Retina Publications

Sun Y, Smith LEH. Retinal Vasculature in Development and Diseases. Annu Rev Vis Sci 2018;4:101-122.Abstract
The retina is one of the most metabolically active tissues in the body, consuming high levels of oxygen and nutrients. A well-organized ocular vascular system adapts to meet the metabolic requirements of the retina to ensure visual function. Pathological conditions affect growth of the blood vessels in the eye. Understanding the neuronal biological processes that govern retinal vascular development is of interest for translational researchers and clinicians to develop preventive and interventional therapeutics for vascular eye diseases that address early drivers of abnormal vascular growth. This review summarizes the current knowledge of the cellular and molecular processes governing both physiological and pathological retinal vascular development, which is dependent on the interaction among retinal cell populations, including neurons, glia, immune cells, and vascular endothelial cells. We also review animal models currently used for studying retinal vascular development.
Totsuka K, Ueta T, Uchida T, Roggia MF, Nakagawa S, Vavvas DG, Honjo M, Aihara M. Oxidative stress induces ferroptotic cell death in retinal pigment epithelial cells. Exp Eye Res 2018;Abstract
The dysfunction and cell death of retinal pigment epithelial (RPE) cells are hallmarks of late-stage dry (atrophic) age-related macular degeneration (AMD), for which no effective therapy has yet been developed. Previous studies have indicated that iron accumulation is a source of excess free radical production in RPE, and age-dependent iron accumulation in RPE is accelerated in patients with dry AMD. Although the pathogenic role of oxidative stress in RPE in the development of dry AMD is widely accepted, the mechanisms of oxidative stress-induced RPE cell death remain elusive. Here, we show that ferroptotic cell death, a mode of regulated necrosis mediated by iron and lipid peroxidation, is implicated in oxidative stress-induced RPE cell death in vitro. In ARPE-19 cells we observed that the ferroptosis inhibitors ferrostatin-1 and deferoxamine (DFO) rescued tert-butyl hydroperoxide (tBH)-induced RPE cell death more effectively than inhibitors of apoptosis or necroptosis. tBH-induced RPE cell death was accompanied by the three characteristics of ferroptotic cell death: lipid peroxidation, glutathione depletion, and ferrous iron accumulation, which were all significantly attenuated by ferrostatin-1 and DFO. Exogenous iron overload enhanced tBH-induced RPE cell death, but this effect was also attenuated by ferrostatin-1 and DFO. Furthermore, mRNA levels of numerous genes known to regulate iron metabolism were observed to be influenced by oxidative stress. Taken together, our observations suggest that multiple modes of cell death are involved in oxidative stress-induced RPE cell death, with ferroptosis playing a particularly important role.
Busch C, Zur D, Fraser-Bell S, Laíns I, Santos AR, Lupidi M, Cagini C, Gabrielle P-H, Couturier A, Mané-Tauty V, Giancipoli E, Ricci GD'A, Cebeci Z, Rodríguez-Valdés PJ, Chaikitmongkol V, Amphornphruet A, Hindi I, Agrawal K, Chhablani J, Loewenstein A, Iglicki M, Rehak M, Rehak M. Shall we stay, or shall we switch? Continued anti-VEGF therapy versus early switch to dexamethasone implant in refractory diabetic macular edema. Acta Diabetol 2018;55(8):789-796.Abstract
AIMS: To compare functional and anatomical outcomes of continued anti-vascular endothelial growth factor (VEGF) therapy versus dexamethasone (DEX) implant in eyes with refractory diabetic macular edema (DME) after three initial anti-VEGF injections in a real-world setting. METHODS: To be included in this retrospective multicenter, case-control study, eyes were required: (1) to present with early refractory DME, as defined by visual acuity (VA) gain ≤ 5 letters or reduction in central subfield thickness (CST) ≤ 20%, after a loading phase of anti-VEGF therapy (three monthly injections) and (2) to treat further with (a) anti-VEGF therapy or (b) DEX implant. Main outcome measures were change in visual acuity (VA) and central subfield thickness (CST) at 12 months. Due to imbalanced baseline characteristics, a matched anti-VEGF group was formed by only keeping eyes with similar baseline characteristics as those in the DEX group. RESULTS: A total of 110 eyes from 105 patients were included (anti-VEGF group: 72 eyes, DEX group: 38 eyes). Mean change in VA at 12 months was - 0.4 ± 10.8 letters (anti-VEGF group), and + 6.1 ± 10.6 letters (DEX group) (P = 0.004). Over the same period, mean change in CST was + 18.3 ± 145.9 µm (anti-VEGF group) and - 92.8 ± 173.6 µm (DEX group) (P < 0.001). Eyes in the DEX group were more likely to gain ≥ 10 letters (OR 3.71, 95% CI 1.19-11.61, P = 0.024) at month 12. CONCLUSIONS: In a real-world setting, eyes with DME considered refractory to anti-VEGF therapy after three monthly injections which were switched to DEX implant and had better visual and anatomical outcomes at 12 months than those that continued treatment with anti-VEGF therapy.
Hoshi S, Okamoto F, Arai M, Hirose T, Sugiura Y, Murakami T, Oshika T. Patching retinal breaks with polyethylene glycol-based synthetic hydrogel sealant for retinal detachment in rabbits. Exp Eye Res 2018;177:117-121.Abstract
The purpose of this study was to evaluate absorbable polyethylene glycol (PEG)-based synthetic hydrogel as a sealant for retinal breaks in rhegmatogenous retinal detachment (RD). A three-port, 25-gauge vitrectomy was performed on nine Dutch pigmented rabbit eyes. Subsequently, RD was induced by creating a retinal break. The retina was then reattached by fluid-air exchange. In six of nine eyes (RD-PEG group), PEG sealant was applied to completely cover the retinal breaks, and then photopolymerized with light; thereafter, intravitreous air was replaced with balanced salt solution (BSS). In the remaining three eyes (RD group), PEG sealant was not applied, but the intravitreous air was replaced with BSS. Ophthalmological examinations and intraocular pressure measurements were conducted preoperatively, and at 1 and 7 days, and 1, 3, and 6 months postoperatively. Histological examinations of the eyes were performed after 6 postoperative months. At surgery, retinal reattachment with PEG sealant was achieved in all eyes in the RD-PEG group. Fundoscopic and optical coherence tomographic examinations revealed that the retina remained attached in all the eyes of the RD-PEG group throughout the 6-month observation period. Histological examination revealed no signs of damage in the retinal layers at the edges of the retinal breaks that were in contact with the sealant. In the RD group, the retinas detached in all eyes within 7 days postoperatively. The PEG sealant closed the retinal breaks and maintained retinal reattachment. Intraocular tamponade was not necessary.
Strauss RW, Muñoz B, Ahmed MI, Bittencourt M, Schönbach EM, Michaelides M, Birch D, Zrenner E, Ervin A-M, Charbel Issa P, Kong J, Wolfson Y, Shah M, Bagheri S, West S, Scholl HPN, Scholl HPN. The Progression of the Stargardt Disease Type 4 (ProgStar-4) Study: Design and Baseline Characteristics (ProgStar-4 Report No. 1). Ophthalmic Res 2018;:1-10.Abstract
BACKGROUND/AIMS: To describe the design and baseline characteristics of patients enrolled in the multicenter, prospective natural history study of Stargardt disease type 4. METHODS: Fifteen eligible patients aged 6 years and older at baseline, harboring disease-causing variants in the PROM1 gene, and with specified ocular lesions were enrolled. They were examined at baseline using a standard protocol, with 6 monthly follow-up visits for a 2-year period including best-corrected ETDRS visual acuity, spectral-domain optical coherence tomography, fundus autofluorescence (FAF), mesopic and scotopic microperimetry (MP). Areas of definitely decreased FAF (DDAF) and questionably decreased FAF were outlined and quantified on FAF images. RESULTS: Amongst the 15 patients (29 eyes) that were enrolled at 5 centers in the USA and Europe, 10 eyes (34.5%) had areas of DDAF with an average lesion area of 3.2 ± 3.5 mm2 (range 0.36-10.39 mm2) at baseline. The mean retinal sensitivity of the posterior pole derived from mesopic MP was 8.8 ± 5.8 dB. CONCLUSIONS: Data on disease progression in PROM1-related retinopathy from this study will contribute to the characterization of the natural history of disease and the exploration of the utility of several modalities to track progression and therefore to potentially be used in future interventional clinical trials.
Grundy SJ, Tshering L, Wanjala SW, Diamond MB, Audi MS, Prasad S, Shinohara RT, Rogo D, Wangmo D, Wangdi U, Aarayang A, Tshering T, Burke TF, Mateen FJ. Retinal Parameters as Compared with Head Circumference, Height, Weight, and Body Mass Index in Children in Kenya and Bhutan. Am J Trop Med Hyg 2018;99(2):482-488.Abstract
The retina shares embryological derivation with the brain and may provide a new measurement of overall growth status, especially useful in resource-limited settings. Optical coherence tomography (OCT) provides detailed quantification of retinal structures. We enrolled community-dwelling children ages 3-11 years old in Siaya, Kenya and Thimphu, Bhutan in 2016. We measured head circumference (age < 5 years only), height, and weight, and standardized these by age and gender. Research staff performed OCT (; Optovue, Inc., Fremont, CA), measuring the peripapillary retinal nerve fiber layer (RNFL) and macular ganglion cell complex (GCC) thicknesses. A neuro-ophthalmologist performed quality control for centration, motion artifact, and algorithm-derived quality scores. Generalized estimating equations were used to determine the relationship between anthropometric and retinal measurements. Two hundred and fifty-eight children (139 females, average age 6.4 years) successfully completed at least one retinal scan, totaling 1,048 scans. Nine hundred and twenty-two scans (88.0%) were deemed usable. Fifty-three of the 258 children (20.5%) were able to complete all six scans. Kenyan children had a thinner average GCC ( < 0.001) than Bhutanese children after adjustment for age and gender, but not RNFL ( = 0.70). In models adjusting for age, gender, and study location, none of standardized height, weight, and body mass index (BMI) were statistically significantly associated with RNFL or GCC. We determined that OCT is feasible in some children in resource-limited settings, particularly those > 4 years old, using the device. We found no evidence for GCC or RNFL as a proxy for height-, weight-, or BMI-for-age. The variation in mean GCC thickness in Asian versus African children warrants further investigation.
Jorge AM, Melles RB, Zhang Y, Lu N, Rai SK, Young LH, Costenbader KH, Ramsey-Goldman R, Lim SS, Esdaile JM, Clarke AE, Urowitz MB, Askanase A, Aranow C, Petri M, Choi H. Hydroxychloroquine prescription trends and predictors for excess dosing per recent ophthalmology guidelines. Arthritis Res Ther 2018;20(1):133.Abstract
BACKGROUND: Hydroxychloroquine (HCQ) retinopathy may be more common than previously recognized; recent ophthalmology guidelines have revised recommendations from ideal body weight (IBW)-based dosing to actual body weight (ABW)-based dosing. However, contemporary HCQ prescribing trends in the UK remain unknown. METHODS: We examined a UK general population database to investigate HCQ dosing between 2007 and 2016. We studied trends of excess HCQ dosing per ophthalmology guidelines (defined by exceeding 6.5 mg/kg of IBW and 5.0 mg/kg of ABW) and determined their independent predictors using multivariable logistic regression analyses. RESULTS: Among 20,933 new HCQ users (78% female), the proportions of initial HCQ excess dosing declined from 40% to 36% using IBW and 38% to 30% using ABW, between 2007 and 2016. Among these, 47% of women were excess-dosed (multivariable OR 12.52; 95% CI 10.99-14.26) using IBW and 38% (multivariable OR 1.98; 95% CI,1.81-2.15) using ABW. Applying IBW, 37% of normal and 44% of obese patients were excess-dosed; however, applying ABW, 53% of normal and 10% of obese patients were excess-dosed (multivariable ORs = 1.61 and 0.1 (reference = normal); both p < 0.01). Long-term HCQ users showed similar excess dosing. CONCLUSION: A substantial proportion of HCQ users in the UK, particularly women, may have excess HCQ dosing per the previous or recent weight-based guidelines despite a modest decline in recent years. Over half of normal-BMI individuals were excess-dosed per the latest guidelines. This implies the potential need to reduce dosing for many patients but also calls for further research to establish unifying evidence-based safe and effective dosing strategies.
Tsoka P, Matsumoto H, Maidana DE, Kataoka K, Naoumidi I, Gravanis A, Vavvas DG, Tsilimbaris MK. Effects of BNN27, a novel C17-spiroepoxy steroid derivative, on experimental retinal detachment-induced photoreceptor cell death. Sci Rep 2018;8(1):10661.Abstract
Retinal detachment (RD) leads to photoreceptor cell death secondary to the physical separation of the retina from the underlying retinal pigment epithelium. Intensifying photoreceptor survival in the detached retina could be remarkably favorable for many retinopathies in which RD can be seen. BNN27, a blood-brain barrier (BBB)-permeable, C17-spiroepoxy derivative of dehydroepiandrosterone (DHEA) has shown promising neuroprotective activity through interaction with nerve growth factor receptors, TrkA and p75. Here, we administered BNN27 systemically in a murine model of RD. TUNEL photoreceptors were significantly decreased 24 hours post injury after a single administration of 200 mg/kg BNN27. Furthermore, BNN27 increased inflammatory cell infiltration, as well as, two markers of gliosis 24 hours post RD. However, single or multiple doses of BNN27 were not able to protect the overall survival of photoreceptors 7 days post injury. Additionally, BNN27 did not induce the activation/phosphorylation of TrkA in the detached retina although the mRNA levels of the receptor were increased in the photoreceptors post injury. Together, these findings, do not demonstrate neuroprotective activity of BNN27 in experimentally-induced RD. Further studies are needed in order to elucidate the paradox/contradiction of these results and the mechanism of action of BNN27 in this model of photoreceptor cell damage.
BACKGROUND/PURPOSE: To report a case of acute recurrent central serous chorioretinopathy that developed after a regimen of corticosteroid enemas and suppositories. METHODS: Observational case report. Fluorescein angiography and spectral domain optical coherence tomography. RESULTS: A 47-year-old male patient with ulcerative colitis managed through hydrocortisone enemas presented to clinic with a 1-day history of blurry vision of his left eye. Posterior segment examination revealed subretinal fluid in the superotemporal macula of the left eye extending centrally. After diagnosis of acute central serous chorioretinopathy, the patient was advised to taper steroid enemas and his visual symptoms and subretinal fluid resolved within the month. Seven years later, several months after using steroid suppositories for the first time since the original central serous chorioretinopathy episode, asymptomatic subretinal fluid accumulation with foveal sparing was found on routine ophthalmic examination. Three months later, most of this fluid had resolved with minimal residual subretinal fluid on clinical examination. CONCLUSION: Acute central serous chorioretinopathy may develop after corticosteroid enema or suppository use, a route of administration that has not been previously reported in association with the disease.
Wallace DK, Dean TW, Hartnett ME, Kong L, Smith LE, Hubbard BG, McGregor ML, Jordan CO, Mantagos IS, Bell EF, Kraker RT, Kraker RT. A Dosing Study of Bevacizumab for Retinopathy of Prematurity: Late Recurrences and Additional Treatments. Ophthalmology 2018;Abstract
PURPOSE: Intravitreal bevacizumab is increasingly used to treat severe retinopathy of prematurity (ROP), but it enters the bloodstream, and there is concern that it may alter development of other organs. Previously we reported short-term outcomes of 61 infants enrolled in a dose de-escalation study, and we report the late recurrences and additional treatments. DESIGN: Masked, multicenter, dose de-escalation study. PARTICIPANTS: A total of 61 premature infants with type 1 ROP. METHODS: If type 1 ROP was bilateral at enrollment, then the study eye was randomly selected. In the study eye, bevacizumab intravitreal injections were given at de-escalating doses of 0.25 mg, 0.125 mg, 0.063 mg, or 0.031 mg; if needed, fellow eyes received 1 dose level higher: 0.625 mg, 0.25 mg, 0.125 mg, or 0.063 mg, respectively. After 4 weeks, additional treatment was at the discretion of the investigator. MAIN OUTCOME MEASURES: Early and late ROP recurrences, additional treatments, and structural outcomes after 6 months. RESULTS: Of 61 study eyes, 25 (41%; 95% confidence interval [CI], 29%-54%) received additional treatment: 3 (5%; 95% CI, 1%-14%) for early failure (within 4 weeks), 11 (18%; 95% CI, 9%-30%) for late recurrence of ROP (after 4 weeks), and 11 (18%; 95% CI, 9%-30%) for persistent avascular retina. Re-treatment for early failure or late recurrence occurred in 2 of 11 eyes (18%; 95% CI, 2%-52%) treated with 0.25 mg, 4 of 16 eyes (25%; 95% CI, 7%-52%) treated with 0.125 mg, 8 of 24 eyes (33%; 95% CI, 16%-55%) treated with 0.063 mg, and 0 (0%; 95% CI, 0%-31%) of 10 eyes treated with 0.031 mg. By 6 months corrected age, 56 of 61 study eyes had regression of ROP with normal posterior poles, 1 study eye had developed a Stage 5 retinal detachment, and 4 infants had died of preexisting medical conditions. CONCLUSIONS: Retinal structural outcomes are very good after low-dose bevacizumab treatment for ROP, although many eyes received additional treatment.
Okunuki Y, Mukai R, Pearsall EA, Klokman G, Husain D, Park D-H, Korobkina E, Weiner HL, Butovsky O, Ksander BR, Miller JW, Connor KM. Microglia inhibit photoreceptor cell death and regulate immune cell infiltration in response to retinal detachment. Proc Natl Acad Sci U S A 2018;115(27):E6264-E6273.Abstract
Retinal detachment (RD) is a sight-threatening complication common in many highly prevalent retinal disorders. RD rapidly leads to photoreceptor cell death beginning within 12 h following detachment. In patients with sustained RD, progressive visual decline due to photoreceptor cell death is common, leading to significant and permanent loss of vision. Microglia are the resident immune cells of the central nervous system, including the retina, and function in the homeostatic maintenance of the neuro-retinal microenvironment. It is known that microglia become activated and change their morphology in retinal diseases. However, the function of activated microglia in RD is incompletely understood, in part because of the lack of microglia-specific markers. Here, using the newly identified microglia marker P2ry12 and microglial depletion strategies, we demonstrate that retinal microglia are rapidly activated in response to RD and migrate into the injured area within 24 h post-RD, where they closely associate with infiltrating macrophages, a population distinct from microglia. Once in the injured photoreceptor layer, activated microglia can be observed to contain autofluorescence within their cell bodies, suggesting they function to phagocytose injured or dying photoreceptors. Depletion of retinal microglia results in increased disease severity and inhibition of macrophage infiltration, suggesting that microglia are involved in regulating neuroinflammation in the retina. Our work identifies that microglia mediate photoreceptor survival in RD and suggests that this effect may be due to microglial regulation of immune cells and photoreceptor phagocytosis.
Strauss RW, Kong X, Bittencourt MG, Ho A, Jha A, Schönbach EM, Ahmed MI, Muñoz B, Ervin A-M, Michaelides M, Birch DG, Sahel J-A, Sunness JS, Zrenner E, Bagheri S, Ip M, Sadda SV, West S, Scholl HPN, Scholl HPN. Scotopic Microperimetric Assessment of Rod Function in Stargardt Disease (SMART) Study: Design and Baseline Characteristics (Report No. 1). Ophthalmic Res 2018;:1-8.Abstract
PURPOSE: To describe the study design and characteristics at first visit of participants in the longitudinal Scotopic Microperimetric Assessment of Rod Function in Stargardt Disease (SMART) study. METHODS: Scotopic microperimetry (sMP) was performed in one designated study eye in a subset of participants with molecularly proven ABCA4-associated Stargardt disease (STGD1) enrolled in a multicenter natural history study (ProgStar). Study visits were every 6 months over a period ranging from 6 to 24 months, and also included fundus autofluorescence (FAF). RESULTS: SMART enrolled 118 participants (118 eyes). At the first visit of SMART, the mean sensitivity in mesopic microperimetry was 11.48 (±5.05; range 0.00-19.88) dB and in sMP 11.25 (±5.26; 0-19.25) dB. For FAF, all eyes had a lesion of decreased autofluorescence (mean lesion size 3.62 [±3.48; 0.10-21.46] mm2), and a total of 76 eyes (65.5%) had a lesion of definitely decreased autofluorescence with a mean lesion size of 3.46 (±3.60; 0.21-21.46) mm2. CONCLUSIONS: Rod function is impaired in STGD1 and can be assessed by sMP. Testing rod function may serve as a potential outcome measure for future clinical treatment trials. This is evaluated in the SMART study.