Two cases of diabetic macular edema with diminished areas of retinal non-perfusion and microaneurysms after intravitreal faricimab injections.

Purpose: To report two cases of diabetic macular edema (DME) treated with intravitreal faricimab injections (IVFs), including the assessment of retinal microaneurysms and extent of retinal capillary non-perfusion using fluorescein angiography (FA) and indocyanine green angiography (IA). Observations: Case 1: A 72-year-old man presented with aflibercept-resistant DME in the left eye, with a best-corrected visual acuity (BCVA) of 20/16. FA showed areas of retinal capillary non-perfusion and focal leakage in the macular area of the left eye. IA revealed numerous microaneurysms in the temporal region of the macula. Four consecutive monthly IVFs were administered to the left eye, and DME eventually diminished. After the loading phase, the BCVA was maintained at 20/16 with reduced visual distortion. FA showed improvement of macular leakage and stable retinal capillary non-perfusion areas, and the foveal avascular zone was clearly observed. The disappearance of numerous microaneurysms was confirmed on IA images.Case 2: An 80-year-old woman developed DME with macular vein occlusion in the left eye after panretinal laser photocoagulation for proliferative diabetic retinopathy. The patient's BCVA was 20/32. DME was resistant to subtenon triamcinolone injections. FA revealed focal areas of retinal capillary non-perfusion and persistent leakage in the macular area of the left eye. IA revealed scattered microaneurysms within the retinal arcade. Four consecutive monthly IVFs were administered to the left eye, and DME eventually diminished. After the loading phase, the BCVA was maintained at 20/32. FA showed improvement of macular leakage and stable retinal capillary non-perfusion areas. The reduction of microaneurysms was confirmed on IA images. Conclusions and importance: These case reports highlight the potential of faricimab as an alternative anti-vascular endothelial growth factor drug for treatment-resistant DME, including reduction of retinal microaneurysms and stabilization of the areas of retinal capillary non-perfusion. However, continuation of a robust treatment regimen may be required to achieve these objectives.

Effects of Lutein Supplementation in Japanese Patients with Unilateral Age-Related Macular Degeneration: The Sakai Lutein Study.

This prospective randomized double-masked study investigated the effects of 20 mg lutein supplementation with two different capsules (beeswax or glycerol fatty acid esters) for 6 months on the fellow eyes of 39 Japanese patients with unilateral age-related macular degeneration, and assessed the factors associated with baseline plasma lutein concentration via lifestyle interviews. Macular pigment optical density (MPOD), determined with the two-wavelength autofluorescence method, increased over time in the beeswax group (ANOVA, p = 0.0451), although the increase from 3 months to 6 months was only marginally significant. No significant increase was observed in the glycerol fatty acid esters group (ANOVA, p = 0.7396). Plasma lutein concentrations significantly increased at 3 and 6 months from baseline in both groups (both p < 0.01). In a multiple regression model, age was negatively associated with higher plasma lutein concentration (p = 0.0305), while consumption of green vegetables was positively associated with baseline plasma lutein concentration (p = 0.0322). In conclusion, a significant increase in MPOD was not fully confirmed with 6 months intake duration despite a significant increase in plasma lutein concentrations. Consumption of green vegetable was confirmed to be associated with plasma lutein concentration after adjusting for other potential factors including age.

Transient extremely shallow anterior chamber caused by ciliochoroidal detachment in a patient with Mycobacterium chelonae keratitis.

PURPOSE: To report a case of Mycobacterium chelonae keratitis that resulted in a transient reduction of anterior chamber depth. OBSERVATIONS: A 46-year-old man with keratoconus and reduced visual acuity (20/286) in his left eye presented with ciliary injection 16 months after femtosecond laser-assisted penetrating keratoplasty (PK). A slit-lamp examination showed a corneal ulcer with infiltrates and edema in both the host and graft between the 3 o'clock and 6 o'clock positions. Microbiologic tests confirmed the presence of M. chelonae. Topical arbekacin and moxifloxacin, erythromycin/colistin ointment, and oral clarithromycin were prescribed. We monitored anterior chamber depth by anterior segment optical coherence tomography (AS-OCT) throughout the recovery period. The anterior chamber depth was normal before treatment, with an intraocular pressure (IOP) of 7 mmHg. Although ciliary injection and infiltrates were gradually resolved, slit-lamp examination and AS-OCT revealed an extreme reduction of anterior chamber depth without corneal perforation, 1 month after beginning treatment. The IOP was 5 mmHg, and ciliochoroidal detachment (CCD) was present. The anterior chamber increased with the resolution of CCD and keratitis. Although hypotony continued despite the resolution of CCD and keratitis, the IOP eventually recovered to ≥10 mmHg at 1 month after remission. Onset and resolution of transient reduction of anterior chamber depth presumably occurred by anterior rotation and recovery of the ciliary body, respectively. Subsequent PK triple surgery enabled visual recovery to 20/100. CONCLUSIONS AND IMPORTANCE: severe anterior segment inflammation due to infectious keratitis may cause CCD and subsequent reduction of anterior chamber depth due to anterior rotation. AS-OCT is a non-invasive and efficient tool for the evaluation of iridociliary structure and the anterior chamber in patients with infectious keratitis.

Changes in Retinal Microvasculature and Visual Acuity After Antivascular Endothelial Growth Factor Therapy in Retinal Vein Occlusion.

Purpose: To investigate the changes in the retinal microvasculature during the course of anti-VEGF therapy in eyes with macular edema due to retinal vein occlusion (RVO) and their association with visual outcomes. Methods: The vessel density (VD) and foveal avascular zone (FAZ) area in the superficial capillary plexus (SCP) and deep capillary plexus (DCP) were quantitatively measured by optical coherence tomography angiography (OCTA) in 48 consecutive eyes with RVO before and 1, 3, 6, 9, and 12 months after anti-VEGF therapy. Anti-VEGF therapy was performed either with ranibizumab or aflibercept following a pro re nata (PRN) regimen. The correlation between post-treatment best-corrected visual acuity (BCVA) and changes in the retinal microvasculature evaluated by OCTA were assessed. Results: The BCVA improved significantly at 12 months (P < 0.001). Better BCVA at 12 months was significantly associated with a better VD in the SCP and DCP both at baseline (R2 = 0.524, P < 0.001 and R2 = 0.457, P < 0.001, respectively) and at 12 months (R2 = 0.521, P < 0.001 and R2 = 0.662, P < 0.001, respectively). Overall, both VD and FAZ did not change significantly during the 12 months. However, the progression of nonperfusion was observed in the SCP in 6 (13%) eyes and in the DCP in 10 (21%) eyes. The number of macular edema recurrence was significantly associated with a decrease in the VD (P = 0.006 [SCP] and P < 0.001 [DCP]) and less visual gain (P = 0.02) after treatment. Conclusions: Anti-VEGF therapy maintains retinal perfusion in most patients with RVO. Preserving retinal perfusion is crucial for better visual outcomes.

Dynamic visualization of RANKL and Th17-mediated osteoclast function.

Osteoclasts are bone resorbing, multinucleate cells that differentiate from mononuclear macrophage/monocyte-lineage hematopoietic precursor cells. Although previous studies have revealed important molecular signals, how the bone resorptive functions of such cells are controlled in vivo remains less well characterized. Here, we visualized fluorescently labeled mature osteoclasts in intact mouse bone tissues using intravital multiphoton microscopy. Within this mature population, we observed cells with distinct motility behaviors and function, with the relative proportion of static - bone resorptive (R) to moving - nonresorptive (N) varying in accordance with the pathophysiological conditions of the bone. We also found that rapid application of the osteoclast-activation factor RANKL converted many N osteoclasts to R, suggesting a novel point of action in RANKL-mediated control of mature osteoclast function. Furthermore, we showed that Th17 cells, a subset of RANKL-expressing CD4+ T cells, could induce rapid N-to-R conversion of mature osteoclasts via cell-cell contact. These findings provide new insights into the activities of mature osteoclasts in situ and identify actions of RANKL-expressing Th17 cells in inflammatory bone destruction.

Use of intravital microscopy and in vitro chemotaxis assays to study the roles of sphingosine-1-phosphate in bone homeostasis.

We describe a method to visualize the migration of osteoclast precursors within intact murine bone -marrow in real time using intravital multiphoton microscopy. Conventionally, cell migration has been evaluated using in vitro systems, such as transmigration assays. Although these methods are convenient for quantification and are highly reproducible, these in vitro assay systems may not accurately reflect in vivo cellular behavior. In addition to in vitro analyses, recent technological progress in two-photon excitation-based laser microscopy has enabled the visualization of dynamic cell behavior deep inside intact living organs. Combining this imaging method with in vitro chemoattraction analyses, we have revealed that sphingosine-1-phosphate (S1P), a lipid mediator enriched in blood, bidirectionally controls the trafficking of osteoclast precursors between the circulation and bone marrow cavities via G protein-coupled receptors (GPCRs).

The role of sphingosine 1-phosphate in migration of osteoclast precursors; an application of intravital two-photon microscopy.

Sphingosine-1-phosphate (S1P), a biologically active lysophospholipid that is enriched in blood, controls the trafficking of osteoclast precursors between the circulation and bone marrow cavities via G protein-coupled receptors, S1PRs. While S1PR1 mediates chemoattraction toward S1P in bone marrow, where S1P concentration is low, S1PR2 mediates chemorepulsion in blood, where the S1P concentration is high. The regulation of precursor recruitment may represent a novel therapeutic strategy for controlling osteoclast-dependent bone remodeling. Through intravital multiphoton imaging of bone tissues, we reveal that the bidirectional function of S1P temporospatially regulates the migration of osteoclast precursors within intact bone tissues. Imaging technologies have enabled in situ visualization of the behaviors of several players in intact tissues. In addition, intravital microscopy has the potential to be more widely applied to functional analysis and intervention.