Retina

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.
Fernandez-Godino R, Pierce EA. C3a triggers formation of sub-retinal pigment epithelium deposits via the ubiquitin proteasome pathway. Sci Rep 2018;8(1):9679.Abstract
The mechanisms that connect complement system activation and basal deposit formation in early stages of age-related macular degeneration (AMD) are insufficiently understood, which complicates the design of efficient therapies to prevent disease progression. Using human fetal (hf) retinal pigment epithelial (RPE) cells, we have established an in vitro model to investigate the effect of complement C3a on RPE cells and its role in the formation of sub-RPE deposits. The results of these studies revealed that C3a produced after C3 activation is sufficient to induce the formation of sub-RPE deposits via complement-driven proteasome inhibition. C3a binds the C3a receptor (C3aR), stimulates deposition of collagens IV and VI underneath the RPE, and impairs the extracellular matrix (ECM) turnover by increased MMP-2 activity, all mediated by downregulation of the ubiquitin proteasome pathway (UPP). The formation of basal deposits can be prevented by the addition of a C3aR antagonist, which restores the UPP activity and ECM turnover. These findings indicate that the cell-based model can be used to test potential therapeutic agents in vitro. The data suggest that modulation of C3aR-mediated events could be a therapeutic approach for treatment of early AMD.
Sood AB, O'Keefe G, Bui D, Jain N. Vogt-Koyanagi-Harada Disease Associated with Hepatitis B Vaccination. Ocul Immunol Inflamm 2018;:1-4.Abstract
PURPOSE: To report a case of Vogt-Koyanagi-Harada (VKH) disease associated with hepatitis B vaccination. METHODS: Case report. RESULTS: A 43-year-old Caucasian male presented with a three-week history of blurry vision, pain, photophobia, and redness in both eyes. Three days prior to the onset of symptoms, he had received the hepatitis B virus vaccine. Clinical evaluation revealed multifocal placoid lesions in the posterior pole, choroidal thickening, and serous macular detachment. Targeted laboratory investigations were negative for infectious or autoimmune markers. After treatment with oral corticosteroids, the patient had resolution of symptoms with near-total recovery of visual function. The patient later reported systemic findings of hearing loss, tinnitus, and integumentary changes. A diagnosis of VKH disease was made and inflammation was managed with oral corticosteroids followed by methotrexate for long-term disease control. CONCLUSIONS: VKH disease is an inflammatory condition primarily affecting the choroid, retinal pigment epithelium, and outer retina. The underlying etiology is unclear, but it can be associated with a viral prodrome suggesting an infectious trigger in a genetically susceptible individual. Our case suggests that hepatitis B vaccination may trigger a similar inflammatory response.
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;125(12):1961-1966.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.
Nowak-Sliwinska P, Alitalo K, Allen E, Anisimov A, Aplin AC, Auerbach R, Augustin HG, Bates DO, van Beijnum JR, Bender HRF, Bergers G, Bikfalvi A, Bischoff J, Böck BC, Brooks PC, Bussolino F, Cakir B, Carmeliet P, Castranova D, Cimpean AM, Cleaver O, Coukos G, Davis GE, De Palma M, Dimberg A, Dings RPM, Djonov V, Dudley AC, Dufton NP, Fendt S-M, Ferrara N, Fruttiger M, Fukumura D, Ghesquière B, Gong Y, Griffin RJ, Harris AL, Hughes CCW, Hultgren NW, Iruela-Arispe LM, Irving M, Jain RK, Kalluri R, Kalucka J, Kerbel RS, Kitajewski J, Klaassen I, Kleinmann HK, Koolwijk P, Kuczynski E, Kwak BR, Marien K, Melero-Martin JM, Munn LL, Nicosia RF, Noel A, Nurro J, Olsson A-K, Petrova TV, Pietras K, Pili R, Pollard JW, Post MJ, Quax PHA, Rabinovich GA, Raica M, Randi AM, Ribatti D, Ruegg C, Schlingemann RO, Schulte-Merker S, Smith LEH, Song JW, Stacker SA, Stalin J, Stratman AN, Van de Velde M, van Hinsbergh VWM, Vermeulen PB, Waltenberger J, Weinstein BM, Xin H, Yetkin-Arik B, Yla-Herttuala S, Yoder MC, Griffioen AW. Consensus guidelines for the use and interpretation of angiogenesis assays. Angiogenesis 2018;Abstract
The formation of new blood vessels, or angiogenesis, is a complex process that plays important roles in growth and development, tissue and organ regeneration, as well as numerous pathological conditions. Angiogenesis undergoes multiple discrete steps that can be individually evaluated and quantified by a large number of bioassays. These independent assessments hold advantages but also have limitations. This article describes in vivo, ex vivo, and in vitro bioassays that are available for the evaluation of angiogenesis and highlights critical aspects that are relevant for their execution and proper interpretation. As such, this collaborative work is the first edition of consensus guidelines on angiogenesis bioassays to serve for current and future reference.
Diaz DJ, Wang JC, Oellers P, Lains I, Sobrin L, Husain D, Miller JW, Vavvas DG, Miller JB. Imaging the Deep Choroidal Vasculature Using Spectral Domain and Swept Source Optical Coherence Tomography Angiography. J Vitreoretin Dis 2018;2(3):146-154.Abstract
Purpose: To evaluate the deeper choroidal vasculature in eyes with various ocular disorders using spectral domain (SD) optical coherence tomography angiography (OCTA) and swept source (SS) OCTA. Methods: Patients underwent OCTA imaging with either SD-OCTA (Zeiss Cirrus Angioplex or Optovue AngioVue) or SS-OCTA (Topcon Triton). Retinal pigment epithelium (RPE) integrity, structural visualization of deep choroidal vessels on en face imaging, and OCTA of deep choroidal blood flow signal were analyzed. Choroidal blood flow was deemed present if deeper choroidal vessels appeared bright after appropriate segmentation. Results: Structural visualization of choroidal vessels was feasible in all eyes by en face imaging. In both SD-OCTA and SS-OCTA, choroidal blood flow signal was present in all eyes with overlying RPE atrophy (100% of eyes with RPE atrophy, 28.6% of all imaged eyes, P < .001). Conclusions: While choroidal vessels can be visualized anatomically in all eyes by en face imaging, choroidal blood flow detection in deep choroidal vessel is largely restricted to areas with overlying RPE atrophy. Intact RPE acts as a barrier for reliable detection of choroidal flow using current OCTA technology, inhibiting evaluation of flow in deeper choroidal vessels in most eyes.
Roh M, Selivanova A, Shin HJ, Miller JW, Jackson ML. Visual acuity and contrast sensitivity are two important factors affecting vision-related quality of life in advanced age-related macular degeneration. PLoS One 2018;13(5):e0196481.Abstract
PURPOSE: Vision loss from age-related macular degeneration (AMD) has a profound effect on vision-related quality of life (VRQoL). The pupose of this study is to identify clinical factors associated with VRQoL using the Rasch- calibrated NEI VFQ-25 scales in bilateral advanced AMD patients. METHODS: We retrospectively reviewed 47 patients (mean age 83.2 years) with bilateral advanced AMD. Clinical assessment included age, gender, type of AMD, high contrast visual acuity (VA), history of medical conditions, contrast sensitivity (CS), central visual field loss, report of Charles Bonnet Syndrome, current treatment for AMD and Rasch-calibrated NEI VFQ-25 visual function and socioemotional function scales. The NEI VFQ visual function scale includes items of general vision, peripheral vision, distance vision and near vision-related activity while the socioemotional function scale includes items of vision related-social functioning, role difficulties, dependency, and mental health. Multiple regression analysis (structural regression model) was performed using fixed item parameters obtained from the one-parameter item response theory model. RESULTS: Multivariate analysis showed that high contrast VA and CS were two factors influencing VRQoL visual function scale (β = -0.25, 95% CI-0.37 to -0.12, p<0.001 and β = 0.35, 95% CI 0.25 to 0.46, p<0.001) and socioemontional functioning scale (β = -0.2, 95% CI -0.37 to -0.03, p = 0.023, and β = 0.3, 95% CI 0.18 to 0.43, p = 0.001). Central visual field loss was not assoicated with either VRQoL visual or socioemontional functioning scale (β = -0.08, 95% CI-0.28 to 0.12,p = 0.44 and β = -0.09, 95% CI -0.03 to 0.16, p = 0.50, respectively). CONCLUSION: In patients with vision impairment secondary to bilateral advanced AMD, high contrast VA and CS are two important factors affecting VRQoL.
Al-Louzi O, Prasad S, M Mallery R. Utility of optical coherence tomography in the evaluation of sellar and parasellar mass lesions. Curr Opin Endocrinol Diabetes Obes 2018;25(4):274-284.Abstract
PURPOSE OF REVIEW: Anterior visual pathway compression is a common feature of sellar region masses. We review the visual pathway neuroanatomy pertaining to sellar and parasellar lesions and describe recent advances in optical coherence tomography (OCT) imaging that have provided a novel quantitative perspective in the evaluation and management of such patients. RECENT FINDINGS: Ultrastructural measurements of optic nerve integrity using OCT, namely peripapillary retinal nerve fiber layer (pRNFL) and the ganglion cell and inner plexiform layer (GCIPL) thicknesses, have been shown to correlate with visual acuity and visual field deficits on perimetry in patients with compressive sellar region masses. In some cases, OCT can visualize early signs of anterior visual pathway involvement in the absence of clinically evident visual field loss or optic disc pallor. OCT is particularly useful when assessing patients who demonstrate less reliable visual field testing. Furthermore, there is growing awareness that pRNFL and GCIPL thinning preoperatively correlate with worse visual recovery following chiasmal decompression, highlighting the prognostic utility of OCT in this patient population. SUMMARY: OCT provides a complimentary, yet critical, role in quantitatively assessing ultrastructural retinal injury in patients with sellar and parasellar lesions compressing the anterior visual pathway and should be incorporated into routine evaluation.
Sveinsdóttir K, Ley D, Hövel H, Fellman V, Hüppi PS, Smith LEH, Hellström A, Hansen Pupp I. Relation of Retinopathy of Prematurity to Brain Volumes at Term Equivalent Age and Developmental Outcome at 2 Years of Corrected Age in Very Preterm Infants. Neonatology 2018;114(1):46-52.Abstract
BACKGROUND: Retinopathy of prematurity (ROP) is a major complication of preterm birth and has been associated with later visual and nonvisual impairments. OBJECTIVES: To evaluate relationships between any stage of ROP, brain volumes, and developmental outcomes. METHODS: This study included 52 very preterm infants (gestational age [mean ± SD]: 26.4 ± 1.9 weeks). Total brain, gray matter, unmyelinated white matter (UWMV), and cerebellar volumes were estimated in 51 out of 52 infants by magnetic resonance imaging at term-equivalent age. Bayley Scales of Infant Development were used to assess developmental outcomes in 49 out of 52 infants at a mean corrected age of 24.6 months. RESULTS: Nineteen out of 52 infants developed any stage of ROP. Infants with ROP had a lower median (IQR) UWMV (173 [156-181] vs. 204 [186-216] mL, p < 0.001) and cerebellar volume (18.3 [16.5-20] vs. 22.3 [20.3-24.7] mL, p < 0.001) than infants without ROP. They also had a lower median (IQR) mental developmental index (72 [56-83] vs. 100 [88-104], p < 0.001) and a lower psychomotor developmental index (80 [60-85] vs. 92 [81-103], p = 0.002). Brain volumes and developmental outcomes did not differ among infants with different stages of ROP. CONCLUSION: Any stage of ROP in preterm infants was associated with a reduced brain volume and an impaired developmental outcome. These results suggest that common pathways may lead to impaired neural and neurovascular development in the brain and retina and that all stages of ROP may be considered in future studies on ROP and development.
Laíns I, Park DH, Mukai R, Silverman R, Oellers P, Mach S, Kim IK, Vavvas DG, Miller JW, Miller JB, Husain D. Peripheral Changes Associated With Delayed Dark Adaptation in Age-related Macular Degeneration. Am J Ophthalmol 2018;190:113-124.Abstract
PURPOSE: To study the association between peripheral changes in age-related macular degeneration (AMD) and dark adaptation (DA). DESIGN: Prospective, cross-sectional study. METHODS: We recruited patients with AMD and a control group (>50 years) without any vitreoretinal disease. Ultra-widefield (UWF) pseudocolor and fundus autofluorescence (FAF) were obtained, and were assessed by 2 graders for the presence of several peripheral changes in perimacular, midperipheral, and far-peripheral zones. All participants were also imaged with 7-field color fundus photographs used for AMD staging (Age-Related Eye Disease Study classification system). Both eyes of study participants were tested with a dark adaptation (DA) extended protocol (20 minutes). Multilevel mixed-effect models (accounting for correlated outcomes between 2 eyes) were used for analyses. RESULTS: We included 128 eyes (n = 72 patients), 75% with AMD and the remainder controls. The presence of reticular pigmentary changes in the midperipheral (ß = 4.3, P = .012) and far-peripheral zones (ß = 8.4, P < .001) was associated with delayed rod-intercept times (RITs), even after adjusting for confounding factors. The presence, number, and extent of peripheral classic drusen did not show a similar association (P ≥ .148). The presence of a mottled decreased FAF pattern in the midperipheral zone was also associated with prolonged RITs (β = 4.4, P = .031). CONCLUSION: Our results suggest an association between DA and the presence of peripheral reticular pigmentary changes, as well as the presence of a peripheral mottled decreased FAF pattern. This provides new insights on the clinical significance of peripheral changes in AMD, and their contribution to impairments on DA.
Tauqeer Z, Yonekawa Y. Familial Exudative Vitreoretinopathy: Pathophysiology, Diagnosis, and Management. Asia Pac J Ophthalmol (Phila) 2018;7(3):176-182.Abstract
Familial exudative vitreoretinopathy (FEVR) is a heritable vitreoretinopathy characterized by anomalous retinal vascular development. The principal feature of the disease is an avascular peripheral retina. This in turn can cause further pathological changes including neovascularization, exudation, hemorrhage, and retinal detachment. The biological basis of the disease is thought to be from defects in the Wnt signaling pathway. Many gene mutations have been implicated, and these can be inherited in an autosomal dominant (most common), autosomal recessive, and X-linked recessive fashion. Examination with wide-field fluorescein angiography is essential and can identify the disease in its earlier stages, enabling timely treatment, in addition to helping identify asymptomatic family members. The current treatment paradigm involves laser photocoagulation of the avascular peripheral retina for neovascular sequelae and vitreoretinal surgery for progressive retinal detachment. Further studies are underway to better characterize this complex vitreoretinopathy.
Yanai R, Chen S, Uchi S-H, Nanri T, Connor KM, Kimura K. Attenuation of choroidal neovascularization by dietary intake of ω-3 long-chain polyunsaturated fatty acids and lutein in mice. PLoS One 2018;13(4):e0196037.Abstract
Dietary ω-3 long-chain polyunsaturated fatty acids (LCPUFAs) and lutein each protect against age-related macular degeneration (AMD). We here examined the effects of ω-3 LCPUFAs and lutein supplementation in a mouse model of AMD. Mice were assigned to four groups: (1) a control group fed an ω-3 LCPUFA-free diet, (2) a lutein group fed an ω-3 LCPUFA-free diet with oral administration of lutein, (3) an ω-3 group fed an ω-3 LCPUFA-supplemented diet, and (4) an ω-3 + lutein group fed an ω-3 LCPUFA-supplemented diet with oral administration of lutein. Mice were fed the defined diets beginning 2 weeks before, and received lutein with an oral gavage needle beginning 1 week before, induction of choroidal neovascularization (CNV) by laser photocoagulation. The area of CNV measured in choroidal flat-mount preparations was significantly reduced in mice fed ω-3 LCPUFAs or lutein compared with those in the control group, and it was reduced in an additive manner in those receiving both ω-3 LCPUFAs and lutein. The concentrations of various inflammatory mediators in the retina or choroid were reduced in mice fed ω-3 LCPUFAs or lutein, but no additive effect was apparent. The generation of reactive oxygen species (ROS) in chorioretinal lesions revealed by dihydroethidium staining as well as the expression of NADPH oxidase 4 (Nox4) in the retina revealed by immunohistofluorescence and immunoblot analyses were attenuated by ω-3 LCPUFAs and lutein in a synergistic manner. Our results thus show that dietary intake of ω-3 LCPUFAs and lutein attenuated CNV in an additive manner and in association with suppression of inflammatory mediator production, ROS generation, and Nox4 expression. Dietary supplementation with both ω-3 LCPUFAs and lutein warrants further study as a means to protect against AMD.

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