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We evaluated the efficacy and safety of loading phase treatment with intravitreal brolucizumab for neovascular age-related macular degeneration (nAMD) with type 1 choroidal neovascularization (CNV). We analyzed consecutive 42 eyes of 40 patients with treatment-naïve nAMD associated with type 1 CNV. Three monthly injections of brolucizumab were completed in 36 eyes (85.7%). In those cases, best-corrected visual acuity (BCVA) was 0.24 ± 0.27 at baseline and improved significantly to 0.12 ± 0.23 after 3 months (P < 0.001). Central macular thickness was 301 ± 110 µm at baseline and decreased significantly to 160 ± 49 µm after 3 months (P < 0.001). Dry macula was achieved in 34 eyes (94.4%) after the loading phase. Central choroidal thickness was 264 ± 89 µm at baseline and decreased significantly to 223 ± 81 µm after 3 months (P < 0.001). Indocyanine green angiography after the loading phase revealed complete regression of polypoidal lesions in 15 of the 19 eyes (78.9%) with polypoidal lesions. Non-infectious intraocular inflammation (IOI) was observed in 8 of 42 eyes (19.0%) during the loading phase, while showing amelioration in response to combination therapy with topical and subtenon injection of steroids. In these eyes, BCVA after 3 months had not deteriorated as compared to that at baseline. These results indicate that loading phase treatment with intravitreal brolucizumab might be effective for improving visual acuity and reducing exudative changes in eyes with nAMD associated with type 1 CNV. Moreover, polypoidal lesions appear to frequently regress after this treatment. However, we must monitor patients carefully for brolucizumab-related IOI, and administer steroid therapy promptly.

GABAergic interneurons play a critical role in tuning neural networks in the central nervous system, and their defects are associated with neuropsychiatric disorders. Currently, the mDlx enhancer is solely used for adeno-associated virus (AAV) vector-mediated transgene delivery into cortical interneurons. Here, we developed a new inhibitory neuron-specific promoter (designated as the mGAD65 promoter), with a length of 2.5 kb, from a mouse genome upstream of exon 1 of the Gad2 gene encoding glutamic acid decarboxylase (GAD) 65. Intravenous infusion of blood-brain barrier-penetrating AAV-PHP.B expressing an enhanced green fluorescent protein under the control of the mGAD65 promoter transduced the whole brain in an inhibitory neuron-specific manner. The specificity and efficiency of the mGAD65 promoter for GABAergic interneurons, which was assessed at the motor cortex, were almost identical to or slightly higher than those of the mDlx enhancer. Immunohistochemical analysis revealed that the mGAD65 promoter preferentially transduced parvalbumin (PV)-expressing interneurons. Notably, the mGAD65 promoter transduced chandelier cells more efficiently than the mDlx enhancer and robustly labeled their synaptic boutons, called the cartridge, targeting the axon initial segments of excitatory pyramidal neurons. To test the ability of the mGAD65 promoter to express a functional molecule, we virally expressed G-CaMP, a fluorescent Ca 2+ indicator, in the motor cortex, and this enabled us to monitor spontaneous and drug-induced Ca 2+ activity in GABAergic inhibitory neurons. These results suggest that the mGAD65 promoter is useful for AAV-mediated targeting and manipulation of GABAergic neurons with the dominance of cortical PV-expressing neurons, including chandelier cells.

Purpose: To investigate clinical outcomes of vitrectomy for intractable diabetic macular edema (DME) in which anti-vascular endothelial growth factor (anti-VEGF) agents or periocular steroid were not effective., Methods: This retrospective study examined 27 eyes of 25 cases. The main measurements included changes in visual acuity (VA) and retinal morphology. Vitrectomies were performed using the Constellation System 25G., Results: Prior to undergoing vitrectomy, patients were treated with anti-VEGF agents or periocular injection of triamcinolone acetonide. The average number of anti-VEGF agent injections was 3.1 ± 2.8. Triamcinolone was used in 15 eyes. There was no significant change in the mean logMAR best-corrected visual acuity (BCVA) between baseline and posttreatment, with values of 0.49 ± 0.29 and 0.55 ± 0.33, respectively (P = 0.31). Compared with preoperative BCVA, postoperative BCVA improved by more than two lines in 4 eyes (14%), remained the same in 17 eyes (63%), and decreased in 6 eyes (23%). Morphologically, retinal thickness improved by more than 50 μm in 16 eyes (59%), remained unchanged in 7 eyes (26%), and increased in 5 eyes (18%). Retinal edema resolved in all of the cases in which macular epiretinal membrane (ERM) or vitreomacular traction (VMT) was detected by optical coherence tomography during pretreatment., Conclusions: Vitrectomy can potentially stabilize the retinal morphology in intractable DME and is likely more effective in DME cases accompanied by ERM or VMT.

Purpose: To investigate changes of vascular density in the choroid of patients with polypoidal choroidal vasculopathy treated with photodynamic therapy (PDT) combined with intravitreal aflibercept., Methods: This study examined 12 eyes of 12 patients, who were diagnosed as polypoidal choroidal vasculopathy. All patents underwent optical coherence tomography before and at 3 months after PDT combined with intravitreal aflibercept treatment. Using en face optical coherence tomography images, we analyzed vascular density of the area outside the polypoidal choroidal vasculopathy lesion and within the PDT exposure area at the level of the choriocapillaris and middle layer of the choroid. In the outer layer of the choroid, the thickest vessel was selected in the area exposed to PDT, with the diameter of the vessel analyzed., Results: The vascular density in the choriocapillaris and middle layer of the choroid significantly decreased from 0.54 ± 0.09 before treatment to 0.44 ± 0.07 after PDT treatment in the choriocapillaris and from 0.53 ± 0.10 to 0.47 ± 0.08 in the middle layer of the choroid, respectively. There was also a significant reduction in the diameter of the largest vessel from 309 ± 85 µm at baseline to 220 ± 52 µm., Conclusion: Photodynamic therapy may cause occlusion of the choriocapillaris and middle vessels in the choroid, as well as stenosis of the large vessels.

Pachychoroid spectrum diseases have attracted increasing attention, though their pathophysiology has yet to be fully elucidated. In this study, we assessed the vascular diameters of vortex veins in pachychoroid spectrum diseases such as central serous chorioretinopathy (CSC), pachychoroid neovasculopathy without polypoidal lesions (PNV), and pachychoroid neovasculopathy with polypoidal lesions (polypoidal choroidal vasculopathy: PCV). In a retrospective case series of 94 eyes with CSC, 60 eyes with PNV and 57 with PCV, we binarized en face optical coherence tomography (OCT) images of choroidal vortex veins and analyzed the mean diameter of vortex veins. The presence of anastomosis between the superior and inferior vortex veins and central choroidal thickness (CCT) were also evaluated using OCT images. CSC showed significantly larger mean diameter of vortex veins than PCV (P < 0.05). Anastomosis between superior and inferior vortex veins was observed in over 90% of eyes with each pachychoroid spectrum disease. The patients with CSC were the youngest, followed by PNV patients, and then patients with PCV. The largest CCT values were observed in CSC eyes, followed by PNV eyes, and then PCV eyes. CCT correlated with the mean diameter of vortex veins (rs = 0.51, P < 0.01). These findings suggest that congestion of vortex veins might show gradual amelioration corresponding to the development of anastomosis between the superior and inferior vortex veins during the course of progression of pachychoroid spectrum diseases. Moreover, the mean diameter of vortex veins can be used as a parameter indicating choroidal congestion.

Purpose: To evaluate the vascular changes in vortex veins at the posterior pole in pachychoroid spectrum diseases, including central serous chorioretinopathy (CSC), pachychoroid neovasculopathy without polypoidal lesions (PNV), and pachychoroid neovasculopathy with polypoidal lesions (polypoidal choroidal vasculopathy [PCV])., Design: Retrospective case-control study., Participants: Ninety-two eyes of 89 patients with CSC, 61 eyes of 59 patients with PNV, 63 eyes of 61 patients with PCV, and 25 healthy control eyes of 25 age- and gender-matched participants for each pachychoroid spectrum disease., Methods: Clinical records of patients with pachychoroid spectrum diseases and healthy controls were reviewed. Multimodal images of each group were analyzed. Swept-source OCT was performed to obtain B-mode and en face images in patients with pachychoroid spectrum diseases and healthy controls. All patients underwent fluorescein angiography, indocyanine green angiography, and OCT., Main Outcome Measures: Vortex vein anastomosis at the watershed, determined using en face OCT, and central choroidal thickness (CCT), measured using B-mode OCT, were examined in patients and healthy controls. Patient ages also were taken into consideration., Results: Patients with CSC were the youngest, followed by patients with PNV, and then those with PCV (P < 0.01, CSC vs. PNV and PNV vs. PCV), whereas CSC eyes showed the highest CCT values, followed by the PNV and then the PCV eyes (P < 0.01, CSC vs. PNV; P < 0.05, PNV vs. PCV). Central choroidal thickness was significantly greater in pachychoroid spectrum diseases than in healthy controls. No significant CCT differences were found among healthy controls. Anastomosis between superior and inferior vortex veins was observed in more than 90% of eyes with pachychoroid spectrum diseases, making this finding significantly more frequent than in healthy controls (P < 0.01, each pachychoroid spectrum disease vs. control). Polypoidal choroidal vasculopathy showed a significantly higher rate of anastomosis than CSC (P < 0.05)., Conclusions: Anastomosis between superior and inferior vortex veins was found to be a common feature in pachychoroid spectrum diseases. Longstanding vortex vein congestion may lead to the development of pachychoroid spectrum diseases. Choroidal congestion may be compensated for by new drainage routes formed via vortex vein anastomosis., (Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the 1-year efficacy of half-fluence photodynamic therapy (HFPDT) combined with intravitreal aflibercept injection on treatment-naïve pachychoroid neovasculopathy (PNV) without polypoidal lesions., Study Design: Retrospective, interventional case series PATIENTS AND METHODS: We retrospectively studied 21 eyes with treatment-naïve PNV and assessed the best-corrected visual acuity (BCVA), central macular thickness (CMT), central choroidal thickness (CCT), pachyvessel vertical diameter, and choroidal neovascularization thickness (CNVT) at the fovea over a 12-month period., Results: The median BCVA was 0.15 at baseline, 0.00 (P < .05) at 3 months, 0.05 at 6 months, and -0.08 (P < .05) at 12 months. The BCVA was significantly improved at 3 months and 12 months as compared with the baseline BCVA. The median CMT was 230 μm at baseline, 140 μm (P < .01) at 3 months, 150 μm (P < .01) at 6 months, and 150 μm (P < .01) at 12 months. The median CCT was 386 μm at baseline, 347 μm (P < .01) at 3 months, 331 μm (P < .01) at 6 months, and 352 μm (P < .01) at 12 months. The median pachyvessel vertical diameter was 309 μm at baseline, 246 μm (P < .01) at 3 months, 232 μm (P < .01) at 6 months, and 242 μm (P < .01) at 12 months. The median CNVT was 28 μm at baseline, 17 μm (P < .01) at 3 months, 19 μm (P < .05) at 6 months, and 21 μm (P < .05) at 12 months. The CMT, CCT, pachyvessel vertical diameter, and CNVT were significantly decreased at 3, 6, and 12 months as compared with those at baseline. Whilst 17 eyes (81.0%) showed no signs of CNV recurrence during the 12-month period, 4 eyes (19.0%) required additional combination therapy., Conclusions: HFPDT combined with intravitreal aflibercept injection may effectively improve BCVA and ameliorate exudative changes in eyes with PNV without polypoidal lesions for up to 1 year.

Purpose: To investigate the clinical characteristics of eyes with cuticular drusen in Japanese individuals, while paying special attention to large colloid drusen (LCD)., Study Design: Retrospective case series., Methods: Eyes with cuticular drusen, from patients of 4 medical institutes in Japan, were investigated. Multimodal imaging findings were used to diagnose cuticular drusen. LCD was defined as cuticular drusen > 200 µm., Results: Twenty-four eyes from 12 patients (8 women, 4 men) were diagnosed with cuticular drusen. The mean age of all patients (n = 12) was 60.8 years. The mean age of patients without additional macular pathology (n = 5) was 55.4 years. Of the 7 patients with additional macular pathology, 6 (85.7%) exhibited age-related macular degeneration-associated macular pathology, including drusenoid pigment epithelial detachment (PED) (8 eyes from 4 patients), geographic atrophy (2 eyes from 1 patient), and occult choroidal neovascularization (1 eye). LCD were found in 6 eyes of 3 patients (25%), those with LCD were on average 53.7 ± 8.7 years old and those without 69.9 ± 14.1 years of age (P = 0.064, Mann-Whitney U test)., Conclusions: Cuticular drusen were predominantly seen in females, and drusenoid PED was most frequently seen in eyes with additional macular pathology. LCD were seen in 25% of eyes with cuticular drusen.

Superior and inferior macular vortex veins are divided by a horizontal watershed passing through the macula. We evaluated macular vortex vein remodeling in eyes with pachychoroid neovasculopathy (PNV). Thirty eyes of 30 patients with treatment-naïve PNV and 30 normal eyes of 30 age-, gender-, and refraction-matched subjects were studied. We assessed the features of macular vortex veins employing en face optical coherence tomography (OCT) and determined central choroidal thickness (CCT) using B-mode OCT. Of the 30 normal eyes, a horizontal watershed was identified in 24 eyes (80%), while venous anastomosis between the superior and inferior vortex veins was observed in 6 eyes (20%). Mean CCT was 233 μm. Of the 30 eyes with PNV, vortex veins were dilated in all 30 eyes with PNV. In 27 of the 30 PNV eyes (90%), the horizontal watershed had disappeared, and collateral veins had instead developed via anastomosis between the superior and inferior vortex veins, making this finding significantly more frequent than in normal eyes (P < 0.001). Mean CCT was 357 μm, significantly thicker than that of normal eyes (P < 0.001). Remodeling of choroidal drainage routes by venous anastomosis between superior and inferior vortex veins was common in eyes with PNV. This observation suggests longstanding congestion of the choroidal veins.

Purpose: To evaluate the clinical characteristics of pachydrusen in central serous chorioretinopathy (CSC) and investigate the relationship between choroidal circulation and pachydrusen., Methods: In a retrospective case series of 302 eyes of 151 patients with treatment-naïve CSC, we assessed the incidence of pachydrusen and their features on indocyanine green angiography (ICGA) and optical coherence tomography (OCT)., Results: Pachydrusen were observed in 82 of the 302 eyes (27.2%). The patients with pachydrusen were significantly older than those without pachydrusen. In 36 of the 82 eyes with pachydrusen, the choriocapillaris perfusion phase of ICGA was recorded. Pachydrusen were localized within the geographic filling delay of the choriocapillaris in 26 of the 36 eyes (72.2%). In the late phase of ICGA, pachydrusen corresponded to punctate hyperfluorescent spots in 69 of the 82 eyes (84.1%) and localized within sites of choroidal vascular hyperpermeability in 45 eyes (54.9%). En face OCT revealed pachydrusen to be localized over the dilated outer choroidal vessels in 70 of the 82 eyes (85.4%). B-mode OCT showed pachydrusen under the retinal pigment epithelium (RPE) in 72 of the 82 eyes (87.8%). There was no significant difference in central choroidal thickness between eyes with and without pachydrusen., Conclusions: Pachydrusen in patients with CSC were frequently localized within the choriocapillaris filling delay and over the dilated outer choroidal vessels. Moreover, they were frequently observed under the RPE and corresponded to punctate hyperfluorescent spots on ICGA. These findings suggest that inner choroidal circulation impairment due to dilatation of outer choroidal vessels might induce pachydrusen.

Autoimmune uveitis is a sight-threatening ocular inflammatory condition in which the retina and uveal tissues become a target of autoreactive immune cells. While microglia have been studied extensively in autoimmune uveitis, their exact function remains uncertain. The objective of the current study was to determine whether resident microglia are necessary and sufficient to initiate and amplify retinal inflammation in autoimmune uveitis. In this study, we clearly demonstrate that microglia are essential for initiating infiltration of immune cells utilizing a murine model of experimental autoimmune uveoretinitis (EAU) and the recently identified microglia-specific marker P2ry12. Initiating disease is the primary function of microglia in EAU, since eliminating microglia during the later stages of EAU had little effect, indicating that the function of circulating leukocytes is to amplify and sustain destructive inflammation once microglia have triggered disease. In the absence of microglia, uveitis does not develop, since leukocytes cannot gain entry through the blood-retinal barrier, illustrating that microglia play a critical role in regulating infiltration of inflammatory cells into the retina., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 the Author(s). Published by PNAS.)

Retinal detachment (RD) is a sight-threatening complication common in many highly prevalent retinal disorders. RD rapidly leads to photoreceptor cell death beginning within 12 h following detachment. In patients with sustained RD, progressive visual decline due to photoreceptor cell death is common, leading to significant and permanent loss of vision. Microglia are the resident immune cells of the central nervous system, including the retina, and function in the homeostatic maintenance of the neuro-retinal microenvironment. It is known that microglia become activated and change their morphology in retinal diseases. However, the function of activated microglia in RD is incompletely understood, in part because of the lack of microglia-specific markers. Here, using the newly identified microglia marker P2ry12 and microglial depletion strategies, we demonstrate that retinal microglia are rapidly activated in response to RD and migrate into the injured area within 24 h post-RD, where they closely associate with infiltrating macrophages, a population distinct from microglia. Once in the injured photoreceptor layer, activated microglia can be observed to contain autofluorescence within their cell bodies, suggesting they function to phagocytose injured or dying photoreceptors. Depletion of retinal microglia results in increased disease severity and inhibition of macrophage infiltration, suggesting that microglia are involved in regulating neuroinflammation in the retina. Our work identifies that microglia mediate photoreceptor survival in RD and suggests that this effect may be due to microglial regulation of immune cells and photoreceptor phagocytosis., Competing Interests: The authors declare no conflict of interest., (Copyright © 2018 the Author(s). Published by PNAS.)

Purpose: To study the association between peripheral changes in age-related macular degeneration (AMD) and dark adaptation (DA)., Design: Prospective, cross-sectional study., Methods: We recruited patients with AMD and a control group (>50 years) without any vitreoretinal disease. Ultra-widefield (UWF) pseudocolor and fundus autofluorescence (FAF) were obtained, and were assessed by 2 graders for the presence of several peripheral changes in perimacular, midperipheral, and far-peripheral zones. All participants were also imaged with 7-field color fundus photographs used for AMD staging (Age-Related Eye Disease Study classification system). Both eyes of study participants were tested with a dark adaptation (DA) extended protocol (20 minutes). Multilevel mixed-effect models (accounting for correlated outcomes between 2 eyes) were used for analyses., Results: We included 128 eyes (n = 72 patients), 75% with AMD and the remainder controls. The presence of reticular pigmentary changes in the midperipheral (ß = 4.3, P = .012) and far-peripheral zones (ß = 8.4, P < .001) was associated with delayed rod-intercept times (RITs), even after adjusting for confounding factors. The presence, number, and extent of peripheral classic drusen did not show a similar association (P ≥ .148). The presence of a mottled decreased FAF pattern in the midperipheral zone was also associated with prolonged RITs (β = 4.4, P = .031)., Conclusion: Our results suggest an association between DA and the presence of peripheral reticular pigmentary changes, as well as the presence of a peripheral mottled decreased FAF pattern. This provides new insights on the clinical significance of peripheral changes in AMD, and their contribution to impairments on DA., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The common marmoset is a small New World primate that has attracted remarkable attention as a potential experimental animal link between rodents and humans. Adeno-associated virus (AAV) vector-mediated expression of a disease-causing gene or a potential therapeutic gene in the brain may allow the construction of a marmoset model of a brain disorder or an exploration of the possibility of gene therapy. To gain more insights into AAV vector-mediated transduction profiles in the marmoset central nervous system (CNS), we delivered AAV serotype 9 (AAV9) vectors expressing GFP to the cisterna magna or the cerebellar cortex. Intracisternally injected AAV9 vectors expanded in the CNS according to the cerebrospinal fluid (CSF) flow, by retrograde transport through neuronal axons or via intermediary transcytosis, resulting in diffuse and global transduction within the CNS. In contrast, cerebellar parenchymal injection intensely transduced a more limited area, including the cerebellar cortex and cerebellar afferents, such as neurons of the pontine nuclei, vestibular nucleus and inferior olivary nucleus. In the spinal cord, both administration routes resulted in labeling of the dorsal column and spinocerebellar tracts, presumably by retrograde transport from the medulla oblongata and cerebellum, respectively. Motor neurons and dorsal root ganglia were also transduced, possibly by diffusion of the vector down the subarachnoid space along the cord. Thus, these two administration routes led to distinct transduction patterns in the marmoset CNS, which could be utilized to generate different disease animal models and to deliver therapeutic genes for the treatment of diseases affecting distinct brain areas.