Drug combination of topical ripasudil and brimonidine enhances neuroprotection in a mouse model of optic nerve injury.

PURPOSE: To determine whether combination of topical ripasudil and brimonidine has more effective neuroprotection on retinal ganglion cells (RGCs) following injury to axons composing the optic nerve. METHODS: Topical ripasudil, brimonidine, or mixture of both drugs were administered to adult mice after optic nerve injury (ONI). The influence of drug conditions on RGC health were evaluated by the quantifications of surviving RGCs, phosphorylated p38 mitogen-activated protein kinase (phospho-p38), and expressions of trophic factors and proinflammatory mediators in the retina. RESULTS: Topical ripasudil and brimonidine suppressed ONI-induced RGC death respectively, and mixture of both drugs further stimulated RGC survival. Topical ripasudil and brimonidine suppressed ONI-induced phospho-p38 in the whole retina. In addition, topical ripasudil suppressed expression levels of TNFα, IL-1ß and monocyte chemotactic protein-1 (MCP-1), whereas topical brimonidine increased the expression level of basic fibroblast growth factor (bFGF). CONCLUSIONS: Combination of topical ripasudil and brimonidine may enhance RGC protection by modulating multiple signaling pathways in the retina.

Vision protection and robust axon regeneration in glaucoma models by membrane-associated Trk receptors.

Activation of neurotrophic factor signaling is a promising therapy for neurodegeneration. However, the transient nature of ligand-dependent activation limits its effectiveness. In this study, we solved this problem by inventing a system that forces membrane localization of the intracellular domain of tropomyosin receptor kinase B (iTrkB), which results in constitutive activation without ligands. Our system overcomes the small size limitation of the genome packaging in adeno-associated virus (AAV) and allows high expression of the transgene. Using AAV-mediated gene therapy in the eyes, we demonstrate that iTrkB expression enhances neuroprotection in mouse models of glaucoma and stimulates robust axon regeneration after optic nerve injury. In addition, iTrkB expression in the retina was also effective in an optic tract transection model, in which the injury site is near the superior colliculus. Regenerating axons successfully formed pathways to their brain targets, resulting in partial recovery of visual behavior. Our system may also be applicable to other trophic factor signaling pathways and lead to a significant advance in the field of gene therapy for neurotrauma and neurodegenerative disorders, including glaucoma.

Vogt-Koyanagi-Harada disease developed during chemotherapy for Hodgkin lymphoma: a case report.

BACKGROUND: Ocular manifestations are known for non-Hodgkin lymphoma, but are rare for Hodgkin lymphoma. We report a case of Vogt-Koyanagi-Harada (VKH) disease presenting as serous retinal detachment and uveitis in both eyes in a child undergoing chemotherapy for Hodgkin lymphoma. CASE PRESENTATION: The patient was a 7-year-old boy with stage IIB Hodgkin lymphoma (nodular lymphocyte predominant type) who was undergoing chemotherapy, including 2 cycles of the OEPA regimen and 1 cycle of the COPDAC regimen. Two days after the end of the COPDAC regimen, the patient complained of headache and of blurred and decreased vision in both eyes. On the basis of optic symptoms, such as uveitis and serous retinal detachment in both eyes, increased cell counts in cerebrospinal fluid, and positivity for human leukocyte antigen (HLA)-DR4 in peripheral blood cells, incomplete VKH disease was diagnosed. Intravenous treatment with high-dose prednisolone (60mg/m2/day) for 7 days improved both visual acuity and serous retinal detachment and enabled the remains of the COPDAC chemotherapy cycle to be administered. With prednisolone treatment, visual acuity improved from 20/500 to 20/20 in the right eye and from 20/63 to 20/25 in the left eye. Because multiple vitiligo lesions later appeared in the abdomen, complete VKH disease was finally diagnosed. CONCLUSION: The onset of VKH disease occurred during chemotherapy for Hodgkin lymphoma. The patient was HLA-DR4-positive and might have had a predisposition to develop autoimmune diseases, including VKH disease. However, the anticancer drugs administered to this patient have not been reported to cause uveitis. Whether Hodgkin lymphoma triggered the development of VKH remains unclear. Early diagnosis of VKH disease and prompt treatment with high-dose prednisone enabled the patient to maintain good visual function despite chemotherapy for Hodgkin lymphoma.

Association Between Days of the Week and Intraocular Pressure: Japan Ningen Dock Study.

PRCIS: The analysis of intraocular pressure (IOP) by day of the week using the mega database showed a periodic weekly pattern with the highest value on Monday. PURPOSE: To evaluate IOP by the day of the week. PATIENTS AND METHODS: Annual health checkup examinees between April 2014 and March 2015 were cross-sectionally evaluated. As a result, 655,818 participants [51.5±10.5 (range: 20-96) years, 40.1% women] from 103 medical centers were included. IOP was measured using a noncontact tonometer. The mean IOPs of each day of the week were compared using multiple comparison test and multiple linear regression analysis. Wednesday was set as the reference. Moreover, weekly IOP variations stratified by sex and age were also evaluated. RESULTS: Mean IOPs from Monday to Sunday were 13.19±2.97, 13.06±2.92, 13.05±2.91, 13.05±2.92, 13.12±2.94, 13.10±2.96, and 13.16±2.78 mm Hg. IOP was significantly higher on Monday, Friday, and Saturday than those on Wednesday ( P <0.001, <0.001, 0.002). After adjusting for factors affecting IOP, the IOPs on Monday and Saturday were higher than those on Wednesday [ß=0.097 (95% CI: 0.074-0.121), P <0.001; ß=0.032 (95% CI: 0.005-0.059), P =0.019]. Men had significantly higher IOPs on Monday and Saturday than on Wednesday [ß=0.142 (95% CI: 0.110-0.173), P <0.001; ß=0.053 (95% CI: 0.017-0.089), P =0.004], whereas women did not have a significant trend. Participants aged below 65 years had higher IOPs on Monday ( P <0.001 in under 60 years; P =0.003 in 60-64 years), while those aged 65 years or older did not ( P =0.856). CONCLUSION: IOP values may have a periodic weekly pattern. The high IOP on Monday was more pronounced in men aged less than 65 years.

Comparative Evaluation of Fundus Image Interpretation Accuracy in Glaucoma Screening Among Different Physician Groups.

Purpose: To examine the variability in glaucoma screening using fundus images among physicians, including non-ophthalmologists. Patients and Methods: Sixty-nine eyes from 69 patients, including 25 eyes with glaucoma, were included from the Jikei University Hospital from July 2019 to December 2022. Fundus images were captured using TRC-NW8 (Topcon Corporation, Tokyo, Japan), and were interpreted by 10 non-ophthalmologists, 10 non-specialist ophthalmologists, and 9 specialists for diagnostic accuracy. We analyzed differences in diagnostic accuracy among the three groups. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and Kappa coefficient were compared, using the Kruskal-Wallis test followed by a post hoc Dunn's test. Results: The sensitivity and specificity were 0.22 and 0.92 for non-ophthalmologists, 0.49 and 0.83 for non-specialist ophthalmologists, and 0.68 and 0.87 for specialists, respectively. Both specialists and non-specialist ophthalmologists showed significantly higher sensitivity than non-ophthalmologists (Dunn's test, P<0.001 and P=0.031). There was no significant difference in specificity among the three groups (Kruskal-Wallis test, P=0.086). The PPV did not differ significantly between the groups (Kruskal-Wallis test, P=0.108), while the NPV was significantly higher in specialists compared to non-ophthalmologists (Dunn's test, P<0.001). Specialists also had a significantly higher Kappa coefficient than non-ophthalmologists and non-specialist ophthalmologists (Dunn's test, P<0.001 and P=0.024). Conclusion: Diagnostic accuracy varied significantly based on the physician's background.

Effects of constitutively active K-Ras on axon regeneration after optic nerve injury.

Visual disturbance after optic nerve injury is a serious problem. Attempts have been made to enhance the intrinsic ability of retinal ganglion cells (RGCs) to regenerate their axons, and the importance of PI3K/Akt and RAF/MEK/ERK signal activation has been suggested. Since these signals are shared with oncogenic signaling cascades, in this study, we focused on a constitutively active form of K-Ras, K-RasV12, to determine if overexpression of this molecule could stimulate axon regeneration. We confirmed that K-RasV12 phosphorylated Akt and ERK in vitro. Intravitreal delivery of AAV2-K-RasV12 increased the number of surviving RGCs and promoted 1.0 mm of axon regeneration one week after optic nerve injury without inducing abnormal proliferative effects in the RGCs. In addition, AAV2-K-RasV12 induced robust RGC axon regeneration, reaching as far as approximately 2.5 mm from the injury site, in eight weeks. Our findings suggest that AAV2-K-RasV12 could provide a good model for speedy and efficient analysis of the mechanism underlying axon regeneration in vivo.

A Novel Visual Field Screening Program for Glaucoma With a Head-Mounted Perimeter.

PRCIS: A novel visual field screening program with a head-mounted perimeter 'imo' could detect glaucoma at all stages in a short time with high accuracy. PURPOSE: The present study aimed to examine the accuracy and availability of a novel glaucoma visual field screening program using a head-mounted visual perimeter 'imo.' PARTICIPANTS AND METHODS: Eyes of 76 non-glaucoma participants and 92 glaucoma patients were examined. All patients underwent visual field tests using the Humphrey Visual Field Analyzer (30-2 or 24-2 Swedish Interactive Thresholding Algorithm standard program) and imo (the visual field screening program). We evaluated five visual field screening program indicators: sensitivity, specificity, positive predictive value, negative predictive value, and testing time. We also evaluated the ability of this visual field screening program to differentiate between glaucoma patients and normal controls using the receiver operating characteristic curves and areas under the receiver operating characteristic curves. RESULTS: The sensitivity, specificity, positive predictive value, and negative predictive value of the visual field screening program were 76%-100%, 91%-100%, 86%-89%, and 79%-100%, respectively. The visual field screening program test time was 46±13 seconds for normal controls and 61±18, 82±21, and 105±16 econds, respectively for mild, moderate, and advanced-stage patients. The areas under the receiver operating characteristic curves were 0.77, 0.97, and 1.0 in the mild, moderate, and advanced stages, respectively. CONCLUSIONS: Visual field screening using a head-mounted perimeter 'imo' detected glaucoma at all stages in a short time with high accuracy.

Neuroprotection and axon regeneration by novel low-molecular-weight compounds through the modification of DOCK3 conformation.

Dedicator of cytokinesis 3 (DOCK3) is an atypical member of the guanine nucleotide exchange factors (GEFs) and plays important roles in neurite outgrowth. DOCK3 forms a complex with Engulfment and cell motility protein 1 (Elmo1) and effectively activates Rac1 and actin dynamics. In this study, we screened 462,169 low-molecular-weight compounds and identified the hit compounds that stimulate the interaction between DOCK3 and Elmo1, and neurite outgrowth in vitro. Some of the derivatives from the hit compound stimulated neuroprotection and axon regeneration in a mouse model of optic nerve injury. Our findings suggest that the low-molecular-weight DOCK3 activators could be a potential therapeutic candidate for treating axonal injury and neurodegenerative diseases including glaucoma.

Factors Determining the Morphology of Peripapillary Retinoschisis.

PURPOSE: We conducted cross-sectional examinations to determine the frequency of peripapillary retinoschisis (PRS) in eyes with glaucoma and suspected glaucoma and analyzed the pathogenesis of PRS by using spectral-domain optical coherence tomography (SD-OCT). PATIENTS AND METHODS: In 1516 cases involving glaucoma and suspected glaucoma, we retrospectively reviewed the disc and macular volume scans obtained by SD-OCT and categorized PRS into two groups based on whether the retinoschisis was closer to the optic nerve over the Bruch's membrane opening (BMO) (ahead group) or did not go past the BMO (behind group) and then compared the characteristics between both groups. RESULTS: The total frequency of PRS was 1.49% (20/1342 eyes) in primary open-angle glaucoma (POAG) eyes and 0.59% (10/1687 eyes) in glaucoma suspects. In the behind group, PRS was mostly detected in the inner layers of the retina (retinal nerve fiber layer: 30.9%, ganglion cell layer: 21.8%, inner plexiform layer: 7.3%). However, in the ahead group, PRS was detected in the outer layers (inner nuclear layer: 10%, outer plexiform layer: 20%, outer nuclear layer: 50%). In addition, the eyes in the ahead group had significantly greater axial lengths and significantly smaller spherical equivalent values. These two differences suggest that the pulling force of the vitreous traction may play an important role in PRS only in the behind group and that the scleral stretching force may play a role in the development of PRS in the ahead group. CONCLUSION: The frequency of PRS in patients with POAG is higher than that in patients with suspected glaucoma. Both forms of PRS are affected by posterior vitreous detachment and axial length elongation. Careful follow-up is required to assess the development of PRS in glaucoma suspects. The pathogenesis of PRS has been elucidated to some degree by classifying the morphological condition of the PRS and BMO.

Vision Improvement after Osimertinib Treatment in Paraneoplastic Optic Neuropathy Associated with Lung Adenocarcinoma.

Treatments for paraneoplastic optic neuropathy (PON), a tumor-related autoimmune disease, include immunosuppression, plasma exchange, and immunoglobulin therapies, as well as treatment of the underlying disease. Herein, we describe the clinical course of an older adult patient with PON whose loss of vision improved after switching between epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatments for cancer. A 76-year-old woman, who had been treated with gefitinib for lung adenocarcinoma for two years, presented with acute bilateral visual disturbances. Her decimal best-corrected visual acuity (BCVA) was 0.3 in the right eye (RE) and 0.7 in the left eye (LE). Slit-lamp examination and funduscopy showed no abnormal findings. Two weeks later, her BCVA decreased to 0.2 in the RE and 0.01 in the LE. Goldman's perimetry showed a defect in the lower nasal RE and extensive visual-field loss in the LE. Single-flash electroretinograms showed normal amplitudes. Magnetic resonance imaging revealed left optic neuritis and showed neither metastatic cancer nor multiple sclerosis. Pattern-reversal visual evoked potentials showed decreased P100 amplitudes in both eyes (BE). Based on a diagnosis of PON from clinical findings, methylprednisolone pulse treatment was administered. However, her BCVA became no light perception in BE two months after the first visit. Because the tumor tissue was found to be positive for the EGFR T790M resistance mutation by bronchoscopy, the EGFR-TKI treatment was changed to osimertinib, decreasing the size of the lung cancer lesions. Her BCVA improved to hand motion in BE. Her final BCVA was 0.01 in the RE, counting fingers 10 cm in the LE. She died at the age of 79 years. To our knowledge, no reports have shown improvement in BCVA in patients with PON after changing EGFR-TKI treatments. This report indicates that some patients may develop severe visual dysfunction without early treatment for the primary tumor.

Effect of Lecithin-Bound Iodine Treatment on Inherited Retinal Degeneration in Mice.

Purpose: Although lecithin-bound iodine (LBI) has been administered orally for retinal diseases, a lack of clinical studies and obscure action mechanism of LBI hinder its large-scale prescription. LBI treatment suppresses chemokine (C-C motif) ligand 2 (CCL2) secretion from retinal pigment epithelial cells in vitro. Herein, we assessed the in vivo effect of LBI treatment on retinal degeneration (RD) in mice. Methods: Mertk-/-Cx3cr1GFP/+Ccr2RFP/+ mice-a model for RD-demonstrate fluorescein-labeled microglia/macrophage to facilitate visualization of CX3CR1-green fluorescent protein (GFP) and CCR2-red fluorescent protein (RFP). An LBI-containing mouse diet was provided to Mertk-/-Cx3cr1GFP/+Ccr2RFP/+ mice ad libitum from postnatal day (POD) 28. CX3CR1-GFP and CCR2-RFP expression was assessed at POD 56 using retinal sectioning and flat mounting. RD severity was assessed at POD 84. Retinal RNA was extracted from the mice of each group to measure chemokine expression. Electroretinography was performed to assess retinal function. Results: CCR2-RFP expression in the retina and retinal pigment epithelial cells was suppressed by LBI treatment compared with that in the control at POD 56. The number of outer nuclear layer nuclei was higher in the group fed with LBI-containing diet than in the control mice at POD 84. Ccl2 and Ccr2 RNA expression was suppressed by LBI intake. Electroretinography showed the LBI-treated group to have a high b-wave amplitude compared with the control group. Conclusions: Suppressing CCR2-RFP-positive macrophage invasion into the retina and CCL2 and CCR2 expression is a potential mechanism underlying LBI-mediated attenuation of RD. Translational Relevance: Life-long LBI administration may become a candidate for treating RD.

Topical ripasudil stimulates neuroprotection and axon regeneration in adult mice following optic nerve injury.

Optic nerve injury induces optic nerve degeneration and retinal ganglion cell (RGC) death that lead to visual disturbance. In this study, we examined if topical ripasudil has therapeutic potential in adult mice after optic nerve crush (ONC). Topical ripasudil suppressed ONC-induced phosphorylation of p38 mitogen-activated protein kinase and ameliorated RGC death. In addition, topical ripasudil significantly suppressed the phosphorylation of collapsin response mediator protein 2 and cofilin, and promoted optic nerve regeneration. These results suggest that topical ripasudil promotes RGC protection and optic nerve regeneration by modulating multiple signaling pathways associated with neural cell death, microtubule assembly and actin polymerization.