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To examine the 16-week outcomes of switching to brolucizumab in eyes with neovascular age-related macular degeneration (nAMD) refractory to aflibercept.Retrospective observational study.Data of eyes with nAMD who switched to brolucizumab because of resistance to aflibercept were collected. The best-corrected visual acuity (BCVA; in logarithm of the minimum angle of resolution), central retinal thickness (CRT), central choroidal thickness (CCT), and exudative status on optical coherence tomography were analyzed.A total of 48 eyes of 48 patients were reviewed. At 4 to 7 weeks after switching, BCVA changed from 0.26 ± 0.19 to 0.25 ± 0.21 (not significant; P = 0.95), but CRT significantly decreased from 298.9 ± 108.4 µm to 241.9 ± 92.5 µm (P 0.001) and CCT from 182.6 ± 89.3 µm to 169.7 ± 82.6 µm (P 0.001). Of the 23 eyes refractory to monthly aflibercept injections, 12 (52.2%) achieved a dry macula, and 8 (34.8%) reduced exudative changes at 1 month. At 16 weeks, 31 eyes (64.6%) achieved the treatment interval ≥ 8 weeks. Two patients (4.2%) dropped out, 7 eyes (14.6%) developed intraocular inflammation (IOI), and 8 eyes (16.7%) switched back to aflibercept because of the failure to extend the treatment interval ≥ 8 weeks.Switching to brolucizumab in eyes refractory to aflibercept conferred favorable outcomes in controlling exudative changes. However, IOI and the regulation of the treatment interval to at least 8 weeks during the maintenance phase disrupted the continuation of brolucizumab treatment.

ObjectiveTo establish a metagenomic profiling method using long-read sequencing for clinical diagnosis of ocular inflammation and detect the etiologic virus of herpetic uveitis.DesignA retrospective, cross-sectional study.ParticipantsThe participants were 44 uveitis patients with a suspected infectious etiology and 22 controls with cataract.MethodsThe anterior aqueous humor (10-20 µl) was subjected to DNA purification, followed by whole genome amplification. The Nanopore MinION™ using the Flongle Flow Cell was used to perform rapid long-read sequencing and the phylogenetic composition of the microorganisms in the specimen was evaluated.Main Outcomes and MeasuresThe detection of the DNA sequence reads of the etiologic virus of herpetic uveitis in the generated FASTQ files from nanopore sequencing and the evaluation of the limits of detection (LOD) of metagenomic analysis compared to multiplex polymerase chain reaction (mPCR) testing for etiologic virus detection of herpetic uveitis.ResultsThe detection rate of nanopore metagenomic analysis was approximately 59.0% as a result of validation against 22 mPCR-positive cases. The LOD was between 103.6and 106copies of virus DNA. The undetectable cases tended to have significantly lower copy numbers by mPCR, suggesting the lower metagenomic analysis sensitivity compared to mPCR. The nine pathogenic microorganisms evaluated by mPCR were also not detected by nanopore in all mPCR-negative cases and controls. The minimum time to obtain analysis results using this method was approximately 190 minutes.Conclusions and RelevanceOur established sequencing protocol from the anterior aqueous humor detected the DNA fragments of etiologic viruses in patients with herpes virus uveitis. Conversely, nanopore metagenomic results contained considerable noise and were found to be less sensitive compared to the conventional mPCR tests for ocular infections.

ImportanceTorque teno virus positivity in the aqueous humor of uveitis patients could be associated with systemic immunodeficiency.ObjectiveWe explored the correlation between the presence of torque teno virus in the aqueous humor of uveitis patients and clinical information, including immunodeficiency history.DesignThis was a retrospective, cross-sectional study.SettingAll participants were recruited at Nagoya University Hospital, Tokyo Medical University Hospital, or Yokkaichi Municipal Hospital between April 2017 and March 2022.ParticipantsThe participants were 58 uveitis patients with a suspected infectious etiology and 24 controls with cataract or age-related macular degeneration.Main Outcomes and MeasuresWe used quantitative polymerase chain reaction to test all subjects for torque teno virus and multiplex polymerase chain reaction to test uveitis subjects for common ocular pathogens. When possible, both serum and aqueous humor samples were tested. Ocular torque teno virus positivity was compared with age, sex, and a history of systemic immunodeficiency with logistic analysis.ResultsTorque teno virus positivity was found in 7 of 31 cases (23%) with herpetic uveitis, 3 of 27 cases (11%) with nonherpetic uveitis, and 0 of 24 controls (0%). Among patients with herpes infection, positivity for torque teno virus was found in 3 of 7 patients (43%) with cytomegalovirus retinitis, 1 of 12 (8%) patients with iridocyclitis, 1 of 7 patients (14%) with acute retinal necrosis, and 2 of 4 patients (50%) with Epstein–Barr virus–related uveitis. Cytomegalovirus retinitis patients showed a significantly higher rate of ocular torque teno virus infection than controls (P= .008). Serum analysis revealed torque teno virus positivity in 9 of 10 cases (90%) with uveitis and in all 8 controls (100%). Age- and gender-adjusted logistic analysis revealed a correlation between ocular torque teno virus positivity and systemic immunodeficiency (P= .01), but no correlations between ocular torque teno virus and age, gender, or viral pathogenic type.Conclusion and RelevanceThis study found that positivity for ocular torque teno virus was correlated with a clinical history of systemic immunodeficiency. This suggests that ocular torque teno virus is a biomarker of systemic immunity.Key pointsQuestionWhat is the correlation between torque teno virus (TTV) in the aqueous humor of patients with uveitis and the clinical characteristics of these patients?FindingsIn this retrospective, cross-sectional study that included 82 patients, ocular TTV was found to be present in 39% of uveitis patients with underlying immunodeficiency and 8% of patients without underlying immunodeficiency; these findings showed statistical significance.MeaningIn patients with uveitis, the presence of ocular TTV may represent systemic immunodeficiency.

PURPOSE To determine the characteristics of eyes diagnosed with Best vitelliform macular dystrophy (BVMD) and autosomal recessive bestrophinopathy (ARB) complicated by choroidal neovascularization (CNV). METHODS This was a retrospective, multicenter observational case series. Fourteen genetically confirmed BVMD patients and 9 ARB patients who had been examined in 2 ophthalmological institutions in Japan were studied. The findings in a series of ophthalmic examinations including B-scan optical coherence tomography (OCT) and OCT angiography (OCTA) were reviewed. RESULTS CNV was identified in 5 eyes (17.9%) of BVMD patients and in 2 eyes (11.1%) of ARB patients. Three of 5 eyes with BVMD were classified as being at the vitelliruptive stage and 2 eyes at the atrophic stage. The CNV in 2 BVMD eyes were diagnosed as exudative because of acute visual acuity reduction, retinal hemorrhage, and intraretinal fluid, while the CNV in 3 BVMD eyes and 2 ARB eyes were diagnosed as non-exudative. The visual acuity of the two eyes with exudative CNV did not improve despite anti-VEGF treatments. None of the eyes with non-exudative CNV had a reduction of their visual acuity for at least 4 years. All of the CNV were located within hyperreflective materials which were detected in 16 eyes (57.1%) of the BVMD eyes and in 7 eyes (38.9%) of the ARB eyes. CONCLUSIONS CNV is a relatively common complication in BEST1-related retinopathy in Asian population as well. The prognosis of eyes with exudative CNV is not always good, and OCTA can detect CNV in eyes possessing hyperreflective materials.

To assess the macular function by focal macular electroretinography and static perimetry in eyes with retinitis pigmentosa.Eighty-eight eyes of 88 retinitis pigmentosa patients were analyzed. The relationships between the focal macular electroretinography components and the mean deviations (MDs) of the Humphrey Field Analyzer 10-2 were determined. Spectral-domain optical coherence tomography was used to determine the integrity of the ellipsoid zone (EZ) and the interdigitation zone.Forward-backward stepwise regression analyses showed that the amplitudes (r = 0.45, P0.01) and implicit times (r = -0.29, P0.01) of the b-waves were significantly correlated with the MDs. Some of the eyes had reduced b-wave amplitudes (1.0 µ V) and disrupted interdigitation zone, despite having a better MD (≥ -10.0 dB) and intact EZ. Subgroup analyses of eyes with better MD (≥ -10.0 dB) showed that the EZ width was correlated with the MDs but not with the b-wave amplitude. The thickness of the EZ-retinal pigment epithelium as an alternative indicator of interdigitation zone was correlated with the b-wave amplitude (r = 0.32, P = 0.04) but not with the MDs (r = -0.10, P = 0.53).The fact that the focal macular electroretinography amplitudes are reduced before the shortening of the EZ in the early stage of retinitis pigmentosa indicates that the focal macular electroretinography amplitudes are an earlier indicator of macular dysfunction than the Humphrey Field Analyzer 10-2 findings.

To investigate the regional differences in the genes and variants causing retinitis pigmentosa (RP) in Japan Retrospective multicenter study In total, 1204 probands of each pedigree clinically diagnosed with nonsyndromic RP were enrolled from 5 Japanese facilities. The regions were divided into the Tohoku region, the Kanto and Chubu regions, and the Kyushu region according to the location of the hospitals where the participants were enrolled. We compared the proportions of the causative genes and the distributions of the pathogenic variants among these 3 regions. The proportions of genetically solved cases were 29.4% in the Tohoku region (n = 500), 29.6% in the Kanto and Chubu regions (n = 196), and 29.7% in the Kyushu region (n = 508), which did not differ statistically (P = .99). No significant regional differences in the proportions of each causative gene in genetically solved patients were observed after correction by multiple testing. Among the 29 pathogenic variants detected in all 3 regions, only p.(Pro347Leu) in RHO was an autosomal dominant variant; the remaining 28 variants were found in autosomal recessive genes. Conversely, 78.6% (275/350) of the pathogenic variants were detected only in a single region, and 6 pathogenic variants (p.[Asn3062fs] in EYS, p.[Ala315fs] in EYS, p.[Arg872fs] in RP1, p.[Ala126Val] in RDH12, p.[Arg41Trp] in CRX, and p.[Gly381fs] in PRPF31) were frequently found in ≥ 4 patients in the single region. We observed region-specific pathogenic variants in the Japanese population. Further investigations of causative genes in multiple regions in Japan will contribute to the expansion of the catalog of genetic variants causing RP.

Background/aimsThe accuracy of pattern deviation (PD) in estimating the damage to the glaucomatous visual field (VF) in the central 10° in eyes with glaucoma and cataract is unclear.MethodsThis retrospective study includes 63 eyes of 52 glaucoma patients who successfully underwent cataract surgery or cataract surgery plus iStent implantation. Using the Humphrey Field Analyser 10–2 test, VF was measured within 6 months preoperatively and postoperatively (VFpreand VFpost, respectively). The mean total deviation values in VFpost(mTDpost) indicates glaucomatous damage without cataract and the difference between this value and mean PD values in VFpre(mPDpre) was evaluated (εmPD). The effect of cataract was then evaluated as the difference between mTDpostand mTDpre(ΔmTD), while the effects of mTDpostand ΔmTD on εmPD were also assessed. In addition, based on preoperative visual acuity (VApre) and VFpre, the optimal model for predicting mTDpostwas identified. The error of this method (εOptimalModel) was estimated as the difference against mTDpost, which was compared with εmPD.ResultsCompared with mTDpre, there was a significant improvement in mTDpost(p=0.028). A significant difference was observed between mPDpreand mTDpost(ppostor ΔmTD (pConclusionsThis study warns clinicians that PD of the central 10° VF might underestimate the glaucomatous VF damage with the progression of glaucoma and overestimate it as a cataract progresses.

To investigate the genetic architecture of age-related macular degeneration (AMD) in a Japanese population.Genome-wide association study (GWAS).Three thousand seven hundred seventy-two patients with AMD and 16 770 control participants from the Japanese population were enrolled in the association analyses.We conducted a meta-analysis of 2 independent GWASs that included a total of 2663 patients with AMD and 9471 control participants using the imputation reference panel for genotype imputation specified for the Japanese population (n = 3541). A replication study was performed using an independent set of 1109 patients with AMD and 7299 control participants.Associations of genetic variants with AMD.A meta-analysis of the 2 GWASs identified 6 loci significantly associated with AMD (P5.0 × 10Our findings imply shared genetic components conferring the risk of both AMD and CSC.Proprietary or commercial disclosure may be found after the references.

Calpain activation induces retinal ganglion cell (RGC) death, while calpain inhibition suppresses RGC death, in animal studies. However, the role of calpain in human retinal disease is unclear. This study investigated a new strategy to study the role of calpain based on real-time imaging. We synthesized a novel fluorescent probe for calpain, acetyl-l-leucyl-l-methionine-hydroxymethyl rhodamine green (Ac-LM-HMRG) and used it for real-time imaging of calpain activation. The toxicity of Ac-LM-HMRG was evaluated with a lactate dehydrogenase cytotoxicity assay, retinal sections, and electroretinograms. Here, we performed real-time imaging of calpain activation in a rat model. First, we administered N-methyl-d-aspartate (NMDA) to induce retinal injury. Twenty minutes later, we administered an intravitreal injection of Ac-LM-HMRG. Real-time imaging was then completed with a noninvasive confocal scanning laser ophthalmoscope. The inhibitory effect of SNJ-1945 against calpain activation was also examined with the same real-time imaging method. Ac-LM-HMRG had no toxic effects. The number of Ac-LM-HMRG-positive cells in real-time imaging significantly increased after NMDA injury, and SNJ-1945 significantly lowered the number of Ac-LM-HMRG-positive cells. Real-time imaging with Ac-LM-HMRG was able to quickly quantify the NMDA-induced activation of calpain and the inhibitory effect of SNJ-1945. This technique, used as a companion diagnostic system, may aid research into the development of new neuroprotective therapies.

Commercially available eye-drops scarcely penetrate the eye because of the cornea, which is located at the surface of the eye and function of barrier to keep out foreign matter. To enhance the pene...

The success of surgical treatment for idiopathic epiretinal membrane (ERM) is measured by postoperative best-corrected visual acuity (BCVA), metamorphopsia, and foveal retinal sensitivity (RS).This study searched for predictive biomarkers of surgical success by determining the association between foveal RS and various aspects of vessel density (VD) in the fovea of patients with ERM. The study examined 25 eyes of 25 patients with ERM who underwent 27-gauge microincision vitrectomy surgery (MIVS). RS was measured with microperimetry (MP-3; NIDEK) at four central points in the fovea with an interpoint distance of 2°. VD was measured with SD-OCT (RS 3000; NIDEK) within the 1-mm2 square defined by the 4 RS points at various depths, including the superficial and deep retinal capillary plexus (SCP and DCP, respectively). Though VD did not change throughout the follow-up period, BCVA and RS significantly improved 1 and 3 months after surgery, respectively (both P

To screen for the 328 bp Alu insertion (c.4052_4053ins328, p.Tyr1352Alafs) in RP1 in a group of retinitis pigmentosa (RP) patients who had been previously identified with a heterozygous deleterious mutation in the gene. Prospective, clinical and experimental study. The Alu insertion in RP1 was screened with an optimized PCR-based method in 26 RP patients with a heterozygous deleterious mutation (nonsense or frameshift) in RP1 that had been identified in a preceding genetic study. The genetic location of the previously identified mutation and its inheritance pattern were assessed. Out of 26 RP patients with a heterozygous deleterious mutation in RP1, 5 (19.2%) were found to carry an additional heterozygous Alu insertion, presumably resulting in a compound heterozygous state. This included 3 patients who had been previously diagnosed as autosomal dominant RP based on genetic findings. They were re-diagnosed as having an autosomal recessive disease following our new findings. In all patients identified with the Alu insertion, the other mutations found in the preceding study were outside the defined region in exon 4 (encoding amino acids 677 to 917) in which truncation mutations have been suggested to exert a dominant negative effect. The founder Alu insertion in RP1 is an important cause of autosomal recessive RP in Japanese patients and can be missed in standard targeted resequencing. Screening optimized for this mutation is warranted, particularly in patients with a heterozygous deleterious mutation outside the defined region in exon 4 of RP1.

To assess the effects of half-dose photodynamic therapy on subretinal fluid and macular neovascularization (MNV) using optical coherence tomography angiography in patients with chronic central serous chorioretinopathy.Clinical information on 168 patients (168 eyes) with chronic central serous chorioretinopathy obtained before and 6 months after treatment with half-dose photodynamic therapy was retrospectively analyzed. Patients were categorized into a success (145 eyes) or failure (23 eyes) group based on the absence or presence of subretinal fluid, respectively, and clinical data were compared between them. Macular neovascularization was studied in 147 cases with available optical coherence tomography angiography images. P0.05 indicated statistical significance.The success group showed a younger patient age, better posttreatment best-corrected visual acuity, and thicker pretreatment central choroidal thickness (all, P0.047) than did the failure group. Regarding MNV analysis, nine, eight, and 130 eyes had definite, possible, and no MNV, respectively, at baseline; among them, 100.0%, 75.0%, and 2.3%, respectively, had MNV at 6 months posttreatment. Patients with definite MNV at baseline were less likely to show successful subretinal fluid resolution.Although half-dose photodynamic therapy is generally effective for the treatment of chronic central serous chorioretinopathy, coexisting MNV may compromise the outcome; thus, optical coherence tomography angiography-based assessment of chronic central serous chorioretinopathy is important.

The purpose of this study was to determine the ocular, sex- and age-specific, anthropometric, and hematologic factors that affect the implicit times and amplitudes of the flicker ERGs recorded with the RETeval system from individuals 40- to 89-years-of-age. Flicker ERGs were recorded with the RETeval system from 330 individuals who had normal fundus and OCT images. Univariate and multivariate regression analyses were performed to identify factors associated with the implicit times and amplitudes of the RETeval flicker ERGs. Univariate regression analyses showed significant correlations between the implicit times and the BCVA, age, axial length, blood sugar level, and BUN in both eyes. Multivariate regression analyses identified age and axial length as two independent factors that were significantly correlated with the implicit times of the RETeval flicker ERGs. Univariate regression analyses also showed significant correlations between the amplitudes and age, platelet count, HDL level, and creatinine level in both eyes. However, smoking habits, body mass index, and blood pressure were not correlated with the RETeval flicker ERGs. We conclude that age and some ophthalmologic and hematologic findings except for anthropometric findings were suggested to significantly affect the measurements of the RETeval flicker ERGs.

Despite the successful identification of causative genes and genetic variants of retinitis pigmentosa (RP), many patients have not been molecularly diagnosed. Our recent study using targeted short-read sequencing showed that the proportion of carriers of pathogenic variants inEYS, the cause of autosomal recessive RP, was unexpectedly high in Japanese patients with unsolved RP. This result suggested that causative genetic variants, which are difficult to detect by short-read sequencing, exist in such patients. Using long-read sequencing technology (Oxford Nanopore), we analysed the whole genomes of 15 patients with RP with one heterozygous pathogenic variant inEYSdetected in our previous study along with structural variants (SVs) inEYSand another 88 RP-associated genes. Two large exon-overlapping deletions involving six exons were identified inEYSin two patients with unsolved RP. An analysis of an independent patient set (n=1189) suggested that these two deletions are not founder mutations. Our results suggest that searching for SVs by long-read sequencing in genetically unsolved cases benefits the molecular diagnosis of RP.

The purpose of this study is to investigate the protective effect of dimethyl fumarate (DMF), the methyl-ester of fumaric acid, against blue-light (BL) exposure in retinal pigment epithelial (RPE) cells. ARPE-19 cells, a human RPE cell line, were cultured with DMF followed by exposure to BL. Reactive oxygen species (ROS) generation, cell viability, and cell death rate were determined. Real-time polymerase chain reaction and Western blotting were performed to determine the change in nuclear factor (erythroid-derived)-like 2 (NRF2) expression. Twenty-seven inflammatory cytokines in the supernatant of culture medium were measured. BL exposure induced ROS generation in ARPE-19 cells, which DMF alleviated in a concentration-dependent manner. BL exposure increased the ARPE-19 cell death rate, which DMF alleviated. BL exposure induced ARPE-19 cell apoptosis, again alleviated by DMF. Under BL exposure, DMF increased the NRF2 mRNA level and promoted NRF2 expression in the nucleus. BL also strongly increased interleukin (IL)-1β and fibroblast growth factor (FGF) expression. BL strongly induced RPE cell damage with apoptotic change while DMF mainly reduced inflammation in BL-induced RPE damage, resulting in blockade of cell death. DMF has a protective effect in RPE cells against BL exposure via activation of the NRF2 pathway.

Purpose To present phenotypic features of 22 patients with S-antigen (SAG) mutations. Design Retrospective cohort study. Participants Twenty-one Japanese patients from 16 families with a homozygous c.924delA mutation and 1 patient with a homozygous c.636delT mutation in the SAG gene. Methods Clinical records on symptoms; best-corrected visual acuity; and Goldmann perimetry, fundus photography, fundus autofluorescence (FAF), OCT, and electroretinography results were reviewed. Main Outcome Measures Best-corrected visual acuity, Goldmann perimetry results, imaging findings, and electroretinography results. Results Ten patients had Oguchi disease and 12 had retinitis pigmentosa (RP) with mean follow-up periods of 13.8 and 10.2 years, respectively. Retinitis pigmentosa patients were older (mean age, 56.0 years) than those with Oguchi disease (mean age, 22.1 years; P Conclusions Retinitis pigmentosa with SAG mutations often shows a characteristic golden sheen surrounding posterior pigmentary retinal degeneration. Oguchi disease can show progressive degeneration in adulthood, rarely resulting in RP.

BackgroundThe genetic profile of retinitis pigmentosa (RP) in East Asian populations has not been well characterised. Therefore, we conducted a large-scale sequencing study to investigate the genes and variants causing RP in a Japanese population.MethodsA total of 1209 Japanese patients diagnosed with typical RP were enrolled. We performed deep resequencing of 83 known causative genes of RP using next-generation sequencing. We defined pathogenic variants as those that were putatively deleterious or registered as pathogenic in the Human Gene Mutation Database or ClinVar database and had a minor allele frequency in any ethnic population of ≤0.5% for recessive genes or ≤0.01% for dominant genes as determined using population-based databases.ResultsWe successfully sequenced 1204 patients with RP and determined 200 pathogenic variants in 38 genes as the cause of RP in 356 patients (29.6%). Variants in six genes (EYS, USH2A, RP1L1, RHO, RP1 and RPGR) caused RP in 65.4% (233/356) of those patients. Among autosomal recessive genes, two known founder variants in EYS [p.(Ser1653fs) and p.(Tyr2935*)] and four East Asian-specific variants [p.(Gly2752Arg) in USH2A, p.(Arg658*) in RP1L1, p.(Gly2186Glu) in EYS and p.(Ile535Asn) in PDE6B] and p.(Cys934Trp) in USH2A were found in ≥10 patients. Among autosomal dominant genes, four pathogenic variants [p.(Pro347Leu) in RHO, p.(Arg872fs) in RP1, p.(Arg41Trp) in CRX and p.(Gly381fs) in PRPF31] were found in ≥4 patients, while these variants were unreported or extremely rare in both East Asian and non-East Asian population-based databases.ConclusionsEast Asian-specific variants in causative genes were the major causes of RP in the Japanese population.

Full Eulerian methods constitute a family of numerical techniques used to simulate fluid-structure interaction problems. In a full Eulerian method, the velocity gradient tensor is used to compute deformation of solid. However, it is difficult to compute solid stress accurately near the interface, where the velocity between fluid and solid changes drastically. In this work, we propose an Eulerian formulation for fluid-structure interaction problems using Lagrangian marker particles with the Reference Map Technique to compute the deformation of solid accurately near material interfaces without using the gradient of the velocity. We illustrate and validate the proposed method through the presentation of various benchmark problems.

To determine the characteristics of eyes diagnosed with Best vitelliform macular dystrophy (BVMD) and autosomal recessive bestrophinopathy (ARB) complicated by choroidal neovascularization (CNV).This was a retrospective, multicenter observational case series. Fourteen genetically confirmed BVMD patients and 9 ARB patients who had been examined in 2 ophthalmological institutions in Japan were studied. The findings in a series of ophthalmic examinations including B-scan optical coherence tomography (OCT) and OCT angiography (OCTA) were reviewed.CNV was identified in 5 eyes (17.9%) of BVMD patients and in 2 eyes (11.1%) of ARB patients. Three of 5 eyes with BVMD were classified as being at the vitelliruptive stage and 2 eyes at the atrophic stage. The CNV in 2 BVMD eyes were diagnosed as exudative because of acute visual acuity reduction, retinal hemorrhage, and intraretinal fluid, while the CNV in 3 BVMD eyes and 2 ARB eyes were diagnosed as non-exudative. The visual acuity of the two eyes with exudative CNV did not improve despite anti-VEGF treatments. None of the eyes with non-exudative CNV had a reduction of their visual acuity for at least 4 years. All of the CNV were located within hyperreflective materials which were detected in 16 eyes (57.1%) of the BVMD eyes and in 7 eyes (38.9%) of the ARB eyes.CNV is a relatively common complication in BEST1-related retinopathy in Asian population as well. The prognosis of eyes with exudative CNV is not always good, and OCTA can detect CNV in eyes possessing hyperreflective materials.

To investigate whether previously reported seasonal variation and winter-dominant prevalence of acute massive submacular hemorrhages (SMHs) caused by age-related macular degeneration (AMD) disappeared, and those caused by retinal microaneurysms (RMAs) emerged.The medical charts of 95 patients (95 eyes) with SMH caused by AMD and 76 patients (76 eyes) with SMH caused by RMAs in 2012-2019 were retrospectively reviewed. For each subject, the month of onset, the mean ambient temperature of that month were recorded.The monthly numbers of cases of SMHs caused by AMD from January to December were 6, 8, 4, 9, 7, 10, 9, 11, 7, 11, 3, and 10. No significant seasonal variation in the monthly incidence was identified (Roger's R = 1.89, p = 0.39). The monthly numbers of SMHs caused by RMAs from January to December were 3, 11, 11, 8, 7, 8, 5, 5, 2, 4, 7, and 5. There was significant seasonal variation in the monthly incidence (Roger's R = 7.67, p = 0.02). There was no significant correlation between the monthly incidence of SMHs caused by RMAs and mean ambient temperature.Our previous study conducted for cases obtained in 1998-2005 showed seasonal cyclic trend in the number of SMHs caused by AMD, with the peak in winter. However, that significant seasonal variation disappeared in 2012-2019 in the present study. Common usage of OCT devices and anti-VEGF drugs might be the reason for the lack of seasonal variation in the cases of SMH caused by AMD.

Background: Glaucoma is a leading cause of blindness worldwide and is characterized by degeneration associated with the death of retinal ganglion cells (RGCs). It is believed that glaucoma is a group of heterogeneous diseases with multifactorial pathomechanisms. Here, we investigate whether anti-inflammation treatment with an ER stress blockade can selectively promote neuroprotection against NMDA injury in the RGCs.Methods: Retinal excitotoxicity was induced with an intravitreal NMDA injection. Microglial activation and neuroinflammation were evaluated with Iba1 immunostaining and cytokine gene expression. A stable HT22 cell line transfected with an NF-kB reporter was used to assess NF-kB activity after hesperidin treatment. CHOP-deficient mice were used as a model of ER stress blockade. Retinal cell death was evaluated with a TUNEL assay.Results: In the NMDA injury group, Iba1-positive microglia increased 6 h after NMDA injection. Also at 6 h, pro-inflammatory cytokines and chemokines increased, including TNFα, IL-1b, IL-6 and MCP-1. In addition, the MCP-1 promoter-driven EGFP signal, which we previously identified as a stress signal in injured RGCs, also increased; hesperidin treatment suppressed this inflammatory response and reduced stressed RGCs. In CHOP-deficient mice that received an NMDA injection, the gene expression of pro-inflammatory cytokines, chemokines, markers of active microglia, and inflammatory regulators was greater than in WT mice. In WT mice, hesperidin treatment partially prevented retinal cell death after NMDA injury; this neuroprotective effect was enhanced in CHOP-deficient mice.Conclusions: These findings demonstrate that ER stress blockade is not enough by itself to prevent RGC loss due to neuroinflammation in the retina, but it has a synergistic neuroprotective effect after NMDA injury when combined with an anti-inflammatory treatment based on hesperidin.

To investigate the regional differences in the genes and variants causing retinitis pigmentosa (RP) in Japan STUDY DESIGN: Retrospective multicenter study METHODS: In total, 1204 probands of each pedigree clinically diagnosed with nonsyndromic RP were enrolled from 5 Japanese facilities. The regions were divided into the Tohoku region, the Kanto and Chubu regions, and the Kyushu region according to the location of the hospitals where the participants were enrolled. We compared the proportions of the causative genes and the distributions of the pathogenic variants among these 3 regions.The proportions of genetically solved cases were 29.4% in the Tohoku region (n = 500), 29.6% in the Kanto and Chubu regions (n = 196), and 29.7% in the Kyushu region (n = 508), which did not differ statistically (P = .99). No significant regional differences in the proportions of each causative gene in genetically solved patients were observed after correction by multiple testing. Among the 29 pathogenic variants detected in all 3 regions, only p.(Pro347Leu) in RHO was an autosomal dominant variant; the remaining 28 variants were found in autosomal recessive genes. Conversely, 78.6% (275/350) of the pathogenic variants were detected only in a single region, and 6 pathogenic variants (p.[Asn3062fs] in EYS, p.[Ala315fs] in EYS, p.[Arg872fs] in RP1, p.[Ala126Val] in RDH12, p.[Arg41Trp] in CRX, and p.[Gly381fs] in PRPF31) were frequently found in ≥ 4 patients in the single region.We observed region-specific pathogenic variants in the Japanese population. Further investigations of causative genes in multiple regions in Japan will contribute to the expansion of the catalog of genetic variants causing RP.

PURPOSE To evaluate retinal vessel density and retinal sensitivity (RS) after macular hole surgery with the superior inverted internal limiting membrane flap technique. METHODS Retrospective, observational case series. Twenty-one patients with idiopathic macular hole underwent 27-gauge vitrectomy with the superior inverted internal limiting membrane flap technique and triamcinolone acetonide. Measurements included RS, which was measured with microperimetry, as well as retinal vessel density in the superficial capillary plexus (SCP) and deep capillary plexus (DCP), which was measured with optical coherence tomography angiography. All parameters were evaluated in the superior and inferior sectors of the macula preoperatively and 1, 3, and 6 months postoperatively. RESULTS Six months postoperatively, retinal thickness in the inferior sector was unchanged, but retinal thickness in the superior sector decreased significantly (P < 0.01). SCP vessel density in both sectors was unchanged at all postoperative time points. DCP vessel density in both sectors increased very significantly at 3 months (P < 0.01) and returned to baseline at 6 months. RS in the inferior sector increased by 47% 3 months postoperatively and by 61% 6 months postoperatively (P < 0.05 and P < 0.001, respectively), but RS in the superior sector increased only at 6 months postoperatively and only by 22% (P < 0.05). CONCLUSION Lower recovery of RS in the superior sector suggests that internal limiting membrane peeling might affect the postoperative visual function.

This study searched for early predictive vascular biomarkers for visual outcomes in eyes with macular edema caused by branch retinal vein occlusion (BRVOME). Twenty-four eyes of 24 subjects with BRVOME were treated with the intravitreal injection of ranibizumab (IVR) for at least 6 months. We measured mean blur rate (MBR) in the optic nerve head (ONH) and vessel density (VD) in the macula with laser speckle flowgraphy and optical coherence tomography angiography, respectively. Six-month post-IVR best-corrected visual acuity (BCVA) was correlated positively with age, pre-IVR BCVA, 1-month post-IVR BCVA, 3-month post-IVR BCVA and pre-IVR systolic blood pressure (P

Cone photoreceptors mediate daylight vision and are the primary cells responsible for vision in humans. Cone dysfunction leads to poor quality daylight vision because rod photoreceptors become saturated and non-functional at high light levels. Here we demonstrate that in mice lacking cone function, AAV-mediated over-expression of Rgs9-anchor protein (R9AP), a critical component of the GTPase complex that mediates the deactivation of the phototransduction cascade, results in desensitization of rod function and a “photopic shift” of the rod-driven electroretinogram. This treatment enables rods to respond to brighter light (up to ∼2.0 log) with increased visually-evoked cortical responses to high intensity stimulation. These results suggest that AAV-mediated transfer of R9ap into rods might be used to improve daylight vision in humans visually handicapped by cone dysfunction.

Purpose To screen for anti-recoverin antibodies in elderly patients with retinitis pigmentosa (RP) with or without cancer and cross-sectionally characterize the seropositive patients clinically. Methods Serum from 75 RP patients who had been tested for mutations in a panel of 83 RP genes and 73 normal controls, all aged 50-80 years, were screened for anti-recoverin antibodies by Western blot using recombinant recoverin, retinal lysate from a marmoset and commercial anti-recoverin antibodies as a control. Results Three RP patients with typical pigmentary degeneration of the 75 (4.0%) were seropositive for anti-recoverin antibody. Pathogenic mutations were identified in two seropositive RP patients. All three patients had visual impairment since childhood and were diagnosed as RP by the age of 30. The severity of the retinopathy varied greatly among these three patients, ranging in visual acuity from light perception OU to 20/30 OU. Retinitis pigmentosa (RP) patients with a history of cancer were more likely to have anti-recoverin antibodies (3/14; 21.4%) than those without (0/61; 0%; p = 0.005, Fischer exact test). All 73 healthy controls with no history of cancer were also seronegative. Conclusion Our results show that serum anti-recoverin antibodies can be detected in typical RP patients with identified pathogenic mutations and that a history of cancer may increase the risk of developing anti-recoverin antibodies.

In patients born blind with retinal dystrophies, understanding the critical periods of cortical plasticity is important for successful visual restoration. In this study, we sought to model childhood blindness and investigate the plasticity of visual pathways. To this end, we generated double-mutant (Pde6c(cpfl1/cpfl1)Gnat1(IRD2/IRD2)) mice with absent rod and cone photoreceptor function, and we evaluated their response for restoring rod (GNAT1) function through gene therapy. Despite the limited effectiveness of gene therapy in restoring visual acuity in patients with retinal dystrophy, visual acuity was, unexpectedly, successfully restored in the mice at the level of the primary visual cortex in this study. This success in visual restoration, defined by changes in the quantified optokinetic response and pattern visually evoked potential, was achieved regardless of the age at treatment (up to 16 months). In the contralateral visual cortex, cortical plasticity, tagged with light-triggered transcription of Arc, was also restored after the treatment in blind mice carrying an Arc promoter-driven reporter gene, dVenus. Our results demonstrate the remarkable plasticity of visual circuits for one of the two photoreceptor mechanisms in older as well as younger mice with congenital blindness due to retinal dystrophies.

In glaucoma, although axonal injury drives retinal ganglion cell (RGC) death, little is known about the underlying pathomechanisms. To provide new mechanistic insights and identify new biomarkers, we combined latest non-targeting metabolomics analyses to profile altered metabolites in the mouse whole retina 2, 4, and 7 days after optic nerve crush (NC). Ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry and liquid chromatography Fourier transform mass spectrometry covering wide spectrum of metabolites in combination highlighted 30 metabolites that changed its concentration after NC. The analysis displayed similar changes for purine nucleotide and glutathione as reported previously in another animal model of axonal injury and detected multiple metabolites that increased after the injury. After studying the specificity of the identified metabolites to RGCs in histological sections using imaging mass spectrometry, two metabolites, i.e., L-acetylcarnitine and phosphatidylcholine were increased not only preceding the peak of RGC death in the whole retina but also at the RGC layer (2.3-fold and 1.2-fold, respectively). These phospholipids propose novel mechanisms of RGC death and may serve as early biomarkers of axonal injury. The combinatory metabolomics analyses promise to illuminate pathomechanisms, reveal biomarkers, and allow the discovery of new therapeutic targets of glaucoma.

The purpose of the study is to investigate the correlation between intraocular anti-retinal antibodies and clinical measurements in patients with rhegmatogenous retinal detachment (RRD) and proliferative vitreoretinopathy (PVR).Aqueous humor and vitreous samples were collected from patients with RRD, PVR, and from control subjects with macular hole. The levels of total protein (TP), IgG, and anti-retinal antibodies were determined with a bicinchoninic acid assay, enzyme-linked immunosorbent assay, and dot blot, respectively. Correlations between these measurements were assessed using Pearson's correlation test. Analysis of variance followed by a post-hoc test or the Student t-test was used to compare differences between groups.The levels of anti-retinal antibodies and IgG were correlated with each other (P 0.010). The IgG concentration was higher in patients with PVR than in controls in both the aqueous humor (P 0.001) and the vitreous (P 0.001), but not in patients with RRD. Conversely, TP levels and anti-retinal antibodies in both ocular fluids from RRD and PVR patients did not significantly differ from the controls. In a subgroup analysis, vitreal anti-retinal antibody levels were correlated with average macular thickness in the re-attached macula following surgery for macula-off RRD/PVR (P = 0.012). Furthermore, patients with post-operative cystoid macular edema had a higher level of vitreal anti-retinal antibodies than those without (P = 0.009).Intravitreal anti-retinal antibodies were increased in the eyes with maculopathy after surgical intervention for RRD/PVR.

Primary open-angle glaucoma (POAG) is the leading cause of irreversible blindness worldwide for which 15 disease-associated loci had been discovered. Among them, only 5 loci have been associated with POAG in Asians. We carried out a genome-wide association study and a replication study that included a total of 7378 POAG cases and 36 385 controls from a Japanese population. After combining the genome-wide association study and the two replication sets, we identified 11 POAG-associated loci, including 4 known (CDKN2B-AS1, ABCA1, SIX6 and AFAP1) and 7 novel loci (FNDC3B, ANKRD55-MAP3K1, LMX1B, LHPP, HMGA2, MEIS2 and LOXL1) at a genome-wide significance level (P

Glaucoma is a leading cause of blindness worldwide and is characterized by degeneration associated with the death of retinal ganglion cells (RGCs). It is believed that glaucoma is a group of heterogeneous diseases with multifactorial pathomechanisms. Here, we investigate whether anti-inflammation treatment with an ER stress blockade can selectively promote neuroprotection against NMDA injury in the RGCs. Retinal excitotoxicity was induced with an intravitreal NMDA injection. Microglial activation and neuroinflammation were evaluated with Iba1 immunostaining and cytokine gene expression. A stable HT22 cell line transfected with an NF-kB reporter was used to assess NF-kB activity after hesperidin treatment. CHOP-deficient mice were used as a model of ER stress blockade. Retinal cell death was evaluated with a TUNEL assay. As results, in the NMDA injury group, Iba1-positive microglia increased 6 h after NMDA injection. Also at 6 h, pro-inflammatory cytokines and chemokine increased, including TNFα, IL-1b, IL-6 and MCP-1. In addition, the MCP-1 promoter-driven EGFP signal, which we previously identified as a stress signal in injured RGCs, also increased; hesperidin treatment suppressed this inflammatory response and reduced stressed RGCs. In CHOP-deficient mice that received an NMDA injection, the gene expression of pro-inflammatory cytokines, chemokines, markers of active microglia, and inflammatory regulators was greater than in WT mice. In WT mice, hesperidin treatment partially prevented retinal cell death after NMDA injury; this neuroprotective effect was enhanced in CHOP-deficient mice. These findings demonstrate that ER stress blockade is not enough by itself to prevent RGC loss due to neuroinflammation in the retina, but it has a synergistic neuroprotective effect after NMDA injury when combined with an anti-inflammatory treatment based on hesperidin.