Short-term results for brolucizumab in treatment-naïve neovascular age-related macular degeneration: a Japanese multicenter study.

PURPOSE: To investigate short-term treatment outcomes of intravitreal brolucizumab (IVBr) for treatment-naïve neovascular age-related macular degeneration (AMD) in a Japanese multicenter study. STUDY DESIGN: Retrospective case control study METHODS: The subjects were 58 eyes of 57 patients with neovascular AMD (43 men and 14 women, mean age 74.6 years) of whom 43 eyes of 42 patients completed initial loading of 3 monthly IVBr injections and were followed for more than 3 months. Best-corrected visual acuity (BCVA) changes, anatomical outcomes, and complications were investigated. RESULTS: Of the 43 eyes that completed loading doses, the AMD subtype was type 1 and type 2 macular neovascularization (MNV) in 51%, polypoidal choroidal vasculopathy (PCV) in 42%, and type 3 MNV in 7%. At 3 months after initiating treatment, BCVA significantly improved (P = 0.002) and central retinal thickness significantly decreased (P < 0.0001). At 3 months, complete retinal and subretinal fluid resolution was achieved in 91% of all eyes and complete regression of polypoidal lesions was achieved in 82% of PCV eyes. Iritis occurred in 8 eyes of 8 patients (14%), but resolved using topical or subtenon corticosteroid injection without visual loss in all cases. CONCLUSIONS: IVBr for treatment-naïve neovascular AMD was effective in the short-term, achieving significantly improved BCVA, good retinal fluid resolution, and a high rate of polypoidal lesion regression. However, iritis was noted in 14% of patients which may limit use of this drug.

The characteristics of choriocapillaris flow void in the unilateral polypoidal choroidal vasculopathy fellow eyes.

To evaluate the morphological characteristics of flow void (FV) in the fellow eyes of the unilateral polypoidal choroidal vasculopathy (PCV). Fifty PCV fellow eyes (PCVF) and 31 age-matched normal ocular circulation controls were recruited in this retrospective study. The number of FV was analyzed according to the size in a centered 5 × 5 mm swept source optical coherence tomography angiography scans. We used indocyanine green angiography images to determine whether choroidal vascular hyperpermeability (CVH) has occurred. For the PCVF, the prevalence rate of CVH was 70% (35 of 50) The number of FVs was significantly lower in 400-25,000 µm2 (P = 0.005), 400-500 µm2 (P = 0.001), 525-625 µm2 (P = 0.001) and 650-750 µm2 (P = 0.018). compared to the controls. And showed no difference in size from 775 to 1125 µm2 between the two groups. The area under the receiver operating characteristic curve of PCVF with CVH and controls was 0.94 (95% CI 0.88-1.00) (P < 0.001). We found that the number of small FVs was significantly lower in the PCV fellow eyes than that in the eyes with control group.

A modified measuring method to investigate the choriocapillaris flow void of polypoidal choroidal vasculopathy with swept source optical coherence tomography angiography.

BACKGROUND: To propose a modified method to investigate the flow void of polypoidal choroidal vasculopathy (PCV) choriocapillaris. METHODS: This paper involves a retrospective study. Included 30 PCV affect eyes, 30 old control eyes, 20 young control eyes, 15 affect eyes with anti-VEGF intravitreal injection treatment, and 8 fellow eyes of anti-VEGF intravitreal injection treatment group. After the choriocapillaris slab [10 µm thick starting 30 µm beneath to the retinal pigment epithelium (RPE)-fit reference] was extracted from macular optical coherence tomography angiography 6×6-mm scans, the flow void was segmented by the Phansalkar method. We analyzed the flow void sizes-frequency histogram in order to investigate the differences of flow void proportion between groups. Then we verified the differences between groups after anti-VEGF intravitreal injection treatment. RESULTS: On the difference curve between the PCV group and Old control group, there was a peak appeared at the flow void sizes range from 900 to 1,125 µm2. The average number of flow void sizes from 900 to 1,125 µm2 was significantly higher in the Old control group than that in the Young control group (P<0.05) and there was no difference between the affect eyes group and the Old control group. The proportion of flow void sizes from 900 to 1,125 µm2 were remarkably higher in the affect eyes group compared to the Old control group (P<0.05), showing no difference between the Young control group and the Old control group. The average number of flow void sizes from 900 to 1,125 µm2 and the proportion of flow void sizes range from 900 to 1,125 µm2 were significantly higher in the treatment group after the treatment (P<0.05) and there was no difference in the fellow eyes of treatment group. The choroidal thickness was significantly reduced after the treatment of the treatment group (P<0.001), while the fellow eyes of the treatment group had no difference. CONCLUSIONS: Our method was specific for the pathological changes in choriocapillaris structures of PCV affect eyes, fellow eyes, and the affect eyes after anti-VEGF treatment.

Changes in complement activation products after anti-VEGF injection for choroidal neovascularization in age-related macular degeneration and pachychoroid disease.

We evaluated changes in the complement system resulting from anti-vascular endothelial growth factor (VEGF) in eyes with age-related choroidal neovascularization (CNV) including neovascular age-related macular degeneration, pachychoroid neovasculopathy, and polypoidal choroidal neovasculopathy. We measured the concentrations of the complement activation products (C3a, C4a), VEGF, and monocyte chemotactic protein-1 in the aqueous humor during intravitreal anti-VEGF injections for CNV. The VEGF level decreased significantly (P < 0.001), while the C3a and C4a levels increased significantly (P < 0.001 for both comparisons) 1 month after two monthly anti-VEGF injections. The VEGF level was correlated with the C3a (R = 0.328, P = 0.007) and C4a (R = - 0.237, P = 0.055) levels at baseline, but the correlation between the VEGF and C3a levels (R = - 0.148, P = 0.242) changed significantly (P = 0.028 by analysis of covariance) after anti-VEGF treatment. The C3a increase after anti-VEGF therapy did not change the visual outcomes in eyes with CNV for 1 year. Dysregulation of the complement system can be induced after anti-VEGF therapy.

RETINAL MICROSTRUCTURE IN POEMS SYNDROME.

PURPOSE: To report a 67-year-old woman with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome, showing bilateral serous retinal detachment. The retinal lesion was evaluated by multimodal imaging using spectral domain optical coherence tomography and an adaptive optics (AO) camera. METHODS: A case report. RESULTS: Optical coherence tomography showed hyperreflective foci mainly in the inner retina in both eyes. The AO images showed many low-reflective dots in the right eye. Three months after hematological treatment, both hyperreflective foci in the optical coherence tomography images and the low-reflective dots in the AO images disappeared. CONCLUSION: Low-reflective dots were detected in AO images of eyes with serous retinal detachment secondary to POEMS syndrome. AO cameras can detect retinal microstructures in living eyes.

Complement Activation Products and Cytokines in Pachychoroid Neovasculopathy and Neovascular Age-Related Macular Degeneration.

Purpose: To investigate the characteristics of complement activation products and angiogenic cytokines in the aqueous humor in eyes with pachychoroid neovasculopathy (PNV) and neovascular age-related macular degeneration (nAMD). Methods: This was a prospective, comparative, observational study. All patients with choroidal neovascularization were classified as PNV without polyps, PNV with polyps (polypoidal choroidal vasculopathy [PCV]), or drusen-associated nAMD according to the presence or absence of pachychoroid features and soft drusen. This study included a total of 105 eyes. Aqueous humor samples were collected from 25 eyes with PNV without polyps, 23 eyes with PCV, and 24 eyes with drusen-associated nAMD before intravitreal anti-vascular endothelial growth factor (VEGF) injection and cataract surgery in 33 control eyes. Clinical samples were measured for complement component 3a (C3a), C4a, C5a, VEGF, and macrophage chemoattractant protein 1 (MCP-1) using a bead-based immunoassay. Results: C3a and MCP-1 levels were significantly higher in PCV (P = 0.032 and P = 0.039, respectively) and drusen-associated nAMD (P = 0.01 for both comparisons) than in controls, and no difference was seen in C3a and MCP-1 levels between PNV and controls (P = 0.747 and P = 0.294, respectively). VEGF levels were significantly higher in PNV (P = 0.016), PCV (P = 0.009), and drusen-associated nAMD (P = 0.043) than in controls. In PNV, the VEGF levels elevated without elevated C3a and MCP-1. Conclusions: PNV, PCV, and drusen-associated nAMD had significantly distinct profiles of complement activation products and cytokines in the aqueous humor.

Evidence for Activation of Lectin and Classical Pathway Complement Components in Aqueous Humor of Neovascular Age-Related Macular Degeneration.

PURPOSE: The complement system is activated via 3 different pathways; the lectin pathway (LP), classical pathway (CP), and alternative pathway. To investigate the possible roles for the LP or CP in the development of neovascular age-related macular degeneration (nAMD), we compared aqueous humor levels of complement proteins of the LP and CP between eyes with nAMD and those with cataract as controls. METHODS: Seventeen eyes from 17 patients with treatment-naïve nAMD and 9 eyes from 9 patients with cataract were studied. Aqueous humor samples were collected before intravitreal aflibercept or ranibizumab injection for the nAMD patients and before cataract surgery for the cataract patients. Aqueous humor levels of complement C4 of the LP and CP, complement C3 of all 3 complement pathways, and mannose-binding lectin-associated serine protease (MASP)-2 of the LP were measured by enzyme-linked immunosorbent assay. Aqueous humor levels of C4a and C3a, the activation products of C4 and C3, respectively, were measured by a bead-based immunoassay. The ratios of C4a to C4 and C3a to C3, representing the degree of C4 and C3 activation, respectively, were calculated in individual patients. RESULTS: The aqueous humor levels of C4, C3, and MASP-2 were significantly lower in the nAMD eyes compared to the controls (p = 0.008, p = 0.011, and p = 0.018, respectively). In contrast, the aqueous humor levels of C4a and C3a, as well as the C4a/C4 and C3a/C3 ratios, were significantly higher in the nAMD eyes compared to the controls (p = 0.039, p = 0.003, p < 0.001, and p < 0.001, respectively). CONCLUSIONS: This study provides evidence for significant intraocular activation of either or both of the LP and CP in nAMD eyes that might be involved in the development of nAMD. The significantly lower levels of MASP-2 in the aqueous humor of the nAMD eyes were likely due to MASP-2 consumption by activation of the LP.

Impact of tear metrics on the reliability of perimetry in patients with dry eye.

BACKGROUND: The application of artificial tears before performing perimetry can improve the reliability and results of perimetry in patients with glaucoma and dry eye (DE). However, the effects of ocular surface and tear film conditions on perimetry measurements and reliability have not been fully characterized. METHODS: This prospective, cross-sectional, multicenter study investigated tear metrics in perimetry and assessed the relationships that existed among ocular surface condition, tear condition, and perimetry reliability. Forty-three eyes (43 patients) with DE disease according to the 2016 Japanese diagnostic criteria of DE and 43 eyes (43 subjects) of age- and visual field mean deviation-matched normal control subjects were studied. Perimetry was performed using the Humphrey Field Analyzer (30-2 SITA-Standard). Schirmer's test, strip meniscometry value, blink rate, tear film break-up time (TFBUT), fluorescein staining of ocular surface, and Dry Eye-related Quality of Life Score (DEQS) were measured. Blink rate was re-measured during perimetry. TFBUT and fluorescein staining were re-evaluated after perimetry. Perimetry reliability was evaluated with fixation loss, false-positive, and false-negative rates. RESULTS: Blink rate during perimetry was significantly lower for both patients with DE and normal controls (both P<0.001). TFBUT after perimetry was significantly higher than before perimetry in patients with DE (P<0.001). Fluorescein staining of ocular surface was significantly increased in patients with DE and normal control subjects (P = 0.002 and P<0.001, respectively). Spearman correlation analysis revealed that blink rate during perimetry was negatively correlated with fixation-loss rate (r = -0.393, P = 0.009) in patients with DE. CONCLUSIONS: Performing perimetry was associated with a significant change in tear condition and ocular surface condition in both patients with DE and normal control subjects. The changes in tear condition and ocular surface condition may impact the reliability of perimetry in patients with DE.

Morphometrical evaluation of the choriocapillaris imaged by swept-source optical coherence tomography angiography.

PURPOSE: To assess the reproducibility of quantitative morphometrical evaluation of the choriocapillaris imaged with swept-source optical coherence tomography angiography (SS-OCTA). SUBJECTS AND METHODS: This observational, cross-sectional case series included 35 eyes of healthy individuals and 32 eyes of 32 patients. Two images of the fovea were taken using SS-OCTA with 3×3 mm squares. Images of the choriocapillaris within 800×800 pixel squares centered at the fovea were analyzed morphometrically using open-source software "AngioTool" that applies a Gaussian recursive filter and multiscale Hessian enhancement. This program's vessel thickness and intensity parameters can be changed to aid vessel detection. We measured the pairs of images per eye with different parameter sets and calculated the intraclass correlation (ICC) for the morphometrical results. After determining the parameters that produced high reproducibility, we evaluated regional variations in 800×800 pixel mm squares within the fovea. RESULTS: The ICCs for vessel area, total vessel length, vessel diameter index, and mean lacunarity were over 0.9 using the parameters of "vessel thickness" 3-4 and intensity 15 in the group including all subjects. When measurements were performed using these same parameter values, the vessel density and mean vessel diameter index were 60.5% and 19.1±0.389, respectively. Vessel density, vessel length, vessel diameter index, and mean lacunarity did not change significantly within an 800×800 pixel square centered at the fovea except for the 200×200 pixel square at the foveal center. CONCLUSION: SS-OCTA images of the choriocapillaris can be measured with high reproducibility by morphometrical evaluation using open-source software with multiscale Hessian enhancement. Such automated morphometric analysis can provide an objective evaluation of the choriocapillaris.

Multimodal Imaging of a Case of Acute Annular Outer Retinopathy.

Background: Acute annular retinopathy (AAOR) is a rare entity showing grayish spots with annular lesions. We report the clinical characteristics of a patient with AAOR derived by using multimodal imaging including spectral-domain optical coherence tomography (OCT), fundus autofluorescence (FAF), and an adaptive optics fundus camera. Case: A 56-year-old man who had fever one month and a half before presenting. He noticed bilateral visual loss after lowering of fever. Clinical findings: Grayish white rings of different sizes were seen in the posterior fundus. Margin of the lesion showed hyperautofluorescence. OCT demonstrated an indistinct ellipsoid zone, disruption of external limiting membrane, and bulging of the retinal pigment epithelium in the annular lesions. We found hyperreflective foci in the inner retina and an indistinct interdigitation zone on the OCT images and indistinct cone mosaic patterns on the AO images at an ophthalmoscopically normal fovea in the left eye. Conclusion: Multimodal imaging showed the damage in the photoreceptors and the retinal pigment epithelium at the annular lesions. OCT and AO imaging can demonstrate abnormal findings in ophthalmoscopically normal areas in eyes with AAOR.