INCIDENCE AND RISK FACTORS OF INTRAOCULAR INFLAMMATION AFTER BROLUCIZUMAB TREATMENT IN JAPAN: A Multicenter Age-Related Macular Degeneration Study.

PURPOSE: To investigate the incidence of intraocular inflammation (IOI) and its risk factors following intravitreal injections of brolucizumab for neovascular age-related macular degeneration in Japan. METHODS: A total of 1,351 Japanese consecutive patients with neovascular age-related macular degeneration who were treated with brolucizumab from May 2020 to May 2022 at 14 institutions were examined. The variables analyzed were the number of brolucizumab injections, time to onset of IOI, and risk factors. RESULTS: Intraocular inflammation developed in 152 eyes (11.3%). Retinal vasculitis and/or retinal occlusion occurred in 53 eyes (3.9%). Ninety-four patients received bilaterally, bilateral IOI occurred in five patients (5.3%). Sixteen eyes (1.2%) had irreversible visual acuity loss and nine eyes (0.67%) had visual loss of three lines or more due to retinal vasculitis and/or retinal occlusion. The cumulative IOI incidence was 4.5%, 10.3%, and 12.2% at 30, 180, and 365 days (1-year), respectively. History of IOI (including retinal vasculitis) and/or retinal occlusion (odds ratio [OR], 5.41; P = 0.0075) and female sex (OR, 1.99; P = 0.0004) were significantly associated with IOI onset. CONCLUSION: The 1-year cumulative incidence of IOI in Japanese neovascular age-related macular degeneration patients treated with brolucizumab was 12.2%. History of IOI (including retinal vasculitis) and/or retinal occlusion and female sex were significant risk factors.

Relationship between pulsation of posterior vortex vein, choroidal thickness, and choroidal vascular hyperpermeability in polypoidal choroidal vasculopathy.

PURPOSE: Posterior vortex vein pulsation on Heidelberg indocyanine green angiography (HRA-IA) video is reported to indicate the presence of congestion in these vessels. This study aimed to determine the relationship between posterior vortex vein pulsation, choroidal thickness, and choroidal vascular hyperpermeability (CVH) in polypoidal choroidal vasculopathy (PCV). METHODS: Forty-three eyes of 43 patients who had not received previous treatment and were diagnosed with PCV using multimodal imaging were included and retrospectively investigated. On initial visit, presence or absence of pulsation in the posterior vortex vein was analysed using HRA-IA. Subfoveal choroidal thickness (SFCT) was assessed, and patients were divided into the SFCT ≥ 200 µm and < 200 µm (P and NP, respectively) groups. Presence or absence of CVH was investigated using IA in the late phase, and the associations between the three parameters were analysed. RESULTS: Posterior vortex vein pulsation was detected in 24/43 eyes (55%). There were 27 eyes in the P group (mean SFCT, 286 ± 48 µm) and 16 eyes in the NP group (mean SFCT, 143 ± 41 µm). Pulsation was detected in 10 eyes (37%) in the P group and 14 eyes (88%) in the NP group. Incidence of pulsation was significantly higher in the NP group (P < 0.05). There were 17 (40%) patients with CVH-13 (48%) and four (25%) in the P and NP groups, respectively (P = 0.1994). There was no correlation between the presence or absence of pulsation and CVH (P = 0.1994). CONCLUSION: Congestion of the vortex vein is potentially associated with the pathogenesis of PCV with a thin choroid.

Short-term outcomes of intravitreal faricimab for treatment-naïve neovascular age-related macular degeneration.

PURPOSE: To investigate the efficacy and safety of loading phase treatment with 3 monthly intravitreal injections of faricimab for neovascular age-related macular degeneration (nAMD). METHODS: We retrospectively analyzed 16-week outcomes of 40 consecutive eyes of 38 patients with treatment-naïve nAMD. Three monthly injections of faricimab were administered to all eyes as a loading phase treatment. Best-corrected visual acuity (BCVA), foveal thickness, central choroidal thickness (CCT), and dry macula achievement were all assessed every 4 weeks. Moreover, the regression of polypoidal lesions was evaluated after the loading phase. RESULTS: BCVA was 0.33 ± 0.41 at baseline and showed significant improvement to 0.22 ± 0.36 at week 16 (P < 0.01). Foveal thickness was 278 ± 116 µm at baseline, decreasing significantly to 173 ± 48 µm at week 16 (P < 0.01). CCT was 214 ± 98 µm at baseline, decreasing significantly to 192 ± 89 µm at week 16 (P < 0.01). Dry macula was achieved in 31 eyes (79.5%) at week 16. Indocyanine green angiography after the loading phase revealed complete regression of polypoidal lesions in 11 of 18 eyes (61.1%) with polypoidal lesions. One eye (2.5%) developed vitritis without visual loss at week 16. CONCLUSION: Loading phase treatment with intravitreal faricimab appears to generally be safe and effective for improving visual acuity and reducing exudative changes in eyes with nAMD.

RETINAL VASCULITIS OR VASCULAR OCCLUSION AFTER BROLUCIZUMAB FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: A Systematic Review of Real-World Evidence.

PURPOSE: Retinal vasculitis or vascular occlusion (RV/RO) have been reported after brolucizumab for neovascular age-related macular degeneration. This systematic literature review evaluated RV/RO events after brolucizumab in real-world practice. METHODS: Systematic literature searches identified 89 publications; 19 were included. RESULTS: Publications described 63 patients (70 eyes) with an RV/RO event following brolucizumab. Mean age was 77.6 years and 77.8% of patients were women; 32 eyes (45.7%) received one brolucizumab injection before RV/RO. Mean (range) time to event from last brolucizumab injection was 19.4 (0-63) days, with 87.5% of events occurring within 30 days. Among eyes with preevent and postevent visual acuity (VA) assessments, 22/42 eyes (52.4%) showed unchanged (±0.08 logMAR) or improved vision from last recorded preevent assessment at latest follow-up, whereas 15/42 eyes (35.7%) showed ≥0.30 logMAR (≥15 letters) VA reduction. Patients with no VA loss were on average slightly younger and had a higher proportion of nonocclusive events. CONCLUSION: Most RV/RO events reported after brolucizumab in early real-world practice occurred in women. Among eyes with VA measurements, approximately half experienced VA loss; overall, about one-third had VA reduction of ≥0.30 logMAR at latest follow-up, with indications of regional variations.

A new insight into pachychoroid diseases: Remodeling of choroidal vasculature.

PURPOSE: Pachychoroid spectrum diseases are regarded as being different manifestations of a common pathogenic process. We suggest that pachychoroid diseases are consequences of chronic vortex vein stasis. METHODS: We describe how we came to this conclusion based on our own recent reports as well as a search of the related literature. RESULTS: Central serous chorioretinopathy (CSC) is the first stage of pachychoroid spectrum diseases. CSC is caused by congestion of choroidal veins, which are branches of the vortex veins. The venous outflow tract of the choroid is divided into four quadrants, based on horizontal and vertical watershed zones, with one or two vortex veins in each quadrant being independently responsible for venous outflow. In acute CSC, vortex vein stasis frequently causes asymmetric dilatation of the vortex veins in the horizontal watershed. The area of geographic filling delay in the choriocapillaris coincides with the area of this asymmetrically dilated vortex veins. With chronic stasis of the vortex veins, venous anastomosis occurs in the watershed zone as a means of compensating for the stasis, and the choriocapillaris becomes occluded in the area of filling delay. The anastomotic vessels dilate, becoming often hyperpermeable, and are then recognizable as pachyvessels. With the development of choriocapillaris ischemia, choroidal neovascularization (CNV) occurs at the site of pachyvessels. This is termed pachychoroid neovasculopathy (PNV). Polypoidal choroidal vasculopathy is regarded as a variant of PNV. CONCLUSIONS: Intervortex venous anastomosis is among the key factors underlying the development of pachychoroid diseases. Remodeling of the venous drainage route though the anastomosis across the watershed zones is apparently a common response to chronic vortex vein stasis.

Choroidal alterations during the clinical course of commotio retinae.

PURPOSE: To analyse the alterations in the choroidal structure of eyes with commotio retinae due to blunt-force trauma. METHODS: This retrospective study included 51 eyes of 50 patients who underwent swept-source optical coherence tomography (SS-OCT) during their initial visit and throughout their clinical course between March 2013 and February 2020. MAIN OUTCOMES AND MEASURES: This study focused on four choroidal measures: comparison of central choroidal thickness (CCT) between the injured and contralateral eyes immediately after injury, changes in the CCT, ratio of choroidal luminal and stromal properties in the injured eye during the clinical course and change in the suprachoroidal structure of the injured eye. RESULTS: In 44 eyes, the CCT was successfully compared between the injured and contralateral eyes. In 30 of these eyes (70%), the CCT in the injured eye was significantly thinner than that in the contralateral eye (P < 0.01). In 33 eyes, the clinical course of the injured eyes was followed. The CCT was increased and decreased by >30 µm in 11 (33%) and 6 eyes (18%), respectively, and remained the same in 16 eyes (49%). The ratio of luminal and stromal areas in the choroid had significantly increased from 1.72 ± 0.54 at the initial visit to 1.87 ± 0.55 at the last visit (P < 0.001). In four eyes, a hemispherical dark space was observed beneath the sclerochoroidal interphase at the initial visit. CONCLUSION: The choroidal structure and its luminal and stromal properties are dynamically altered during the clinical course of commotio retinae.

Comparison of the regressive effects of aflibercept and brolucizumab on pigment epithelial detachment.

BACKGROUND: To compare the regressive effects of aflibercept and brolucizumab on pigment epithelial detachment (PED) in age-related macular degeneration. METHODS: Eighty-three eyes of 83 patients diagnosed with type 1 macular neovascularization were included and retrospectively analysed using multimodal imaging. Forty-nine eyes were treated with intravitreal aflibercept injections (IVA group), and 34 eyes were treated with brolucizumab (IVBr group), with three consecutive injections administered as induction therapy. Before treatment and 1, 2, and 3 months after the first treatment, the maximum height (MH) and maximum diameter (MD) of the PED were measured using optical coherence tomography in each treatment group. RESULTS: In the IVA group, MH at baseline (228 ± 169 µm) diminished to 180 ± 150 (P = 0.2558), 165 ± 140 (P = 0.0962), and 150 ± 129 µm (P = 0.0284) at 1, 2, and 3 months after treatment, respectively; the reduction at 3 months was significant. In contrast, in the IVBr group, the MH was 307 ± 254 µm before treatment, and it decreased to 183 ± 156 µm (P = 0.0113), 139 ± 114 µm (P = 0.0003), and 125 ± 126 µm (P < 0.0001) at 1, 2, and 3 months after treatment, respectively, and the reduction at 1 month was significant. In both groups, the MD did not regress significantly. CONCLUSIONS: The results suggested that the MH of PED after IVBr treatment regressed faster than that after IVA treatment.

Intravitreal Aflibercept versus Brolucizumab for Treatment-Naive Neovascular Age-Related Macular Degeneration with Type 1 Macular Neovascularization: Comparison of Short-Term Outcomes.

INTRODUCTION: The purpose of this study was to evaluate the outcomes of loading-phase treatment with intravitreal aflibercept (IVA) or brolucizumab (IVBr) for treatment-naïve neovascular age-related macular degeneration (nAMD) associated with type 1 macular neovascularization (MNV). METHODS: We retrospectively studied 108 consecutive eyes undergoing IVA and 103 consecutive eyes administered IVBr. Best-corrected visual acuity (BCVA), central macular thickness (CMT), central choroidal thickness (CCT), dry macula achievement, polypoidal lesion regression, and development of intraocular inflammation (IOI) were all assessed. RESULTS: During the loading-phase treatment, IOI was detected in 18 eyes (17.5%) in the IVBr but none of those in the IVA group (p < 0.01). The loading-phase treatment was completed in 101 eyes in the IVA and 85 eyes in the IVBr group. In those cases, BCVA improved significantly, and CMT and CCT showed significant reductions after the loading-phase treatment in both groups (all p < 0.01). The CCT reduction was significantly greater with IVBr than with IVA (32 ± 28 µm vs. 40 ± 25 µm, p < 0.01). The dry macula achievement rate was significantly higher in the IVBr than in the IVA group (71.3 vs. 85.9%, p < 0.05). We observed complete regression of polypoidal lesions significantly more frequently with IVBr than with IVA (47.5 vs. 77.3%, p < 0.01). DISCUSSION/CONCLUSION: Loading-phase treatment with IVA or IVBr for treatment-naïve nAMD with type 1 MNV effectively improved BCVA and diminished exudative changes. The CCT reduction, dry macula achievement, and polypoidal lesion regression rates were all significantly greater in the IVBr than in the IVA group. The incidence of IOI was significantly higher with IVBr than with IVA.

Surgical outcomes of vitrectomy for intractable diabetic macular edema.

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.

Variation of vortex veins at the horizontal watershed in normal eyes.

PURPOSE: To assess the vascular pattern of choroidal vortex veins at the horizontal watershed zone in normal eyes using optical coherence tomography (OCT). METHODS: We retrospectively studied 207 normal eyes of 207 patients whose fellow eyes were diagnosed with unilateral retinal diseases without choroidal involvement. Venous anastomosis between the superior and inferior vortex veins and deviation of the horizontal watershed zone were evaluated using 12 × 12-mm en face OCT images. Central choroidal thickness (CCT) was measured on B-mode OCT images. RESULTS: Vortex vein anastomosis was observed in 92 eyes (44.4%) at the horizontal watershed zone. Superior or inferior deviation of the horizontal watershed was ascertained in 69 eyes (33.3%). The frequency of the anastomosis and deviation did not differ significantly between age groups (P = 0.56 and 0.96, respectively). Mean CCT of all eyes was 221 ± 80 µm. CCT was significantly greater in eyes with anastomosis than in those without (233 ± 73 µm vs 210 ± 83 µm, P < 0.05). However, CCT did not differ significantly between eyes with and without deviation of the horizontal watershed zone (223 ± 74 µm vs 219 ± 82 µm). CONCLUSIONS: Venous anastomosis at the horizontal watershed zone as well as superior or inferior deviation of the zone were frequently observed in normal eyes. CCT was greater in eyes with than in those without anastomosis, suggesting subclinical vortex vein congestion.

REDUCED VASCULAR DENSITY IN THE CHOROID AFTER TREATMENT WITH PHOTODYNAMIC THERAPY COMBINED WITH AFLIBERCEPT IN PATIENTS WITH POLYPOIDAL CHOROIDAL VASCULOPATHY.

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.

TRPC5 regulates axonal outgrowth in developing retinal ganglion cells.

The TRPC5 ion channel is activated upon depletion of intracellular calcium stores, as well as by various stimuli such as nitric oxide (NO), membrane stretch, and cold temperatures. TRPC5 is abundantly expressed in the central nervous system where it has important neuronal functions. In the chick retina, TRPC5 expression was shown to be restricted to amacrine cells (ACs) and Müller glial cells, although its expression was also observed in the ganglion cell layer (GCL) in displaced ACs, as determined by their characteristic cell morphology. However, it is possible that this expression analysis alone might be insufficient to fully understand the expression of TRPC5 in retinal ganglion cells (RGCs). Hence, we analyzed TRPC5 expression by in situ hybridization and immunostaining in the developing mouse retina, and for the first time identified that developing and mature RGCs strongly express TRPC5. The expression begins at E14.5, and is restricted to ACs and RGCs. It was reported that TRPC5 negatively regulates axonal outgrowth in hippocampal neurons. We thus hypothesized that TRPC5 might have similar functions in RGCs since they extend very long axons toward the brain, and this characteristic significantly differs from other retinal cell types. To elucidate its possible involvement in axonal outgrowth, we inhibited TRPC5 activity in developing RGCs which significantly increased RGC axon length. In contrast, overexpression of TRPC5 inhibited axonal outgrowth in developing RGCs. These results indicate that TRPC5 is an important negative regulator of RGC axonal outgrowth. Since TRPC5 is a mechanosensor, it might function to sense abnormal intraocular pressure changes, and could contribute to the death of RGCs in diseases such as glaucoma. In this case, excessive Ca2+ entry through TRPC5 might induce dendritic and axonal remodeling, which could lead to cell death, as our findings clearly indicate that TRPC5 is an important regulator of neurite remodeling.

Retinal Detachment-Induced Müller Glial Cell Swelling Activates TRPV4 Ion Channels and Triggers Photoreceptor Death at Body Temperature.

Using region-specific injection of hyaluronic acid, we developed a mouse model of acute retinal detachment (RD) to investigate molecular mechanisms of photoreceptor cell death triggered by RD. We focused on the transient receptor potential vanilloid 4 (TRPV4) ion channel, which functions as a thermosensor, osmosensor, and/or mechanosensor. After RD, the number of apoptotic photoreceptors was reduced by ∼50% in TRPV4KO mice relative to wild-type mice, indicating the possible involvement of TRPV4 activation in RD-induced photoreceptor cell death. Furthermore, TRPV4 expressed in Müller glial cells can be activated by mechanical stimuli caused by RD-induced swelling of these cells, resulting in release of the cytokine MCP-1, which is reported as a mediator of Müller glia-derived strong mediator for RD-induced photoreceptor death. We also found that the TRPV4 activation by the Müller glial swelling was potentiated by body temperature. Together, our results suggest that RD adversely impacts photoreceptor viability via TRPV4-dependent cytokine release from Müller glial cells and that TRPV4 is part of a novel molecular pathway that could exacerbate the effects of hypoxia on photoreceptor survival after RD.SIGNIFICANCE STATEMENT Identification of the mechanisms of photoreceptor death in retinal detachment is required for establishment of therapeutic targets for preventing loss of visual acuity. In this study, we found that TRPV4 expressed in Müller glial cells can be activated by mechanical stimuli caused by RD-induced swelling of these cells, resulting in release of the cytokine MCP-1, which is reported as a mediator of Müller glia-derived strong mediator for RD-induced photoreceptor death. We also found that the TRPV4 activation by the Müller glial swelling was potentiated by body temperature. Hence, TRPV4 inhibition could suppress cell death in RD pathological conditions and suggests that TRPV4 in Müller glial cells might be a novel therapeutic target for preventing photoreceptor cell death after RD.

Clinical characteristics of pachydrusen in central serous chorioretinopathy.

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.

Development of Age-Related Macular Degeneration (AMD) in the Fellow Eye of Patients with AMD Treated by Treat-and-Extend Intravitreal Therapy with Aflibercept.

PURPOSE: To evaluate the development of neovascular age-related macular degeneration (nAMD) in the fellow eye in patients with unilateral nAMD treated by a treat-and-extend (TAE) regimen with intravitreal aflibercept injections. METHODS: We retrospectively studied 104 patients with treatment-naïve unilateral nAMD. We assessed best-corrected visual acuity (BCVA) and exudative changes in the treated eyes and development of nAMD in the fellow eye for 2 years. RESULTS: The subjects included 46 patients with typical AMD (tAMD), 44 with polypoidal choroidal vasculopathy (PCV), and 14 with retinal angiomatous proliferation (RAP). BCVA was significantly improved after the loading phase in all subtypes. Forty-six patients (44.2%) had no recurrence within 2 years after the loading phase, including 12 (26.1%) with tAMD, 23 (52.2%) with PCV, and 11 (78.6%) with RAP (p < 0.01). Eleven patients (10.6%) developed nAMD in the fellow eye within 2 years, including 4 (8.7%) with tAMD, 0 (0%) with PCV, and 7 (50.0%) with RAP (p < 0.001). CONCLUSIONS: Patients with RAP had significantly more frequent development of nAMD in the fellow eye compared to other subtypes, while they showed significantly less recurrence during the TAE regimen with intravitreal aflibercept injections. Development of nAMD in the fellow eye should be monitored in RAP when the injection interval is extended.

Two-year results of a treat-and-extend regimen with aflibercept for polypoidal choroidal vasculopathy.

PURPOSE: To evaluate the effects of aflibercept therapy using a treat-and-extend regimen on treatment-naïve polypoidal choroidal vasculopathy (PCV). METHODS: In a retrospective interventional case series of 58 eyes of 58 patients with PCV, we assessed best-corrected visual acuity (BCVA), central macular thickness (CMT), central choroidal thickness (CCT), and number of injections for 2 years. Polypoidal lesions were also evaluated before treatment and after the loading phase by indocyanine green angiography. RESULTS: BCVA significantly improved after the loading phase and was maintained in the maintenance phase. CMT and CCT significantly reduced after the loading phase and were maintained throughout the follow-up period. The number of injections averaged 7.72 in the first year and 4.67 in the second year. The average number of polypoidal lesions per patient was 2.43 before treatment. In 32 patients (55.2%), polypoidal lesions regressed completely after the loading phase; these patients also needed significantly fewer injections compared to other patients. CCT at baseline was positively correlated with the decreased amount of CCT after 2 years and negatively correlated with the number of injections for 2 years. CONCLUSIONS: Treat-and-extend intravitreal therapy with aflibercept may be effective for improving BCVA and exudative change in eyes with PCV. The regression of polypoidal lesions after the loading phase and thicker choroid at baseline might lead to fewer total number of intravitreal injections of aflibercept.

Two-Year Outcomes of a Treat-and-Extend Regimen Using Intravitreal Aflibercept Injections for Typical Age-Related Macular Degeneration.

PURPOSE: The aim of this study was to evaluate the efficacy of a treat-and-extend (TAE) regimen using intravitreal injection of aflibercept (IVA) for typical age-related macular degeneration (tAMD). METHODS: We retrospectively studied 61 treatment-naïve eyes with tAMD. Best-corrected visual acuity (BCVA), central macular thickness (CMT), central choroidal thickness (CCT), number of injections, and complications during 2 years were evaluated. RESULTS: BCVA significantly improved by on average 0.13 logMAR units, and CMT and CCT significantly decreased after 2 years. The number of injections was on average 13.6. In the second year, eyes with classic choroidal neovascularization (CNV) needed significantly fewer treatments than eyes with occult CNV. Fourteen eyes, which developed subfoveal fibrosis, showed significantly poorer BCVA after 2 years. Subfoveal fibrosis was significantly common in classic CNV. CONCLUSION: A TAE regimen using IVA for tAMD might be effective for improving BCVA and exudative changes. The exudation may be suppressed with fewer treatments in classic CNV compared to occult CNV.

TREAT-AND-EXTEND REGIMEN WITH AFLIBERCEPT FOR RETINAL ANGIOMATOUS PROLIFERATION.

PURPOSE: To evaluate the effects of aflibercept therapy using a treat-and-extend regimen on treatment-naïve retinal angiomatous proliferation (RAP) and development of retinal pigment epithelium (RPE) atrophy. METHODS: We retrospectively studied 17 treated eyes with RAP and 13 untreated fellow eyes. We assessed best-corrected visual acuity (BCVA) in logarithm of the minimal angle of resolution (logMAR) units and recorded the total number of injections for 12 months. Central macular thickness (CMT) and central choroidal thickness (CCT) were assessed by optical coherence tomography (OCT), and RPE atrophy extent in the macular area was assessed by fundus autofluorescence. RESULTS: Average BCVA in eyes with RAP was 0.57 logMAR units (Snellen 20/74 or approximately 56.5 ETDRS letters) before treatment and significantly improved to 0.38 (Snellen 20/48 or approximately 66 ETDRS letters, P < 0.01) after 3 months and 0.32 (Snellen 20/42 or approximately 69 ETDRS letters, P < 0.01) after 12 months. Average CMT was 340 µm before treatment and significantly reduced to 133 µm (P < 0.001) after 3 months and 130 µm (P < 0.001) after 12 months. Average CCT was 147 µm before treatment, 123 µm (P < 0.01) after 3 months, and 131 µm (P < 0.01) after 12 months. Average total number of injections was 7.2. Average area of RPE atrophy enlarged by 1.00 mm in treated eyes compared with 0.34 mm in fellow eyes (P < 0.01). The enlarged area of RPE atrophy was inversely correlated with central choroidal thickness after 12 months (rs = -0.49, P < 0.01) and positively correlated with the number of injections (rs = 0.58, P < 0.01). CONCLUSION: Treat-and-extend intravitreal therapy with aflibercept may be effective for improvement and stabilization of visual acuity and exudative change in eyes with RAP. However, choroidal thinning during the treatment regimen may accelerate enlargement of RPE atrophy.

Receptor interacting protein kinase mediates necrotic cone but not rod cell death in a mouse model of inherited degeneration.

Retinitis pigmentosa comprises a group of inherited retinal photoreceptor degenerations that lead to progressive loss of vision. Although in most cases rods, but not cones, harbor the deleterious gene mutations, cones do die in this disease, usually after the main phase of rod cell loss. Rod photoreceptor death is characterized by apoptotic features. In contrast, the mechanisms and features of subsequent nonautonomous cone cell death remain largely unknown. In this study, we show that receptor-interacting protein (RIP) kinase mediates necrotic cone cell death in rd10 mice, a mouse model of retinitis pigmentosa caused by a mutation in a rod-specific gene. The expression of RIP3, a key regulator of programmed necrosis, was elevated in rd10 mouse retinas in the phase of cone but not rod degeneration. Although rd10 mice lacking Rip3 developed comparable rod degeneration to control rd10 mice, they displayed a significant preservation of cone cells. Ultrastructural analysis of rd10 mouse retinas revealed that a substantial fraction of dying cones exhibited necrotic morphology, which was rescued by Rip3 deficiency. Additionally, pharmacologic treatment with a RIP kinase inhibitor attenuated histological and functional deficits of cones in rd10 mice. Thus, necrotic mechanisms involving RIP kinase are crucial in cone cell death in inherited retinal degeneration, suggesting the RIP kinase pathway as a potential target to protect cone-mediated central and peripheral vision loss in patients with retinitis pigementosa.

One-year results of treat-and-extend regimen with intravitreal faricimab for treatment-naïve neovascular age-related macular degeneration.

PURPOSE: To evaluate 1-year outcomes of loading phase treatment followed by maintenance therapy using a treat-and-extend (TAE) regimen with intravitreal faricimab for neovascular age-related macular degeneration (nAMD). STUDY DESIGN: Retrospective, interventional case series. METHODS: We retrospectively studied 40 eyes of 38 consecutive patients with treatment-naïve nAMD, assessing best-corrected visual acuity (BCVA), foveal thickness, central choroidal thickness (CCT), total number of injections over 1 year, and intended injection interval at the last visit. RESULTS: Thirty eyes (75.0%) had completed the 1-year intravitreal faricimab treatment. Their BCVA showed significant improvement, with significant reductions in foveal thickness and CCT. The total number of injections during the 1-year treatment period was 6.6 ± 0.7. The intended injection interval at the last visit was 12.7 ± 3.3 weeks. Of the 10 eyes (25.0%) failing to complete the 1-year faricimab treatment, 1 eye developed intraocular inflammation after the loading phase treatment but showed no recurrence of exudative changes, and no further treatment was required. Moreover, 5 eyes switched to intravitreal brolucizumab injection due to persistent exudative changes with an 8-week interval of faricimab injections. The remaining 4 eyes either dropped out or the patient died. CONCLUSIONS: A loading phase treatment followed by a TAE regimen with intravitreal faricimab appears to be generally safe and effective for improving visual acuity and ameliorating exudative changes in eyes with nAMD. However, there might be cases in which exudative changes cannot be adequately controlled with injections of faricimab every 8 weeks in the maintenance phase.