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Yumi Kotoda,1 Sohei Hishiyama,2 Jaehoon Shim,3,4 Hiroki Kobayashi,2 Ayasa Takamino,2 Masako Abe,2 Kenji Kashiwagi,1 Takashi Matsukawa,2 Masakazu Kotoda2 1Department of Ophthalmology, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan; 2Department of Anesthesiology, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan; 3F.M. Kirby Neurobiology Center and Department of Neurology, Boston Children’s Hospital, Boston, MA, USA; 4Department of Neurobiology, Harvard Medical School, Boston, MA, USACorrespondence: Masakazu Kotoda, Department of Anesthesiology, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, Japan, Tel +81-55-273-9690, Email mkotoda@yamanashi.ac.jpPurpose: Corneal pain is one of the most common eye symptoms caused by various types of epithelial injuries, including traumatic abrasion, chemical injury, ulcers, ultraviolet exposure, and infection. However, current therapeutic options for corneal pain are limited. In this study, we synthesized a novel quaternary ammonium compound, N-propylamiodarone bromide (NPA), and employed a rodent model of corneal injury to investigate whether NPA offers prolonged corneal analgesia through transient receptor potential vanilloid 1 (TRPV1) channel-mediated selective cellular entry, without hindering corneal epithelial recovery.Methods: In the corneal injury model, 24 adult Wistar rats received a topical application of normal saline, oxybuprocaine, or NPA (n = 8 each), and corneal pain sensitivity was assessed using the von Frey technique. Another set of 32 rats with intact corneas received oxybuprocaine, capsaicin (a TRPV1 agonist), or NPA with or without capsaicin (n = 8 each), followed by a mechanical sensitivity evaluation. Potential adverse effects on normal epithelial recovery were evaluated using fluorescence and hematoxylin–eosin staining in an additional 8 rats with corneal injury.Results: In the corneal injury model, NPA produced significantly longer-lasting analgesia than oxybuprocaine (duration of the maximum effect: 215 ± 11 vs 25 ± 2 min, P < 0.001). None of the animals presented any signs of eye irritability. In contrast to injured eyes, NPA alone did not significantly increase mechanical sensitivity in naïve eyes. However, the co-administration of NPA and capsaicin produced significantly longer-lasting corneal anesthesia than oxybuprocaine (duration of the maximum effect: 165 ± 15 vs 31 ± 2 min, P < 0.001). NPA did not hamper wound healing.Conclusion: The novel quaternary ammonium NPA produced long-lasting analgesia against corneal injury without hampering corneal recovery, suggesting that it is a potential candidate for analgesic medicine targeting corneal pain.Keywords: analgesics, capsaicin, corneal injury, pain, TRPV1 channel

Yumi Kotoda, 1 Masakazu Kotoda, 2 Masakazu Ogiwara, 3 Hiroyuki Kinouchi, 3 Hiroyuki Iijima 1 1Department of Ophthalmology, University of Yamanashi, Chuo, Yamanashi 409-3898, Japan; 2Department of Anesthesiology, University of Yamanashi, Chuo, Yamanashi 409-3898, Japan; 3Department of Neurosurgery, University of Yamanashi, Chuo, Yamanashi 409-3898, JapanCorrespondence: Yumi Kotoda 1110 Shimokato, Chuo, Yamanashi 409-3898, JapanTel +81-55-273-9657Fax +81-55-273-6757Email ykanai@yamanashi.ac.jpPurpose: The purpose of this study was to quantitatively investigate light sensitivity asymmetry both between left and right eyes and between upper and lower quadrant in the 30-degree visual field of patients with visual field defects caused by pituitary adenoma.Patients and Methods: Preoperative Humphrey 30– 2 perimetry results were reviewed retrospectively using the charts of 28 pituitary adenoma patients who underwent surgery. Inter-eye light sensitivity comparisons of the temporal and nasal hemifields between the left and right eyes were conducted in each patient to study left-right asymmetry. Upper-lower asymmetry was investigated by comparing the frequency of severe scotoma (light sensitivity 5 dB or less) in the upper and lower visual field quadrants in the temporal and nasal hemifields.Results: Left-right asymmetry was demonstrated in 61% of cases in the temporal hemifield and in 57% of cases in the nasal hemifield. Severe scotoma test points were investigated in the worse eye of each patient and were more frequent in the superotemporal quadrant of the visual field compared with the inferotemporal quadrant (P = 0.00029) and in the inferonasal quadrant compared to the superonasal quadrant (P = 0.00268).Conclusion: Asymmetric visual field defects between left and right eyes are common in patients with pituitary adenoma. Severe scotoma is more frequent in the upper quadrant of the temporal hemifield and in the lower quadrant of the nasal hemifield.Keywords: bitemporal hemianopsia, pituitary adenoma, asymmetry, Humphrey perimetry, light sensitivity

Purpose: To investigate whether genetic and clinical characteristics differ depending on generations using 326 patients (male/female, 259/67; mean age, 55.4 ± 12.5 years) with simple CSC., Methods: All patients were diagnosed with simple CSC, defined as a retinal pigment epithelium alteration area equal to or smaller than 2-disc areas based on multimodal imaging at the initial presentation. We cross-sectionally evaluated clinical characteristics at the initial visit and genotyped CFH rs800292 and rs1329428 for all patients using TaqMan technology., Results: As generations decreased, the proportion of males, subfoveal choroidal thickness, and prevalence of fibrin significantly increased ( p  < 0.001, p  < 0.001, and p  = 0.012, respectively), and the best-corrected visual acuity improved ( p  < 0.001); in contrast, the prevalence of pachydrusen significantly decreased ( p  < 0.001). The younger presentation was significantly associated with male and risk variants (T allele) of CFH rs1329428 ( p  = 9.1 × 10 -7 and p  = 0.042, respectively), and patients were estimated to present 2 years younger per one T allele of CFH rs1329428 ( p  = 0.042, β = -1.95, stepwise regression analysis)., Conclusion: Clinical and genetic characteristics differed significantly among patients with simple CSC, depending on their generation.

Purpose: We compared 12-month outcomes of eyes with polypoidal choroidal vasculopathy (PCV) with or without complete regression of polyps observed one month after three monthly intravitreal administrations (loading phase) of aflibercept (2.0 mg/0.05 mL) or brolucizumab (6.0 mg/0.05 mL)., Methods: All patients underwent indocyanine green angiography at both baseline and 3 months after initial injection and were followed up monthly with an as-needed regimen for up to 12 months. A total of 62 patients with PCV were included: 30 eyes were treated with brolucizumab, and 32 were treated with aflibercept. Eyes with complete regression of polyps (regression group) had significantly smaller maximum polyp diameter and were more frequently treated with brolucizumab than those without complete regression (non-regression) group., Results: Best corrected visual acuity was comparable between the two groups at 12 months. Although the 12-month retreatment-free proportion was comparable between the two groups (33.0% versus 27.0%, p = 0.59), a retreatment-free period was significantly longer in the regression group than in the non-regression group (8.3 ± 3.3 versus 6.5 ± 3.6 months, p = 0.022), and the number of additional injections was significantly fewer in the regression group than in the non-regression group (1.2 ± 1.2 versus 3.0 ± 2.6, p = 0.007)., Conclusions: Complete regression of polyps observed after the initial phase possibly prolongs the retreatment-free period and reduces the number of additional injections irrespective of aflibercept or brolucizumab.

Purpose: To compare the genetic and clinical characteristics of central serous chorioretinopathy (CSC) in patients with and without steroid use., Methods: A total of 407 consecutive patients with CSC were included. Demographic data and clinical factors, including subfoveal choroidal thickness, bilateral involvement, descending tracts, pachydrusen, fibrin, and dome-shaped pigment epithelial detachment, were obtained. Variants of complement factor H (CFH)   I62V (rs800292) and rs1329428 were genotyped in all cases using TaqMan technology., Results: Of the total patients, 48 (11.8%) were steroid users. The majority of males were non-steroid users (82.5%) than steroid users (58.3%) (p = 9.8 × 10 -5 ). Demographic data and the prevalence of clinical factors were comparable between the two groups (all p-values > 0.10). Risk allele frequencies of CFH rs800292 and rs1329428 were also comparable between the two groups (p = 0.76, rs800292: steroid users = 52.1% vs. non-steroid users = 50.4%; p = 0.62, rs1329428: steroid users = 47.9% vs. non-steroid users = 45.3%)., Conclusions: Except for the male/female ratio, there were no significant differences in the clinical presentation or genetic characteristics, including variants of the CFH gene, between the two groups., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Yoneyama et al.)

Purpose: To investigate the characteristics of patients with over a 12-month remission after 3 monthly intravitreal aflibercept injections followed by a pro re nata regimen for exudative age-related macular degeneration (AMD)., Methods: One hundred forty-four eyes with exudative AMD were included. All patients received 3 monthly intravitreal aflibercept injections as a loading dose, followed by an as-needed regimen for 60 months. Patients were classified into the remission and recurrence groups depending on the presence or absence of a 12-month remission. ARMS2 A69S and CFH I62V were genotyped in all cases., Results: During the study, 82 eyes (56.9%) showed 12 months or more remission at least once. The cumulative incidence rate of a 12-month remission showed a plateau pattern and converged to 60% (y = -166.26x-2.172 + 0.6, R2 = 0.8168). Patients in the remission group were younger than those in the recurrence group (P < 0.001) and had less risk allele frequency of the ARMS2 gene than the recurrence group (P < 0.001). The longer the remission interval was prolonged, the better visual acuity was achieved at the 60-month visit (P < 0.001)., Conclusion: Fifty-seven percent of patients showed a 12-month remission or more at least once during a 60-month follow-up, suggesting that patients with no reactivation can prolong the treatment interval.

Purpose: To compare the one-year visual and anatomic outcomes of an as-needed regimen of brolucizumab and aflibercept for polypoidal choroidal vasculopathy (PCV)., Study Design: A retrospective comparative study., Methods: A retrospective medical chart review was performed for consecutive 56 eyes from 56 patients with PCV initially treated with thee monthly intravitreal aflibercept (n = 33, 2.0 mg/0.05 ml) or brolucizumab (n = 23, 6.0 mg/0.05 ml) followed by as-needed administration, followed up for at least 12 months. All patients were followed up monthly, and fluorescein and indocyanine green angiography (ICGA) were performed at baseline, 3-month, and 12-month visits., Results: At the 12-month visit, best-corrected visual acuity significantly improved from 0.30 ± 0.31 to 0.21 ± 0.29 (p = 0.042) in the brolucizumab-treated group and from 0.24 ± 0.25 to 0.14 ± 0.25 (p = 7.7×10 -3 ) in the aflibercept-treated group, suggesting comparable visual improvement in both groups. Central retinal thickness and subfoveal choroidal thickness decreased by 38.4% and 14.2%, respectively, in the brolucizumab-treated group and by 34.8% and 13.9%, respectively, in the aflibercept-treated group at the 12-month visit. The mean number of additional injections was significantly higher in the aflibercept-treated group (2.9 ± 2.7) than in the brolucizumab-treated group (1.3 ± 1.2, p = 0.045). The complete resolution of polypoidal lesions on ICGA was higher in the brolucizumab-treated group than in the aflibercept-treated group (3-month visit: 56.5% vs 30.3%, 12-month visit: 56.5% vs 30.3%)., Conclusions: In treatment-naïve eyes with PCV, the as-needed administration regimen of brolucizumab was comparable to aflibercept in terms of visual and anatomical outcomes, with fewer additional injections during the 12-month follow-up., (© 2023. Japanese Ophthalmological Society.)

Background: Postoperative pain and inflammation are significant complications following surgery. Strategies that aim to prevent excessive inflammation without hampering natural wound-healing are required for the management of postoperative pain and inflammation. However, the knowledge of the mechanisms and target pathways involved in these processes is lacking. Recent studies have revealed that autophagy in macrophages sequesters pro-inflammatory mediators, and it is therefore being recognized as a crucial process involved in regulating inflammation. In this study, we tested the hypothesis that autophagy in macrophages plays protective roles against postoperative pain and inflammation and investigated the underlying mechanisms., Methods: Postoperative pain was induced by plantar incision under isoflurane anesthesia in mice lacking macrophage autophagy (Atg5flox/flox LysMCre +) and their control littermates (Atg5flox/flox). Mechanical and thermal pain sensitivity, changes in weight distribution, spontaneous locomotor activity, tissue inflammation, and body weight were assessed at baseline and 1, 3, and 7 days after surgery. Monocyte/macrophage infiltration at the surgical site and inflammatory mediator expression levels were evaluated., Results: Atg5flox/flox LysMCre + mice compared with the control mice exhibited lower mechanical and thermal pain thresholds and surgical/non-surgical hindlimb weight-bearing ratios. The augmented neurobehavioral symptoms observed in the Atg5flox/flox LysMCre + mice were associated with more severe paw inflammation, higher pro-inflammatory mediator mRNA expression, and more monocytes/macrophages at the surgical site., Conclusion: The lack of macrophage autophagy augmented postoperative pain and inflammation, which were accompanied by enhanced pro-inflammatory cytokine secretion and surgical-site monocyte/macrophage infiltration. Macrophage autophagy plays a protective role in postoperative pain and inflammation and can be a novel therapeutic target., (© 2023. The Author(s).)

We aimed to investigate whether a treat-and-extend regimen of intravitreal brolucizumab (6.0 mg/0.05 mL) is effective for eyes with exudative age-related macular degeneration (AMD) refractory to aflibercept for 12 months. Sixty eyes from 56 patients receiving brolucizumab for exudative AMD refractory to aflibercept were included. Patients received a mean of 30.1 aflibercept administrations for a mean 67.9-month follow-up. All patients exhibited exudation on optical coherence tomography (OCT) despite regular 4-8 weeks of aflibercept administration. Visit 1 was scheduled at the same interval from the last aflibercept injection to the baseline. The treatment interval was extended or shortened by 1-2 weeks depending on the presence or absence of exudation on OCT. After switching to brolucizumab, the follow-up interval significantly extended at 12 months (before switching: 7.6 ± 3.8 weeks vs. at 12 months: 12.1 ± 6.2 weeks, p = 1.3 × 10 -7 ). Forty-three percent of the eyes achieved a dry macula at 12 months after switching. However, the best-corrected visual acuity did not improve at any visit. Morphologically, the central retinal thickness and subfoveal choroidal thickness significantly decreased from baseline at 12 months ( p = 3.6 × 10 -3 and 1.0 × 10 -3 , respectively). Switching to brolucizumab can be considered to extend the treatment interval in eyes with exudative AMD refractory to aflibercept.

Hyperreflective foci (HRF) are the findings observed in optical coherence tomography (OCT) in several retinal diseases and are believed to be associated with the increased risk of atrophy in eyes with age-related macular degeneration (AMD). In this study, we investigated the clinical and genetic characteristics of intermediate AMD with HRF. We reviewed the medical charts for 155 patients with intermediate AMD, in whom macular neovascularization (MNV) was observed in the contralateral eye. The presence or absence of an HRF was evaluated using a spectral-domain OCT volume scan spanning the macular region. Patients were followed longitudinally for at least 12 months, and the maximum follow-up period was 60 months. Genotyping of ARMS2 A69S and CFH I62V was performed in all participants. Of the 155 patients (mean age: 77.8 ± 7.6 years, male/female: 103/52), HRF was observed in 53 eyes (34.2%) and was significantly associated with type-3 MNV (p = 1.0 × 10 -5 ) in the contralateral eye, pseudodrusen (p = 5.0 × 10 -4 ), thinner subfoveal choroidal thickness (p = 0.013), and risk of ARMS2 A69S (p = 0.023). During follow-up (40.8 ± 17.5), 38 eyes (24.5%) developed advanced AMD. The mean time to the onset of advanced AMD was 29.8 ± 12.9 months in eyes with intermediate AMD. HRF was associated with MNV (p = 1.0 × 10 -3 ), but not with atrophy., (© 2022. The Author(s).)

Photoreceptor degeneration caused by genetic defects leads to retinitis pigmentosa, a rare disease typically diagnosed in adolescents and young adults. In most cases, rod loss occurs first, followed by cone loss as well as altered function in cells connected to photoreceptors directly or indirectly. There remains a gap in our understanding of retinal cellular responses to photoreceptor abnormalities. Here, we utilized single-cell transcriptomics to investigate cellular responses in each major retinal cell type in retinitis pigmentosa model (P23H) mice vs. wild-type littermate mice. We found a significant decrease in the expression of genes associated with phototransduction, the inner/outer segment, photoreceptor cell cilium, and photoreceptor development in both rod and cone clusters, in line with the structural changes seen with immunohistochemistry. Accompanying this loss was a significant decrease in the expression of genes involved in metabolic pathways and energy production in both rods and cones. We found that in the Müller glia/astrocyte cluster, there was a significant increase in gene expression in pathways involving photoreceptor maintenance, while concomitant decreases were observed in rods and cones. Additionally, the expression of genes involved in mitochondrial localization and transport was increased in the Müller glia/astrocyte cluster. The Müller glial compensatory increase in the expression of genes downregulated in photoreceptors suggests that Müller glia adapt their transcriptome to support photoreceptors and could be thought of as general therapeutic targets to protect against retinal degeneration., (© 2021. The Author(s).)

The group of retinal degenerations, retinitis pigmentosa (RP), comprises more than 150 genetic abnormalities affecting photoreceptors. Finding degenerative pathways common to all genetic abnormalities may allow general treatment such as neuroprotection. Neuroprotection may include enhancing the function of cells that directly support photoreceptors, retinal pigment epithelial cells, and Müller glia. Treatment with fibroblast growth factor 21 (FGF21), a neuroprotectant, from postnatal week 4-10, during rod and cone loss in P23H mice (an RP model) with retinal degeneration, preserved photoreceptor function and normalized Müller glial cell morphology. Single-cell transcriptomics of retinal cells showed that FGF21 receptor Fgfr1 was specifically expressed in Müller glia/astrocytes. Of all retinal cells, FGF21 predominantly affected genes in Müller glia/astrocytes with increased expression of axon development and synapse formation pathway genes. Therefore, enhancing retinal glial axon and synapse formation with neurons may preserve retinal function in RP and may suggest a general therapeutic approach for retinal degenerative diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. S.T. is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Kenilworth, NJ, USA, and a stockholder in Merck & Co., Kenilworth, NJ, USA., (© 2021 The Author(s).)

Aims/hypothesis: Proliferative diabetic retinopathy (PDR) with retinal neovascularisation (NV) is a leading cause of vision loss. This study identified a set of metabolites that were altered in the vitreous humour of PDR patients compared with non-diabetic control participants. We corroborated changes in vitreous metabolites identified in prior studies and identified novel dysregulated metabolites that may lead to treatment strategies for PDR., Methods: We analysed metabolites in vitreous samples from 43 PDR patients and 21 non-diabetic epiretinal membrane control patients from Japan (age 27-80 years) via ultra-high-performance liquid chromatography-mass spectrometry. We then investigated the association of a novel metabolite (creatine) with retinal NV in mouse oxygen-induced retinopathy (OIR). Creatine or vehicle was administered from postnatal day (P)12 to P16 (during induced NV) via oral gavage. P17 retinas were quantified for NV and vaso-obliteration., Results: We identified 158 metabolites in vitreous samples that were altered in PDR patients vs control participants. We corroborated increases in pyruvate, lactate, proline and allantoin in PDR, which were identified in prior studies. We also found changes in metabolites not previously identified, including creatine. In human vitreous humour, creatine levels were decreased in PDR patients compared with epiretinal membrane control participants (false-discovery rate <0.001). We validated that lower creatine levels were associated with vascular proliferation in mouse retina in the OIR model (p = 0.027) using retinal metabolomics. Oral creatine supplementation reduced NV compared with vehicle (P12 to P16) in OIR (p = 0.0024)., Conclusions/interpretation: These results suggest that metabolites from vitreous humour may reflect changes in metabolism that can be used to find pathways influencing retinopathy. Creatine supplementation could be useful to suppress NV in PDR. Graphical abstract.

Pathological choroidal angiogenesis, a salient feature of age-related macular degeneration, leads to vision impairment and blindness. Endothelial cell (EC) proliferation assays using human retinal microvascular endothelial cells (HRMECs) or isolated primary retinal ECs are widely used in vitro models to study retinal angiogenesis. However, isolating pure murine retinal endothelial cells is technically challenging and retinal ECs may have different proliferation responses than choroidal endothelial cells and different cell/cell interactions. A highly reproducible ex vivo choroidal sprouting assay as a model of choroidal microvascular proliferation was developed. This model includes the interaction between choroid vasculature (EC, macrophages, pericytes) and retinal pigment epithelium (RPE). Mouse RPE/choroid/scleral explants are isolated and incubated in growth-factor-reduced basal membrane extract (BME) (day 0). Medium is changed every other day and choroid sprouting is quantified at day 6. The images of individual choroid explant are taken with an inverted phase microscope and the sprouting area is quantified using a semi-automated macro plug-in to the ImageJ software developed in this lab. This reproducible ex vivo choroidal sprouting assay can be used to assess compounds for potential treatment and for microvascular disease research to assess pathways involved in choroidal micro vessel proliferation using wild type and genetically modified mouse tissue.

Objective: Increasing numbers of reports have described atypical femoral fracture (AFF) in patients being treated with oral bone resorption inhibitors, such as bisphosphonates. Most AFF patients undergo surgical treatment. However, there is little information about post-operative rehabilitation and patient activity levels after surgery for such fractures. Here we report the outcome of surgical treatment and postoperative rehabilitation for AFF at a single center in Japan., Methods: We retrospectively reviewed 13 patients (14 AFFs) who underwent surgery at Nagano Matsushiro General Hospital between January 2013 and December 2016. The clinical backgrounds of the patients were evaluated., Results: The patients comprised 1 man (1 AFF) and 12 women (13 AFFs). The mean age at surgery was 77.7±7.1 years (mean±SD). Before AFF occurred, 12 of the 13 patients had used bisphosphonates for osteoporosis. An intramedullary nail was inserted in all patients. Partial weight bearing was started on average 2 weeks after surgery, and full weight-bearing gait was permitted on average 3 weeks after surgery. The average time to bone union was 9.9±6.1 months, ranging from 3 to 23 months. None of the patients required additional surgical procedures, including revision surgery for pseudoarthrosis (nonunion) or delayed union. Before AFF, 12 patients walked independently, and 1 patient walked with a single cane. At the final follow-up (mean duration: 34.5±15.7 months), 8 patients could walk independently and 5 patients walked with a single cane., Conclusions: We recognized that rigid fixation for AFF supported early weight-bearing gait after surgery., Competing Interests: CONFLICTS OF INTEREST: We have no conflicts of interest to declare., (©2020 The Japanese Association of Rehabilitation Medicine.)