RETINAL HYPOPERFUSION DETECTED BY WIDE-FIELD OPTICAL COHERENCE TOMOGRAPHIC ANGIOGRAPHY IN A CASE OF RETINAL RACEMOSE HEMANGIOMA.

PURPOSE: Retinal racemose hemangioma is a rare, unilateral, nonhereditary, arteriovenous malformation characterized by the appearance of dilated and tortuous retinal vessels. Retinal racemose hemangioma can develop complications associated with retinal ischemia, such as vitreous hemorrhage, retinal vein occlusion, and neovascular glaucoma. Here, a case of retinal racemose hemangioma with retinal hypoperfusion detected by wide-field swept-source optical coherence tomographic angiography was reported, which was not unambiguously illustrated by fluorescein angiography. METHODS: Case report. RESULTS: A 57-year-old woman was referred to our hospital for the evaluation of severe retinal vascular tortuosity, dilation, and retinal hemorrhages in the left eye. Fundus examination revealed arteriovenous communications temporal to the fovea and multiple microaneurysms surrounded by retinal hemorrhages at the midperipheral temporal fundus. In fluorescein angiography, multiple hyperfluorescent lesions with leakage corresponding to microaneurysms were observed in the temporal and lower midperipheral areas; however, nonperfused areas were apparently absent. By contrast, wide-field optical coherence tomographic angiography clearly showed low-density retinal capillaries in the superotemporal quadrant in comparison with those in the inferotemporal quadrant. CONCLUSION: Wide-field optical coherence tomographic angiography detected sparse retinal capillaries, which were not well illustrated by fluorescein angiography, in a patient with retinal racemose hemangioma. This indicates the presence of low-grade retinal hypoperfusion caused by altered retinal hemodynamics, potentially leading to ischemia-related retinal disorders during a prolonged course, in patients with clinically quiescent retinal racemose hemangioma.

Two-year clinical outcomes of triple therapy with photodynamic therapy, anti-vascular endothelial growth factor agent, and triamcinolone acetonide for neovascular age-related macular degeneration.

PURPOSE: To analyze the 2-year treatment outcomes of triple therapy with standard-fluence photodynamic therapy (PDT), intravitreal injection of ranibizumab (IVR)/aflibercept (IVA), and sub-tenon injection of triamcinolone acetonide (STTA) for neovascular age-related macular degeneration (nAMD) in Japanese patients. STUDY DESIGN: A retrospective, clinical case-series study. METHODS: Forty-four eyes of 44 patients with treatment-naïve nAMD followed for more than 24 months were evaluated. Initial treatment was given with triple therapy and retreatment with IVR/IVA as a pro re nata regimen. Best-corrected visual acuity (BCVA), central retinal thickness (CRT), the number of treatments, and intraocular pressure elevation were analyzed. RESULTS: The mean age was 73.3 ± 10.0 years. The mean BCVA significantly improved from 0.61 ± 0.30 at baseline to 0.50 ± 0.46 at 24 months (p = 0.034). CRT significantly improved from 373 ± 162 µm at baseline to 200 ± 107 µm at 24 months (p < 0.001). The number of treatments given during the 2-year treatment period was 2.7 ± 1.8. No retreatments were necessary in 18 of 44 eyes (40.9%), with no significant difference between IVR (46.4%) or IVA (31.3%) used during the 2-year follow-up of triple therapy (p = 0.51). Four eyes (9.1%) temporarily required glaucoma eye drop treatments. CONCLUSION: In nAMD patients, induction treatment with triple therapy resulted in approximately 40% of the patients requiring no retreatment for 2 years. The type of anti-VEGF agents used made no difference in the results.

Impact of the COVID-19 Pandemic on Anti-Vascular Endothelial Growth Factor Therapy for Diabetic Macular Edema in Japan.

Anti-vascular endothelial growth factor (VEGF) therapy for diabetic macular edema (DME) improves visual acuity. However, repeated injections during routine outpatient visits are required to maintain this effect. The recent sudden global outbreak of coronavirus disease 2019 (COVID-19) had a major impact on daily life, including medical care, such as the provision of VEGF therapy. We retrospectively investigated the relationship between the number of anti-VEGF injections for DME and the number of new COVID-19-positive patients at 23 centers in Japan. We also surveyed ophthalmologists regarding the impact of the COVID-19 pandemic on anti-VEGF therapy. In the third and fourth waves of the pandemic, when the number of infected patients increased, the number of injections significantly decreased. In the first, third, and fourth waves, the number of injections increased significantly during the last month of each wave. Approximately 60.9% of ophthalmologists reported that the number of injections decreased after the pandemic. Of the facilities, 52.2% extended the clinic visit intervals; however, there was no significant difference in the actual number of injections given between before and after the pandemic. Although the number of injections temporarily decreased, Japanese ophthalmologists maintained the total annual number of anti-VEGF injections for DME during the pandemic.

Insidious progression of atrophic lesions in a case of posterior polar annular choroidal dystrophy.

Purpose: To describe the clinical course of a case of posterior polar annular choroidal dystrophy (PPACD) followed for 5 years. Observations: A 64-year-old female patient presented with blurred vision. The patient had no subjective symptoms of night blindness or visual field defects. At the initial visit, the patient's visual acuity was 20/20 in both eyes. Bilateral fundus examination revealed atrophic lesions surrounding the optic nerve head, extending to the temporal arcades in an annular pattern. Fundus autofluorescence (FAF) revealed hypoautofluorescent areas corresponding to atrophic lesions, and Goldmann perimetry revealed ring scotomas consistent with lesions in the fundus. Swept-source optical coherence tomography revealed retinal pigment epithelium atrophy, loss of the choriocapillaris, and dilation of the choroidal medium and large vessels in the atrophic area. Full-field electroretinography revealed a mild reduction in the combined rod-cone response. Laser speckle flowgraphy revealed a cold color in the posterior pole of both eyes. Based on clinical and imaging findings, the patient was diagnosed with PPACD and followed up for 5 years. At the 5-year visit, visual acuity remained unchanged, while FAF and Goldmann perimetry revealed a slight enlargement of the atrophic lesions and scotoma in both eyes, respectively. Conclusions and Importance: In the present case, atrophic lesions insidiously progressed and resulted in a slight enlargement of the hypoautofluorescent area and scotoma over a 5-year follow-up period, indicating that PPACD is a gradually progressive dystrophy.

Multimodal Imaging Findings in Retinopathy Associated with Facioscapulohumeral Muscular Dystrophy before and after Treatment with Intravitreal Aflibercept and Laser Photocoagulation.

A 52-year-old man with a history of facioscapulohumeral dystrophy (FSHD) and hypertension presented with decreased vision in his left eye (OS) of several weeks' duration. The best-corrected visual acuity was 1.0 in both eyes (OU), with fundus soft exudates in the right eye (OD) and exudative maculopathy OS. Optical coherence tomography (OCT) showed macular edema and hard exudates OS, and OCT angiography (OCTA) showed nonperfusion areas and arterial tortuosity OU and a capillary aneurysm OS. After photocoagulation of the nonperfusion areas OU and intravitreal injection of aflibercept OS, the macular edema OS decreased and subjective symptoms improved. However, the nonperfusion area OS was enlarged on OCTA. We report the OCTA findings before and after antivascular endothelial growth factor treatment in a patient with FSHD.

Noninvasive Imaging of a Vasoproliferative Retinal Tumor Treated with Cryopexy.

Optical coherence tomographic angiography (OCTA) has emerged as a rapid, noninvasive imaging modality to visualize the vascular networks in the retina and choroid. Here, we report the clinical findings in a case of primary vasoproliferative retinal tumor (VPRT) observed by the wide-field swept-source OCTA. A 74-year-old male patient with central vision loss and metamorphopsia in his left eye was referred to our hospital. At the first visit, the best-corrected visual acuity was 20/20 OD and 20/40 OS. Fundus examination revealed the presence of the epiretinal membrane and inferotemporal reddish retinal tumor in the left eye. Fluorescein angiography and indocyanine green angiography (ICGA) showed leaky characteristics and sharply defined structure of vessels in the retinal tumor, respectively. The patient was diagnosed with the VPRT with secondary epiretinal membrane and underwent pars plana vitrectomy with internal limiting membrane peeling, retinal photocoagulation, and triple freeze and thaw procedure using cryopexy. Whereas wide-field swept-source OCTA preoperatively depicted the flow signals as distinctive vascular structures similar to ICGA, the tumor color turned out to be ischemic white, and the flow signals detected by wide-field OCTA disappeared after the surgery, indicating that the freezing effect of transscleral cryopexy sufficiently reached the surface of the tumor. In sum, wide-field swept-source OCTA is a useful imaging modality that can be noninvasively and repetitively performed to determine the treatment effect in cases of peripheral retinal tumors such as VPRT.

Placental growth factor stabilizes VEGF receptor-2 protein in retinal pigment epithelial cells by downregulating glycogen synthase kinase 3 activity.

Placental growth factor (PlGF) belongs to the vascular endothelial growth factor (VEGF) family of proteins that participate in angiogenesis and vasculogenesis. Anti-VEGF therapy has become the standard treatment for ocular angiogenic disorders in ophthalmological practice. However, there is emerging evidence that anti-VEGF treatment may increase the risk of atrophy of the retinal pigment epithelium (RPE), which is important for the homeostasis of retinal tissue. Whereas the cytoprotective role of VEGF family molecules, particularly that of VEGF A (VEGFA) through its receptor VEGF receptor-2 (VEGFR-2), has been recognized, the physiological role of PlGF in the retina is still unknown. In this study, we explored the role of PlGF in the RPE using PlGF-knockdown RPE cells generated by retrovirus-based PlGF-shRNA transduction. We show that VEGFA reduced apoptosis induced by serum starvation in RPE cells, whereas the antiapoptotic effect of VEGFA was abrogated by VEGFR-2 knockdown. Furthermore, PlGF knockdown increased serum starvation-induced cell apoptosis and unexpectedly reduced the protein level of VEGFR-2 in the RPE. The antiapoptotic effect of VEGFA was also diminished in PlGF-knockdown RPE cells. In addition, we found that glycogen synthase kinase 3 activity was involved in proteasomal degradation of VEGFR-2 in RPE cells and inactivated by PlGF via AKT phosphorylation. Overall, the present data demonstrate that PlGF is crucial for RPE cell viability and that PlGF supports VEGFA/VEGFR-2 signaling by stabilizing the VEGFR-2 protein levels through glycogen synthase kinase 3 inactivation.

Relationship between Brachial-Ankle Pulse Wave Velocity and Fundus Arteriolar Area Calculated Using a Deep-Learning Algorithm.

PURPOSE: Retinal vessels reflect alterations related to hypertension and arteriosclerosis in the physical status. Previously, we had reported a deep-learning algorithm for automatically detecting retinal vessels and measuring the total retinal vascular area in fundus photographs (VAFP). Herein, we investigated the relationship between VAFP and brachial-ankle pulse wave velocity (baPWV), which is the gold standard for arterial stiffness assessment in clinical practice. METHODS: Retinal photographs (n = 696) obtained from 372 individuals who visited the Keijinkai Maruyama Clinic for regular health checkups were used to analyze VAFP. Additionally, the baPWV was measured for each patient. Automatic retinal-vessel segmentation was performed using our deep-learning algorithm, and the total arteriolar area (AA) and total venular area (VA) were measured. Correlations between baPWV and several parameters, including AA and VA, were assessed. RESULTS: The baPWV was negatively correlated with AA (R = -0.40, n = 696, P < 2.2e-16) and VA (R = -0.36, n = 696, P < 2.2e-16). Independent variables (AA, sex, age, and systolic blood pressure) selected using the stepwise method showed a significant correlation with baPWV. The estimated baPWV, calculated using a regression equation with variables including AA, showed a better correlation with the measured baPWV (R = 0.70, n = 696, P < 2.2e-16) than the estimated value without AA (R = 0.68, n = 696, P < 2.2e-16). CONCLUSIONS: AA and VA were significantly correlated with baPWV. Moreover, baPWV estimated using AA correlated well with the actual baPWV. VAFP may serve as an alternative biomarker for evaluating systemic arterial stiffness.

Subretinal fluid accumulation in a patient with polycythemia vera after receiving a prostaglandin I2 analogue treatment.

Purpose: To report a case of polycythemia vera (PV) with subretinal fluid accumulation after the administration of prostaglandin I2 (PGI2) analogue. Observations: A 57-year-old woman diagnosed as having PV was referred to our department for the evaluation of severe metamorphopsia in the left eye, which gradually progressed after the initiation of oral administration of PGI2 mimetics. At the first visit, the patient's best-corrected visual acuities (BCVAs) were 20/20 OD and 20/30 OS. Fundus examination and optical coherence tomography revealed the presence of subretinal fluid (SRF) in the left eye and multiple serous pigment epithelial detachments (PEDs) in both eyes. Fluorescein angiography revealed central serous chorioretinopathy (CSC)-like lesions, consisting of dye pooling corresponding to the PEDs in both eyes and dye leakage in the left eye. Indocyanine green angiography and laser speckle flowgraphy revealed dilated choroidal veins and reduced choroidal blood flow, respectively. The central choroidal thickness (CCT) measured at the first visit showed a relatively thickened choroid in the left eye. Laboratory data showed mild pancytosis. The patient was diagnosed as having CSC associated with a background of PV, presumably triggered by the PGI2 analogue. One month after cessation of drug administration, the patient's BCVA improved, the CCT slightly decreased, and serous retinal detachment and PED disappeared in the left eye. Conclusions and importance: Our case of PV presenting with CSC-like lesions after PGI2 analogue administration indicates the possible risk of SRF accumulation by PGI2 analogues in patients with PV.

Imbalanced choroidal circulation in eyes with asymmetric dilated vortex vein.

PURPOSE: Asymmetric dilated vortex vein (ADVV) observed in eyes with pachychoroid spectrum diseases is thought to be due to congestion of choroidal blood flow. The purpose of this study was to quantitatively investigate the blood flow velocity of ADVV using laser speckle flowgraphy (LSFG). STUDY DESIGN: Retrospective case series. METHODS: This was a retrospective case series with 23 eyes of 18 patients with ADVV on en-face OCT. A pair of choroidal veins from ADVV side (defined as ADVV vein) and non-ADVV side (defined as non-ADVV vein) was selected in each eye under the following criteria: (i) equivalent proximity to the deviated watershed, (ii) does not overlap with retinal blood vessels in the en-face OCT image, (iii) has approximately the same blood vessel diameter. Rubber bands were placed on the selected choroidal veins on the LSFG color map. Mean blur rate (MBR) values of ADVV and non-ADVV veins were statistically compared. RESULTS: The average MBR was 10.11 ± 1.9 in the ADVV veins and 13.49 ± 6.2 in the non-ADVV veins, showing significantly lower values in the ADVV veins (P = 0.03). The blood vessel diameter of the ADVV was 10.26 ± 3.0 and in the non-ADVV veins, 10.63 ± 2.9 pixels; not significantly different (P = 0.66). The distance from the deviated watershed to the ADVV was 53.3 ± 24.8 and to the non-ADVV veins, 46.80 ± 20.3 pixels; not significantly different (P = 0.41). CONCLUSION: In eyes with ADVV, the blood flow velocity in the ADVV veins was lower than in the non-ADVV veins, suggesting anatomical congestion of ADVV.

Outer Retinal Abnormalities in a Patient with Danon Disease.

PURPOSE: To report outer retinal abnormalities evaluated using high-resolution imaging modalities in a patient with Danon disease. METHODS: Case report. RESULTS: A 26-year-old woman, diagnosed with Danon disease based on genetic testing, was referred to our department for further evaluation of ocular findings. Her best-corrected VA was 20/20, and color vision was normal. Fundus examination revealed pigmentary changes consisting of mottled depigmentation and pigmentation in the peripheral retina of both eyes. Spectral-domain optical coherence tomography revealed disruptions of the ellipsoid and interdigitation zones, irregularity of the retinal pigment epithelium, and hyperreflectivity of the outer nuclear layer. In addition, an adaptive optics retinal camera demonstrated the ambiguous macular cone mosaic pattern. CONCLUSION: Danon disease is caused by a primary deficiency in lysosomal associated membrane protein 2, an important constituent of the lysosomal membrane that plays a crucial role in the process of autophagy. It is possible that the findings of spectral-domain optical coherence tomography and adaptive optics retinal camera are early changes associated with the accumulation of autophagosomes and/or phagosomes due to lysosomal associated membrane protein 2 dysfunction in the photoreceptors, eventually followed by outer retinal degeneration, such as thinning of both the photoreceptor and retinal pigment epithelium layers at the fovea.

The Impact of Interval between Recurrence and Reinjection in Anti-VEGF Therapy for Diabetic Macular Edema in Pro Re Nata Regimen.

BACKGROUND: Pro re nata (PRN) regimen using anti-vascular endothelial growth factor (VEGF) agent is popular for the treatment of diabetic macular edema (DME). We investigated the influence of waiting time (WT) and interval between the date of recurrence of edema and re-injection on treatment efficacy. METHODS: This retrospective study conducted at 7 sites in Japan enrolled patients who received intravitreal injection of ranibizumab (IVR) and aflibercept (IVA) in 1+PRN regimen. Enrolled patients were divided into 2 groups: prompt group (less than 1 week) and deferred group (3 weeks or more). Central retinal thickness (CRT) and best corrected visual acuity (BCVA) were measured every month for 1 year. RESULTS: CRT in the deferred group was significantly higher than that in the prompt group at 2, 5, 6, 7, and 12 months (p < 0.05). BCVA in the prompt group was significantly better than that in the deferred group at 7, 10, and 12 months (p < 0.05). CONCLUSION: The prompt group was superior in anatomical and functional improvement of DME in anti-VEGF therapy than the deferred group. Our data suggests that shorter WT is recommended for better visual prognosis in the treatment for DME.

ROCK1 Mediates Retinal Glial Cell Migration Promoted by Acrolein.

Objective: Acrolein is a highly reactive aldehyde that covalently binds to cellular macromolecules and subsequently modulates cellular function. Our previous study demonstrated that acrolein induces glial cell migration, a pathological hallmark of diabetic retinopathy; however, the detailed cellular mechanism remains unclear. The purpose of this study was to investigate the role of acrolein in retinal glial cell migration by focusing on rho-associated coiled-coil-containing protein kinases (ROCKs). Methods: Immunofluorescence staining for ROCK isoforms was performed using sections of fibrovascular tissue obtained from the eyes of patients with proliferative diabetic retinopathy (PDR). Rat retinal Müller glial cell line, TR-MUL5, was stimulated with acrolein and the levels of ROCK1 were evaluated using real-time PCR and western blotting. Phosphorylation of the myosin-binding subunit of myosin light chain phosphatase [myosin phosphatase target subunit 1, (MYPT1)] and myosin light chain 2 (MLC2) was assessed. The cell migration rate of TR-MUL5 cells exposed to acrolein and/or ripasudil, a non-selective ROCK inhibitor, was measured using the Oris cell migration assay. Results: ROCK isoforms, ROCK1 and ROCK2, were positively stained in the cytosol of glial cells in fibrovascular tissues. In TR-MUL5 cells, the mRNA expression level of Rock1, but not Rock2, was increased following acrolein stimulation. In line with the PCR data, western blotting showed increase in ROCK1 and cleaved ROCK1 protein in TR-MUL5 cells stimulated with acrolein. N-acetylcysteine (NAC) suppressed acrolein-associated Rock1 upregulation in TR-MUL5 cells. Acrolein augmented the phosphorylation of MYPT1 and MLC2 and increased the cell migration rate of TR-MUL5 cells, both of which were abrogated by ripasudil. Conclusions: Our study demonstrated that ROCK1 mediates the migration of retinal glial cells promoted by the unsaturated aldehyde acrolein.

Macrophage-like iPS-derived Suppressor Cells Reduce Th1-mediated Immune Response to a Retinal Antigen.

PURPOSE: To investigate the immunotherapeutic effects of macrophage-like induced pluripotent stem (iPS) cell-derived suppressor cells (SCs) in ocular immune response and experimental autoimmune uveoretinitis (EAU). METHODS: The genes of Oct3/4, Sox2, Klf4, and c-Myc were transferred to B cells enriched from the spleen cells of C57BL/6 mice by using retrovirus vectors. Transferred B cells were cultured for 17 days to obtain colonies of iPS cells. Through additional steps, iPS-SCs were induced. An antigen-specific T cell proliferation assay was performed with CD4+ T cells collected from draining lymph nodes of the mice immunized with human interphotoreceptor retinoid-binding protein (hIRBP) peptide and co-cultured with iPS-SCs. Cytokine concentrations in the culture supernatant were examined. Mice were immunized with hIRBP peptide to induce EAU. The iPS-SCs were administered into the mice one day before the induction of EAU. RESULTS: The iPS-SCs decreased hIRBP-specific T cell proliferation depending on the number of cells. Productions of tumor necrosis factor-α and interferon-γ were significantly decreased; however, transforming growth factor-ß1, nitric oxide, interleukin (IL)-13, IL-17A, and IL-17 F levels were elevated in the supernatant when the collected T cells were co-cultured with iPS-SCs. The iPS-SCs had immunosuppressant effects even without cell-to-cell contact, and their effects were non-specific to the antigen preloaded on iPS-SCs. EAU was significantly milder in the mice administered iPS-SCs prior to immunization. CONCLUSIONS: Macrophage-like iPS-SCs reduced Th1 immune response to a retinal antigen and Th1-mediated EAU in mice. These results showed the possibility of the application of iPS technology to the treatment of noninfectious ocular inflammation, endogenous uveitis, in the future.

Expression of Vascular Endothelial Growth Factor-C in the Trabecular Meshwork of Patients with Neovascular Glaucoma and Primary Open-Angle Glaucoma.

To investigate the expression of vascular endothelial growth factor (VEGF)-C and vascular endothelial growth factor receptor (VEGFR)3 in the trabecular meshwork (TM) of patients with glaucoma and cultured TM cells. Methods: The expressions of VEGF-C in angle tissues collected by trabeculectomy from patients with glaucoma and non-glaucomatous choroidal malignant melanoma were analyzed by immunohistochemistry. Additionally, VEGF-C concentrations were determined in the aqueous humor of patients with glaucoma by ELISA. The expressions of VEGFR3, which is a receptor of VEGF-C in cultured TM cells, were analyzed by Western blot analysis and immunocytochemistry. Cultured TM cells were stimulated by oxidative stress, hypoxia, or high glucose conditions, and VEGF-C concentrations in supernatants and cell lysates were determined by ELISA. Results: VEGF-C immunoreactivity was positive in TM tissues of glaucoma patients, but not in those of non-glaucomatous controls. VEGF-C concentrations in the aqueous humor of patients with neovascular glaucoma and primary open-angle glaucoma were lower than those with non-glaucoma patients. VEGFR3 was expressed in cultured TM cells. VEGF-C concentrations in supernatants or cell lysates of TM cells cultured under oxidative stress and hypoxia were significantly elevated compared with those under steady conditions (p < 0.05). VEGF-C concentrations in supernatants and cell lysates of TM cells cultured in high glucose were significantly higher than those in low glucose (p < 0.01). Conclusions: VEGF-C was expressed in TM tissues of patients with glaucoma, which was secreted from cultured TM cells under various pathological conditions. These results suggest that VEGF-C may be involved in the pathology of glaucoma.

Comparison of clinical characteristics in patients with acute zonal occult outer retinopathy according to anti-retinal antibody status.

PURPOSE: To evaluate the clinical characteristics of patients with acute zonal occult outer retinopathy (AZOOR), according to the presence or absence of anti-retinal antibodies (ARAs) that are frequently detected in autoimmune retinopathy. METHODS: Retrospective observational case series. This study included 33 patients with acute-stage AZOOR who had been followed up for more than 6 months after the initial visit. The median follow-up period was 26 months. Immunoblot analyses were used to detect autoantibodies for recoverin, carbonic anhydrase II, and α-enolase in serum from these patients. Main outcome measures comprised clinical factors at the initial and final visits, including best-corrected visual acuity, mean deviation on Humphrey perimetry, and retinal morphology, which were statistically compared between patients with AZOOR who exhibited ARAs and those who did not. RESULTS: At least one serum ARA was detected in 42% of patients with AZOOR. There were no significant differences in clinical factors between the two groups, including follow-up period, best-corrected visual acuity and mean deviation at the initial and final visits, a-wave amplitude on single-flash electroretinography at the initial visit, and frequencies of improvement of the macular ellipsoid zone and AZOOR recurrence. CONCLUSIONS: Our findings suggest that the presence of ARAs did not influence visual outcomes or outer retinal morphology in patients with AZOOR.

Outcomes of a 2-year treat-and-extend regimen with aflibercept for diabetic macular edema.

This prospective, open-label, single-arm, non-randomized clinical trial, assessed the efficacy of a 2-year treat-and-extend (T&E) regimen involving intravitreal aflibercept injection (IAI), with the longest treatment interval set to 16 weeks, and adjunct focal/grid laser in diabetic macula edema (DME) patients. We examined 40 eyes (40 adults) with fovea-involving DME from 8 Japanese centers between April 2015 and February 2017. Participants received IAI with an induction period featuring monthly injections and a subsequent T&E period featuring 8-16-week injection interval, adjusted based on optical coherence tomography findings. The primary endpoints were mean changes in the best-corrected visual acuity (BCVA) and central subfield macular thickness (CST) from baseline. Thirty patients (75%) completed the 2-year follow-up. The mean BCVA and CST changed from 60.5 ± 15.6 letters and 499.2 ± 105.6 µm at baseline to 66.6 ± 17.1 letters (P = 0.217) and 315.2 ± 79.0 µm (P < 0.001), respectively, after 2 years. The treatment interval was extended to 12 and 16 weeks in 6.7% and 66.7% of patients, respectively, at the end of 2 years. The T&E aflibercept regimen with the longest treatment interval set to 16 weeks, with adjunct focal/grid laser may be a rational 2-year treatment strategy for DME.

Treat-and-extend therapy with aflibercept for diabetic macular edema: a prospective clinical trial.

PURPOSE: To investigate the efficacy and safety of a treat-and-extend (T&E) regimen using aflibercept (Eylea) for diabetic macular edema (DME). STUDY DESIGN: Prospective, open-label, multicenter, single-arm, nonblinded clinical study. METHODS: Forty eyes of 40 patients with DME received a T&E regimen of intravitreal aflibercept injection (IAI) with the longest treatment interval set to 16 weeks and adjunct focal/grid laser for 1 year. An intent-to-treat analysis was performed using the same last-observation-carried-forward method. A per-protocol analysis was also performed for patients who completed a 1-year T&E regimen. The primary endpoints were mean changes in best-corrected visual acuity (BCVA) and central subfield macular thickness (CST) from baseline. Secondary endpoints included IAI-interval extension and resultant IAI numbers and the association between an early response to IAI and final BCVA gain at 1 year. RESULTS: Thirty-one patients (77.5%) completed the 1-year aflibercept T&E regimen. In these per-protocol participants, the mean CST improvement/reduction was 187.3 ± 145.0 µm (P < .001), but the mean BCVA gain was limited to 4.3 ± 12.2 letters (P = .782). Subanalysis revealed that eyes that gained ≥ 4 letters (median at week 12) after the initial 3 consecutive IAIs (induction phase) achieved greater vision improvement (13.8 ± 9.5 letters) than did the residual eyes (- 4.3 ± 9.2 letters) at 1 year (P < .001). Treatment intervals were extended to 12 and 16 weeks in 16.1% (5/31) and 45.2% (14/31) of the patients, respectively. The mean IAI number was 7.0 ± 1.1. CONCLUSIONS: The results of this study suggest that although the BCVA improvement might be somewhat less than that of frequent treatment, a T&E aflibercept regimen with the longest treatment interval set to 16 weeks is a realizable rational strategy for DME treatment over 1 year.