Retina

Georgiou M, Robson AG, Fujinami K, Leo SM, Vincent A, Nasser F, Cabral De Guimarães TA, Khateb S, Pontikos N, Fujinami-Yokokawa Y, Liu X, Tsunoda K, Hayashi T, Vargas ME, Thiadens AAHJ, de Carvalho ER, Nguyen X-T-A, Arno G, Mahroo OA, Martin-Merida MI, Jimenez-Rolando B, Gordo G, Carreño E, Carmen A, Sharon D, Kohl S, Huckfeldt RM, Wissinger B, Boon CJF, Banin E, Pennesi ME, Khan AO, Webster AR, Zrenner E, Héon E, Michaelides M. KCNV2-associated Retinopathy: Genetics, Electrophysiology and Clinical Course - KCNV2 Study Group Report 1. Am J Ophthalmol 2020;Abstract
PURPOSE: To investigate genetics, electrophysiology and clinical course of KCNV2-associated retinopathy in a cohort of children and adults. STUDY DESIGN: Multicenter international clinical cohort study. METHODS: Review of clinical notes and molecular genetic testing. Full-field electroretinography (ERG) incorporating the international standards were reviewed and quantified and compared with age and recordings from control subjects. RESULTS: In total 230 disease-associated alleles were identified from 117 patients, corresponding to 75 different KCNV2 variants, with 28 being novel. The mean age of onset was 3.9 years old. All patients were symptomatic before the age of 12 years (age range: 0-11 years). Decreased visual acuity was present in all patients, and four other symptoms were common: reduced color vision (78.6%), photophobia (53.5%), nyctalopia (43.6%), and nystagmus (38.6%). After a mean follow of 8.4 years, the mean best corrected visual acuity (BCVA, ±SD) decreased from 0.81 LogMAR (0.27 LogMAR) to 0.90 LogMAR (0.31 LogMAR). Full-field ERGs showed pathognomonic waveform features. Quantitative assessment revealed a wide range of ERG amplitudes and peak times, with a mean rate of age-associated reduction indistinguishable from the control group. Mean amplitude reductions for the DA 0.01 ERG, DA 10 ERG a-wave, LA30Hz and LA3 ERG b-wave were 55%, 21%, 48% and 74% respectively. Peak times showed stability across 6 decades. CONCLUSION: In KCNV2-retinopathy full-field ERGs are diagnostic, and consistent with largely stable peripheral retinal dysfunction. Report No.1 highlights the severity of the clinical phenotype and established a large cohort of patients, emphasizing the unmet need for trials of novel therapeutics.
Efstathiou NE, Moustafa GA, Maidana DE, Konstantinou EK, Notomi S, Barbisan PRT, Georgakopoulos CD, Miller JW, Vavvas DG. Acadesine suppresses TNF-α induced complement component 3 (C3), in retinal pigment epithelial (RPE) cells. PLoS One 2020;15(12):e0244307.Abstract
RATIONALE: Age-related macular degeneration (AMD) is the most prevalent form of irreversible blindness in the developed world. Aging, inflammation and complement dysregulation affecting the retinal pigment epithelium (RPE), are considered significant contributors in its pathogenesis and several evidences have linked tumor necrosis factor alpha (TNF-α) and complement component 3 (C3) with AMD. Acadesine, an analog of AMP and an AMP-activated protein kinase (AMPK) activator, has been shown to have cytoprotective effects in human clinical trials as well as having anti-inflammatory and anti-vascular exudative effects in animals. The purpose of this study was to evaluate if acadesine is able to suppress TNF-α induced C3 in RPE cells. METHODS: ARPE-19 and human primary RPE cells were cultured and allowed to grow to confluence. TNF-α was used for C3 induction in the presence or absence of acadesine. Small molecule inhibitors and siRNA were used to determine if acadesine exerts its effect via the extracellular or intracellular pathway and to evaluate the importance of AMPK for these effects. The expression level of C3 was determined by immunoblot analysis. RESULTS: Acadesine suppresses TNF-α induced C3 in a dose dependent manner. When we utilized the adenosine receptor inhibitor dipyridamole (DPY) along with acadesine, acadesine's effects were abolished, indicating the necessity of acadesine to enter the cell in order to exert it's action. However, pretreatment with 5-iodotubericidin (5-Iodo), an adenosine kinase (AK) inhibitor, didn't prevent acadesine from decreasing TNF-α induced C3 expression suggesting that acadesine does not exert its effect through AMP conversion and subsequent activation of AMPK. Consistent with this, knockdown of AMPK α catalytic subunit did not affect the inhibitory effect of acadesine on TNF-α upregulation of C3. CONCLUSIONS: Our results suggest that acadesine suppresses TNF-α induced C3, likely through an AMPK-independent pathway, and could have potential use in complement over activation diseases.
Sohn EH, Mullins RF, Eliott D. Reply. Retina 2020;40(11):e68-e69.
Hicks PM, Haaland B, Feehan M, Crandall AS, Pettey JH, Nuttall E, Self W, Hartnett ME, Bernstein P, Vitale A, Shakoor A, Shulman JP, Sieminski SF, Kim I, Owen LA, Murtaugh MA, Noyes A, Deangelis MM. Systemic Disease and Ocular Comorbidity Analysis of Geographically Isolated Federally Recognized American Indian Tribes of the Intermountain West. J Clin Med 2020;9(11)Abstract
BACKGROUND: The American Indian Navajo and Goshute peoples are underserved patient populations residing in the Four Corners area of the United States and Ibupah, Utah, respectively. METHODS: We conducted a cross-sectional study of epidemiological factors and lipid biomarkers that may be associated with type II diabetes, hypertension and retinal manifestations in tribal and non-tribal members in the study areas (n = 146 participants). We performed multivariate analyses to determine which, if any, risk factors were unique at the tribal level. Fundus photos and epidemiological data through standardized questionnaires were collected. Blood samples were collected to analyze lipid biomarkers. Univariate analyses were conducted and statistically significant factors at < 0.10 were entered into a multivariate regression. RESULTS: Of 51 participants for whom phenotyping was available, from the Four Corners region, 31 had type II diabetes (DM), 26 had hypertension and 6 had diabetic retinopathy (DR). Of the 64 participants from Ibupah with phenotyping available, 20 had diabetes, 19 had hypertension and 6 had DR. Navajo participants were less likely to have any type of retinopathy as compared to Goshute participants (odds ratio (OR) = 0.059; 95% confidence interval (CI) = 0.016-0.223; < 0.001). Associations were found between diabetes and hypertension in both populations. Older age was associated with hypertension in the Four Corners, and the Navajo that reside there on the reservation, but not within the Goshute and Ibupah populations. Combining both the Ibupah, Utah and Four Corners study populations, being American Indian ( = 0.022), residing in the Four Corners ( = 0.027) and having hypertension ( < 0.001) increased the risk of DM. DM ( < 0.001) and age ( = 0.002) were significantly associated with hypertension in both populations examined. When retinopathy was evaluated for both populations combined, hypertension ( = 0.037) and living in Ibupah ( < 0.001) were associated with greater risk of retinopathy. When combining both American Indian populations from the Four Corners and Ibupah, those with hypertension were more likely to have DM ( < 0.001). No lipid biomarkers were found to be significantly associated with any disease state. CONCLUSIONS: We found different comorbid factors with retinal disease outcome between the two tribes that reside within the Intermountain West. This is indicated by the association of tribe and with the type of retinopathy outcome when we combined the populations of American Indians. Overall, the Navajo peoples and the Four Corners had a higher prevalence of chronic disease that included diabetes and hypertension than the Goshutes and Ibupah. To the best of our knowledge, this is the first study to conduct an analysis for disease outcomes exclusively including the Navajo and Goshute tribe of the Intermountain West.
Sun Y, Smith LEH. Notice of Withdrawal: Retinal Vasculature in Development and Diseases. Annu Rev Vis Sci 2020;Abstract
This article was withdrawn on October 15, 2020, at the request of the journal editors, with agreement from the authors, owing to a substantial amount of unattributed or improperly cited text overlap with other sources. In accordance with Annual Reviews' commitment to transparency, the original PDF of the article remains available for download at .
Zhang Y, Wang K, Pan J, Yang S, Yao H, Li M, Li H, Lei H, Jin H, Wang F. Exosomes mediate an epithelial-mesenchymal transition cascade in retinal pigment epithelial cells: Implications for proliferative vitreoretinopathy. J Cell Mol Med 2020;Abstract
Exosomes have recently emerged as a pivotal mediator of many physiological and pathological processes. However, the role of exosomes in proliferative vitreoretinopathy (PVR) has not been reported. In this study, we aimed to investigate the role of exosomes in PVR. Transforming growth factor beta 2 (TGFß-2) was used to induce epithelial-mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells, as an in vitro model of PVR. Exosomes from normal and EMTed RPE cells were extracted and identified. We incubated extracted exosomes with recipient RPE cells, and co-cultured EMTed RPE cells and recipient RPE cells in the presence of the exosome inhibitor GW4869. Both experiments suggested that there are further EMT-promoting effects of exosomes from EMTed RPE cells. MicroRNA sequencing was also performed to identify the miRNA profiles in exosomes from both groups. We identified 34 differentially expressed exosomal miRNAs (P <. 05). Importantly, miR-543 was found in exosomes from EMTed RPE cells, and miR-543-enriched exosomes significantly induced the EMT of recipient RPE cells. Our study demonstrates that exosomal miRNA is differentially expressed in RPE cells during EMT and that these exosomal miRNAs may play pivotal roles in EMT induction. Our results highlight the importance of exosomes as cellular communicators within the microenvironment of PVR.
Maidana DE, Notomi S, Ueta T, Zhou T, Joseph D, Kosmidou C, Caminal-Mitjana JM, Miller JW, Vavvas DG. ThicknessTool: automated ImageJ retinal layer thickness and profile in digital images. Sci Rep 2020;10(1):18459.Abstract
To develop an automated retina layer thickness measurement tool for the ImageJ platform, to quantitate nuclear layers following the retina contour. We developed the ThicknessTool (TT), an automated thickness measurement plugin for the ImageJ platform. To calibrate TT, we created a calibration dataset of mock binary skeletonized mask images with increasing thickness masks and different rotations. Following, we created a training dataset and performed an agreement analysis of thickness measurements between TT and two masked manual observers. Finally, we tested the performance of TT measurements in a validation dataset of retinal detachment images. In the calibration dataset, there were no differences in layer thickness between measured and known thickness masks, with an overall coefficient of variation of 0.00%. Training dataset measurements of immunofluorescence retina nuclear layers disclosed no significant differences between TT and any observer's average outer nuclear layer (ONL) (p = 0.998), inner nuclear layer (INL) (p = 0.807), and ONL/INL ratio (p = 0.944) measurements. Agreement analysis showed that bias between TT vs. observers' mean was lower than between any observers' mean against each other in the ONL (0.77 ± 0.34 µm vs 3.25 ± 0.33 µm) and INL (1.59 ± 0.28 µm vs 2.82 ± 0.36 µm). Validation dataset showed that TT can detect significant and true ONL thinning (p = 0.006), more sensitive than manual measurement capabilities (p = 0.069). ThicknessTool can measure retina nuclear layers thickness in a fast, accurate, and precise manner with multi-platform capabilities. In addition, the TT can be customized to user preferences and is freely available to download.
Shire DB, Gingerich MD, Wong PI, Skvarla M, Cogan SF, Chen J, Wang W, Rizzo JF. Micro-Fabrication of Components for a High-Density Sub-Retinal Visual Prosthesis. Micromachines (Basel) 2020;11(10)Abstract
We present a retrospective of unique micro-fabrication problems and solutions that were encountered through over 10 years of retinal prosthesis product development, first for the Boston Retinal Implant Project initiated at the Massachusetts Institute of Technology and at Harvard Medical School's teaching hospital, the Massachusetts Eye and Ear-and later at the startup company Bionic Eye Technologies, by some of the same personnel. These efforts culminated in the fabrication and assembly of 256+ channel visual prosthesis devices having flexible multi-electrode arrays that were successfully implanted sub-retinally in mini-pig animal models as part of our pre-clinical testing program. We report on the processing of the flexible multi-layered, planar and penetrating high-density electrode arrays, surgical tools for sub-retinal implantation, and other parts such as coil supports that facilitated the implantation of the peri-ocular device components. We begin with an overview of the implantable portion of our visual prosthesis system design, and describe in detail the micro-fabrication methods for creating the parts of our system that were assembled outside of our hermetically-sealed electronics package. We also note the unique surgical challenges that sub-retinal implantation of our micro-fabricated components presented, and how some of those issues were addressed through design, materials selection, and fabrication approaches.
Wons J, Kempen J, Garweg JG. HIV-induced Retinitis. Ocul Immunol Inflamm 2020;28(8):1259-1268.Abstract
PURPOSE: To provide an overview of the current knowledge on the Human Immunodeficiency Virus (HIV)-associated retinopathies. METHODS: A PubMed search was performed, using the key terms "HIV Retinopathy OR Retinitis" and "HIV AND Retinitis" to find manuscripts published within the last ten years. RESULTS: If left untreated, HIV infection causes a progressive immunodeficiency caused by depletion of CD4-positive T lymphocytes. Noninfectious HIV retinopathy, clinically manifested by cotton wool spots. Once the CD4 count drops below 200 c/μl, immunodeficiency creates a vulnerability for systemic opportunistic infections. Within the posterior segment of the eye, cytomegalovirus (CMV) retinitis has to be distinguished from infections with other members of the herpes virus family, as well as from toxoplasmosis, tuberculosis, and syphilis. Upon restoration of the immune system, immune recovery uveitis may manifest in one third of CMV affected eyes. CONCLUSION: Targeted antiviral treatment and secondary recurrence prophylaxis prevent vision loss of the retina prior to immune recovery.
Agranat JS, Douglas VP, Douglas KA, Miller JB. A guarded light pipe for direct visualization during primary scleral buckling on the Ngenuity platform. Int J Retina Vitreous 2020;6:42.Abstract
Background: Visualization during scleral buckling is traditionally achieved via indirect ophthalmoscopy. Recent advances have utilized the surgical microscope and a 25 gauge cannula-based endoillumination system, also known as a Chandelier lighting system. This report details an improved approach using a guarded 25 or 27 gauge light pipe and the Ngenuity digital three dimensional platform. Methods: A standard Alcon light pipe is modified with a silicone guard to expose only 5 mm of the tip of the light pipe. The guard is created from the silicone that is already opened to secure the ends of the encircling band most often employed sleeve (e.g. 70, 270). This guarded light pipe is then inserted into the cannula as an alternative to a Chandelier lighting system. Results: This is a technical report of a surgical visualization technique using a three dimensional digital visualization platform with a modified handheld vitrectomy light pipe. Conclusion: The utilization of a guarded light pipe for visualization during primary scleral buckling is a promising, effective, and efficient technique. The three dimensional digital display allows for better educational impact and surgical communication with trainees and ancillary members of the surgical team.
Yu G, Seto BK, Yamada K, Zeng K, Arroyo JG. Combined Pneumatic and Enzymatic Vitreolysis for Severe Cases of Vitreomacular Traction. Retin Cases Brief Rep 2020;Abstract
PURPOSE: To evaluate the efficacy of combined pneumatic and enzymatic vitreolysis for treatment of severe cases of vitreomacular traction (VMT). METHODS: We analyzed a retrospective, consecutive series of five patients diagnosed with severe VMT refractory to pneumatic vitreolysis (PV) who then received an additional ocriplasmin injection while their gas bubble from PV was still present between February 2015 to February 2019. VMT release was confirmed using spectral domain optical coherence tomography (OCT). RESULTS: Four out of 5 patients treated with combined pneumatic and enzymatic vitreolysis achieved VMT release by day 28, and all cases eventually achieved complete VMT release. In addition to having VMT refractory to PV, patient characteristics included broad adhesion diameter (>1500 μm, n=1), presence of epiretinal membrane (n=2), age > 65 years (n=4), and pseudophakia (n=1). Visual acuity (VA) improved by 3 or more lines at 6 months in both of the patients with initial vision worse than 20/50 on an ETDRS chart but not in those whose vision was already fairly good (i.e. VA > 20/60). None of the patients experienced the following complications after receiving this combined treatment: retinal tears or detachments, vitreous floaters, and ellipsoid zone changes. CONCLUSION: Sequential, combined pneumatic and enzymatic vitreolysis resulted in VMT release in all 5 cases (4 cases by 28 days) and may be a potentially useful alternative to surgical intervention for refractory VMT cases.
Jakobiec FA, Barrantes PC, Yonekawa Y, Lad EM, Proia AD. Subretinal Mononuclear Cells in Coats' Disease Studied with RPE65 and CD163: Evidence for Histiocytoid Pigment Epithelial Cells. Am J Ophthalmol 2020;Abstract
PURPOSE: To evaluate the mononuclear cells in the subretinal exudate in Coats' disease. DESIGN: Retrospective case series. METHODS: Five enucleated globes and one cytology sample with Coats' disease and one case of chronic retinal detachment following repair of an open globe injury were examined immunohistochemically to identify the intraretinal and subretinal exudative cells. The two biomarkers were RPE65 for retinal pigment epithelium and CD163 for histiocytes, each tagged with different chromogens, yellow for pigment epithelium and purple for CD163+ monocytes/histiocytes. Expressions were sought of both biomarkers together or singly. A color shift to red in the cells' chromogenic reaction indicated the simultaneous presence of the two biomarkers. RESULTS: The majority of the mononuclear cells in Coats' disease were CD163 (purple) positive, and a minority were RPE65 (yellow) positive. An intermediate number of cells were RPE65/CD163 positive (orange-red). The eye with a chronic retinal detachment had an equal distribution of CD163 positive and RPE65/CD163 positive cells. CONCLUSIONS: The retinal pigment epithelium has several well-delineated phenotypes and functions. In normal visual physiology, the pigment epithelium supports the photoreceptors and participates in their renewal by phagocytosis of the tips of the photoreceptors. The expression of CD163, a feature of hematopoietically derived monocytes, together with RPE65 in the retinal pigment epithelium, supports differentiation toward histiocytes. Yellow staining detached pigment epithelial cells were rare. The presence of histiocytoid pigment epithelium at the level of Bruch's membrane probably also has implications for macular degeneration.
Begaj T, Marmalidou A, Papakostas TD, Diaz DJ, Kim LA, Wu DM, Miller JB. Outcomes of primary rhegmatogenous retinal detachment repair with extensive scleral-depressed vitreous removal and dynamic examination. PLoS One 2020;15(9):e0239138.Abstract
There are multiple surgical approaches to the repair of rhegmatogenous retinal detachment (RRD). Here, we evaluated the outcomes of small-gauge pars plana vitrectomy (PPV), alone or in combination with scleral buckle (SB-PPV), for RRD repair using a standardized technique by 3 vitreoretinal surgeons: "extensive" removal of the vitreous with scleral depression and dynamic examination of the peripheral retina. One hundred eighty seven eyes of 180 consecutive patients treated for primary RRD by three vitreoretinal surgeons at a tertiary academic medical center from September 2015 to March 2018 were analyzed. Most RRDs occurred in males (134 [71.3%] eyes), affected the left eye (102 [54.3%]), and were phakic (119 [63.3%]). PPV alone was performed in 159 eyes (84.6%), with a combined SB-PPV used in the remaining 29 eyes (15.4%); focal endolaser was used in all (100%) cases. The single surgery anatomic success rate was 186 eyes (99.5%) at 3 months, and 187 (100%) at last follow up. Overall best-corrected visual acuity (BCVA) had significantly improved at 3 months ([Snellen 20/47] P<0.00005) and last follow up ([Snellen 20/31] P<0.00005), as compared to day of presentation ([Snellen 20/234]). Our findings suggest that "extensive" removal of the vitreous and dynamic peripheral examination with scleral depression may lead to high single surgery success in primary uncomplicated RRD repair.
Williams PR, Benowitz LI, Goldberg JL, He Z. Axon Regeneration in the Mammalian Optic Nerve. Annu Rev Vis Sci 2020;6:195-213.Abstract
The damage or loss of retinal ganglion cells (RGCs) and their axons accounts for the visual functional defects observed after traumatic injury, in degenerative diseases such as glaucoma, or in compressive optic neuropathies such as from optic glioma. By using optic nerve crush injury models, recent studies have revealed the cellular and molecular logic behind the regenerative failure of injured RGC axons in adult mammals and suggested several strategies with translational potential. This review summarizes these findings and discusses challenges for developing clinically applicable neural repair strategies.
Harris JM, Han IC, Sachdeva MM, Zhang AY, Zebardast N. Post-operative intracranial gas migration with optic nerve infiltration and atrophy following retinal detachment repair. Am J Ophthalmol Case Rep 2020;20:100920.Abstract
Purpose: To report a patient with post-operative gas migration into the optic nerve and lateral ventricles after retinal detachment repair. Observations: A 78-year-old pseudophakic man developed a temporal visual field cut in his non-operative, right eye 3 weeks after repair of a recurrent, shallow, macula-involving retinal detachment with perfluoropropane intraocular gas in the left eye. Visual acuity in the right eye measured 20/40, and static perimetry demonstrated temporal visual field loss that respected the vertical midline. Dilated fundus examination of the right eye was unrevealing for any retinal cause, raising suspicion for an intracranial etiology. An urgent CT scan of the brain demonstrated gas in all segments of the left optic nerve and lateral ventricles, consistent with intracranial gas migration along the optic nerve. Given the absence of systemic neurologic symptoms, cautious observation was advised on consultation with neuroradiology and neurosurgery, and follow-up CT scan 1 week later showed resolution of the intracranial gas. By 10-weeks post-operatively, vision returned to 20/20 in the right eye with persistent temporal field loss, and the left eye was hand motions (20/70 pre-operatively) with evidence of optic nerve atrophy and severe cupping. Conclusions: Intracranial gas migration is a rare complication of retinaldetachment repair with intraocular gas and may occur in the setting of structural defects of the optic nerve and high post-operative intraocular pressure. Clinicians should be alert to this rare but serious complication, which can cause neurologic symptoms and result in vision loss in both the operative and non-operative eyes.

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