study assessed the efficacy and safety of ranibizumab as a one loading dose + pro re nata (one + PRN) regimen with/without focal/grid laser among treatment-naïve patients suffering from macular edema (ME) following branch retinal vein occlusion (BRVO). ZIPANGU was a phase IV, prospective, randomized, open-label, active-controlled, 12-month, two-arm, multicenter study. Treatment-naïve patients with visual impairment (19-73 letters) caused by ME, defined as central subfield thickness (CSFT) 300 µm, due to BRVO were randomly assigned to ranibizumab monotherapy (n = 29) or combination therapy (ranibizumab + focal/grid short-pulse laser, n = 30). The primary endpoint was the number of ranibizumab injections. Secondary endpoints were mean changes in best-corrected visual acuity (BCVA) and CSFT, and safety. There were no statistically significant differences in the mean number of ranibizumab injections between monotherapy (4.3 injections) vs. combination (4.1 injections) therapy, or in CSFT. BCVA improvement in the monotherapy arm (22.0 letters) was better than the combination therapy arm (15.0 letters) (p = 0.035). Overall, both regimens appeared to be safe and well tolerated. One + PRN ranibizumab is safe and efficacious in treatment-naïve patients with ME secondary to BRVO. A conjunctive laser treatment did not lead to better functional outcomes or fewer ranibizumab injections.

Biallelic mutations in G‐Protein coupled receptor kinase 1 (GRK1) cause Oguchi disease, a rare subtype of congenital stationary night blindness (CSNB). The purpose of this study was to identify disease causing GRK1 variants and use in‐depth bioinformatic analyses to evaluate how their impact on protein structure could lead to pathogenicity. Patients’ genomic DNA was sequenced by whole genome, whole exome or focused exome sequencing. Disease associated variants, published and novel, were compared to nondisease associated missense variants. The impact of GRK1 missense variants at the protein level were then predicted using a series of computational tools. We identified twelve previously unpublished cases with biallelic disease associated GRK1 variants, including eight novel variants, and reviewed all GRK1 disease associated variants. Further structure‐based scoring revealed a hotspot for missense variants in the kinase domain. In addition, to aid future clinical interpretation, we identified the bioinformatics tools best able to differentiate disease associated from nondisease associated variants. We identified GRK1 variants in Oguchi disease patients and investigated how disease‐causing variants may impede protein function in‐silico., In this study, Poulter et al. expand the number of mutations in Rhodopsin Kinase (GRK1), associated with Oguchi disease, from 13 to 21. The authors compare disease associated mutations with likely nonpathogenic variants in a range of bioinformatic prediction software. In silico analyses of the mutations, using a homology model, suggest mutations result in one of three potential mechanisms of disease: loss of protein, loss of kinase function or a failure of prenylation leading to mislocalisation of the protein.

To describe the characteristics of Japanese patients with hydroxychloroquine (HCQ) retinopathy developing within 3 years of treatment outset.Retrospective case series METHODS: Three patients with HCQ retinopathy developing within 3 years of treatment outset have been identified in Japan since HCQ became available in 2015. Their medical charts, containing optical coherence tomography (OCT), fundus autofluorescence imaging, and visual field tests, were reviewed.The treatment durations and cumulative doses until onset were 29-36 months and 182-326 g, respectively. The first patient had possible pre-existing maculopathy, although the abnormalities were ambiguous. The second and third patients had impaired renal function. The patients did not complain of severe visual disturbance at diagnosis, but visual field loss and disruption of the outer retinal segments consisting of a parafoveal pattern in the first case and a pericentral pattern (localized, 8 or more degrees from the center of the fovea) in the second and third cases were clearly observed on OCT. Even after HCQ discontinuation, their retinopathy showed slight progression on the visual field tests and OCT images. A blood sample was obtained from 1 patient on the day after HCQ discontinuation, and the whole blood level of HCQ was measured using validated liquid chromatography-tandem mass spectrometry. The HCQ level 27 h after the last dose was high, at 2240 ng/mL (suggested threshold 1733 ng/mL).Ophthalmologic screening from the initiation of HCQ treatment detected 3 cases of HCQ retinopathy developing within 3 years of treatment outset, including a patient with a high blood level of HCQ.

Background: To compare the effectiveness of intravitreal ranibizumab (IVR) and intravitreal aflibercept (IVA) performed with the treat-and-extend (TAE) regimen on eyes with diabetic macular edema (DME). Patients and methods: This is a retrospective study of 125 eyes of 125 treatment-na&iuml, ve DME patients who received anti-VEGF injections at three consecutive monthly intervals as the loading phase. The changes in the best-corrected visual acuity (BCVA), central retinal thickness (CRT), diabetic retinopathy severity scale (DRSS), and total injection numbers were compared between the two anti-VEGF agents. Results: Among 125 eyes, 26 eyes completed the treatment with the TAE regimen for 24 months (20.8%). Thirteen eyes of 13 patients (mean age, 70.9 &plusmn, 6.0 years) received intravitreal injections of 0.5 mg ranibizumab, and 13 eyes of 13 patients (65.9 &plusmn, 8.6 years) received 2 mg aflibercept. No significant differences were detected in the baseline demographics. At 24 months, BCVA was significantly improved in both groups, from 0.31 &plusmn, 0.19 to 0.10 &plusmn, 0.12 logMAR units for IVR and 0.41 &plusmn, 0.19 to 0.16 &plusmn, 0.28 logMAR units for IVA (p = 1.29 &times, 10&minus, 9). CRT was significantly reduced in both groups, 440.9 &plusmn, 69.3 to 307.5 &plusmn, 66.4 &mu, m for IVR and 473.9 &plusmn, 71.5 to 317.8 &plusmn, 71.2 &mu, m for IVA (p = 3.55 &times, 9). No significant differences were detected in the improvements of BCVA, CRT in both groups, and the total injection numbers for 24 months (11.0 &plusmn, 1.2 for the IVA group and 12.0 &plusmn, 1.0 the IVR group). DRSS was significantly improved in both groups (p = 0.0004 for IVR and p = 0.009 for IVA). Conclusion: No significant differences were detected in the improvements of BCVA or CRT and injection numbers between the IVR and IVA groups treated with the TAE regimen. These results indicate that the results of the treatment with both agents with the TAE regimen were equally effective, but only 20.8% of patients completed 24 months of continuous treatment with the TAE regimen. Synopsis: There are no significant differences regarding effectiveness between the IVR and IVA groups treated with the TAE regimen for DME eyes.

The study reports a case with metastatic cutaneous malignant melanoma that developed Vogt-Koyanagi-Harada-like uveitis during pembrolizumab treatment. The uveitis improved by discontinuation of pembrolizumab and use of oral and topical steroids. Full-field flicker ERGs were used to monitor the retinal function before and after the steroid treatments.A 68-year-old women presented with blurred vision in both eyes 3 months after beginning pembrolizumab adjuvant therapy for a malignant melanoma on the lower thigh. Optical coherence tomography showed a serous retinal detachment (SRD) in the right eye and marked choroidal thickening in both eyes. Fluorescein angiography showed spotted hyperfluorescence in the right eye and leakage of fluorescein from both optic disks. Indocyanine green angiography showed dark hypofluorescent spots in both eyes. She was diagnosed with Vogt-Koyanagi-Harada-like uveitis induced by pembrolizumab and discontinued the pembrolizumab. She was then treated with oral prednisolone and topical betamethasone. One week later, the symptoms were improved, and 1 month later the choroidal thickening in both eyes and the SRD of the right eye were not present. The implicit time of the full-field flicker ERGs recorded by RETeval system was significantly delayed at the initial examination but improved within a few weeks after the steroid replacement treatment.Our case with Vogt-Koyanagi-Harada-like uveitis induced by pembrolizumab had a reduction in the degree of uveitis after discontinuation of the pembrolizumab and use of oral prednisolone and topical betamethasone. Flicker ERGs were helpful in monitoring the retinal function before and after the steroid treatment.

Background Acquired color anomalies caused by cerebral trauma are classified as either achromatopsias or dyschromatopsias (Zeki, Brain 113:1721–1777, 1990). The three main brain regions stimulated by color are V1, the lingual gyrus, which was designated as human V4 (hV4), and the fusiform gyrus, designated as V4α. (Zeki, Brain 113:1721–1777, 1990). An acquired cerebral color anomaly is often accompanied by visual field loss (hemi- and quadrantanopia), facial agnosia, prosopagnosia, visual agnosia, and anosognosia depending on the underlying pathology (Bartels and Zeki, Eur J Neurosci 12:172–193, 2000), (Meadows, Brain 97:615–632, 1974), (Pearman et al., Ann Neurol 5:253–261, 1979). The purpose of this study was to determine the characteristics of a patient who developed dyschromatopsia following a traumatic injury to her brain. Case presentation The patient was a 24-year-old woman who had a contusion to her right anterior temporal lobe. After the injury, she noticed color distortion and that blue objects appeared green in the left half of the visual field. Although conventional color vision tests did not detect any color vision abnormalities, short wavelength automated perimetry (SWAP) showed a decrease in sensitivity consistent with a left hemi-dyschromatopsia. Magnetic resonance imaging (MRI) detected abnormalities in the right fusiform gyrus, a part of the anterior temporal lobe. At follow-up 14 months later, subjective symptoms had disappeared, but the SWAP abnormalities persisted and a thinning of the sectorial ganglion cell complex (GCC) was detected. Conclusion The results indicate that although the subjective symptoms resolved early, a reduced sensitivity of SWAP remained and the optical coherence tomography (OCT) showed GCC thinning. We conclude that local abnormalities in the anterior section of fusiform gyrus can cause mild cerebral dyschromatopsia without other symptoms. These findings indicate that it is important to listen to the symptoms of the patient and perform appropriate tests including the SWAP and OCT at the early stage to objectively prove the presence of acquired cerebral color anomaly.

To report our findings in a case of lens fragment-induced uveitis associated with supernormal flicker electroretinograms (ERGs) twenty months after the cataract surgery. This is an observational case report. Full-field flicker ERGs were recorded with the RETeval system. Optical coherence tomography (OCT) and slit-lamp biomicroscopy were used to assess the uveitis during the follow-up period. A 70-year-old man, who had undergone cataract surgery 20 months earlier, visited our hospital with a complaint of decreased vision in his right eye. Slit-lamp biomicroscopy revealed corneal edema and a lens fragment was detected in the inferior part of the anterior chamber. OCT showed cystoid macular edema, and flicker ERGs showed a marked increase in the amplitude and a delay in the implicit time in the right eye. These abnormalities of the flicker ERGs improved gradually after the removal of lens fragment and application of topical anti-inflammatory medications. Our case of lens-induced uveitis had supernormal flicker ERG amplitudes. Clinicians should be aware that eyes with uveitis can have larger-than-normal ERG amplitudes.

Purpose To describe the functional phenotypic features of East Asian patients with RP1L1-associated occult macular dystrophy (i.e., Miyake disease). Design An international multi-center retrospective cohort study. Methods Twenty-eight participants (53 eyes) with Miyake disease were enrolled at three centres: in Japan, China, and Korea. Ophthalmological examinations including spectral-domain optic coherence tomography (SD-OCT) and multifocal electroretinogram (mfERG) were performed. Patients were classified into three functional groups based on mfERG: Group 1, paracentral dysfunction with relatively preserved central/peripheral function; Group 2, homogeneous central dysfunction with preserved peripheral function; and Group 3, widespread dysfunction over the recorded area. Three functional phenotypes were compared in clinical parameters and SD-OCT morphological classification (severe phenotype, blurred/flat ellipsoid zone and absence of the interdigitation zone; mild phenotype, preserved ellipsoid zone). Results There were eight eyes in Group 1, 40 eyes in Group 2, and five eyes in Group 3. The patients in Group 1 showed significantly later onset (P=.005) and shorter disease duration (P=.002), compared with those in Group 2. All eight eyes in Group 1 showed the mild morphological phenotype, while 43/45 eyes in Groups 2 and 3 presented the severe phenotype, which identified a significant association between the functional grouping and the morphological classification (P Conclusions A spectrum of functional phenotypes of Miyake disease was first documented with identifying three functional subtypes. Patients with paracentral dysfunction had the mildest phenotype, and those with homogeneous central or widespread dysfunction showed overlapping clinical findings with severe photoreceptor changes, suggesting various extents of visual impairment.

In the original publication, under section, BRVO treatment practice pattern, the sentence in p. 369 was published as.

PurposeBiallelic mutations in G-Protein coupled receptor kinase 1 (GRK1) cause Oguchi disease, a rare subtype of congenital stationary night blindness (CSNB). The purpose of this study was to identify pathogenic GRK1 variants and use in-depth bioinformatic analyses to evaluate how their impact on protein structure could lead to pathogenicity.MethodsPatients’ genomic DNA was sequenced by whole genome, whole exome or focused exome sequencing. Pathogenic variants, published and novel, were compared to nondisease associated missense variants. The impact of GRK1 missense variants at the protein level were then predicted using a series of computational tools.ResultsWe identified eleven previously unpublished cases with biallelic pathogenic GRK1 variants, including seven novel variants, and reviewed all GRK1 pathogenic variants. Further structure-based scoring revealed a hotspot for missense variants in the kinase domain. Additionally, to aid future clinical interpretation, we identified the bioinformatics tools best able to differentiate pathogenic from non-pathogenic variants.ConclusionWe identified new GRK1 pathogenic variants in Oguchi disease patients and investigated how disease-causing variants may impede protein function, giving new insights into the mechanisms of pathogenicity. All pathogenic GRK1 variants described to date have been collated into a Leiden Open Variation Database (http://dna2.leeds.ac.uk/GRK1_LOVD/genes/GRK1).

Aims/Introduction To determine the current clinical preferences of anti‐vascular endothelial growth factor (VEGF) treatment protocols for diabetic macular edema (DME) in Japan. Materials and Methods This was a descriptive cross‐sectional study. Answers to a questionnaire consisting of 16 questions were obtained from 176 of 278 (63.3%) surveyed ophthalmologists. Results The results showed that 81.2% preferred intravitreal injections of anti‐VEGF antibodies as the first‐line therapy. The most important indicators for beginning anti‐VEGF therapy were: the best‐corrected visual acuity in 44.3% and the retinal thickness in 30.7%. In the loading phase, 53.4% preferred a single injection, and in the maintenance phase, 75.0% preferred the pro re nata regimen. Financial limitation (85.8%) was reported as the most important difficulty in the treatment. For combination therapy with anti‐VEGF treatment, panretinal photocoagulation, focal photocoagulations and a sub‐Tenon steroid injection were preferred. The contraindications for anti‐VEGF therapy were: prior cerebral infarction (72.7%). Regarding the use of both approved anti‐VEGF agents in Japan, ranibizumab and aflibercept, 39.8% doctors used them appropriately. Conclusions Our results present the current clinical preferences of anti‐VEGF treatment for DME in Japan. The best‐corrected visual acuity and the retinal thickness are important indicators to institute this therapy. The majority of the ophthalmologists use anti‐VEGF treatment as first‐line therapy and prefer the 1 + pro re nata regimen.

Background/aims To investigate the yearly change of real-world outcomes for best corrected visual acuity (BCVA) after 2-year clinical intervention for treatment-naïve diabetic macular oedema (DMO). Methods Retrospective analysis of aggregated, longitudinal medical records obtained from 27 retina specialised institutions in Japan from Survey of Treatment for DMO database. A total of 2049 treatment-naïve centre involving DMO eyes of which the initial intervention started between 2010 and 2015, and had been followed for 2 years, were eligible. As interventions, antivascular endothelial growth factor (VEGF) agents, local corticosteroids, macular photocoagulation and vitrectomy were defined. In each eye, baseline and final BCVA, the number of each intervention for 2 years was extracted. Each eye was classified by starting year of interventional treatment. Results Although baseline BCVA did not change by year, 2-year improvement of BCVA had been increased, and reached to +6.5 letters in the latest term. There is little difference among starting year about proportions of eyes which BCVA gained >15 letters, in contrast to those which lost >15 letters were decreased by year. The proportion of eyes receiving anti-VEGF therapy was dramatically increased, while those receiving the other therapies were gradually decreased. The proportion of eyes which maintained socially good vision of BCVA>20/40 has been increased and reached to 59.0% in the latest term. Conclusion For recent years, treatment patterns for DMO have been gradually but certainly changed; as a result, better visual gain, suppression of worsened eyes and better final BCVA have been obtained. Anti-VEGF therapy has become the first-line therapy and its injection frequency has been increasing.

Focal choroidal excavation (FCE) is described as an excavated lesion of the choroid that can be detected by optical coherence tomography (OCT). While the exact pathogenesis of FCE remains unclear, it has been proposed in some cases that there is an association with the inflammation in the outer retina. We present a case of FCE development that was detected by spectral domain OCT (SD-OCT) and found to be associated with multiple evanescent white dot syndrome (MEWDS). A 40-year-old Japanese woman was diagnosed with MEWDS based on multiple white dots observed from the posterior pole to the midperiphery, along with yellow granularity in the fovea. SD-OCT revealed separation between the retinal pigment epithelium (RPE) and Bruch’s membrane (BM) and discontinuations of the ellipsoid zone, RPE, and BM. At 4 weeks after onset, several of the white dots disappeared, the yellow granularity in the fovea became small, and we detected nonconforming choroidal excavation under the central fovea. The choroidal excavation gradually deepened and changed to a conforming pattern. These findings suggest that the degree of the impairment caused by inflammation and the plasticity of the BM and RPE complex may be associated with different types of acquired FCE.

Purpose To determine whether there is a significant correlation between the amplitude of the photopic negative response (PhNR) and the peripapillary retinal nerve fiber layer thickness (pRNFLT) in eyes of young, healthy subjects. Methods We analyzed 136 eyes of 136 young, healthy subjects (89 males and 47 females; age, 20–29 years). The PhNRs were recorded with the RETeval system without mydriasis using red flashes on a blue background. PhNR amplitude was measured at two points: at 72 ms (P72) and at the negative trough following the b-wave (Pmin). Univariate and multivariable linear regression analyses were performed to identify the independent variables that were significantly correlated with P72 and Pmin. The variables included age, sex, axial length, pRNFLT, intraocular pressure (IOP), a-wave amplitude, b-wave amplitude, and pupillary area during the electroretinogram recordings. Results The amplitudes of P72 and Pmin were significantly larger in female subjects (P = 0.021 and P = 0.001, respectively). Univariate analyses showed that PhNR amplitudes were significantly correlated with pRNFLT (P72: r = 0.246, P = 0.004; Pmin: r = 0.219, P = 0.011). Female sex was significantly and negatively correlated with P72 (r = –0.206; P = 0.016) and Pmin (r = –0.271; P = 0.001). Multivariable regression analyses showed that greater pRNFLT was an independent factor significantly associated with a larger P72 (r = 0.283; P = 0.004) and Pmin (r = 0.299; P = 0.002). Female sex was an independent factor that was significantly associated with a larger Pmin (r = –0.208; P = 0.022). Conclusions These findings indicate that PhNR amplitude is significantly associated with pRNFLT and female sex in young, healthy subjects. Translational Relevance The amplitude of the PhNR recorded with RETeval is smaller in subjects with thinner pRNFLT not only in glaucoma patients but also in young healthy subjects.

Purpose To determine the course of occult macular dystrophy (OMD, Miyake's disease) and to propose stages of OMD based on the optical coherence tomographic (OCT) findings. Methods Sixty-one patients from 33 families with OMD who carried one of the proven variants of the RP1L1 gene were studied at seven centers in Japan. Ophthalmological examinations including the best-corrected visual acuity (BVCA) and OCT were performed. Results The median age at the last visit was 50 years with a range of 10 to 88 years, and the median age at the symptom onset was 30 years with a range of 3 to 60 years. There were significant negative correlations between the duration of OMD and BCVA, the central retinal thickness (CRT) and the thickness between external limiting membrane and retinal pigment epithelium (ERT). The BCVA gradually decreased for 10 years after symptom onset and was stable thereafter. Kaplan-Meier survival curves of the BCVA and retinal thickness showed that all of the patients had retained a vision of 1.0 logMAR, and over 80% of the patients had retained 50% thickness of the normal CRT and ERT for at least 60 years after symptom onset. The stages of OMD based on the visual symptoms and OCT findings are proposed. Conclusions The photoreceptors do not become completely atrophic even at the late stage, which may account for the good retinal pigment epithelium (RPE) structure and normal-appearing fundus. The proposed stages facilitate the investigation of the pathogenicity of OMD and provide information to determine the effectiveness of therapeutic procedures.

Background To compare the effectiveness of intravitreal ranibizumab (IVR) and intravitreal aflibercept (IVA) performed with the Treat-and-Extend (TAE) regimen on eyes with diabetic macular edema (DME).Patients and methods This was a retrospective study of 125 eyes of 125 treatment naïve DME patients who received anti-VEGF injections at 3 consecutive monthly intervals as the loading phase. Of these 125 eyes, 26 eyes completed the treatment with the TAE regimen for at least 24 months. Among the 26 eyes, 13 eyes of 13 patients (mean age, 70.9±6.0 years) received intravitreal injections of 0.5 mg ranibizumab and 13 eyes of 13 patients (65.9±8.6 years) received 2 mg aflibercept. The changes in the best-corrected visual acuity (BCVA), central retinal thickness (CRT), diabetic retinopathy severity (DRS), and total injection numbers were compared between the two anti-VEGF agents.Results No significant differences were detected in the baseline demographics. At 24 months, the BCVA was significantly improved in both groups; from 0.31±0.19 to 0.10±0.12 logMAR units for IVR and 0.41±0.19 to 0.16±0.28 logMAR units for IVA ( P=1.29x10 -9 ). The CRT was significantly reduced in both groups; 440.9±69.3 to 307.5±66.4 μm for IVR and 473.9±71.5 to 317.8±71.2 μm for IVA ( P=3.55x10 -9 ). No significant differences were detected in the improvements of the BCVA and the CRT in both groups, and the total injection numbers were significant fewer for the IVA group (11.0±1.2) than the IVR group (12.0±1.0). The DRS was significantly improved in both groups ( P =0.0004 for IVR and P =0.009 for IVA).Conclusion No significant differences were detected in the improvements of the BCVA or CRT and injection numbers between IVR and IVA groups treated with the TAE regimen. These results indicate that the results of the treatment with both agents with the TAE regimen were equally effective.

To determine the parameters of the anterior segment of eyes that are significantly associated with the refractive error in healthy young Japanese university students. This was a cross-sectional observational study of 229 healthy Japanese university students (men: women,147:82) whose age ranged between 20 to 29 years. Univariate and multivariate linear regression analyses were performed to identify the factors that were significantly correlated with the refractive error. The independent variables included age, sex, axial length, anterior chamber depth, corneal diameter, curvature of anterior surface of cornea, and central corneal thickness. The mean refractive error (spherical equivalent) was −4.1 ± 2.7 diopters (D) with a range of −12.5 to +0.5 D, and the mean axial length was 25.4 ± 1.3 mm with a range of 22.4 to 29.0 mm. Pearson univariate correlation analysis found that the refractive error was significantly and negatively correlated with the axial length (R = −0.82, P P P = 0.001). Multiple regression analysis showed that the refractive error was significantly associated with a longer axial length (P P P

Neovascular glaucoma (NVG) is a terminal severe complication in eyes with proliferative diabetic retinopathy (PDR), and PDR eyes with vitreous hemorrhage (VH) which undergo vitrectomy may have higher risk of postoperative NVG. The incidence and the prognostic factor of postoperative NVG after 25-gauge vitrectomy with advanced surgical options remain unclear. We retrospectively reviewed medical records of 268 eyes of 268 consecutive PDR patients with VH who underwent 25-gauge vitrectomy and 12 months follow-up at seven centers. Preoperative ocular factors (visual acuity, tractional retinal detachment, panretinal photocoagulation [PRP]), demographics and clinical factors (sex, age, diabetic duration, HbA1c, hypertension, anticoagulant medication, and kidney function), surgical procedures, and postoperative complications were compared between patients who developed postoperative NVG (9.3%) and those who did not. NVG eyes was significantly younger (P = 0.026), had shorter diabetic duration (P = 0.022), higher HbA1c (P = 0.028), absence of PRP (P = 0.039) and higher frequency of postoperative VH (P = 0.0075) than non-NVG eyes. Logistic regression analysis identified postoperative VH (P = 0.014), shorter diabetic duration (P = 0.029), and no PRP (P = 0.028) as prognostic factors for postoperative NVG. This multicenter study indicates that younger age, uncontrolled diabetes, no PRP, and postoperative VH are risk factors of post-vitrectomy NVG.

Congenital stationary night blindness (CSNB), in the complete form, is caused by dysfunctions in ON-bipolar cells (ON-BCs) which are secondary neurons of the retina. We describe the first disease causative variant associated with CSNB in the dog. A genome-wide association study using 12 cases and 11 controls from a research colony determined a 4.6 Mb locus on canine chromosome 32. Subsequent whole-genome sequencing identified a 1 bp deletion in LRIT3 segregating with CSNB. The canine mutant LRIT3 gives rise to a truncated protein with unaltered subcellular expression in vitro. Genetic variants in LRIT3 have been associated with CSNB in patients although there is limited evidence regarding its apparently critical function in the mGluR6 pathway in ON-BCs. We determine that in the canine CSNB retina, the mutant LRIT3 is correctly localized to the region correlating with the ON-BC dendritic tips, albeit with reduced immunolabelling. The LRIT3-CSNB canine model has direct translational potential enabling studies to help understand the CSNB pathogenesis as well as to develop new therapies targeting the secondary neurons of the retina.

Purpose To record electroretinograms (ERGs) from intrinsically photosensitive retinal ganglion cells (ipRGCs) of glaucoma patients. Methods ERGs were recorded in 10 normal subjects and 15 patients with glaucoma. The ERG illumination system was built to achieve receptor-silent substitution, and comprised an optical diffuser and four-in-one light-emitting diodes. Results The ERG recordings of ipRGC from normal subjects showed an “on” response and an “off” response. The mean (±SD) implicit time for the on and off responses in normal subjects was 103.0 ± 24.9 and 337.9 ± 45.8 ms, respectively, with corresponding amplitudes of 7.7 ± 2.8 and 7.3 ± 3.4 μV, respectively. In glaucoma patients, the implicit time of the on and off responses was 135.0 ± 28.9 and 368.2 ± 17.3 ms, respectively. The corresponding amplitudes of the on and off responses in these patients were 0.47 ± 0.18 and 0.66 ± 0.32 μV, respectively. Conclusions The results demonstrate successful ERG recording of ipRGCs from advanced glaucoma patients, with marked reductions in amplitude, although not implicit time, compared with normal subjects.

Purpose The zebrafish is an established animal model commonly used in biological, neuroscience, and genetic research. We have developed a new light stimulating system using white light-emitting diodes (LEDs) to elicit ERGs from zebrafish larvae. The purpose of this study was to record full-field ERGs and to evaluate the inter-trial reliability of the ERGs recorded with our system from zebrafish larvae. Methods The stimulating device used white LEDs that were attached to a stereomicroscope, and the location of the recording electrode on the cornea could be monitored while the eye was being stimulated. Full-field scotopic and photopic ERGs were recorded from larvae at the age of 5–7 days post-fertilization (dpf). Intensity–response curves were constructed from the ERGs. Inter-trial reliability of the ERGs recorded by our system was evaluated. Results This stimulating system could be used for efficient and reliable ERG recordings from 5–7 dpf larvae. The amplitudes, implicit times, and the waveforms of the scotopic and photopic ERGs were similar to those reported in earlier studies. Inter-trial reliability of the amplitudes of the photopic ERG b-waves was excellent with an intra-class correlation coefficient of 0.98. Conclusion We conclude that this new light stimulation system using white LEDs attached to a stereomicroscope will be helpful in recording reliable ERGs from zebrafish larvae.

Purpose To evaluate the effects of unilateral intravitreal ranibizumab (IVR) on the ocular circulation of the fellow eyes. Methods Fifteen eyes of 15 patients with macular edema (average age 69.6 ± 11.8 years) were studied. Eleven eyes had diabetic macular edema (DME) and four eyes had macular edema associated with a branch retinal vein occlusion. Each eye received 0.5 mg of IVR. The blood circulation on the optic nerve head of the treated and untreated eyes were determined by laser speckle flowgraphy (LSFG, Softcare Co., Ltd) before, 1 day, and 1 week after the IVR. The mean blur rate (MBR) and the relative changes of the MBRs determined as dMBR(%) = 100−(MBR before/MB after) × 100) were evaluated. The central macular thickness (CMT) and the rate of reduction in the thickness (dCMT = 100−(CMT before/CMT after) × 100) were also evaluated. Results The mean dMBR was significantly higher in the treated eyes than the untreated eyes at 1 day (−16.4 ± 17.0% vs 2.31 ± 19.3%) and at 1 week (−12.0 ± 14.6% vs 4.50 ± 25.9%) after the IVR (P = 0.02, paired t tests). Conclusion These findings indicate that if ranibizumab enters the systemic circulation, the concentration is not high enough to affect the ocular circulation of the fellow eyes.

To determine the annual incidence of visual impairment in a Japanese population during a 10-year period. We examined the physical disability certificates issued yearly between 2004 and 2013 in Mie prefecture, Japan. During this period 2468 visually impaired people were registered under the newly defined Act on Welfare of the Physically Disabled Persons’ criteria. The age, sex distribution, and causes of visual impairment were determined from the certificates. The major causes of visual impairment during the ten-year period were glaucoma (23.3%), diabetic retinopathy (17.3%), retinitis pigmentosa (12.2%), macular degeneration (9.0%), chorioretinal degeneration or high myopia (7.4%), optic atrophy (5.8%), stroke or brain tumor (5.4%) and cataracts (3.7%). The incidence of glaucoma was significantly higher throughout the period (2004–2013), and that of diabetic retinopathy was lower between 2007 and 2013. The incidence of retinitis pigmentosa did not change significantly during the 10-year period. The incidence of macular degeneration tended to increase between 2004 and 2007, but it decreased significantly between 2007 and 2013. The results indicate that in Japan, the rates of the major causes of visual impairment altered in the most recent 10-year period reflecting the recent changes in the social background and advances in ocular and systemic treatment.

Tuberous sclerosis complex (TSC) 1 or TSC2 is mutated in most TSC patients. TSC2 mutations are more frequently associated with worse outcomes, earlier age at seizure onset, more severe intellectual disability, and higher tuber load than TSC1. The degree of white matter involvement is thought to be associated with the severity of neurological impairment. At present, genotype-phenotype correlations and relationship between tuber burden and neurological disability in TSC are debatable. We presented a 43-year-old patient with TSC2 mutation, whose symptom was only incomplete quadrantic visual field deficit in spite of multiple brain tubers. The visual field deficit was thought to be due to a small lesion in the upper medial part of the optic radiation revealed by diffusion tensor imaging. Her brain tubers showed normal findings in magnetic resonance spectroscopy. Our case suggested that neurological and neuropsychiatric manifestations of TSC are affected by the quality rather than number of the lesions. In addition, MRS may be useful to identify the correlation between brain tubers and neurological disability in TSC patients.

Purpose. To compare the effective fields of the Optos 200Tx® and Clarus 500™, two ultra-widefield ophthalmoscopes, based on their ability to image branches of retinal vessel in the four retinal quadrants. Methods. Ninety retinal images from 90 patients with various eye diseases were studied. All patients had undergone 200° retinal imaging to obtain a single image of Optos (O) and the montage of two images of the Clarus (C). The highest number of traceable vessel branches in the four retinal quadrants was determined by two masked raters. An image was classified as “O > C” when the number of identifiable branch was greater in the Optos than the Clarus, as “O = C” when the number was equal and as “O Results. The appearance probability of “O > C” was significantly higher at the upper temporal quadrant than “O p<0.01 for both raters). In contrast, the appearance probability of “O C” (p<0.01 for both raters). There were no significant differences in the appearance probability between “O > C” and “O p>0.50 for both raters). Conclusions. These results demonstrate that the effective field of views was different between the two devices at different retina quadrants. Further studies are needed to clarify possible factors such as artifacts by the eyelashes, differences in the depth of focus, motion of the device, and different locations of the images on the effective field of views.

GUCA1A gene variants are associated with autosomal dominant (AD) cone dystrophy (COD) and cone-rod dystrophy (CORD). GUCA1A-associated AD-COD/CORD has never been reported in the Japanese population. The purpose of this study was to investigate clinical and genetic features of GUCA1A-associated AD-COD/CORD from a large Japanese cohort. We identified 8 variants [c.C50_80del (p.E17VfsX22), c.T124A (p.F42I), c.C204G (p.D68E), c.C238A (p.L80I), c.T295A (p.Y99N), c.A296C (p.Y99S), c.C451T (p.L151F), and c.A551G (p.Q184R)] in 14 families from our whole exome sequencing database composed of 1385 patients with inherited retinal diseases (IRDs) from 1192 families. Three variants (p.Y99N, p.Y99S, and p.L151F), which are located on/around EF-hand domains 3 and 4, were confirmed as “pathogenic”, whereas the other five variants, which did not co-segregate with IRDs, were considered “non-pathogenic”. Ophthalmic findings of 9 patients from 3 families with the pathogenic variants showed central visual impairment from early to middle-age onset and progressive macular atrophy. Electroretinography revealed severely decreased or non-recordable cone responses, whereas rod responses were highly variable, ranging from nearly normal to non-recordable. Our results indicate that the three pathogenic variants, two of which were novel, underlie AD-COD/CORD with progressive retinal atrophy, and the prevalence (0.25%, 3/1192 families) of GUCA1A-associated IRDs may be low among Japanese patients.

To determine whether an intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) in eyes with diabetic macular edema (DME) affects the vascular infarction-related molecules (VIRMs). Nineteen eyes with DME were treated with 0.5 mg of intravitreal ranibizumab (IVR), and 22 eyes with DME were treated with 2 mg of intravitreal aflibercept (IVA). Blood was collected before, 1 week and 1 month after the injections. Aqueous humor was collected before and 1 month after the injections. The concentration of the VIRMs (cardiac myoglobin, cardiac troponin, intercellular adhesion molecule, monocyte chemotactic protein-1, matrix metalloproteinase-8, placental growth factor [PlGF], tenascin-C, tissue inhibitor of metalloproteinase-1, thrombospondin-2, vascular cell adhesion molecule-1, and VEGF) were determined by the multiplex assay. After the single injection of both types of anti-VEGF agents, the concentration of aqueous VEGF decreased significantly (P P

Purpose To identify prognostic factors for revitrectomy in patients who underwent vitrectomy for complications with proliferative diabetic retinopathy (PDR) in multicentre study. Methods Consecutive 452 eyes of 452 patients with PDR undergoing 25-gauge microincision vitrectomy system (MIVS) in seven centres were retrospectivity reviewed. Preoperative ocular factors (baseline visual acuity [VA], vitreous haemorrhage [VH], tractional retinal detachment [TRD] and retinal photocoagulation), general factors (sex, age, diabetes duration, HbA1c level, hypertension, anti-coagulant medication and estimated glomerular filtration rate), surgical procedures (preoperative anti-vascular endothelial growth factor injection, internal limiting membrane peeling, combined cataract surgery, retinal break, and tamponade), postoperative complications for revitrectomy and postoperative VA at 6 months were evaluated. Results In the follow-up period of 6 months, revitrectomy was performed in 56 eyes (26.3%), and postoperative complications for revitrectomy were VH in 31 eyes (15%), TRD in 13 eyes (6.2%) and membrane proliferation in 12 eyes (5.2%). The mean LogMAR improvement from baseline to 6 months in revitrectomy group (0.39) was significantly worse than in single vitrectomy group (0.74). Diabetic duration, low baseline VA, less simple VH, TRD and air tamponade were statistical risk factors of revitrectomy, and logistic regression analysis identified low baseline VA and air tamponade also as prognostic factors of revitrectomy. Conclusion Our results indicated that prognosis of VA was worse in PDR patients with revitrectomy and low baseline VA and air as the tamponade material were the potential prognostic factors of revitrectomy.

A single variant (p.G38D) in the GNAT1 gene, encoding the rod-specific transducin α-subunit in phototransduction, has been reported only in one French family with Nougaret-type autosomal dominant congenital stationary night blindness (CSNB). We identified a Japanese family with Nougaret-type CSNB and cone-rod dystrophy (CORD). Five patients with CSNB and two patients with childhood-onset CORD were recruited. We performed a comprehensive ophthalmic examination including electroretinography (ERG). Disease-causing variants were identified by whole exome sequencing, with candidates confirmed by Sanger sequencing in nine family members. The GNAT1 variant (p.G38D) was identified in all four CSNB patients, whereas the two CORD patients carried biallelic truncated known ABCA4 variants as well as the GNAT1 variant. Clinically, no remarkable findings were observed in fuduscopy, fundus autofluorescence, or optical coherence tomography images from the CSNB patients. No response was detectable by rod ERG. The a-waves of standard and bright flash ERG were delayed and broadened rather than biphasic, and b/a-wave amplitude ratio was negative. Cone and 30-Hz flicker responses were normal, and overall, the ERG findings were compatible with previous descriptions of Nougaret-type CSNB. ERG of the CORD patients with macular atrophy showed non-recordable rod response and severely decreased standard flash, cone and 30-Hz flicker responses. This is the second report of a Nougaret-type CSNB family with the GNAT1 variant. Our novel findings suggest that coexistence of the GNAT1 and biallelic ABCA4 variants is associated with an overlapping phenotype with both Nougaret-type CSNB and CORD.

Biallelic variants in the EYS gene are a major cause of autosomal recessive inherited retinal disease (IRD), with a high prevalence in the Asian population. The purpose of this study was to identify pathogenic EYS variants, to determine the clinical/genetic spectrum of EYS-associated retinal disease (EYS-RD), and to discover disease-associated variants with relatively high allele frequency (1%-10%) in a nationwide Japanese cohort. Sixty-six affected subjects from 61 families with biallelic or multiple pathogenic/disease-associated EYS variants were ascertained by whole-exome sequencing. Three phenotype groups were identified in EYS-RD: retinitis pigmentosa (RP; 85.94%), cone-rod dystrophy (CORD; 10.94%), and Leber congenital amaurosis (LCA; 3.12%). Twenty-six pathogenic/disease-associated EYS variants were identified, including seven novel variants. The two most prevalent variants, p.(Gly843Glu) and p.(Thr2465Ser) were found in 26 and twelve families (42.6%, 19.7%), respectively, for which the allele frequency (AF) in the Japanese population was 2.2% and 3.0%, respectively. These results expand the phenotypic and genotypic spectrum of EYS-RD, accounting for a high proportion of EYS-RD both in autosomal recessive RP (23.4%) and autosomal recessive CORD (9.9%) in the Japanese population. The presence of EYS variants with relatively high AF highlights the importance of considering the pathogenicity of non-rare variants in relatively prevalent Mendelian disorders.

Purpose To determine the clinical and genetic characteristics of patients with GUCY2D-associated retinal disorder (GUCY2D-RD). Methods Fifteen patients from 12 families with inherited retinal disorder (IRD) and harboring GUCY2D variants were ascertained from 730 Japanese families with IRD. Comprehensive ophthalmological examinations, including visual acuity (VA) measurement, retinal imaging, and electrophysiological assessment were performed to classify patients into three phenotype subgroups; macular dystrophy (MD), cone-rod dystrophy (CORD), and Leber congenital amaurosis (LCA). In silico analysis was performed for the detected variants, and the molecularly confirmed inheritance pattern was determined (autosomal dominant/recessive [AD/AR]). Results The median age of onset/examination was 22.0/38.0 years (ranges, 0-55 and 1-73) with a median VA of 0.80/0.70 LogMAR units (ranges, 0.00-1.52 and 0.10-1.52) in the right/left eye, respectively. Macular atrophy was identified in seven patients (46.7%), and two had diffuse fundus disturbance (13.3%), and six had an essentially normal fundus (40.0%). There were 11 patients with generalized cone-rod dysfunction (78.6%), two with entire functional loss (14.3%), and one with confined macular dysfunction (7.1%). There were nine families with ADCORD, one with ARCORD, one with ADMD, and one with ARLCA. Ten GUCY2D variants were identified, including four novel variants (p.Val56GlyfsTer262, p.Met246Ile, p.Arg761Trp, p.Glu874Lys). Conclusions This large cohort study delineates the disease spectrum of GUCY2D-RD. Diverse clinical presentations with various severities of ADCORD and the early-onset severe phenotype of ARLCA are illustrated. A relatively lower prevalence of GUCY2D-RD for ADCORD and ARLCA in the Japanese population was revealed. Translational Relevance The obtained data help to monitor and counsel patients, especially in East Asia, as well as to design future therapeutic approaches.

The International Society for Clinical Electrophysiology of Vision (ISCEV) standard for full-field electroretinography (ERG) describes a minimum protocol for clinical testing but encourages additional ERG testing when appropriate. This ISCEV extended protocol describes methods to record and evaluate a light-adapted (LA) ERG stimulus–response series with increasing flash strengths. The LA ERG stimulus–response series (also referred to as the luminance–response or intensity–response series in the published literature) can characterise generalised cone system function more comprehensively than the ISCEV standard LA ERGs alone. The amplitude of LA ERG a-waves, arising from cones and cone off-bipolar cells, typically shows a saturating function. The LA ERG b-wave amplitudes, which arise primarily from activity of retinal bipolar cells, show an amplitude peak followed by a nonzero plateau (the “photopic hill” phenomenon). This ISCEV extended protocol specifies a stimulus–response series suitable to evaluate generalised dysfunction affecting the LA retina, to aid in distinguishing between the on- and off-responses of the cone system and to monitor ERG changes in these characteristics. The LA ERG stimulus–response series for a- and b-waves is recorded to a sequence of nine flash stimuli ranging from 0.03 to 300 cd s m−2, superimposed on a standard background of 30 cd m−2. A shorter protocol is also presented to measure the mid-range of the function (the “photopic hill”) using 5 flash stimuli.

To describe the clinical and genetic characteristics of the cohort enrolled in the East Asian studies of occult macular dystrophy (OMD).International, multicenter, retrospective cohort studies.A total of 36 participants from 21 families with a clinical diagnosis of OMD and harboring pathogenic RP1L1 variants (i.e., Miyake disease) were enrolled from 3 centers in Japan, China, and South Korea.A detailed history was obtained, and comprehensive ophthalmological examinations including spectral-domain OCT were performed. All detected sequence variants in the RP1L1 gene were reviewed, and in silico analysis was performed, including allele frequency analyses and pathogenicity predictions.Onset of disease, visual acuity (VA) converted to the logarithm of the minimum angle of resolution (logMAR), OCT findings, and effect of detected variants.Eleven families from Japan, 6 from South Korea, and 4 from China were recruited. There were 12 female and 24 male participants. The median age of onset was 25.5 years (range, 2-73), and the median age at the latest examination was 46.0 years (range, 11-86). The median VA (logMAR) was 0.65 (range, -0.08-1.22) in the right eye and 0.65 (-0.08-1.10) in the left eye. A significant correlation between onset of disease and VA was revealed. The Classical morphologic phenotype showing both blurred ellipsoid zone and absence of interdigitation zone of the photoreceptors was demonstrated in 30 patients (83.3%), and subtle photoreceptor architectural changes were demonstrated in 6 patients (16.6%). Eight pathogenic RP1L1 variants were identified, including 6 reported variants and 1 novel variant: p.R45W, p.T1194M/p.T1196I (complex), p.S1199C, p.G1200A, p.G1200D, p.V1201G, and p.S1198F, respectively. Two variants were recurrent: p.R45W (11 families, 52.4%) and p.S1199C (5 families, 23.8%). The pathogenic missense variants in 10 families (47.6%) were located within the previously reported unique motif, including 6 amino acids (1196-1201).There is a large spectrum of clinical findings in Miyake disease, including various onset of disease and VA, whereas the characteristic photoreceptor microstructures were shared in most cases. Two hot spots including amino acid numbers 45 and 1196-1201 in the RP1L1 gene were confirmed in the East Asian population.

X-linked congenital retinoschisis (XLRS) is an inherited retinal disorder characterized by reduced central vision and schisis of the macula and peripheral retina. XLRS is caused by mutations in the RS1 gene. We have identified 37 different mutations in the RS1 gene, including 12 novel mutations, in 67 Japanese patients from 56 XLRS families. We present clinical features of these patients in relation to the associated mutations.

We investigated the rates of the use of steroids in Japanese central serous chorioretinopathy (CSC) cases and differences in the characteristics of CSC with and without steroids. A total of 538 eyes of 477 patients diagnosed with CSC, with 3 months or more of follow-up between April 2013 and June 2017 at 8 institutions. Patients with CSC with more than 3 months of follow-up were identified by OCT and fluorescein angiography at 8 institutions. Data collected included patient demographics, history of corticosteroid medication and smoking, spherical errors, findings of angiography, subfoveal choroidal thickness, and changes through the follow-up period. Differences in these findings were analyzed in cases with and without corticosteroid treatment. Among the 477 patients (344 men,133 women), 74 (15.5%) (39 men, 35 women) underwent current or prior steroid treatment. Cases with steroids were higher age (p = 0.0403) and showed no male prevalence, more bilateral involvement (p < 0.0001), and the affected eyes had multiple pigment epithelial detachment (p

The aim of this study was to determine the action of molecules in carbohydrate metabolism disorders during pregnancy. The concentration of different types of cytokines and vascular endothelial growth factor (VEGF) in the plasma were measured in 4 groups of women: Group I, normal pregnancy (n = 10); Group II, patients with gestational DM (n = 12); Group III, pregnant patients with preexisting DM (n = 16); and Group IV, diabetic non-pregnant women (n = 22). The plasma VEGF concentration was significantly higher in the women in Group IV than in other groups (P

Purpose To evaluate real-world evidence for intraocular pressure (IOP) elevation after subtenon triamcinolone acetonide injection (STTA) in 1252 Japanese patients (1406 eyes) in the Japan Clinical REtina STudy group (J-CREST). Methods This was a multicentre retrospective study of the medical records of 1252 patients (676 men (758 eyes); mean age: 63.8 ± 12.9 years) who received STTA in participating centres between April 2013 and July 2017. Results IOP elevation was observed in 206 eyes (14.7%) and IOP increase ≥ 6 mmHg was found in 328 eyes (23.3%). In total, 106 eyes (7.5%) needed medication and two eyes (0.14%) needed surgical procedures. Younger age, higher baseline IOP, and steroid dose were risk factors associated with IOP elevation. Risk factors associated with IOP increase ≥ 6 mmHg were younger age, lower baseline IOP, steroid dose, and higher incidences of diabetic macular oedema (DME) and uveitis. In contrast, with steroid dose fixed at 20 mg, a lower incidence of DME was a risk factor for increased IOP, suggesting that STTA had dose-dependent effects on IOP increase, especially in patients with DME. Conclusion Our real-world evidence from a large sample of Japanese patients who received STTA showed that the incidence of IOP elevation after STTA was 14.7%, and was associated with younger age, higher baseline IOP, and steroid dose. Thus, IOP should be monitored, especially in patients with younger age, higher baseline IOP, and higher incidences of DME and uveitis.

Glia play important roles in neural function, including but not limited to amino acid recycling, ion homeostasis, glucose metabolism, and waste removal. During retinal degeneration and subsequent retinal remodeling, Müller cells (MCs) are the first cells to show metabolic and morphological alterations in response to stress. Metabolic alterations in MCs chaotically progress in retina undergoing photoreceptor degeneration; however, what relationship these alterations have with neuronal stress, synapse maintenance, or glia-glia interactions is currently unknown. The work described here reconstructs a MC from a pathoconnectome of early retinal remodeling retinal pathoconnectome 1 (RPC1) and explores relationships between MC structural and metabolic phenotypes in the context of neighboring neurons and glia. Here we find variations in intensity of osmication inter- and intracellularly, variation in small molecule metabolic content of MCs, as well as morphological alterations of glial endfeet. RPC1 provides a framework to analyze these relationships in early retinal remodeling through ultrastructural reconstructions of both neurons and glia. These reconstructions, informed by quantitative metabolite labeling via computational molecular phenotyping (CMP), allow us to evaluate neural-glial interactions in early retinal degeneration with unprecedented resolution and sensitivity.

Purpose To evaluate the effects of intravitreal aflibercept (IVA) on the number of microaneurysms and sizes of nonperfused areas (NPAs) in eyes with diabetic macular edema (DME). Design Interventional, prospective study. Participants Twenty-five eyes of 25 DME patients (average age, 64.0±8.8 years) were treated with 3 consecutive monthly IVA injections. Methods Fluorescein angiography (FA) and OCT were performed before the IVA injections (baseline) and at 1 week after the IVA treatment. The number of microaneurysms and the ischemic index (ISI), a measure of NPA, were determined. The correlations between central retinal thickness (CRT) and number of microaneurysms and the ISI were also determined. Main Outcome Measures The mean number of microaneurysms and NPA evaluated as the ISI. Results At baseline, the mean CRT was 485.7±90.6 μm. After treatment, the mean CRT was reduced significantly to 376.9±81.6 μm (P = 0.1 × 10–5, repeated analysis of variance). The mean number of microaneurysms was decreased significantly from 49.6±33.2 at baseline to 24.8±18.1 at 3 months after the initial treatment. This was a 50.4±21.2% reduction (P = 0.3 × 10–5, paired t test). The mean ISI was also decreased significantly from 55.5±20.4% at baseline to 28.8±16.8% after treatment (P = 0.3 × 10–5, paired t test). This was a reduction of 43.3±28.5%. A significant correlation was found between the CRT and number of microaneurysms at both baseline (r = 0.56; P = 0.004) and after treatment (r = 0.53; P = 0.006). A significant correlation was found between CRT and ISI at baseline (r = –0.39; P = 0.03) but not after treatment (r = –0.06; P = 0.79). Conclusions The reduction in the number of microaneurysms was correlated with reduction in CRT.