Yuji Nakano

Purpose: To evaluate the impact of dominant eye involvement on binocular visual function and vision-related quality of life (VR-QoL), and to determine the monocular metamorphopsia threshold associated with binocular symptom perception in patients with unilateral epiretinal membrane (ERM). Methods: This prospective single-center study included patients with unilateral ERM. Ocular dominance was determined using the hole-in-card test. Best-corrected visual acuity (BCVA), monocular and binocular metamorphopsia measured with M-CHARTS, aniseikonia, stereopsis, and VR-QoL using VFQ-25 were evaluated. Patients were classified according to whether ERM involved the dominant or non-dominant eye. Results: Sixty-eight patients were enrolled, including 35 patients in the non-dominant eye group and 33 in the dominant eye group. Horizontal binocular metamorphopsia scores were significantly higher in the dominant eye group than in the non-dominant eye group (p < 0.05). No significant differences were observed in BCVA, stereopsis, or VFQ-25 composite scores between the groups. Binocular metamorphopsia scores significantly correlated with VFQ-25 composite scores only in the dominant eye group. Receiver operating characteristic (ROC) analysis demonstrated that a mean monocular metamorphopsia score of 0.55 was the optimal threshold for binocular symptom perception in eyes with dominant eye involvement (AUC = 0.66; 95% CI, 0.48–0.85) Conclusion: Dominant eye involvement was associated with greater binocular metamorphopsia and a stronger association between metamorphopsia and VR-QoL in unilateral ERM. A mean monocular metamorphopsia score of ≥ 0.55 may represent a preliminary threshold associated with binocular symptom perception and may help guide future clinical assessment.

Background: Axial elongation may influence the structural characteristics and surgical prognosis of epiretinal membrane (ERM), but its impact across different axial length (AL) categories remains unclear. Methods: We retrospectively analyzed 557 eyes from 515 patients with ERM who underwent vitrectomy and were followed for at least 6 months. Eyes were stratified by AL into normal to mild myopia (NM; p < 0.001) but not in the EHM group (p = 0.091). Although preoperative BCVA was comparable among groups, postoperative BCVA was significantly better in the HM group (−0.02 ± 0.17 logMAR) compared with the NM (0.03 ± 0.20 logMAR) and EHM (0.21 ± 0.43 logMAR) groups (p < 0.05). Outer retinal cystoid lesions were significantly more frequent in the EHM group (p < 0.05), whereas the prevalence of EZ disruption, inner retinal cystoid lesions, and EP did not differ significantly among groups. Conclusions: Eyes with ERM and extreme high myopia exhibited limited postoperative visual improvement and a higher prevalence of outer retinal cystoid lesions, suggesting that axial elongation may adversely affect surgical prognosis.

Background/Objectives: To investigate and compare the clinical characteristics of epiretinal membrane (ERM) and associated diseases: macular pseudohole (MPH), ERM foveoschisis (ERM-FS), and lamellar macular hole (LMH). Methods: We retrospectively reviewed of all patients who underwent vitrectomy with at least 6 months follow-up, all eyes were classified into four groups: ERM, MPH, ERM-FS, and LMH. Age, gender, presence of glaucoma, preoperative spherical equivalent, axial length (AL), preoperative and postoperative best-corrected visual acuity (BCVA), metamorphopsia using M-CHARTS^®, and frequency of overlapping associated diseases were investigated. The association between pre- and postoperative BCVA and these clinical factors was analyzed. Results: After enrolling 718 eyes of 662 patients, eyes were classified as ERM (592 eyes), MPH (76 eyes), ERM-FS (63 eyes), and LMH (42 eyes). Overlapping cases included MPH+ERM-FS (17 eyes), ERM-FS+LMH (14 eyes), MPH+LMH (18 eyes), and MPH+ERM-FS+LMH (3 eyes). The AL was significantly longer (p < 0.05) in MPH, ERM-FS, and LMH versus ERM. In all groups, BCVA significantly improved after vitrectomy. Although preoperative BCVA was not significantly different among the four groups, postoperative BCVA was significantly worse for LMH versus ERM (p < 0.001). Preoperative metamorphopsia was significantly more severe in ERM (0.52 ± 0.51) versus MPH (0.34 ± 0.29) (p < 0.05). Postoperative BCVA correlated with preoperative BCVA and age in all groups except LMH. Conclusions: Associated diseases often overlap and were more myopic than ERM. Postoperative BCVA was worse in LMH, while preoperative metamorphopsia was severe in ERM. These results highlight the importance of both clinical and functional evaluations in determining surgical indications and predicting visual outcomes.

FROUNT is an intracellular protein that promotes pseudopodia formation by binding to the chemokine receptors CCR2 and CCR5 on macrophages. Recently, disulfiram (DSF), a drug treatment for alcoholism, was found to have FROUNT inhibitory activity. In this study, we investigated the effect of DSF eye drops in a rat corneal alkali burn model. After alkali burn, 0.5% DSF eye drops (DSF group) and vehicle eye drops (Vehicle group) were administered twice daily. Immunohistochemical observations and real-time reverse transcription-polymerase chain reaction (RT-PCR) analyses were performed at 6 h and 1, 4, and 7 days after alkali burn. Results showed a significant decrease in macrophage accumulation in the cornea in the DSF group, but no difference in neutrophils. RT-PCR showed decreased expression of macrophage-associated cytokines in the DSF group. Corneal scarring and neovascularization were also suppressed in the DSF group. Low-vacuum scanning electron microscopy imaging showed that macrophage length was significantly shorter in the DSF group, reflecting the reduced extension of pseudopodia. These results suggest that DSF inhibited macrophage infiltration by suppressing macrophage pseudopodia formation.

Many studies have demonstrated the therapeutic effects of hydrogen in pathological conditions such as inflammation; however, little is known about its prophylactic effects. The purpose of this study is to investigate the prophylactic effects of hydrogen-rich water instillation in a rat corneal alkali burn model. Hydrogen-rich water (hydrogen group) or physiological saline (vehicle group) was instilled continuously to the normal rat cornea for 5 min. At 6 h after instillation, the cornea was exposed to alkali. The area of corneal epithelial defect (CED) was measured every 6 h until 24 h after alkali exposure. In addition, at 6 and 24 h after injury, histological and immunohistochemical observations were made and real-time reverse transcription polymerase chain reaction (RT-PCR) was performed to investigate superoxide dismutase enzyme (SOD)1, SOD2, and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) mRNA expression. CED at 12 h and the number of inflammatory infiltrating cells at 6 h after injury were significantly smaller in the hydrogen group than the vehicle group. Furthermore, SOD1 expression was significantly higher in the hydrogen group than the vehicle group at both 6 and 24 h, and the number of PGC-1α-positive cells was significantly larger in the hydrogen group than the vehicle group at 6 h after injury. In this model, prophylactic instillation of hydrogen-rich water suppressed alkali burn-induced inflammation, likely by upregulating expression of antioxidants such as SOD1 and PGC-1α. Hydrogen has not only therapeutic potential but also prophylactic effects that may suppress corneal scarring following injury and promote wound healing.

The effects of each subtype-selective peroxisome proliferator activated receptor (PPAR) agonist (α, β/δ, γ) on corneal epithelial wound healing were investigated using a rat corneal alkali burn model. After the alkali burn, each PPAR agonist or vehicle ophthalmic solution was instilled topically onto the rat’s cornea. Corneal epithelial healing processes were evaluated by fluorescein staining. Pathological analyses and real-time reverse transcription polymerase chain reactions were performed to evaluate Ki67 (proliferative maker) expression and inflammatory findings. The area of the corneal epithelial defect at 12 h and 24 h after the alkali burn was significantly smaller in each PPAR group than in the vehicle group. Ki67 mRNA expression was increased in the PPARβ/δ group, whereas mRNA expressions of inflammatory cytokines were suppressed in all of the PPAR agonist groups. Nuclear factor kappa B (NF-κB) was the most suppressed in the PPARγ group. The accelerated corneal epithelial healing effects of each PPAR ligand were thought to be related to the promotion of proliferative capacity and inhibition of inflammation.

The effects of peroxisome proliferator-activated receptor (PPAR)β/δ ophthalmic solution were investigated in a rat corneal alkali burn model. After alkali injury, GW501516 (PPARβ/δ agonist) or vehicle ophthalmic solution was topically instilled onto the rat’s cornea twice a day until day 7. Pathological findings were evaluated, and real-time reverse transcription polymerase chain reaction was performed. GW501516 strongly suppressed infiltration of neutrophils and pan-macrophages, and reduced the mRNA expression of interleukin-6, interleukin-1β, tumor necrosis factor alpha, and nuclear factor-kappa B. On the other hand, GW501516 promoted infiltration of M2 macrophages, infiltration of vascular endothelial cells associated with neovascularization in the wounded area, and expression of vascular endothelial growth factor A mRNA. However, 7-day administration of GW501516 did not promote neovascularization in uninjured normal corneas. Thus, the PPARβ/δ ligand suppressed inflammation and promoted neovascularization in the corneal wound healing process. These results will help to elucidate the role of PPARβ/δ in the field of ophthalmology.

Peroxisome proliferator-activated receptor alpha (PPARα) and gamma (PPARγ) agonists have anti-inflammatory and anti-neovascularization effects, but few reports have tested the combination of PPARα and PPARγ agonists. In this study, we investigated the therapeutic effects of ophthalmic solutions of agonists of PPARα, PPARγ, and the combination in a rat corneal alkali burn model. After alkali injury, an ophthalmic solution of 0.05% fenofibrate (PPARα group), 0.1% pioglitazone (PPARγ group), 0.05% fenofibrate + 0.1% pioglitazone (PPARα+γ group), or vehicle (vehicle group) was topically instilled onto the rat’s cornea twice a day. After instillation, upregulation was seen of PPAR mRNA corresponding to each agonist group. Administration of agonists for PPARα, PPARγ, and PPARα+γ suppressed inflammatory cells, neovascularization, and fibrotic changes. In addition, the PPARγ agonist upregulated M2 macrophages, which contributed to wound healing, whereas the PPARα agonist suppressed immature blood vessels in the early phase. Administration of PPARα+γ agonists showed therapeutic effects in corneal wound healing, combining the characteristics of both PPARα and PPARγ agonists. The results indicate that the combination of PPARα and γ agonists may be a new therapeutic strategy.

The eye is provided with immune protection against pathogens in a manner that greatly reduces the threat of inflammation-induced vision loss. Immune-mediated inflammation and allograft rejection are greatly reduced in the eye, a phenomenon called ‘immune privilege’. Corneal tissue has inherent immune privilege properties with underlying three mechanisms: (1) anatomical, cellular, and molecular barriers in the cornea; (2) an immunosuppressive microenvironment; and (3) tolerance related to regulatory T cells and anterior chamber-associated immune deviation. This review describes the molecular mechanisms of the immunosuppressive microenvironment and regulatory T cells in the cornea that have been elucidated from animal models of ocular inflammation, especially those involving corneal transplantation, it also provides an update on immune checkpoint molecules in corneal and systemic immune regulation, and its relevance for dry eye associated with checkpoint inhibitor therapy.