Efficacy of combined anti-VEGF and photodynamic therapy for bilateral diffuse uveal melanocytic proliferation

RATIONALE: Bilateral diffuse uveal melanocytic proliferation (BDUMP) is an extremely rare retinal exudative disease with physical disorders and no established treatment standard. We describe treatment courses in 3 cases of BDUMP. PATIENTS CONCERNS: Three male patients complained active vision loss. One male patient in his 70s (patient 1) was treated with prednisolone, mesalazine, and ciclosporin for hypoplastic anemia and ulcerous colitis. One male patient in his 60s (patient 2) was on prednisolone therapy for adult Still disease. Another male patient in his 70s (patient 3) was on prednisolone therapy for polymyalgia rheumatica, giant cell arteritis, and pancreatic body tumor. DIAGNOSES: Retinal specialists diagnosed these patients with BDUMP based on characteristic fundus findings of multiple red patches and retinal exudate. INTERVENTIONS: Two patients (patients 1 and 2) with poor response to anti-vascular endothelial growth factor (VEGF) monotherapy and/or triamcinolone acetonide sub-Tenon injection were treated with combined anti-VEGF therapy and photodynamic therapy. One patient (patient 3) was treated with 3 rounds of monthly anti-VEGF monotherapy. OUTCOMES: Retinal exudates were resolved in all patients. No recurrence of retinal exudates was observed for at least 10 months, 2 years, or 4 months after the therapy in patients 1, 2, and 3, respectively. However, best-corrected visual acuity of the right eye was low (20/200) compared with that of the left eye (20/22) in patient 2 despite exudate resolution, due to permanent outer retinal damage secondary to long-term retinal exudate. LESSONS SUBSECTIONS: Combined anti-VEGF therapy and photodynamic therapy may be a feasible therapeutic option for treatment-resistant exudate in patients with BDUMP. Early diagnosis of BDUMP and prompt administration of combination therapy are crucial

Reduction of lipid accumulation rescues Bietti’s crystalline dystrophy phenotypes

眼の難病クリスタリン網膜症の発症メカニズムを解明 --治療薬の有力候補発見により創薬研究の進展に期待--. 京都大学プレスリリース. 2018-03-27.Bietti’s crystalline dystrophy (BCD) is an intractable and progressive chorioretinal degenerative disease caused by mutations in the CYP4V2 gene, resulting in blindness in most patients. Although we and others have shown that retinal pigment epithelium (RPE) cells are primarily impaired in patients with BCD, the underlying mechanisms of RPE cell damage are still unclear because we lack access to appropriate disease models and to lesion-affected cells from patients with BCD. Here, we generated human RPE cells from induced pluripotent stem cells (iPSCs) derived from patients with BCD carrying a CYP4V2 mutation and successfully established an in vitro model of BCD, i.e., BCD patient-specific iPSC-RPE cells. In this model, RPE cells showed degenerative changes of vacuolated cytoplasm similar to those in postmortem specimens from patients with BCD. BCD iPSC-RPE cells exhibited lysosomal dysfunction and impairment of autophagy flux, followed by cell death. Lipidomic analyses revealed the accumulation of glucosylceramide and free cholesterol in BCD-affected cells. Notably, we found that reducing free cholesterol by cyclodextrins or δ-tocopherol in RPE cells rescued BCD phenotypes, whereas glucosylceramide reduction did not affect the BCD phenotype. Our data provide evidence that reducing intracellular free cholesterol may have therapeutic efficacy in patients with BCD

One-Year Outcome Predictors of Strabismus Surgery from Anterior Segment Optical Coherence Tomography with Multiple B-Scan Averaging

Strabismologists are eager to identify preoperative or intraoperative strabismus surgery outcome predictors because of the variable effects in each patient. Conjunctival closure position recession after rectus muscle recession is effective for correcting large angle strabismus. The elasticity of the conjunctiva and Tenon’s capsule is important for strabismus surgery management. In this longitudinal study, we evaluated the prognosis of conjunctiva and Tenon’s capsule thickness (CTT) near the limbus 1 year after strabismus surgery with a limbal conjunctival incision using swept-source anterior segment optical coherence tomography with multiple B-scan averaging. Also, we identified preoperative and/or intraoperative parameters associated with corrective effects 1 year after surgery in 15 consecutive treatment-naïve patients with exotropia or esotropia who underwent recession and resection. The 1-year CTT was greater than the preoperative CTT on the resection side (269 ± 111 vs 183 ± 53 μm, P < 0.001) but was smaller on the recession side (137 ± 54 vs 183 ± 71 μm, P = 0.02). The corrective effect of surgery (1.6 ± 0.3°/mm) was most strongly correlated with preoperative CTT on the recession side (P = 0.005, β = −0.73). Hence, CTT on the recession side may provide adjunctive information for strabismus treatment

Effects of Intravitreous Aflibercept Injection in Pachychoroid Neovasculopathy: Comparison with Typical Neovascular Age-Related Macular Degeneration

Purpose: To compare the 12-month efficacy of intravitreous aflibercept (IVA) injection between eyes with pachychoroid neovasculopathy and neovascular age-related macular degeneration (AMD). Methods: Retrospective, comparative case series analysis. Twenty-seven eyes with pachychoroid neovasculopathy and sixty-three eyes with neovascular AMD. All patients received three initial monthly, followed by bimonthly, IVA injections. Results: Twelve months after initial treatment, the mean best-corrected visual acuity (BCVA) had improved both in pachychoroid neovasculopathy (from 0.28 to 0.14 logMAR; P = 0.001) and neovascular AMD (from 0.40 to 0.29 logMAR; P < 0.001). Twelve months after initial treatment, eyes with pachychoroid neovasculopathy exhibited decreased mean central retinal thickness (CRT) and subfoveal choroidal thickness (both, P < 0.001) and presence of polyps (P = 0.039) and improved integrity of external limiting membrane (ELM) (P = 0.008) and ellipsoid zone band (P = 0.001). At the 12-month follow-up, 77% and 68% of eyes with pachychoroid neovasculopathy and neovascular AMD, respectively, exhibited dry macula (P = 0.30). Baseline CRT was correlated with 12-month BCVA in eyes with pachychoroid neovasculopathy (P = 0.02). In eyes with neovascular AMD, CRT (P = 0.005) and presence of intact ELM (P = 0.007) were significant predictors of 12-month BCVA. Conclusion: Periodic IVA injection leads to anatomical and functional improvement in eyes with pachychoroid neovasculopathy and in eyes with neovascular AMD

KUS121, an ATP regulator, mitigates chorioretinal pathologies in animal models of age-related macular degeneration

Age-related macular degeneration (AMD) is a leading cause of blindness among elderly people. The appearance of drusen is a clinical manifestation and a harbinger of both exudative and atrophic AMD. Recently, antibody-based medicines have been used to treat the exudative type. However, they do not restore good vision in patients. Moreover, no effective treatment is available for atrophic AMD. We have created small chemicals (Kyoto University Substances; KUSs) that act as ATP regulators inside cells. In the present study, we examined the in vivo efficacy of KUS121 in C-C chemokine receptor type 2-deficient mice, a mouse model of AMD. Systemic administration of KUS121 prevented or reduced drusen-like lesions and endoplasmic reticulum stress, and then substantially mitigated chorioretinal pathologies with significant preservation of visual function. Additionally, we confirmed that long-term oral administration of KUS121 caused no systemic complications in drusen-affected monkeys. ATP regulation by KUSs may represent a novel strategy in the treatment of drusen and prevention of disease progression in AMD

Macular retinal circulation in healthy eyes examined by optical coherence tomography angiography extended interscan time analysis.

PurposeTo examine whether extended interscan time (IST) on optical coherence tomography angiography (OCTA) can detect slow retinal blood flow, which is undetectable on default IST, in the healthy macula.MethodsOCTA (OCT-A1, Canon Inc.) scanning of a macular area measuring 4 × 4 mm2 of 14 healthy eyes of 14 healthy volunteers with no history or evidence of systemic and macular diseases was performed. ISTs were set at 7.6 (IST7.6, default setting), 12.0 (IST12.0), and 20.6 msec (IST20.6). Ten OCTA images were acquired at each IST, and an averaged image was created. For each averaged OCTA image obtained at IST7.6, IST12.0, and IST20.6, we defined the area surrounded by the innermost capillary ring as the foveal avascular zone (FAZ). We qualitatively evaluated the delineation of the capillaries consisting of the FAZ and quantitatively measured the FAZ area at each IST.ResultsExtensions from IST7.6 to IST12.0 and IST20.6 could newly delineated retinal capillaries that were undetectable at the default IST; new capillaries were detected in 10 (71%) eyes at IST12.0 and 11 (78%) eyes at IST20.0. The FAZ areas were 0.334 ± 0.137 mm2, 0.320 ± 0.132 mm2, and 0.319 ± 0.129 mm2 for IST7.6, IST12.0, and IST20.0, respectively; the FAZ areas at IST12.0 and IST20.0 were significantly decreased compared with that at IST7.6 (p = 0.004 and 0.002, respectively).ConclusionIn OCTA for healthy participants, extensions of the ISTs newly detected retinal capillaries with slow blood flow around FAZ. The FAZ shapes varied with different ISTs. Thus, the blood flow dynamics are not physiologically uniform around FAZ. Compared with conventional OCTA, this protocol enables a more detailed evaluation of retinal circulation and provides a better understanding of the physiological circulatory status of the healthy retina, and may enable the assessment of circulation in the very early stages in diseased eyes

Intraocular Vascular Endothelial Growth Factor Levels in Pachychoroid Neovasculopathy and Neovascular Age- Related Macular Degeneration

Citation: Hata M, Yamashiro K, Ooto S, et al. Intraocular vascular endothelial growth factor levels in pachychoroid neovasculopathy and neovascular agerelated macular degeneration. Invest Ophthalmol Vis Sci. 2017;58:292-298. DOI:10.1167/iovs.16-20967 PURPOSE. To investigate the difference in intraocular vascular endothelial growth factor (VEGF) concentration between pachychoroid neovasculopathy and neovascular age-related macular degeneration (nAMD) and its associations with responses to three monthly anti-VEGF injections as an initial treatment for the two conditions. METHODS. This study included nine eyes with treatment-naïve pachychoroid neovasculopathy and 21 eyes with treatment-naïve nAMD. Before the initial intravitreal anti-VEGF injection, aqueous humor samples were collected and the concentration of VEGF was measured using enzyme-linked immunosorbent assay. The concentration was compared between the two conditions, and its associations with responses to anti-VEGF therapy were investigated. RESULTS. The mean VEGF concentration in pachychoroid neovasculopathy was significantly lower than that in nAMD (63.4 6 17.8 pg/ml and 89.8 6 45.0 pg/ml, respectively; P ¼ 0.035). The VEGF concentration was associated with the presence or absence of drusen (b ¼ 0.503, P ¼ 0.004). After anti-VEGF therapy, 6 (66.7%) of 9 eyes with pachychoroid neovasculopathy and 17 (81.0%) of 21 eyes with nAMD achieved dry macula (P ¼ 0.640). Dry macula at 3 months and 12 months was significantly associated with a low VEGF concentration in pachychoroid neovasculopathy (P ¼ 0.013 and P ¼ 0.042, respectively), but not in nAMD (P ¼ 0.108 and P ¼ 0.219). CONCLUSIONS. The mean VEGF concentration in pachychoroid neovasculopathy was lower than that in nAMD, suggesting that the way in which VEGF is involved in angiogenesis may differ between pachychoroid neovasculopathy and nAMD

Deterioration of phagocytosis in induced pluripotent stem cell-derived retinal pigment epithelial cells established from patients with retinitis pigmentosa carrying Mer tyrosine kinase mutations

Retinitis pigmentosa (RP) is an incurable retinal degenerative disease with an unknown mechanism of disease progression. Mer tyrosine kinase (MERTK), which encodes a receptor of the Tyro3/Axl/Mer family of tyrosine kinases, is one of the causal genes of RP. MERTK is reportedly expressed in the retinal pigment epithelium (RPE) and is essential for phagocytosis of the photoreceptor outer segment. Here, we established induced pluripotent stem cells (iPSC) from patients with RP having homozygous or compound heterozygous mutations in MERTK, and from healthy subjects; the RP patient- and healthy control-derived iPSCs were differentiated into RPE cells. Although cytoskeleton staining suggested that polarity may have been disturbed mildly, there were no apparent morphological differences between the diseased and normal RPE cells. The internalization of photoreceptor outer segments in diseased iPSC-RPE cells was significantly lower than that in normal iPSC-RPE cells. This in vitro disease model may be useful for elucidating the mechanisms of disease progression and screening treatments for the disease

Annual trends of ophthalmic surgeries in Japan’s super-aged society, 2014–2020: a national claims database study

Abstract This study aimed to analyze the trends and factors influencing the number of ophthalmic surgeries in Japan using the open data from the National Database of Health Insurance Claims and Specific Health Checkups of Japan published by the Ministry of Health, Labour and Welfare. We calculated the number of cataract, glaucoma, and vitreoretinal surgeries, categorized by sex, age, and surgical type, for the fiscal years (FY) 2014 to 2020. The number of cataract surgeries remained stable at approximately 1.45 million cases from FY 2014 to 2018, increased to nearly 1.6 million cases in FY 2019, and decreased to 1.45 million cases in FY 2020. Among glaucoma surgeries, surgical treatments were increased 1.8 times over 7 years, from 33,000 to 60,000 cases. Laser treatment remained steady at around 55,000 cases from FY 2014 to 2017 and then increased to approximately 60,000 cases. The number of vitreoretinal surgeries was increased 1.2 times from FY 2014 to 2019, from 120,000 to 140,000, and decreased to 130,000 by FY 2020. Trends in ophthalmic surgeries over the past 7 years may be influenced by population aging, minimally invasive surgery, and the coronavirus disease pandemic. These findings have implications on surgical decision-making and resource allocation