Foveal Thickness Fluctuations in Anti-VEGF Treatment for Central Retinal Vein Occlusion.

Purpose: The aim of this study was to examine the effects of foveal thickness (FT) fluctuation (FTF) on 2-year visual and morphological outcomes of eyes with central retinal vein occlusion (CRVO) undergoing anti-VEGF treatment for recurrent macular edema (ME) based on a pro re nata regimen. Design: Retrospective, observational case series. Participants: We analyzed 141 treatment-naive patients (141 eyes) with CRVO-ME at a multicenter retinal practice. Methods: We assessed FT using OCT at each study visit. Patients were divided into groups 0, 1, 2, and 3 according to increasing FTF. Main Outcome Measures: We evaluated the logarithm of the minimal angle of resolution (logMAR) best-corrected visual acuity (BCVA), the length of the foveal ellipsoid zone (EZ) band defect measured using OCT, and the association of FTF with VA and EZ band defect length. Results: The mean baseline logMAR BCVA and FT were 0.65 ± 0.52 (Snellen equivalent range: 20/20-20/2000) and 661.1 ± 257.4 µm, respectively. The mean number of anti-VEGF injections administered was 5.6 ± 3.6. At the final examination, the mean logMAR BCVA and FT values were significantly improved relative to the baseline values (both P < 0.01). During the observation, BCVA longitudinally improved in Groups 0 and 1, remained unchanged in Group 2, and worsened in Group 3. Likewise, the length of the foveal EZ band defect did not increase in Group 0; however, it gradually increased in Groups 1, 2, and 3. Foveal thickness fluctuation was significantly and positively associated with the logMAR BCVA and length of the foveal EZ band defect at the final examination (P < 0.01). The final logMAR BCVA of patients developing neovascular complications was 1.27 ± 0.72 (Snellen equivalent range: 20/50-counting fingers), which was significantly poorer than that of patients without complications (P < 0.001). There was no significant difference in the neovascular complication rate among the FTF groups (P = 0.106, Fisher exact test). Conclusions: In eyes receiving anti-VEGF treatment for CRVO-ME, FTF can longitudinally impair the visual acuity and foveal photoreceptor status during the observation period, thus influencing the final outcomes. However, neovascular complications, which would also lead to a poor visual prognosis, may not be associated with FTF. Financial Disclosures: The authors have no proprietary or commercial interest in any materials discussed in this article.

Customization of a passive surgical support robot to specifications for ophthalmic surgery and preliminary evaluation.

PURPOSE: To customize a passive surgery support robot for ophthalmic surgery and preliminarily evaluate its performance. STUDY DESIGN: Prospective observational study. METHODS: The range of motion of the arm was analyzed during ophthalmic surgery and, based on this analysis, a commercially available passive robot was customized for surgical support for ophthalmic surgery; following which a prototype robot was constructed. To examine the effects on the brachial muscle during surgical operations with and without the prototype robot, surface electromyograms of the biceps and triceps were analyzed after performing continuous curvilinear capsulorrhexis (CCC) and suturing the sclerocorneal wound in a cataract surgery simulation. Six surgeons performed cataract surgery, and the degree of arm stability and muscle fatigue during surgery were evaluated using a visual analog scale. RESULTS: During surgery, the prototype robot enabled fixation of the elbow and wrist at any position within the surgeon's range of motion, expanding the range of motion of the hand and fingers and stabilizing operability. Surface electromyography showed a significant decrease in the mean amplitude value of the biceps brachii during both CCC and suturing (p < 0.0001). No significant difference was observed in the triceps brachii. The arm stability and muscle fatigue were improved by 83.3% on the visual analog scale with the prototype robot compared with that without protpotype robot. CONCLUSION: The use of a passive prototype robot may improve arm stability and reduce muscle fatigue during ophthalmic surgery.

Binocular metamorphopsia in patients with branch retinal vein occlusion: a multi-center study.

PURPOSE: The pathology of branch retinal vein occlusion (BRVO), a retinal circulatory disease, is related to monocular metamorphopsia-related vision impairment of the affected eyes, but the association of binocular metamorphopsia in such patients is unclear. This study aimed to examine the frequency of binocular metamorphopsia and its association with the clinical characteristics of patients with BRVO. METHODS: A total of 87 patients who were treated for BRVO-associated macular edema (ME) were included in this study. At baseline and 1 and 3 months after the initiation of anti-vascular endothelial growth factor (VEGF) treatment, we quantified metamorphopsia in the affected eyes and binocular metamorphopsia using the M-CHARTS® diagnostic tool. RESULTS: At baseline, 53 and 7 patients had metamorphopsia in the affected eyes and binocular metamorphopsia, respectively. Although the visual acuity improved significantly after the initiation of anti-VEGF treatment, the mean M-CHARTS score in the affected eyes did not change from the baseline score. At 3 months, 9 patients showed binocular metamorphopsia; it was significantly associated with metamorphopsia in the affected eyes with a 95% confidence interval of 0.021-0.122 (ß = 0.306, p = 0.006). CONCLUSION: Metamorphopsia in the affected eyes can cause binocular metamorphopsia in patients with BRVO-ME.

Foveal Thickness Fluctuation in Anti-VEGF Treatment for Branch Retinal Vein Occlusion: A Long-term Study.

PURPOSE: Branch retinal vein occlusion (BRVO) causes macular edema (ME), which can be controlled with anti-VEGF treatments. However, these treatments are not curative, necessitating additional anti-VEGF treatments at recurrence. Long-term results, optimal anti-VEGF treatment regimens, and the comprehensive effects of ME recurrence are largely unknown. Thus, we aimed to examine the effects of foveal thickness (FT) fluctuation (FTF) on the visual and morphologic outcomes of anti-VEGF treatments for BRVO-ME administered via a pro re nata regimen. DESIGN: A retrospective, observational case series. SUBJECTS: This study analyzed 309 treatment-naïve patients (309 eyes) with BRVO-ME between 2012 and 2021 at a multicenter retinal practice. METHODS: The FT was assessed using OCT at each study visit. MAIN OUTCOME MEASURES: We evaluated the logarithm of the minimal angle of resolution (logMAR) best corrected visual acuity (BCVA) and the defect length of the foveal ellipsoid zone (EZ) band using OCT. RESULTS: At baseline, the mean logMAR BCVA was 0.30 ± 0.30 and the mean FT was 503 ± 162 µm. The number of anti-VEGF injections for BRVO-ME was 5.8 ± 4.6 during the mean follow-up period (50.6 ± 22.2 months). At the final examination, the mean logMAR BCVA and FT values were significantly improved compared with those at the baseline. Multiple regression analyses showed that age, baseline logMAR BCVA, and FTF were significantly associated with the final logMAR BCVA (ß = 0.20, 0.35, and 0.30, respectively). Foveal thickness fluctuation (divided into groups 0-3 in ascending order of FTF) was significantly associated with logMAR BCVA and the defect length of the foveal EZ band at the final examination. The defect lengths of the foveal EZ band were longitudinally shortened in groups 0 and 1 and were slightly prolonged in groups 2 and 3. The logMAR BCVA showed improvements in groups 0 and 1 and worsened slightly in groups 2 and 3. CONCLUSIONS: Foveal thickness fluctuation was significantly associated with visual acuity and foveal photoreceptor status. Thus, the morphologic and functional prognoses of eyes with BRVO may improve with the identification of the characteristics of eyes with greater FTF and consequently controlling the FTF more strictly.

Retinal Vascular Resistance Significantly Correlates With Visual Acuity After 1 Year of Anti-VEGF Therapy in Central Retinal Vein Occlusion.

Purpose: To investigate whether the resistivity of all retinal vessels, termed total capillary resistance (TCR), after anti-vascular endothelial growth factor (VEGF) treatment was correlated with the outcomes of patients with macular edema secondary to central retinal vein occlusion (CRVO). Methods: In total, 67 patients with nonischemic CRVO were enrolled in this retrospective observational case series. In each patient, we examined visual acuity; central retinal thickness (CRT); mean blur rate (MBR), which represents retinal blood flow velocity; and TCR. MBR and TCR were measured by laser speckle flowgraphy. Results: During the 1-year follow-up period, nine of 67 eyes (13.4%) converted to the ischemic type (converted group), whereas 58 eyes (86.6%) remained unchanged (nonischemic group). Mean CRT significantly decreased in all groups; however, the mean visual acuity significantly improved only in the nonischemic group. Mean MBR significantly increased in the nonischemic group but remained unchanged in the converted group. Mean TCR was significantly reduced in the nonischemic group but remained unchanged in the converted group. Multiple linear regression analysis revealed that MBR and TCR were the independent factors with the strongest and second strongest correlations with visual acuity after treatment, respectively. Conclusions: These findings suggest that measurements of the independent factors MBR and TCR are useful for evaluating anti-VEGF treatments in patients with CRVO. Translational Relevance: Development of clinically relevant technologies.

Review of clinical studies and recommendation for a therapeutic flow chart for diabetic macular edema.

Diabetic macular edema (DME), characterized by exudative fluid accumulation in the macula, is the most common form of sight-threatening retinopathy in patients with diabetes. The management of DME has changed considerably in recent years, especially following the development of intravitreal anti-vascular endothelial growth factor therapy which has emerged as a first-line therapy for center-involved DME. Laser treatment, intravitreal steroid therapy, and vitrectomy are also important treatment options for DME. We believe that it is important to choose the most appropriate treatment option for DME based on the clinical evidences, in addition to the careful consideration of individual patients' general or ocular condition, DME characteristics, patients' motivation, and compliance to the treatment in real-world clinical practice. In this review, we have summarized important clinical evidences for the main treatments for DME, presented an expert review for these evidences, and proposed a recommended therapeutic flow chart for DME. We hope that our review of the clinical evidences and the recommended therapeutic flow chart for DME will contribute to better treatment outcome for DME.

Retinal Microvascular Resistance Estimated from Waveform Analysis Is Significantly Higher With a Threshold Value in Central Retinal Vein Occlusion.

Purpose: Evaluation of blood flow is useful for understanding the severity of central retinal vein occlusion (CRVO). Actual blood flow may be determined by the resistivity of the retinal vein in CRVO. We have previously evaluated mean blur rate (MBR) to reflect total retinal blood flow velocity in CRVO cases using laser speckle flowgraphy (LSFG). This study evaluated retinal total vascular resistance in CRVO cases using the new index of total capillary resistance (TCR) from LSFG. Methods: We measured the TCR of 68 CRVO patients who visited Nagasaki University Hospital between 2009 and 2016 and 42 age-matched controls without systemic disease. We compared TCRs among control eyes, CRVO fellow eyes, and CRVO affected eyes. A CRVO threshold value was then obtained from the receiver operating characteristic curve. Results: MBR was significantly lower for CRVO affected eyes (20.3 ± 8.2) than for control eyes (37.5 ± 8.4; P < 0.01) and CRVO fellow eyes (36.4 ± 10.0; P < 0.01, Dunn's test). TCR was significantly higher for CRVO affected eyes (1.20 ± 0.55) than for control eyes (0.68 ± 0.2; P < 0.01) and CRVO fellow eyes (0.81 ± 0.28; P < 0.01, Dunn's test). The threshold for the presence of CRVO was 0.93 and area under the curve was 0.84. Conclusions: By measuring TCR in addition to MBR, more detailed information regarding CRVO pathology can be obtained. Translational Relevance: Comparison of values before and after treatment may be useful for evaluating the effects of treatment.

Factors associated with extremely poor visual outcomes in patients with central retinal vein occlusion.

Here, we examined prognostic factors for extremely poor visual outcomes in patients with central retinal vein occlusion (CRVO) in actual practices. We included 150 consecutive eyes with treatment-naïve acute CRVO from four different facilities and observed them for over 24 months. Macular edema (ME) was treated with one or three monthly anti-vascular endothelial growth factor injections (1 or 3 + pro re nata). According to the final Snellen visual acuity (VA), we divided the patients into very poor VA (< 20/200) and control (≥ 20/200) groups and examined risk factors for poor final visual outcomes. The baseline Snellen VA was hand motion to 20/13. The mean number of anti-VEGF injections for ME was 5.3 ± 3.7 during the follow-up period. In total, 49 (32.7%) patients exhibited a very poor final VA; this group comprised significantly older patients with a significantly poorer baseline VA (P < 0.01 for both) than the control group. Comorbid internal carotid artery disease and diabetic retinopathy were significantly associated with a poor final VA. In actual clinical practice, visual outcomes may be extremely poor despite ME treatment in certain patients with CRVO, with advanced age, poor baseline VA, and comorbid internal carotid artery disease and diabetic retinopathy being significant risk factors.

One-year results of anti-vascular endothelial growth factor therapy combined with triamcinolone acetonide for macular edema associated with branch retinal vein occlusion.

PURPOSE: To compare anti-vascular endothelial growth factor (anti-VEGF) monotherapy with anti-VEGF therapy combined with sub-Tenon's capsule injections of triamcinolone acetonide (STTA) in patients with macular edema (ME) associated with branch retinal vein occlusion (BRVO). STUDY DESIGN: Retrospective observational study METHODS: This study included 186 eyes: 138 eyes received intravitreal injection of ranibizumab (IVR), and the remaining 48 eyes received IVR combined with STTA therapy. If additional IVR were necessary, STTA were performed simultaneously. RESULTS: Both groups showed a rapid reduction in ME. The changes in logMAR visual acuity (VA) from baseline to 12 months were - 0.26 ± 0.26 in the IVR and - 0.20 ± 0.26 in the IVR with STTA groups (P = 0.209). The changes in mean central foveal thickness from baseline to 12 months were - 226.9 ± 208.2 µm in the IVR and - 236.0 ± 214.0 µm in the IVR with STTA groups (P = 0.798). The required number of IVR was 3.4 ± 1.9 in the IVR group, and 3.4 ± 1.6 in the IVR and STTA group (P = 0.950). There were no significant differences in any parameters between the two groups. CONCLUSION: There were no clear differences between combination therapy of anti-VEGF with STTA and anti-VEGF monotherapy for the treatment of patients with ME associated with BRVO. The number of anti-VEGF injections in patients who received the combination therapy was not reduced as compared with the number of anti-VEGF injections in patients who received the monotherapy.

Hyperreflective Foci in the Outer Retinal Layers as a Predictor of the Functional Efficacy of Ranibizumab for Diabetic Macular Edema.

Anti-VEGF drugs are as the first-line therapies for diabetic macular edema (DME). In this study, we investigated the association between hyperreflective foci in the outer retinal layers and functional efficacy in DME patients who received intravitreal ranibizumab (IVR) injections. We retrospectively reviewed 77 eyes of 71 patients with DME treated with pro re nata IVR injections for at least 12 months. We evaluated how baseline hyperreflective foci in the outer retinal layers on spectral domain optical coherence tomography images were associated with an improvement in logarithm of the minimum angle of resolution visual acuity (logMAR VA) at 12 months. Forty-three eyes with hyperreflective foci in the outer retinal layers had greater VA improvement than 34 eyes without such foci at 12 months. Multivariate analyses demonstrated that both logMAR VA and hyperreflective foci in the outer retinal layers at baseline were associated with VA improvement. Structural analyses revealed that the central subfield thickness was decreased and that the ellipsoid zone of photoreceptors was improved more significantly in eyes with hyperreflective foci in the outer layers than eyes without such lesions. Baseline hyperreflective foci in the outer retinal layers predict the functional efficacy of IVR injections for DME.

Predictor of Early Remission of Diabetic Macular Edema under As-Needed Intravitreal Ranibizumab.

The early remission of diabetic macular edema (DME) often occurs in eyes treated with anti-vascular endothelial growth factor (VEGF) treatment. We retrospectively reviewed and characterized eyes with early remission of DME at six months in 80 eyes under pro re nata (PRN) intravitreal ranibizumab (IVR) injections. The number of eyes without center-involved DME gradually increased and 14 and 20 eyes achieved remission of DME at 3 or 6 months, respectively, under the PRN regimen following three monthly loading doses. In particular, eyes with early remission at 6 months had smaller CSF thickness than those without the remission before and after the treatment except at the 1-month visit (P < 0.05); however, the changes in CSF thickness did not differ between them. VA and its changes were not different between eyes with and without remission. Multivariate analysis revealed that smaller CSF thickness at baseline predicted the early remission of DME under PRN IVR injections (odds ratio, 0.989; 95% confidence interval, 0.982-0.997; P = 0.008). These data elucidate the clinical characteristics of early remission of DME under PRN IVR injections and suggest that smaller CSF thickness at baseline is a novel predictor of early remission under PRN IVR injections for DME.

Branch Retinal Vein Occlusion: Treatment Outcomes According to the Retinal Nonperfusion Area, Clinical Subtype, and Crossing Pattern.

This prospective study examined 58 eyes with branch retinal vein occlusion (BRVO) to investigate the effects of the nonperfusion area (NPA), clinical subtype, and crossing pattern on the 2-year outcomes of ranibizumab therapy for the macular edema (ME). All eyes received three initial monthly injections, followed by additional pro re nata (PRN) injections. The final best corrected visual acuity (BCVA) and ranibizumab injection number were not associated with the macular NPA or total NPA at baseline or month 12, and they showed no significant differences between the clinical subtypes. However, the incidence of neovascular changes was higher in the major BRVO group than in the macular BRVO group (P = 0.030). Twelve and 19 of the 34 eyes with major BRVO exhibited arterial overcrossing and venous overcrossing, respectively. At baseline, the total NPA did not differ according to the crossing pattern, however, the total NPA was significantly larger in the venous overcrossing group at month 12 (P = 0.047). At month 24, the incidence of neovascular changes was higher in the venous overcrossing group (P = 0.030). Following ranibizumab therapy for BRVO-associated ME, the clinical subtype and the arteriovenous crossing pattern may be associated with neovascular changes.

Anti-Hexokinase 1 Antibody as a Novel Serum Biomarker of a Subgroup of Diabetic Macular Edema.

Diabetic retinopathy (DR) induces the breakdown of the blood-retinal barrier and promotes neuroinflammation, although autoimmune responses to sequestered retinal antigens remain poorly understood. In this study, we investigated the autoantibodies for retinal antigens in sera from diabetic macular edema (DME) patients. Screening by immunoblotting demonstrated that IgG from 7 of 10 DME sera samples reacted to an ~102-kDa autoantigen from porcine retinas. Immunoprecipitation with autoantibodies from DME sera and subsequent mass spectrometry enabled us to identify hexokinase 1 as an autoantigen reactive to IgG from DME sera. IgG in 7 of 10 DME sera partially colocalized to hexokinase 1 in the outer plexiform layer of rodent retinas. Quantitative analyses using enzyme-linked immunosorbent assays revealed that the serum titers of this autoantibody were significantly higher in the DME sera than those in the sera from diabetic patients without DME, and 20 (24.1%) of the 83 DME serum samples had higher IgG titers than the cutoff value (mean + 2 standard deviations of the sera from diabetic patients without DR). Multivariate logistic regression analysis confirmed that the higher titer of anti-hexokinase 1 IgG was clinically feasible for the diagnosis of DME. These data identify anti-hexokinase 1 antibody as a serum biomarker of a subset of DME.

Anti-Fumarase Antibody as a Predictor of Functional Efficacy of Anti-VEGF Therapy for Diabetic Macular Edema.

Purpose: To evaluate whether baseline titers of anti-fumarase antibody are associated with visual prognosis after anti-VEGF treatment for diabetic macular edema (DME). Methods: In this retrospective study, we investigated 52 eyes of 52 DME patients who received intravitreal injections of anti-VEGF drugs (ranibizumab or aflibercept) after blood sampling at baseline. Optical coherence tomography (OCT) images were obtained at every monthly visit. The serum titer of anti-fumarase antibody at baseline was measured using ELISA. We evaluated the relationship between the titer of anti-fumarase antibody at baseline and visual acuity (VA) improvement at 12 months. Results: The serum titer of anti-fumarase IgG was related to the logMAR visual acuity (VA; R = 0.329, P = 0.017) and the disrupted ellipsoid zone (EZ; R = 0.364, P = 0.008) at baseline. The titer of this autoantibody was not associated with logMAR VA (R = -0.007, P = 0.980) but was associated with VA improvement (R = 0.465, P < 0.001) at 12 months upon anti-VEGF treatment. The transverse length of the disrupted EZ line was shortened at 12 months (P < 0.001), and restoration of the EZ line was correlated to the autoantibody titer (R = 0.396, P = 0.004) compared with the decrease in central subfield (CSF) thickness. Multivariate analysis showed that pretreatment logMAR VA (ß = 0.296, P = 0.045) and the autoantibody titer (ß = 0.328, P = 0.017) were associated with VA improvement after anti-VEGF treatment. In contrast, the titer was not associated with logMAR VA at 12 months. Conclusions: Anti-fumarase antibody is a novel serum biomarker predicting better functional efficacy of anti-VEGF treatment for DME.

FIXATION STATUS AFTER RESOLUTION OF MACULAR EDEMA ASSOCIATED WITH BRANCH RETINAL VEIN OCCLUSION.

PURPOSE: To evaluate fixation status of eyes with branch retinal vein occlusion (BRVO) and to investigate its association with other clinical parameters. METHODS: This study included 57 consecutive eyes with BRVO after resolution of macular edema. Fixation status was determined by microperimetry. Defect length of the foveal ellipsoid zone band was measured by optical coherence tomography, and retinal perfusion status was assessed by optical coherence tomography angiography. RESULTS: In microperimetry, the mean fixation rate around the gravitational center of all fixation points (defined as the fixation center) was found to be 79.8 ± 18.9%, which was significantly associated with defect length of the foveal ellipsoid zone band (P < 0.001) and distance between the foveal and fixation centers (P = 0.012). The integrity of the ellipsoid zone band at the fixation center was intact in 55 eyes (96.5%). Fixation centers were located within and outside the foveal avascular zone in 33 (57.9%) and 24 (42.1%) eyes, respectively; among the latter eyes, all fixation centers were perfused. Downward deviation of fixation points was rare, despite variations in the occluded area; there was a significant difference in distribution of deviation between eyes with superotemporal and inferotemporal BRVO (P < 0.001). CONCLUSION: In eyes with BRVO, fixation status was strongly associated with visual acuity, morphologic damage, and retinal perfusion status both in the foveal area and at the fixation center after resolution of macular edema. This information regarding fixation status could facilitate vision management in patients with BRVO.

Granular lesions of short-wavelength and near-infrared autofluorescence in diabetic macular oedema.

OBJECTIVES: To document and characterise hyper- and hypo-reflective lesions, which we describe as 'granular' on short-wavelength autofluorescence (SW-AF) and near-infrared (NIR)-AF images in diabetic macular oedema (DMO). METHODS: Consecutive 103 eyes of 78 patients suffering from centre-involving DMO were reviewed retrospectively. Mosaics of hyper- and hypo-fluorescent dots on both SW-AF and NIR-AF signals were delineated and defined as granular lesions in the macula. We evaluated the association of such lesions with the logarithm of the minimum angle of resolution visual acuity (logMAR VA) and spectral-domain optical coherence tomography (SD-OCT) images. RESULTS: Diffuse mosaics of hyper- and hypo-fluorescent dots were delineated in 36 and 45 eyes on SW-AF and NIR-AF images, respectively, and both AF images defined granular lesions in 33 eyes. These lesions were delineated in both the fovea and extrafoveal areas on NIR-AF images but were limited to the parafoveal and perifoveal subfields on SW-AF images. There was a significant difference in logMAR VA between eyes with and without granular lesions (0.358 ± 0.269 vs. 0.185 ± 0.234; P = 0.001). Granular lesions were associated with the mosaic pattern on NIR-AF images (P < 0.001) but not with other parameters on SW-AF and NIR-AF images. The retinal thickness in the central subfield was greater in eyes with granular lesions (538.0 ± 163.6 µm vs. 448.8 ± 120.2 µm; P = 0.003). Granular lesions were associated with ELM disruption and hyper-reflective foci in the outer retinal layers (P = 0.004 and P = 0.037, respectively). CONCLUSIONS: Granular lesions defined on both SW-AF and NIR-AF images were related to retinal oedema with photoreceptor damage and concomitant VA reduction in DMO.

Anti-fumarase antibody promotes the dropout of photoreceptor inner and outer segments in diabetic macular oedema.

AIMS/HYPOTHESIS: In diabetic macular oedema (DMO), blood components passing through the disrupted blood-retinal barrier cause neuroinflammation, but the mechanism by which autoantibodies induce neuroglial dysfunction is unknown. The aim of this study was to identify a novel autoantibody and to evaluate its pathological effects on clinically relevant photoreceptor injuries. METHODS: Biochemical purification and subsequent peptide fingerprinting were applied to identify autoantigens. The titres of autoantibodies in DMO sera were quantified and their associations with clinical variables were evaluated. Two animal models (i.e. passive transfer of autoantibodies and active immunisation) were characterised with respect to autoimmune mechanisms underlying photoreceptor injuries. RESULTS: After screening serum IgG from individuals with DMO, fumarase, a Krebs cycle enzyme expressed in inner segments, was identified as an autoantigen. Serum levels of anti-fumarase IgG in participants with DMO were higher than those in diabetic participants without DMO (p < 0.001) and were related to photoreceptor damage and visual dysfunction. Passively transferred fumarase IgG from DMO sera in concert with complement impaired the function and structure of rodent photoreceptors. This was consistent with complement activation in the damaged photoreceptors of mice immunised with fumarase. Fumarase was recruited to the cell surface by complement and reacted to this autoantibody. Subsequently, combined administration of anti-fumarase antibody and complement elicited mitochondrial disruption and caspase-3 activation. CONCLUSIONS/INTERPRETATION: This study has identified anti-fumarase antibody as a serum biomarker and demonstrates that the generation of this autoantibody might be a pathological mechanism of autoimmune photoreceptor injuries in DMO.

Medium- to long-term survival and functional examination of human iPSC-derived retinas in rat and primate models of retinal degeneration.

BACKGROUND: We have previously reported that xeno-transplanted human ESC-derived retinas are able to mature in the immunodeficient retinal degeneration rodent models, similar to allo-transplantations using mouse iPSC-derived retina. The photoreceptors in the latter developed outer segments and formed synapses with host bipolar cells, driving light responses of host retinal ganglion cells. In view of clinical application, here we further confirmed the competency of human iPSC-derived retina (hiPSC-retina) to mature in the degenerated retinas of rat and monkey models. METHODS: Human iPSC-retinas were transplanted in rhodopsin mutant SD-Foxn1 Tg(S334ter)3LavRrrc nude rats and two monkeys with laser-induced photoreceptor degeneration. Graft maturation was studied by immunohistochemistry and its function was examined by multi-electrode array (MEA) recording in rat retinas and visually-guided saccade (VGS) in a monkey. FINDINGS: A substantial amount of mature photoreceptors in hiPSC-retina graft survived well in the host retinas for at least 5 months (rat) to over 2 years (monkey). In 4 of 7 transplanted rat retinas, RGC light responses were detected at the grafted area. A mild recovery of light perception was also suggested by the VGS performance 1.5 years after transplantation in that monkey. INTERPRETATION: Our results support the competency of hiPSC-derived retinas to be clinically applied for transplantation therapy in retinal degeneration, although the light responses observed in the present models were not conclusively distinguishable from residual functions of degenerating host retinas. The functional analysis may be further elaborated using other models with more advanced retinal degeneration.

Baerveldt or Ahmed glaucoma valve implantation with pars plana tube insertion in Japanese eyes with neovascular glaucoma: 1-year outcomes.

PURPOSE: To describe the 1-year surgical outcomes of both Baerveldt glaucoma implant (BGI) and the Ahmed glaucoma valve (AGV) implant with pars plana tube insertion in Japanese eyes with neovascular glaucoma (NVG). PATIENTS AND METHODS: This was a retrospective study of 21 eyes of 18 patients who had undergone BGI (10 eyes) or AGV (11 eyes) implantation. The 1-year surgical outcomes in the two groups were compared. Surgical success was defined as an intraocular pressure (IOP) of 6-21 mmHg (criterion A) or 6-18 mmHg (criterion B) with >20% reduction regardless of the use of antiglaucoma medications. RESULTS: The mean preoperative IOP was 33.9±6.6 mmHg in the BGI group and 30.9±5.3 mmHg in the AGV group (P=0.31). The IOP at 1-year was lower in the BGI group at 10.3±5.9 mmHg than in the AGV group at 14.8±3.3 mmHg (P=0.044). The mean number of glaucoma medications at 1 year was 1.0±1.3 in the BGI group and 1.4±1.4 in the AGV group (P=0.57). The incidence of postoperative complications during the 1-year follow-up was not statistically different between the two groups; however, one eye in the BGI group lost light perception after additional surgery for Hoffman elbow exposure. The 1-year success rates of the BGI group was 60.0% and that in the AGV group was 90.9% based on criterion A (P=0.095), and 50.0% and 81.8% based on criterion B (P=0.074). CONCLUSIONS: Significant reductions of the IOP and number of glaucoma medications were achieved at 1 year after both types of implants in Japanese eyes with NVG.

Diabetic Nonperfused Areas in Macular and Extramacular Regions on Wide-Field Optical Coherence Tomography Angiography.

Purpose: To investigate the nonperfused areas (NPAs) in each subfield segmented by large arterioles on wide-field swept-source optical coherence tomography angiography (SS-OCTA) images in diabetic retinopathy. Methods: We retrospectively reviewed 101 consecutive eyes of 67 patients with severe nonproliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR), for whom 12 × 12-mm SS-OCTA images centered on the optic disc were acquired. Both eyes were included in 34 patients. NPAs in the whole retinal layers were measured in each subfield segmented by large arterioles encompassing both the superficial and deep layers. We compared the percentage of NPAs between individual subfields, considering the overlapping of the feeding arterioles. Results: Extramacular areas had higher rates of NPAs than macular areas in the inner (0.75-3 mm) and outer (3-5.5 mm) rings (P < 0.001 in both comparisons). The arteriolar arcades contacting the NPAs on the extramacular side were significantly longer than those contacting the NPAs on the macular side (P < 0.001). In particular, the extramacular areas between two arteriolar branches had a higher percentage of NPAs than those between two arterioles. The macular NPAs were greater in eyes with PDR than in those with severe NPDR, whereas there were no differences in the NPAs in the outer ring of extramacular areas. Conclusions: Wide-field OCTA images delineated that large arterioles residing in both the superficial and deep layers appear to be the perfusion boundaries, and the overlapping perfusion mediated via collateral vessels may affect the likelihood of diabetic NPAs in each subfield.