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Purpose: To investigate the association of systemic oxidative stress level with myopic choroidal neovascularization (mCNV) and its clinical outcomes. Design: Retrospective case-control study. Participants: This retrospective study included 52 eyes of 52 healthy participants (mean age: 62.5 years), 30 eyes of 30 patients (mean age: 59.6 years) with high myopia (HM) but without mCNV, and 23 eyes of 23 patients (mean age: 61.8 years) with HM and mCNV who received intravitreal anti-VEGF antibody injections (IVIs) using a pro re nata regimen during the 6-month follow-up after the first IVI. Methods: Clinical findings, including oxidative stress parameters, such as diacron reactive oxygen metabolites (dROMs), biological antioxidant potential (BAP), and the BAP/dROM ratio (B/d ratio), were analyzed. Main Outcome Measures: Clinical features and oxidative stress parameters. Results: Both BAP and the B/d ratio were significantly lower in the HM/mCNV group than in the HM/no mCNV group (P = 0.002 and P = 0.012, respectively) and than in the control group (P = 0.001 and P = 0.026, respectively). In a multiple logistic regression analysis, axial length (odds ratio 1.878, P = 0.042) and the B/d ratio (odds ratio 0.470, P = 0.026) were significantly associated with mCNV. Dividing the patients into high and low B/d ratio groups (with a cutoff of 5.2) showed that subfoveal choroidal thickness (SFCT) was lower (P = 0.002) and the number of IVI treatments was higher (P = 0.029) in the low B/d ratio group than in the high B/d ratio group. In multiple regression analyses, only the B/d ratio was significantly associated with SFCT (β = 0.684, P = 0.006). Conclusions: The oxidative stress level in eyes with HM differed according to mCNV, SFCT, and the number of IVI treatments. Measuring oxidative stress parameters might be useful in eyes with HM both for assessing the risk of developing mCNV and determining disease activity. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Abstract We aimed to investigate the impact of glutathione trisulfide (GSSSG) on lipopolysaccharide (LPS)-induced inflammation in retinal glia. Inflammatory responses in mouse-derived glial cells and Wistar rat retinas were stimulated with administration of LPS. Cell survival and proinflammatory cytokine production were examined using the Calcein-AM assay, and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Retinal microglia were visualized with immunohistochemistry for Iba1. Administration of LPS (10 µg/mL) or GSSSG (less than 100 µM) did not affect survival of cultured primary Müller cells and established microglial cells (BV-2). RT-qPCR and ELISA indicated that GSSSG inhibited LPS-induced gene upregulation and protein secretion of proinflammatory cytokines in these glial cells and rat retinas. GSSSG inhibited LPS-induced activation of TGF-β-activated kinase 1 (TAK1), which is an upstream kinase of NF-κB, in BV-2 cells. Finally, in vivo experiments indicated that intravitreal administration of GSSSG but not its relative glutathione disulfide (GSSG) inhibited LPS (500 ng)-induced accumulation of Iba1-immunopositive microglia in rat retinas. Taken together, GSSSG has the potential to prevent pathogenesis of inflammation-associated ocular diseases by inhibiting proinflammatory cytokine expression in retinal glial cells.

Abstract Background The dysfunction of optic nerve head (ONH) hemodynamics has been suggested to be involved in the pathogenesis of normal-tension glaucoma (NTG). The aim of this study was to compare vasoreactivity in the ONH, nailfold, and facial skin in response to cold-water provocation in NTG patients and healthy controls. Methods We performed cold-water provocation in 14 eyes of 14 NTG patients and 15 eyes of 15 age-matched control subjects. Laser speckle flowgraphy-derived tissue-area mean blur rate (MT), skin blood flowmetry-derived pulse wave amplitude (PA), nailfold capillaroscopy-derived nailfold capillary diameter, and other clinical parameters were recorded at baseline and 4 and 6 min after the cold stimulus. We compared changes (as percentages) in these variables in the NTG and control subjects with a linear mixed-effects model and evaluated correlations between these changes with Spearman’s rank correlation coefficient. Results The interaction term between the NTG group (reference, control group) and the 4-min protocol step (reference, baseline) significantly affected the changes in MT, nailfold capillary diameter and PA (β = -9.51%, P = 0.017, β = -20.32%, P = 0.002; β = + 18.06%, P = 0.017, respectively). The change in MT was positively correlated with the change in nailfold capillary diameter, and negatively correlated with the change in PA (r = 0.39, P = 0.036; r = -0.40, P = 0.031, respectively). Conclusion NTG patients showed abnormal vasoconstriction in the ONH and nailfold and vasodilation in the facial skin in response to cold-water provocation.

Purpose: To investigate clinical factors associated with foveal avascular zone (FAZ) parameters obtained using OCT angiography (OCTA) with assistance from a previously developed artificial intelligence (AI) platform in eyes with open-angle glaucoma (OAG). Design: Retrospective longitudinal. Participants: This study followed up 885 eyes of 558 patients with OAG for ≥ 2 years; all eyes underwent ≥ 5 Humphrey visual-field (VF) tests and had 3.0 × 3.0 mm macular OCTA scans available. Methods: Average total deviation (TD) in the superior, superocentral, inferocentral, and inferior sectors of the Humphrey 24-2 program was calculated. We collected 3.0 × 3.0 mm macular OCTA images from each patient and used a previously developed AI platform with these images to obtain FAZ parameters, including FAZ area, FAZ circularity index (CI), and FAZ perimeter. Multivariable linear mixed-effects models were used to analyze the relationship between FAZ parameters, TD or TD slope in each quadrant, and systemic factors, adjusting for potential confounding factors, including axial length. Main Outcome Measures: Ophthalmic and systemic variables, FAZ parameters, and TD or TD slope in each quadrant. Results: The multivariable model showed that FAZ parameters were correlated with both TD and TD slope in the inferocentral quadrant (β = −0.244 - 0.168, P < 0.001). Both upper-half and lower-half FAZ parameters were better associated with TD-inferocentral and TD-inferocentral slope than TD-superocentral or TD-superocentral slope in terms of β size and statistical significance, indicating that there was no evident vertical anatomical correspondence between TD in the central quadrant and FAZ parameters. Foveal avascular zone area enlargement was associated with female gender (β = 0.242, P = 0.003). Loss of FAZ circularity was associated with both aging and comorbid sleep apnea syndrome (SAS) (yes: 1, no: 0) (β = −0.188, P < 0.001; β = −0.261, P = 0.031, respectively). Foveal avascular zone perimeter elongation was associated with aging and female gender (β = 0.084, P = 0.040; β = 0.168, P = 0.042, respectively). Conclusions: Artificial intelligence-assisted OCTA-measured FAZ enlargement and irregular shape might be good markers of ocular hypoperfusion and associated inferocentral VF defect progression in eyes with OAG. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Neurosteroids are rapidly emerging as important new therapies in neuropsychiatry, with one such agent, brexanolone, already approved for treatment of postpartum depression, and others on the horizon. These steroids have unique properties, including neuroprotective effects that could benefit a wide range of brain illnesses including depression, anxiety, epilepsy, and neurodegeneration. Over the past 25 years, our group has developed ex vivo rodent models to examine factors contributing to several forms of neurodegeneration in the retina. In the course of this work, we have developed a model of acute closed angle glaucoma that involves incubation of ex vivo retinas under hyperbaric conditions and results in neuronal and axonal changes that mimic glaucoma. We have used this model to determine neuroprotective mechanisms that could have therapeutic implications. In particular, we have focused on the role of both endogenous and exogenous neurosteroids in modulating the effects of acute high pressure. Endogenous allopregnanolone, a major stress-activated neurosteroid in the brain and retina, helps to prevent severe pressure-induced retinal excitotoxicity but is unable to protect against degenerative changes in ganglion cells and their axons under hyperbaric conditions. However, exogenous allopregnanolone, at a pharmacological concentration, completely preserves retinal structure and does so by combined effects on gamma-aminobutyric acid type A receptors and stimulation of the cellular process of macroautophagy. Surprisingly, the enantiomer of allopregnanolone, which is inactive at gamma-aminobutyric acid type A receptors, is equally retinoprotective and acts primarily via autophagy. Both enantiomers are also equally effective in preserving retinal structure and function in an in vivo glaucoma model. These studies in the retina have important implications for the ongoing development of allopregnanolone and other neurosteroids as therapeutics for neuropsychiatric illnesses.

Abstract Anti-oxidative intraocular irrigating solutions (IISs) based on reactive persulfides, such as oxidized glutathione disulfide (GSSG), are commonly used worldwide. However, even with GSSG-based IISs, it has been shown that oxidative stress can occur during surgery, posing a risk to intraocular tissues. This study compared two IISs: one containing GSSG and one containing an oxidized glutathione trisulfide (GSSSG). Experimental in vivo irrigation with the IISs in rabbits showed that there was less leakage into the anterior chamber of rabbit serum albumin during perfusion with a 300-μM GSSSG IIS than with a 300-μM GSSG IIS. Experimental in vivo cataract surgery in rabbits showed that aqueous flare was suppressed 3 days after surgery with a 600-μM GSSSG IIS, but not with a 300-μM GSSSG or 300-μM GSSG IIS. Furthermore, an in vitro experiment, without any live tissue, showed that reactive oxygen species were suppressed more strongly with a 600-μM GSSSG IIS than with a 300-μM GSSG IIS. Thus, this study found that novel IISs based on GSSSG had anti-inflammatory and anti-oxidative effects during and after intraocular surgery and may decrease the rate of complications after surgery.

Glaucoma is a multifactorial neurodegenerative disease characterized by a progressive optic neuropathy resulting in visual field defects. Elevated intraocular pressure (IOP) is the greatest risk factor for the development of glaucoma, and IOP reduction therapy is the only treatment currently available. However, there are many cases in which retinal degeneration progresses despite sufficient control of IOP. Therefore, it is important to elucidate the pathophysiology of glaucoma that is resistant to current IOP lowering therapies. Experiments using animal glaucoma models show the relationships between microglial neuroinflammatory responses and damage of retinal ganglion cells (RGCs). Inhibition of neuroinflammatory pathways associated with microglial activation appears to be neuroprotective, indicating that microglia may be an important therapeutic target for RGC protection. In this review, we will focus on microglia-induced neuroinflammation in the pathogenesis of glaucoma to offer new insights into the possibility of developing novel neuroprotective therapies targeting microglia.

Purpose: Vogt-Koyanagi-Harada (VKH) disease after vaccination for coronavirus disease 2019 (COVID-19) is rare, and the prognosis for this condition and its effect on ocular blood flow remains unclear. The purpose of this paper is to present the first case of de novo VKH disease after the second vaccination for COVID-19 with an mRNA vaccine that was successfully treated with systemic steroid therapy and monitored with laser speckle flowgraphy (LSFG). Observations: A 30s-year-old Japanese woman reported bilateral decreased visual function 2 weeks after receiving a second dose of the BNT162b2 mRNA vaccine. Best-corrected visual acuity was 20/50 OD and 20/70 OS. Optical coherence tomography revealed bilateral serous retinal detachment over the swollen choroidal layer. LFSG showed decreased blood flow in the peripapillary region of both eyes. This case was diagnosed as complete VKH syndrome, and the patient underwent systemic steroid therapy. After treatment, the retinal detachment disappeared, choroidal thickness decreased, and ocular blood flow increased. Three months later, visual acuity recovered to 20/20 in both eyes. Conclusions: Caution should be exercised in cases with visual symptoms after COVID-19 vaccination, even after more than one dose and more than one week after vaccination. LSFG may be a useful way to measure the ocular blood flow response to treatment and determine the prognosis for VKH disease after COVID-19 vaccination.

Koji Nishiguchi et al. identify three genetic variants within the EYS gene that are associated with retinitis pigmentosa using a genome-wide association study. They demonstrate that one of these variants (G843E) causes retinal dysfunction in zebrafish, suggesting a causal role for EYS in retinitis pigmentosa.

Abstract Background Group B streptococcus (GBS), a gram-positive coccus that occasionally causes neonatal sepsis or invasive infection in the elderly, has been considered a rare cause of endogenous bacterial endophthalmitis (EBE). However, the number of invasive GBS infections is increasing, particularly in elderly patients with underlying conditions such as diabetes mellitus (DM), cardiovascular disease and cancer. We report 6 cases of EBE caused by GBS and review the literature. Methods Retrospective case series and literature review. Results In the current case series, 6 eyes of 6 patients developed EBE caused by GBS. The average age was 73.5 years. The focus of infection included the urinary tract, cellulitis, arthritis, peritonitis, catheter-associated infection and endocarditis. Four patients had DM. While all 6 strains were sensitive to β-lactams (penicillins and cephems), 4 strains were resistant to levofloxacin (no data for 1 isolate). Each case was treated with the systemic antibiotic to which the individual strain was sensitive. All cases showed poor visual acuity at presentation (decimal visual acuity: less than 0.03). Vitrectomy with intravitreal antibiotics injection was performed in 4 cases. Visual acuity recovered in 4 cases and did not recover in 2 cases, even after vitrectomy. The literature review of 53 eyes of 41 patients revealed that 60% of eyes finally lost all vision, and death occurred in 2 cases. Initial visual acuity of less than counting fingers was associated with a final outcome of lost vision. Of 41 patients, 13 (32%) had DM as an underlying medical condition. The most common extra-ocular infection focus was endocarditis (37%). Conclusions DM is common in patients with EBE caused by GBS. While the 4 cases in the current report had a relatively good visual acuity outcome, despite poor initial visual acuity, the literature review indicated that EBE caused by GBS is generally a severe condition with a poor prognosis. The current study also indicates the importance of considering the possibility of endocarditis on encountering EBE caused by GBS.

In an ex vivo rat ocular hypertension (OHT) model, the neurosteroid allopregnanolone (AlloP) exerts neuroprotective effects via enhancement of both GABAA receptors and autophagy. We now examine whether its enantiomer (ent-AlloP), which is largely inactive at GABA receptors, offers similar neuroprotection in ex vivo and in vivo rat OHT models. Ex vivo rat retinal preparations were incubated in a hyperbaric condition (10 and 75 mmHg) for 24 h. An in vivo ocular hypertension (OHT) model was induced by intracameral injection of polystyrene microbeads. We examined pharmacological effects of AlloP, ent-AlloP, picrotoxin (a GABAA receptor antagonist), and 3-MA (an autophagy inhibitor) histologically and biochemically. We found that both AlloP and ent-AlloP have marked neuroprotective effects in the retina, but effects of the unnatural enantiomer are independent of GABAA receptors. Electron microscopic analyses show that pressure elevation significantly increased autophagosomes (APs) in the nerve fiber layer and addition of AlloP also increased APs and degenerative autophagic vacuoles (AVds). ent-AlloP markedly increased APs and AVds compared to AlloP. Examination of LC3B-II and SQSTM1 protein levels using immunoblotting revealed that AlloP increased LC3B-II, and ent-AlloP further enhanced LC3B-II and suppressed SQSTM1, indicating that autophagy is a major mechanism underlying neuroprotection by ent-AlloP. In an rat in vivo OHT model, single intravitreal ent-AlloP injection prevented apoptotic cell death of retinal ganglion cells similar to AlloP. However, even in this model, ent-AlloP was more effective in activating autophagy than AlloP. We conclude that ent-AlloP may be a prototype of potential therapeutic for treatment of glaucoma as an autophagy enhancer without affecting GABA receptors.

Purpose: Polypoidal choroidal vasculopathy (PCV) is a subtype of age-related macular degeneration that is seen frequently in Asians. Nevertheless, it is rare for this condition to be combined with retinitis pigmentosa (RP). The purpose of this paper is to present findings from this rare combination in a Japanese patient, and to describe its successful treatment with intravitreal aflibercept (IVA). Observations: The patient was a 71-year-old Japanese woman with RP (diagnosed at the age of 30) and PCV. She noticed a decrease in vision in her right eye 6 months previously. Decimal best-corrected visual acuity (BCVA) was 0.05 in her right eye. Optical coherence tomography and indocyanine green angiography (IA) revealed serous retinal detachment (SRD) and PCV in her right eye. The SRD was initially resolved after 3 monthly treatments with IVA, but recurrences began 5 months later, requiring four more treatments with IVA, performed about every 4 months within the next 12 months, for successful resolution. There were no recurrences of PCV in 7 more months of follow-up, as confirmed with IA at the final appointment. Final decimal BCVA in the right eye improved to 0.15. Furthermore, macular retinal sensitivity, measured with microperimetry, increased after the treatment, and RP-related visual field narrowing, determined by Goldmann perimetry, did not progress throughout follow up of 26 months. Conclusion: More than 2 years of follow up showed that IVA may be effective for treating PCV, even in RP patients, and can increase central visual function without causing progression of RP-related visual field narrowing.

Laser retinal photocoagulation is the gold standard treatment for diabetic retinopathy. We describe 3 cases in which bullous exudative retinal detachment (ERD) developed after pattern scan laser photocoagulation (PASCAL) in diabetic retinopathy. ERD spontaneously resolved in all 3 cases with various visual courses. This case series highlights 2 key points: first, ERD can occur regardless of gender, age, glycemic control, or vitreous status and despite a moderate number of laser shots, even with PASCAL; second, ERD in nonvitrectomized eyes may cause irreversible visual loss, even if the ERD resolves within 1 month.

Abstract Systemic oxidative stress is thought to be an important factor in the pathogenesis of glaucoma. In particular, low systemic antioxidative capacity, which normally counters oxidative stress, may contribute to glaucoma. Thus, we investigated the association between biological antioxidant potential (BAP), a biomarker of systemic antioxidative capacity, and glaucoma severity in patients with open-angle glaucoma (OAG). This study included 480 eyes of 240 patients with OAG and 66 healthy control eyes. We measured the BAP serum level with a free radical analyzer and compared it with a weighted estimate of the number of retinal ganglion cells (wrgc), derived from circumpapillary retinal nerve fiber layer thickness and visual field mean deviation. We found that wrgc was uncorrelated with BAP in the overall, male, and female OAG patients, but was correlated in young (aged ≤ 65 years) male OAG patients (better eye: r = 0.33, P = 0.02; worse eye: r = 0.27, P = 0.047). Furthermore, a mixed-effects regression analysis revealed that BAP was an independent contributing factor to wrgc in young male OAG patients (P = 0.02). Thus, systemic antioxidant capacity was associated with glaucomatous damage in relatively young male patients, suggesting that anti-oxidant therapy might be more effective in these patients.

PurposeTo investigate the clinical significance of color visual acuity (CVA) in preperimetric glaucoma (PPG) and open-angle glaucoma (OAG).MethodsA total of 123 eyes of 73 subjects (22 normal eyes, 14 PPG eyes, and 87 OAG eyes; mean age: 44.9 ± 10.1 years, age range: 21-64 years) were enrolled. CVA was tested for red, green-yellow, blue-green and blue-purple with a newly developed test.ResultsThere was no statistical difference in clinical background factors, including age, sex, intraocular pressure, or spherical equivalent between the three groups. Red VA and blue-green VA were significantly worse in the OAG eyes than in the normal eyes (P = 0.008 and P = 0.015, respectively), although green-yellow VA and blue-purple VA were not significantly worse. Furthermore, red VA and blue-green VA were significantly correlated with MD in a group of eyes with either PPG or OAG (r = -0.23, P = 0.023; r = -0.25, P = 0.012, respectively), but green-yellow VA and blue-purple VA were not.ConclusionRed VA and blue-green VA were detectably worse in eyes with OAG, in close association with the degree of functional loss. This suggests that measuring CVA with the new color test described here may be a promising supplement to existing methods of detecting glaucoma and evaluating its severity.

Purpose. To compare clinical findings, including ocular blood flow and intima-media thickness (IMT) of the carotid artery, in mild nonproliferative diabetic retinopathy (NPDR) and no diabetic retinopathy (NDR) patients, and to determine risk factors contributing to mild NPDR. Methods. In 129 subjects (129 eyes) with type-2 diabetes patients and mild NPDR or NDR, standard statistical techniques were used to determine associations between clinical findings, including diabetes duration, blood levels of creatinine and hemoglobin A1c (HbA1c), central macular thickness (CMT; measured with optical coherence tomography), mean blur rate (MBR; measured with laser speckle flowgraphy), and ultrasound-measured carotid IMT. Results. Diabetes duration, IMT, and CMT were significantly higher in the mild NPDR patients than the NDR patients (P=0.004, P=0.004, and P=0.003, respectively), while conversely, MBR in the overall optic nerve head (MBR-A) was lower in the mild NPDR patients. Furthermore, a logistic regression analysis showed that diabetes duration (OR, 1.11; P=0.006), diastolic blood pressure (OR, 0.93; P=0.025), heart rate (OR, 1.07; P=0.004), IMT (OR, 8.65; P=0.005), and CMT (OR, 1.03; P=0.007) were independent contributing factors to mild NPDR. Spearman’s rank correlation test also showed that IMT was negatively correlated with MBR-A (P=0.011). Conclusions. Increased IMT showed a close association with ocular ischemia in patients with type-2 diabetes and contributed to the presence of mild NPDR. These findings suggest that IMT may be an early biomarker of mild NPDR.

Purpose. To evaluate the efficacy of epiretinal membrane (ERM) surgery for patients with ERM and glaucoma. Methods. We reviewed the medical records of 20 consecutive ERM patients with glaucoma, who underwent 27-gauge microincision vitrectomy surgery (27GMIVS) with internal limiting membrane (ILM) peeling. The preoperative and 6-month postoperative visual field was tested with the Humphrey Field Analyzer (HFA) 24-2 program. Changes in threshold sensitivity in the HFA test points were analyzed point-by-point, with points classified into groups based on sensitivity as abnormal (less than 5th percentile in pattern deviation) or normal (all other points) and based on location as central (12 central points) or peripheral (all other points) with a linear mixed-effects model. Results. Visual acuity and mean deviation improved postoperatively (P

Objective: We combined heads-up 3-dimensional (3D) 27-gauge microincision vitrectomy surgery (27GMIVS) with a very low-intensity illumination system. Methods: This study was based on a retrospective, interventional case series of 6 eyes of 6 patients with macular disease. All patients underwent heads-up 3D 27GMIVS and the power of the intraocular illuminator was set to its minimum level, 1% (approximately 0.1 lm), throughout the surgery. Results: We found that the procedure was easy when the heads-up 3D system was used, but not through the eyepiece of a microscope. All surgeries were successfully finished without any complications. Postoperative visual acuity was restored or maintained in all eyes during the follow-up period. Conclusion: Heads-up, 3D system-assisted 27GMIVS with minimal illumination enabled excellent intraoperative visualization of retinal tissues, caused minimal phototoxicity to the macular retinal cells, and might therefore represent the next step in the development of an ideal, minimally invasive method of treating macular disease.

PURPOSE:The internal limiting membrane (ILM) is a normal part of the retina, and the outcomes of ILM removal have not been fully investigated. ILM flap inversion is a recently developed technique that increases the success rate of macular hole (MH) surgery. Thus, we compared the anatomical closure rate and visual outcome in patients undergoing microincision vitrectomy surgery (MIVS) with ILM flap inversion or conventional ILM peeling for the treatment of MH. METHODS:The medical records of 90 eyes with MH were reviewed retrospectively. The patients were classified into two groups based on MIVS procedure (group 1: ILM flap inversion, 46 eyes; group 2: ILM peeling, 44 eyes). RESULTS:Preoperative characteristics were similar in the two groups, and there were no significant differences in 1 month- or 6 month-postoperative VA between the groups (P = 0.25 and P = 0.42, respectively). However, the surgical success rate was significantly higher in group 1 than group 2 (P = 0.04; 46/46: 100% and 41/44: 93%, respectively). Multiple regression analysis revealed that axial length and MH diameter were independent factors predicting 6-month postoperative BCVA in group 2 (P = 0.001 and P = 0.03, respectively), and that MH diameter was an independent factor predicting 6-month postoperative VA in group 1 (P = 0.03). Logistic regression analysis revealed that axial length (OR = 2.11; P = 0.02; area under the curve: 0.94; cut off score: 28.4 mm) was an independent factor indicating surgical failure in group 2. CONCLUSION:Our results suggest that MIVS with ILM flap inversion might be best suited to treat MH, particularly in patients with high myopia.

Purpose. Nerve conduction velocity (NCV) is an indicator of neuronal damage in the distal segment of the peripheral nerves. Here, we determined the association between NCV and other systemic and ocular clinical findings, in type 2 diabetes patients with early diabetic retinopathy (DR). Methods. This study included 42 eyes of 42 type 2 diabetes patients (median age: 54 years) with no DR or with mild nonproliferative DR. Standard statistical techniques were used to determine associations between clinical findings. Results. Sural sensory conduction velocity (SCV) and tibial motor conduction velocity (MCV) were significantly lower in mild nonproliferative DR patients than patients with no DR (P=0.008 and P=0.01, resp.). Furthermore, logistic regression analyses revealed that sural SCV and tibial MCV were independent factors contributing to the presence of mild nonproliferative DR (OR 0.83, P=0.012 and OR 0.69 P=0.02, resp.). Tibial MCV was correlated with choroidal thickness (CT) (P=0.01), and a multiple regression analysis revealed that age, tibial MCV, and carotid intima-media thickness were independent associating factors with CT (P=0.035, P=0.015, and P=0.008, resp.). Conclusions. Our findings suggest that reduced NCV may be closely associated with early DR in type 2 diabetes patients. Thus, reduced nerve conduction is a potential early biomarker of DR.

Objective: To report intraoperative optical coherence tomography (iOCT)-assisted 27-gauge microincision vitrectomy surgery (MIVS) in eyes with vitreoretinal disease. Methods: A retrospective, interventional case series performed at a single center, including 6 eyes with retinal disease that underwent iOCT-assisted 27-gauge MIVS. Results: The advantages of iOCT were most notable when it was used to evaluate, in real time, different macular areas: the pre-macula, in vitreomacular traction or epiretinal membrane; the intra-macula, in macular edema or macular hole; and the sub-macula, in macular detachment. Real-time imaging and the minimization of shadows cast on the underlying tissues by the 27-gauge instrumentation made it possible to quickly select the best procedure at each critical juncture of the surgery. No patients experienced any complications. Conclusion: Real-time iOCT imaging during 27-gauge MIVS provided excellent intraoperative visualization of retinal tissues without causing significant obstructions to the surgeon. The positive feedback from the system allowed the surgeon to better judge the necessity of additional surgical procedures.

There is no consensus on the diagnosis or treatment policy for Preperimetric Glaucoma (PPG) because the pathogenesis of PPG is not clear at this time. Preperimetric Glaucoma Prospective Observational Study (PPGPS) is a first multicenter, prospective, observational study to clarify the pathogenesis of PPG. This article indicates study design, patient baseline characteristics, and analysis focused on optic nerve head (ONH) blood flow in PPG, as well as the intraocular pressure (IOP) -lowering effect and ONH blood flow-improving effects of Tafluprost.In this study, 122 eyes from 122 subjects (mean age: 53.1 ± 14.3) newly diagnosed as PPG were enrolled. The circumpapillary retinal nerve fiber layer thickness (cpRNFLT) was evaluated with optical coherence tomography (OCT). The ONH blood flow was measured with laser speckle flowgraphy. The therapeutic effect of Tafluprost was evaluated at Month 0 (ONH blood flow-improving effect) and Month 4 (IOP-lowering effect).The untreated IOP, cpRNFLT, and baseline Mean deviation (MD) value was 16.4 ± 2.5 mmHg, 80.4 ± 8.2 μm, and -0.48 ± 1.29 dB, respectively. In the site-specific visual field evaluation using the sector map, there was no appreciable site-specific visual field defect in the eye with PPG. The inferior region of cpRNFLT in 4-quadrant OCT sector analysis and 6 o'clock region in 12-o'clock OCT sector analysis was the highest rate of abnormality in PPG eyes. Topical administration of Tafluprost significantly reduced IOP from 16.4 ± 2.5 mmHg at baseline to 14.5 ± 2.3 mmHg at Month 4 (P < 0.001, paired t-test). In the linear regression analysis, there was a significant relationship between the increase of ONH blood flow and baseline value.PPGPS is a first prospective study focusing on the pathology of PPG. This study is expected to elucidate the pathology of PPG, with evidence useful for determining a treatment strategy for PPG.

PURPOSE:Innovative laser speckle flowgraphy (LSFG) enables noninvasive evaluation of retinal microcirculation and the usefulness has been reported in the field of ophthalmology. LSFG has allowed us to measure the real time changes of retinal blood flow without pupillary dilatations and contrast media. Herein, we investigated the change of retinal blood flow in normal pregnant women during gestation using LSFG. METHODS:A prospective cohort study was conducted in 53 pregnant women who visited our institution between January, 2013 and July, 2014. Finally, a total of 41 participants without any obstetric complications were available for evaluation. Retinal blood flow was measured with LSFG in a total of 4 times during pregnancy (T1. 11-13 weeks, T2. 19-21 weeks, T3. 28-30 weeks, T4. 34-36 weeks) and mean blur rate (MBR), blowout score (BOS), flow acceleration index (FAI), and resistive index (RI) are analyzed from these measurements. Relations between LSFG parameters and mean arterial blood pressure (MAP) are determined throughout pregnancy. RESULTS:MBR showed no significant changes throughout pregnancy. BOS showed a tendency to increase in the 3rd trimester. FAI values showed a slight increase from the 1st to 2nd trimester while a significant decrease was noted in the 3rd trimester. RI exhibited no changes between the 1st and 2nd trimesters, values decreased significantly after the 3rd trimester. MAP was positively correlated with BOS, and negatively correlated with FAI and RI. CONCLUSION:The present study clearly demonstrated that profiles of LSFG parameters demonstrated a decrease of resistance in retinal blood vessels. These changes in indices provide a highly sensitive reflection of physiological changes in vascular resistance due to pregnancy. Thus, LSFG may be useful, as a non-invasive, diagnostic tool to detect pregnancy related disorders such as preeclampsia.

PURPOSE:To investigate the relationship between various characteristics of a normal population and laser speckle flowgraphy (LSFG) measurements of mean blur rate (MBR) in the optic nerve head (ONH). METHODS:A total of 189 eyes of 189 normal subjects (93 male, 96 female, mean age 45 ± 14 years old, age range: 20-72) without any history of hypertension, hyperlipidemia or diabetes were enrolled. ONH microcirculation was measured with LSFG and overall MBR (MA), vessel-area MBR (MV), and tissue-area MBR (MT) were derived from these measurements. The statistical association of these measurements with characteristics such as sex, age, intraocular pressure (IOP) and systolic blood pressure (SBP) was then determined. RESULTS:There was a trend towards decreased IOP and MV and increased SBP with age (P = 0.002, P = 0.035, and P = 0.006, respectively). Furthermore, IOP, MV and SBP were correlated with age (r = -0.23, P = 0.011; r = -0.24, P < 0.001; and r = 0.30, P < 0.001, respectively). Separate multiple regression analyses of independent contributing factors revealed that sex and IOP contributed to MA (P < 0.001 and P = 0.002, respectively), sex, IOP, and age contributed to MV (P < 0.001, P = 0.003, and P = 0.024, respectively), while only IOP contributed to MT (P = 0.003). CONCLUSION:In a normal population, MBR was affected by IOP in both the large vessel and capillary areas of the ONH, but not by SBP. MV was also affected by age and sex, while MT was stable independent of age or sex.

PURPOSE:To investigate the influence of various risk factors on thinning of the lamina cribrosa (LC), as measured with swept-source optical coherence tomography (SS-OCT; Topcon). METHODS:This retrospective study comprised 150 eyes of 150 patients: 22 normal subjects, 28 preperimetric glaucoma (PPG) patients, and 100 open-angle glaucoma patients. Average LC thickness was determined in a 3 x 3 mm cube scan of the optic disc, over which a 4 x 4 grid of 16 points was superimposed (interpoint distance: 175 μm), centered on the circular Bruch's membrane opening. The borders of the LC were defined as the visible limits of the LC pores. The correlation of LC thickness with Humphrey field analyzer-measured mean deviation (MD; SITA standard 24-2), circumpapillary retinal nerve fiber layer thickness (cpRNFLT), the vertical cup-to-disc (C/D) ratio, and tissue mean blur rate (MBR) was determined with Spearman's rank correlation coefficient. The relationship of LC thickness with age, axial length, intraocular pressure (IOP), MD, the vertical C/D ratio, central corneal thickness (CCT), and tissue MBR was determined with multiple regression analysis. Average LC thickness and the correlation between LC thickness and MD were compared in patients with the glaucomatous enlargement (GE) optic disc type and those with non-GE disc types, as classified with Nicolela's method. RESULTS:We found that average LC thickness in the 16 grid points was significantly associated with overall LC thickness (r = 0.77, P < 0.001). The measurement time for this area was 12.4 ± 2.4 minutes. Average LC thickness in this area had a correlation coefficient of 0.57 with cpRNFLT (P < 0.001) and 0.46 (P < 0.001) with MD. Average LC thickness differed significantly between the groups (normal: 268 ± 23 μm, PPG: 248 ± 13 μm, OAG: 233 ± 20 μm). Multiple regression analysis showed that MD (β = 0.29, P = 0.013), vertical C/D ratio (β = -0.25, P = 0.020) and tissue MBR (β = 0.20, P = 0.034) were independent variables significantly affecting LC thickness, but age, axial length, IOP, and CCT were not. LC thickness was significantly lower in the GE patients (233.9 ± 17.3 μm) than the non-GE patients (243.6 ± 19.5 μm, P = 0.040). The correlation coefficient between MD and LC thickness was 0.58 (P < 0.001) in the GE patients and 0.39 (P = 0.013) in the non-GE patients. CONCLUSION:Cupping formation and tissue blood flow were independently correlated to LC thinning. Glaucoma patients with the GE disc type, who predominantly have large cupping, had lower LC thickness even with similar glaucoma severity.

Hiroshi Kunikata1, Toshiaki Abe2, Jiro Kinukawa1, Kohji Nishida1,31Department of Ophthalmology and Visual Science, Tohoku University Graduate School of Medicine, Sendai, Japan; 2Division of Clinical Cell Therapy, Tohoku University Graduate School of Medicine, Sendai, Japan; 3Department of Ophthalmology, Osaka University Medical School, Suita, JapanPurpose: To report the preoperative best-corrected visual acuity (BCVA) and foveal thickness (FT) values that lead to a postoperative decimal BCVA of ≥ 1.0 after surgical removal of an idiopathic epiretinal membrane (ERM).Methods: This is a retrospective case series of 73 eyes that underwent surgery for removal of an idiopathic ERM. All eyes had been treated by a single surgeon using a 25-gauge transconjunctival sutureless vitrectomy and indocyanine green-assisted internal limiting membrane peel. The BCVA and FT were measured at baseline and 6 months postoperatively.Results: A postoperative decimal BCVA ≥ 1.0 was obtained in eyes with a preoperative decimal BCVA ≥ 0.3 but not in those with a preoperative decimal BCVA ≤ 0.2. The incidence of obtaining a postoperative decimal BCVA ≥ 1.0 was significantly (P = 0.002) higher in eyes with a preoperative decimal BCVA ≥ 0.5 (50%) than in eyes with a preoperative decimal BCVA < 0.5 (11%). Additionally, a postoperative decimal BCVA of ≥ 1.0 was obtained in 51% of the eyes that had a preoperative FT < 400 µm, compared with only 21% of eyes with a preoperative FT ≥ 400 µm (P = 0.01). The incidence of obtaining a postoperative decimal BCVA ≥ 1.0 was significantly higher in eyes with preoperative decimal BCVA ≥ 0.5 and FT < 400 µm (60%) than in eyes with preoperative decimal BCVA ≥ 0.5 and FT ≥ 400 µm (20%; P = 0.03 ) or preoperative BCVA < 0.5 and FT ≥ 400 µm (7%; P < 0.001).Conclusions: These findings indicate that eyes with both preoperative BCVA ≥ 0.5 and FT < 400 µm have a significantly better chance of obtaining a postoperative decimal BCVA ≥ 1.0 following idiopathic ERM removal.Keywords: 25-gauge vitrectomy, optical coherence tomography, epimacular membrane, epiretinal membrane, visual acuity, foveal thickness

Noriko Himori, Hiroshi Kunikata, Takaaki Otomo, Nobuo Fuse, Kohji NishidaDepartment of Ophthalmology and Visual Science, Tohoku University Graduate School of Medicine, Sendai, JapanAbstract: A 20-year-old woman was involved in a traffic accident while riding a motorcycle. The vision in her right eye was severely reduced. At the first examination, the eyelids of her right eye were severely swollen, and the eye could barely be seen. The fundus was not visible. She had no light perception in her vision. Computed tomography revealed a severe blow-out fracture in her right eye. Surgery was immediately performed to correct the fracture and the eye globe was replaced in the orbit. On the fourth postoperative day, the right fundus was visible and a cherry-red spot and milky-white edema were seen. Fluorescein angiography showed an arterial filling defect. Four months later, her visual acuity was light perception. Our case shows that a central retinal artery occlusion can be a complication of a blow-out fracture of the lower orbital wall and can lead to severe visual loss even with early surgical repair.Keywords: central retinal artery occlusion, blow out fracture, trauma, young adult

PURPOSE:Recent studies have shown that the risk of cerebro- and cardiovascular events (CVEs) is higher in patients with primary aldosteronism (PA) than in those with essential hypertension (EH), and that silent brain infarction (SBI) is a risk factor and predictor of CVEs. Here, we evaluated the relationship between findings from laser speckle flowgraphy (LSFG), a recently introduced non-invasive means of measuring mean blur rate (MBR), an important biomarker of ocular blood flow, and the occurrence of SBI in patients with PA. METHODS:87 PA patients without symptomatic cerebral events (mean 55.1 ± 11.2 years old, 48 male and 39 female) were enrolled in this study. We measured MBR in the optic nerve head (ONH) with LSFG and checked the occurrence of SBI with magnetic resonance imaging. We examined three MBR waveform variables: skew, blowout score (BOS) and blowout time (BOT). We also recorded clinical findings, including age, blood pressure, and plasma aldosterone concentration. RESULTS:PA patients with SBI (15 of 87 patients; 17%) were significantly older and had significantly lower BOT in the capillary area of the ONH than the patients without SBI (P = 0.02 and P = 0.03, respectively). Multiple logistic regression analysis revealed that age and BOT were independent factors for the presence of SBI in PA patients (OR, 1.15, 95% CI 1.01-1.38; P = .03 and OR, 0.73, 95% CI 0.45-0.99; P = .04, respectively). CONCLUSION:PA patients with SBI were older and had lower MBR BOT than those without SBI. Our analysis showed that age was a risk factor for SBI, and that BOT was a protective factor, in patients with PA. This suggests that BOT, a non-invasive and objective biomarker, may be a useful predictor of SBI and form part of future PA evaluations and clinical decision-making.

Purpose. To determine the correlation of reduced retinal thickness in the central papillomacular bundle (CPB) to central visual function, including central retinal sensitivity and visual acuity, in glaucoma patients. Methods. This study enrolled 50 eyes of 50 patients with open-angle glaucoma who were carefully screened for comorbid conditions that can cause decreased central visual function, such as cataracts or macular diseases. We used a novel CPB analysis comprising a program for optical coherence tomography that measured RNFL thickness and GCC thickness in the CPB and divided lengthwise into three parts (upper, middle, and lower CPB). The relationship of these parameters, including conventional macular thickness, to visual field sensitivity in four central standard automated perimetry points (the central four thresholds) and BCVA was analyzed. Results. The two parameters most highly correlated with central four thresholds were macular GCCT and macular RNFLT. The two parameters most highly correlated with BCVA were middle CPB (mid-CPB) GCCT and mid-CPB RNFLT. A multiple regression analysis revealed that mid-CPB GCCT was an independent factor impacting central retinal thresholds and BCVA. Conclusions. Our results suggest that mid-CPB RNFLT and GCCT, parameters of a novel papillomacular bundle analysis, are candidate biomarkers of decreased central visual function in glaucomatous eyes.

Purpose. To assess the association between optic nerve head (ONH) microcirculation, central papillomacular bundle (CPB) structure, and visual function in eyes with treatment naive normal tension glaucoma (NTG). Methods. This study included 40 eyes of 40 patients with NTG and 20 eyes of 20 normal patients. We used laser speckle flowgraphy (LSFG) to measure mean blur rate (MBR) in all eyes and calculated the ratio of MBR in the horizontal quadrants of tissue area ONH (temporal/nasal ratio of MBR in the tissue area: T/N MT). Clinical findings also included retinal nerve fiber layer thickness (RNFLT) and ganglion cell complex thickness (GCCT) in the CPB and macular areas, best-corrected visual acuity (BCVA), mean deviation (MD), and refractive error. Results. T/N MT was correlated with both BCVA and MD. The OCT parameters most highly correlated with T/N MT were macular RNFLT and mid-CPB RNFLT. Furthermore, T/N MT, mid-CPB RNFLT, and macular RNFLT were higher in NTG than in normal eyes. A discrimination analysis revealed that T/N MT and refractive error were independent factors indicating NTG. Conclusions. Our results suggest that T/N MT is a candidate biomarker of NTG. Furthermore, T/N MT reflects visual function, including acuity and sensitivity, and CPB structure.

Purpose. We evaluated the ability of novel optical coherence tomography (OCT) parameters to predict postoperative best-corrected visual acuity (BCVA) in macula-off rhegmatogenous retinal detachment (RRD) eyes. Methods. We reviewed the medical records of 56 consecutive eyes with macula-off RRD. Clinical findings were analyzed including the relationship between preoperative OCT findings and 6-month postoperative BCVA. Results. Six-month postoperative BCVA was significantly correlated with preoperative findings including retinal height at the fovea, total and inner layer cross-sectional macular area within 2 mm of the fovea, and preoperative BCVA (P

Purpose. To determine the feasibility of using 25-gauge microincision vitrectomy surgery (25GMIVS) to treat vitreoretinal disease in glaucomatous eyes which have previously undergone trabeculectomy (TLE). Methods. A consecutive, interventional case series. We performed 25GMIVS in 15 glaucomatous eyes that had undergone TLE. Follow-up period was 11.5 months. Results. 25GMIVS was successfully used and led to improvement in visual acuity (P

We describe a new technique for removing a large intraocular foreign body by 25-gauge microincision vitrectomy surgery (25G-MIVS). Noncomparative interventional case series were performed at a single centre. Two patients with a long smooth intraocular vitreal foreign body underwent phacoemulsification and aspiration, intraocular lens implantation, 25G-MIVS, and extraction of the foreign body. The foreign body was removed through a posterior capsulorhexis, anterior continuous curvilinear capsulorhexis, and a corneal incision. In both cases, the foreign body was safely removed through the corneal incision, and IOL was implanted and well positioned. The surgical incision did not require suturing. No postoperative complications associated with this technique were found. The corneal endothelial cell density was maintained over 2000 cells/mm2 in both cases during recent follow-up examinations. Our findings indicate that 25G-MIVS with this technique can be used to extract a long slender smooth foreign body. It is safe, without complications, and can be performed without enlarging the 25-gauge sclerotomy.