Alteration of treatment choices and the visual prognosis for diabetic macular edema in the era of anti-VEGF drugs: Analysis of the STREAT-DME 2 study.

PURPOSE: To assess the real-world outcome of best-corrected visual acuity (BCVA) following 2-year intervention for treatment-naïve diabetic macular edema (DME) since the approval of anti-vascular endothelial growth factor (VEGF) therapy. METHODS: A total of 1,780 treatment-naïve eyes with DME for which intervention was initiated between 2015 and 2019, and which were followed for 2 years, were extracted from the longitudinal medical records of 37 retinal disease institutions in Japan. Interventions included anti-VEGF therapy, topical corticosteroid therapy, macular photocoagulation, and vitrectomy. The baseline and final BCVA, and the number and timing of interventions were recorded. Eyes were classified according to the year in which intervention was initiated. RESULTS: Over a 2-year period, BCVA improved annually, finally reaching 7 letters. The proportion of eyes in which good vision was maintained (BCVA >20/40) increased to 73.3% in the latest period. The administration of anti-VEGF therapy remained stable, accounting for approximately 90% of eyes. Notably, the proportion of eyes receiving anti-VEGF drugs as first-line treatment increased dramatically to approximately 80%. CONCLUSION: Anti-VEGF therapy has become the first-line treatment since the approval of anti-VEGF drugs for DME. These findings reflect the evolution of DME treatment and highlight the superiority of anti-VEGF therapy and its increased uptake over time.

A pilot study of diabetic retinopathy in a porcine model of maturity onset diabetes of the young type 3 (MODY3).

Diabetic retinopathy (DR) is a leading cause of blindness in the working population. Because novel therapeutic intervention require testing, there is an urgent need for reliable animal models that faithfully replicate DR. Pig eyes have many similarities to human eyes anatomically and physiologically. Thus, attempts have been made to establish porcine models of DR by surgical, pharmaceutical or genetical induction of insulin deficiency, and dietary intervention. A previous study reported a transgenic pig model of maturity onset diabetes of the young type 3 (MODY3) developed signs of severe DR such as hemorrhage and proliferative tissue at the surface of the retina. However, the course of development of DR has not been studied in detail in this model. The purpose of this study was to investigate the early phase of DR in a MODY3. MODY3 and wild-type (WT) pigs underwent fundus photography and fluorescein angiogram (FA) before they developed cataracts. Animals were euthanized at age 1, 4, 7, and 10 months. Whole-mount retina and 10-µm thick paraffinized sections were stained with isolectin B4, and vessel density was determined by MATLAB software. At 4 and 7 months, retinal arterioles were immediately cannulated, and vasomotor action was measured by incubation with bradykinin and sodium nitroprusside. In the MODY3 pigs, fasting blood sugar levels gradually increased up to 500 mg/dL. Vascular tortuosity and yellowish spindle-shaped lesions were confirmed in MODY3 pigs at the age of 7 months; however, no microaneurysms were detected on FA. Compared with age-matched WT pigs, MODY3 pigs showed a significant decrease in blood vessel density in the intermediate and deep vascular plexus at 4 and 7 months of age and a slight decrease in capillary density in the superficial vascular plexus at 7 months of age. In MODY3 pigs, electron microscopy revealed thickening of the capillary basement membrane and leukostasis in the major blood vessels at 10 months of age. Bradykinin-induced dilation of retinal arterioles was diminished in MODY3 pigs as early as 7 months of age. Within 1 year after birth, MODY3 pigs show all typical early vascular lesions of diabetes except for microaneurysm formation. This pilot study suggests that the MODY3 pigs may serve as a suitable DR model to test effects of newly developed compounds on DR.

Dilation of porcine retinal arterioles to nobiletin, a polymethoxyflavonoid: Roles of nitric oxide and voltage-dependent potassium channel.

We examined the effects of nobiletin, a polymethoxyflavonoid, on the retinal microvascular diameter to determine if they depend on the endothelium and/or smooth muscle to reveal the signaling mechanisms involved in this vasomotor activity. Porcine retinal arterioles were isolated, cannulated, and pressurized without flow in vitro. Video microscopic techniques recorded diametric responses to nobiletin. The retinal arterioles dilated in a nobiletin concentration-dependent (100 pM-10 µM) manner and decreased by 50% after endothelial removal. The nitric oxide (NO) synthase inhibitor, Nω-nitro-L-arginine methyl ester (L-NAME), reduced nobiletin-induced vasodilation comparable to denudation. Blockade of soluble guanylyl cyclase by 1H-[1,2,4] oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ) produced a similar inhibitory effect as that by L-NAME. Nobiletin-induced vasodilation was also inhibited by the nonselective potassium channel inhibitor, tetraethylammonium (TEA), and the voltage-gated K (Kv) inhibitor, 4-aminopyridine. Co-administration of L-NAME and TEA almost eliminated nobiletin-induced vasodilation. Nobiletin elicits both endothelium-dependent and -independent dilation of retinal arterioles mediated by NO release and Kv channel activation, respectively.

The Effect of Anti-Autotaxin Aptamers on the Development of Proliferative Vitreoretinopathy.

This study investigated the effect of anti-autotaxin (ATX) aptamers on the development of proliferative vitreoretinopathy (PVR) in both in vivo and in vitro PVR swine models. For the in vitro study, primary retinal pigment epithelial (RPE) cells were obtained from porcine eyes and cultured for cell proliferation and migration assays. For the in vivo study, a swine PVR model was established by inducing retinal detachment and injecting cultured RPE cells (2.0 × 106). Concurrently, 1 week after RPE cell injection, the anti-ATX aptamer, RBM-006 (10 mg/mL, 0.1 mL), was injected twice into the vitreous cavity. Post-injection effects of the anti-ATX aptamer on PVR development in the in vivo swine PVR model were investigated. For the in vitro evaluation, the cultured RPE cell proliferation and migration were significantly reduced at anti-ATX aptamer concentrations of 0.5-0.05 mg and at only 0.5 mg, respectively. Intravitreal administration of the anti-ATX aptamer also prevented tractional retinal detachment caused by PVR in the in vivo PVR model. We observed that the anti-ATX aptamer, RBM-006, inhibited PVR-related RPE cell proliferation and migration in vitro and inhibited the progression of PVR in the in vivo model, suggesting that the anti-ATX aptamer may be effective in preventing PVR.

The Effect of Sodium-Dependent Glucose Cotransporter 2 Inhibitor Tofogliflozin on Neurovascular Coupling in the Retina in Type 2 Diabetic Mice.

We investigated the effect of tofogliflozin, a sodium-dependent glucose cotransporter 2 inhibitor (SGLT2i), on retinal blood flow dysregulation, neural retinal dysfunction, and the impaired neurovascular coupling in type 2 diabetic mice. Tofogliflozin was added to mouse chow to deliver 5 mg/kg/day and 6-week-old mice were fed for 8 weeks. The longitudinal changes in the retinal neuronal function and blood flow responses to systemic hyperoxia and flicker stimulation were evaluated every 2 weeks in diabetic db/db mice that received tofogliflozin (n =6) or placebo (n = 6) from 8 to 14 weeks of age. We also evaluated glial activation and vascular endothelial growth factor (VEGF) expression by immunofluorescence. Tofogliflozin treatment caused a sustained decrease in blood glucose in db/db mice from 8 weeks of the treatment. In tofogliflozin-treated db/db mice, both responses improved from 8 to 14 weeks of age, compared with vehicle-treated diabetic mice. Subsequently, the electroretinography implicit time for the oscillatory potential was significantly improved in SGLT2i-treated db/db mice. The systemic tofogliflozin treatment prevented the activation of glial fibrillary acidic protein and VEGF protein expression, as detected by immunofluorescence. Our results suggest that glycemic control with tofogliflozin significantly improved the impaired retinal neurovascular coupling in type 2 diabetic mice with the inhibition of retinal glial activation.

Effect of Leaking Foveal Microaneurysms on the Treatment of Center-Involving Diabetic Macular Edema: A Pilot Study.

PURPOSE: Evaluate the effect of foveal leaking microaneurysms (MAs) on the required number of intravitreal ranibiz-umab (IVR) injections in the treatment of center-involving diabetic macular edema (DME) when treated with focal/grid laser. DESIGN: A pilot study of prospective, nonrandomized, multicenter clinical trial. METHODS: This study enrolled 21 eyes with DME for which pro re nata IVR injections were combined with short-pulse focal/grid laser. At 12 months, best-corrected visual acuity (BCVA), central subfield macular thickness (CMT), and the required number of IVRs to maintain CMT < 300 µm were compared between eyes with or without foveal leaking MAs, termed the MA(+) and MA(-) groups, respectively. RESULTS: Significant CMT improvements (p < 0.0001) and increased BCVA of 4.0 ± 8.5 letters were observed at 12 months. The MA(-) group required significantly fewer IVRs than did the MA(+) group (mean: 4.9 ± 3.0 vs. 8.6 ± 3.0; p = 0.0306). In the latter 6 months of the 1-year follow-up, 50% (4/8) of MA(-) eyes did not require any IVR administration to sustain CMT < 300 µm. CONCLUSIONS: A combination therapy of short-pulse focal/grid laser and reduced IVR injections appeared noninferior to previous reports of IVR monotherapy. Further large-scale investigations are warranted.

Correlation between short- and long-term effects of intravitreal ranibizumab therapy on macular edema after branch retinal vein occlusion: a prospective observational study.

BACKGROUND: The correlation between the short- and long-term effects of intravitreal ranibizumab (IVR) on macular edema after branch retinal vein occlusion (BRVO) remains unclear. We assessed the correlation between the short- and long-term effects of IVR on macular edema after BRVO. METHODS: Twenty-one eyes with macular edema after BRVO were enrolled in this prospective observational study. We measured the foveal thickness (FT) and the best-corrected visual acuity (BCVA) before, 1 day after, and 1 month after IVR (0.5 mg) and then at least every 2 months thereafter until 6 months after the injection. If the macular edema recurred, another injection was administered. The primary endpoint was the change from baseline in the BCVA (ΔVA). RESULTS: The mean logarithm of the minimum angle of resolution VA improved significantly (p = 0.01, p < 0.0001, respectively) after 1 day from 0.65 ± 0.28 to 0.51 ± 0.21 (20/89 to 20/63, Snellen equivalent) and after 6 months to 0.29 ± 0.24 (20/39, Snellen equivalent). The mean FT decreased significantly (p < 0.0001) after 1 day from 482 ± 85 µm to 349 ± 75 µm and after 6 months to 305 ± 84 µm. The 1-day VA was significantly (r = 0.68, p = 0.0007) positively correlated with the 6-month VA. The 1-day ΔVA was significantly (r = 0.79, p < 0.0001) positively correlated with the 6-month ΔVA. CONCLUSIONS: The short-term effects of IVR may predict the long-term effects of IVR in macular edema secondary to BRVO. TRIAL REGISTRATION: Trial registration number: UMIN000027003 . Retrospectively registered. (April/15/2017).

Short-term effects of intravitreal ranibizumab therapy on diabetic macular edema.

BACKGROUND: The short-term effects of intravitreal ranibizumab (IVR) on diabetic macular edema (DME) remains unclear. We assessed the short-term effects of IVR on DME. METHODS: Eighteen eyes of 14 patients with DME were enrolled in this prospective interventional case series. After intravitreal ranibizumab was injected into treatment-naïve eyes with DME, we measured the foveal thickness (FT) before and 2 h, 1 day, 1 week, and 1 month later and the best-corrected visual acuity (BCVA) at all times except 2 h and compared the changes to baseline (ΔFT and ΔVA). RESULTS: The mean FT decreased significantly (p < 0.0001) from 452 ± 77 to 429 ± 65 microns after 2 h. The mean logarithm of the minimum angle of resolution BCVA improved significantly (p = 0.032) after 1 month from 0.41 ± 0.24 to 0.32 ± 0.21 (20/51 to 20/42, Snellen equivalent). The ΔFT after 2 h was significantly (r = 0.53, p = 0.025) correlated with the ΔFT after 1 month. The ΔVA after 1 day was significantly (r = 0.59, p = 0.01) correlated with the ΔVA after 1 month. CONCLUSIONS: The structural effects of IVR for DME occurred within 2 h, whereas the functional effects occurred after 1 month. The short-term effects (within 1 day) of IVR may predict the therapeutic outcome 1 month after IVR in patients with DME. TRIAL REGISTRATION: The trial registration number: UMIN000026118 (Feb/13/2017). Retrospectively registered.

SHORT-TERM EFFECT OF INTRAVITREAL RANIBIZUMAB THERAPY ON MACULAR EDEMA AFTER BRANCH RETINAL VEIN OCCLUSION.

PURPOSE: To assess the short-term effect of intravitreal ranibizumab (IVR) on macular edema after branch retinal vein occlusion. METHODS: Twenty-three eyes with macular edema after branch retinal vein occlusion were enrolled in a prospective observational study. After administering one IVR injection (0.5 mg) for the first time, the authors measured the foveal thickness (FT) before and 2 hours, 1 and 3 days, 1 week, and 1 month later and the best-corrected visual acuity at all times except 2 hours, and determined the changes from baseline (ΔFT and ΔVA). RESULTS: The mean FT decreased significantly (P < 0.0001) from 522 ± 131 µm to 458 ± 96 µm after 2 hours. The mean logarithm of the minimum angle of resolution (logMAR) visual acuity improved significantly (P < 0.05) after 1 day from 0.69 ± 0.40 to 0.55 ± 0.34 (20/98-20/70, Snellen equivalent). The ΔFT after 2 hours was significantly positively correlated with the ΔFT after 1 week (r = 0.76, P < 0.001) and 1 month (r = 0.67, P < 0.001). The ΔVA after 1 day was correlated positively with the ΔVA after 1 week (r = 0.80, P < 0.001) and 1 month (r = 0.59, P < 0.01). CONCLUSION: Structural and functional effects of IVR for branch retinal vein occlusion occurred within 1 day. The short-term effects of IVR may predict the outcome of the therapy at 1 week and 1 month after IVR in macular edema secondary to branch retinal vein occlusion.

SYSTEMIC RISK FACTORS IN BILATERAL PROLIFERATIVE DIABETIC RETINOPATHY REQUIRING VITRECTOMY.

PURPOSE: The visual outcome after vitrectomy for proliferative diabetic retinopathy (PDR) is often poor. Bilateral vitrectomy has been especially associated with a poor visual prognosis in patients with PDR. The authors investigated the systemic risk factors for PDR requiring bilateral vitrectomy compared with unilateral vitrectomy. METHODS: The authors retrospectively reviewed 86 consecutive patients with Type 2 diabetes mellitus with PDR who underwent vitrectomy. These patients were divided into 2 groups: bilateral vitrectomy within 1 year (n = 25) and unilateral vitrectomy (n = 61). The authors compared the systemic risk factors: age, sex, duration of diabetes, hemoglobin A1c, body mass index, estimated glomerular filtration rate, uric albumin, hypertension, dyslipidemia, history of ischemic heart disease, arteriosclerosis obliterans, and smoking. RESULTS: There were significantly more cases with severe renal dysfunction in the bilateral vitrectomy group compared with the unilateral one (estimated glomerular filtration rate <30 mL/minute/1.73 m; bilateral cases = 5/25; unilateral cases = 2/61; P = 0.02). CONCLUSION: The authors found that severe renal dysfunction may be a risk factor in PDR requiring bilateral vitrectomy, indicating that careful attention needs to be paid to prevent the progression of diabetic retinopathy to severe PDR in the other eye if patients have severe unilateral PDR and severe renal dysfunction.

Enhanced vitreous imaging optical coherence tomography in primary macular holes.

The aim of the current pilot study is to investigate the efficacy of a novel enhanced vitreous imaging (EVI) in primary macular holes (MHs) using a spectral-domain optical coherence tomography (SD-OCT). Thirty-four eyes of 32 consecutive patients with a MH were examined in one time cross-sectional study. The vitreomacular interface was assessed using SD-OCT with conventional and EVI technique. Twenty-three of the 34 eyes did not show a Weiss ring, and in 22 of those, we observed a MH with an open roof or operculum and a detached posterior vitreous cortex with conventional vitreous imaging. Using EVI-OCT, we visualized the reflection of the posterior vitreous with a vitreopapillary attachment. One of the 23 eyes without a Weiss ring had a central round retinal defect without an operculum, and the conventional SD-OCT showed an empty vitreous, suggesting a complete posterior vitreous detachment. However, the EVI-OCT revealed the reflection of the posterior vitreous, and the cortex appeared to still be completely attached. In all the 23 eyes without a Weiss ring, EVI-OCT detected the reflection of the posterior vitreous and vitreopapillary attachment. In all 11 eyes with a Weiss ring (stage 4 hole), EVI-OCT showed an optically empty space in the posterior vitreous cavity without a vitreopapillary attachment. EVI-OCT may be a new reliable method for preoperative evaluations to determine the presence or absence of a complete posterior vitreous detachment in macular diseases with an indistinct Weiss ring.

Vasodilatory mechanisms of unoprostone isopropyl in isolated porcine retinal arterioles.

PURPOSE: To clarify the vasodilatory mechanism of unoprostone isopropyl (UI), we examined its effects on the retinal microvascular diameter to determine the dependence on the endothelium and/or smooth muscle to reveal the signaling mechanisms involved in this vasomotor activity. METHODS: Porcine retinal arterioles were isolated, cannulated, and pressurized without flow in vitro. Video microscopic techniques recorded the diametric responses to UI. RESULTS: The retinal arterioles dilated in response to UI in a dose-dependent (100 pM-10 µM) manner. The nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) inhibited UI-induced vasodilation. The large-conductance Ca2+-activated K channel (BKCa channel) blocker iberiotoxin also inhibited UI-induced vasodilation. The residual vasodilation after L-NAME was eliminated with co-administration of iberiotoxin. CONCLUSIONS: UI elicits dilation of the retinal arterioles mediated by NO release and BKCa channel activation.

Effect of intravitreal Rho kinase inhibitor ripasudil (K-115) on feline retinal microcirculation.

Ripasudil (K-115) is a novel Rho kinase inhibitor with a potent intraocular pressure-lowering effect. However, it is unclear whether ripasudil affects the retinal blood flow (RBF). We investigated the effect of ripasudil on feline retinal microcirculation. Ripasudil (5 µM, 50 µM or 5 mM; n = 5 each concentration) or vehicle (PBS; n = 5) was injected intravitreally. The vessel diameter (D) and blood velocity (V) were measured by laser Doppler velocimetry simultaneously in the first-order retinal arterioles and the RBF was calculated. The measurements started 5 min before the injection and were performed every 10 min for 120 min. After the intravitreal injection, the retinal circulatory parameters did not change significantly in PBS or 5 µM of ripasudil. The blood V and RBF increased significantly compared to baseline, whereas the vessel D did not change significantly in 50 µM and 5 mM of ripasudil. The V in 50 µM, and the V and RBF in 5 mM of ripasudil significantly increased compared to those in PBS. Intravitreal administration of ripasudil increased the blood V and RBF in cats, suggesting that ripasudil has the potential to improve the retinal blood flow.

Role of Ca2+ -dependent and Ca2+ -sensitive mechanisms in sphingosine 1-phosphate-induced constriction of isolated porcine retinal arterioles in vitro.

Although sphingosine 1-phosphate (S1P), a bioactive lipid derived from activated platelets, has a variety of physiologic effects on vessels, no reports have described the effect of S1P on the retinal circulation. We examined the effect and underlying mechanism of the vasomotor action of S1P on porcine retinal arterioles. The porcine retinal arterioles were isolated, cannulated, and pressurized without flow for in vitro study. S1P-induced diameter changes were recorded using videomicroscopic techniques. S1P elicited concentration-dependent (1 nM-10 µM) vasoconstriction of the retinal arterioles that was abolished by the S1P receptor 2 (S1PR2) antagonist JTE-013. S1P-induced vasoconstriction was abolished by the Rho kinase (ROCK) inhibitor H-1152 and was inhibited partly by the protein kinase C (PKC) inhibitor Gö-6983. The inhibition of phospholipase C by U73122 and L-type voltage-operated calcium channels (L-VOCCs) by nifedipine inhibited S1P-induced vasoconstriction; a combination of both inhibitors abolished S1P-induced vasoconstriction. Furthermore, inhibition of myosin light chain kinase (MLCK) by ML-9 significantly blocked S1P-induced vasoconstriction; further coadministration of ML-9 with H-1152 or Gö-6983 abolished S1P-induced vasoconstriction. The current data suggest that S1P elicits vasoconstriction of the retinal arterioles via S1PR2 in vascular smooth muscle cells and this vasoconstriction may be mediated by the Ca2+ -sensitive pathway via activation of PKC leading to activation of ROCK and the Ca2+ -dependent pathway via activation of L-VOCCs resulting in activation of MLCK.

Changes in retinal blood flow in patients with macular edema secondary to branch retinal vein occlusion before and after intravitreal injection of bevacizumab.

PURPOSE: To investigate the effect of intravitreal bevacizumab (IVB) injections for macular edema secondary to acute branch retinal vein occlusion on the retinal microcirculation. METHODS: The study was a prospective, interventional case series. Central macular thickness using spectral-domain optical coherence tomography and retinal blood flow (RBF) in untreated eyes with macular edema secondary to acute branch retinal vein occlusion in occluded (V1) and opposite venules in affected eyes (V2) and the equivalent venules in contralateral eyes (V3), using laser Doppler velocimetry during follow-up and after IVB injection, were measured. RESULTS: In 33 eyes with acute branch retinal vein occlusion of <2 months of duration at the first visit, changes in the retinal microcirculation for 1 month was observed; the macular edema improved spontaneously, and the RBF was unchanged in 15 of 33 eyes, and the RBF increased by 23.3% in 18 eyes with persistent macular edema. Twenty-four eyes received an IVB injection (1.25 mg per 0.05 mL). The RBF did not change significantly during follow-up. In 8 of 24 eyes (33%) with improved macular edema 3 months after the treatment, the average RBF values before injection were significantly higher compared with that of eyes with recurrent edema. CONCLUSION: One IVB injection might have little effect on the retinal microcirculation in patients with macular edema secondary to acute branch retinal vein occlusion at least 3 months after the injection. However, the increased RBF in the occluded venules before injection might be associated with improved macular edema after the IVB injection.

Successful prism treatment for cyclic esotropia: A case report.

Purpose: To report a case of cyclic esotropia successfully treated with prismatic correction. Observations: A 9-year-old girl presented with intermittent esotropia and diplopia occurring over the previous 4 months. The patient had 30 prism diopters (PD) of esotropia at both distance and near. Ocular motility testing, other ophthalmic examinations, and brain magnetic resonance imaging revealed no abnormalities. At the third visit, the patient had 6 PD of intermittent esotropia without diplopia, and the eye position diary demonstrated esotropia every other day, which led to a diagnosis of cyclic esotropia with a 48-h cycle. The cyclic pattern persisted for 9 months following the initial visit. However, during a subsequent regular visit, the patient reported a newfound ability to self-adjust from "esotropic" days to "straight" days by tightly closing the eyes immediately after waking up in the morning, particularly when wishing to avoid strabismus. To address the condition, we affixed a Fresnel membrane prism on the glasses to compensate for the latent deviation on a "straight" day. During the subsequent 18 months, the esotropia completely resolved, and the patient was followed up with gradual decreases in prism power. Conclusions and Importance: Correcting latent deviation using a prism lens is a simple approach without potential side effects. The present findings suggest that this approach is a viable treatment option for cyclic esotropia during its early and periodic stages.

Effects of switching from intravitreal injection of aflibercept to faricimab on ocular blood flow in patients with diabetic macular edema.

We assessed the short-term effects of switching from intravitreal aflibercept (IVA) to intravitreal faricimab (IVF) on ocular blood flow in patients with treatment-resistant diabetic macular edema (DME). The medical records of 15 patients with DME who had received IVA injection ≥ 3 months before were retrospectively reviewed. The best-corrected visual acuity, central macular thickness (CMT) on optical coherence tomography, and mean blur rate (MBR) of all disc areas on laser speckle flowgraphy were measured before, 1 week after, and 4 weeks after IVA and IVF, respectively. The changes in visual acuity showed no significant difference after switching from IVA to IVF (P = 0.732). The mean CMT decreased significantly during the follow-up period (both P < 0.001). MBR showed no significant difference during the follow-up period (P = 0.26). However, it decreased significantly 4 weeks after IVF (P = 0.01) compared with the baseline value, but not 4 weeks after IVA (P = 0.074). A significant association was observed between decreased MBR and decreased CMT in patients who received IVF (correlation coefficient: 0.501, P = 0.005) but not in those who received IVA (P = 0.735). Thus, IVF maintained ocular blood flow reduction, although no significant differences in visual acuity and CMT changes were observed compared to IVA.

Impairment of flicker-induced increase in retinal blood flow in diabetic pigs.

PURPOSE: To evaluate retinal blood flow (RBF) regulation in response to RBF stress in maturity-onset diabetes of the young type 3 (MODY3) pigs. STUDY DESIGN: Case-control study. METHODS: MODY3 pigs (diabetes mellitus [DM] group, n = 8) transfected with the human mutant hepatocyte nuclear factor-1⍺ and normal pigs of the same age (normal group, n = 8) were used as subjects. After confirming DM onset, the experiment was performed under inhalation anesthesia with isoflurane at 2 months of age before the cataract progressed. Ocular blood flow was assessed by calculating the optic papillary mean blur rate using laser speckle flowgraphy, modified for pig eye measurements. After baseline ocular blood flow measurements, flicker stimulation (12 Hz, 3 min) was applied, and ocular blood flow was measured over time. RESULTS: Blood glucose was 81.8 ± 5.1 mg/dL in the normal group and 311.4 ± 23.1 mg/dL in the DM group (mean ± standard error). The percent change in ocular blood flow at 3 min after flicker stimulation was +31.0 ± 10.9% in the normal group and -6.6 ± 6.5% in the DM group compared to the preload value, and the difference was statistically significant (Mann-Whitney test, P = 0.015). CONCLUSION: RBF response to flicker stimulation is reduced at 2 months of age in MODY3 pigs, suggesting that retinal neurovascular coupling is impaired from the early onset of DM.

Oral Intake of Hydrogen Water Improves Retinal Blood Flow Dysregulation in Response to Flicker Stimulation and Systemic Hyperoxia in Diabetic Mice.

Purpose: To examine the effects of hydrogen water on retinal blood flow (RBF) dysregulation in diabetes, we evaluated changes in RBF in response to flicker stimulation and systemic hyperoxia in diabetic mice. Methods: Twelve type 2 diabetic mice were divided into a group that received non-hydrogen water (n = 6, control group) and the other that received hydrogen-rich water (0.6-0.8 mM) (n = 6, HRW group) from six weeks of age. Body weight, blood glucose, intraocular pressure, and blood pressure were evaluated from eight to 14 weeks of age. RBF was measured in the vascular area of the optic disc as mean blur rate using laser speckle flowgraphy in the resting state and response to flicker stimulation and hyperoxia. We evaluated glial activation and oxidative stress based on immunofluorescence expression. Results: At 14 weeks, blood glucose level was significantly lower in the HRW group, though still elevated. RBF changes improved significantly in the HRW group compared with the control group from eight weeks of age and persisted throughout the study. Immunofluorescent expression of glial fibrillary acidic protein, particularly in the outer plexiform layer, was significantly decreased in the HRW group. Among oxidative stress markers, 3-nitrotyrosine was significantly suppressed in the HRW group. Conclusions: Hydrogen-rich water intake significantly improved RBF dysregulation in diabetic mice. Hydrogen may improve impaired neurovascular coupling function in diabetic mice by suppressing gliosis and oxidative stress in the retina. Translational Relevance: This study highlights the potential of oral intake of hydrogen-rich water to mitigate retinal dysfunction in diabetic mice.

Optimization of individualized faricimab dosing for patients with diabetic macular edema: Protocol for the SWAN open-label, single-arm clinical trial.

PURPOSE: In patients with diabetic macular edema (DME) from YOSEMITE/RHINE, dual angiopoietin-2/vascular endothelial growth factor-A (VEGF-A) inhibition with faricimab resulted in visual/anatomic improvements with extended dosing. The SWAN trial (jRCTs031230213) will assess the efficacy, durability, and safety of faricimab during the treatment maintenance phase in patients with DME using a treat-and-extend (T&E)-based regimen adapted to clinical practice and the characteristics of patients achieving extended dosing intervals. METHODS: SWAN is a 2-year, open-label, single-arm, interventional, multicenter trial enrolling adults with center-involving DME. All patients will receive three initial faricimab 6.0 mg doses every 4 weeks (Q4W). From week 12 onwards, in patients without active DME, dosing intervals will be extended in 8-week increments up to Q24W. In contrast, patients with active DME (central subfield thickness [CST] >325 µm and intraretinal fluid [IRF] or subretinal fluid [SRF] resulting in vision loss/disease aggravation) will receive a dose within a day and the dosing interval will be shortened by 4 weeks to a minimum of Q8W relative to the previous dosing interval. Recruitment commenced in August 2023 across a planned 16 sites in Japan. RESULTS: The primary endpoint is change in best-corrected visual acuity (BCVA) from baseline at 1 year (averaged over weeks 52, 56, and 60). Key secondary endpoints include: change from baseline in BCVA, CST, and National Eye Institute Visual Function Questionnaire scores over time; proportion of patients with BCVA (decimal visual acuity) ≥0.5, ≥0.7, ≥1.0, or ≤0.1; proportion of patients with absence of DME, and IRF and/or SRF over time. Safety endpoints include incidence/severity of ocular/nonocular adverse events. CONCLUSIONS: The SWAN trial is expected to provide evidence to support individualized faricimab dosing regimens, with the potential to reduce the burden of frequent treatments on patients, caregivers, and healthcare systems.