INVESTIGATION OF ENROFLOXACIN-ASSOCIATED RETINAL TOXICITY IN NONDOMESTIC FELIDS.

PubMed

Newkirk, Kim M; Beard, L Kathryn; Sun, Xiaocun; Ramsay, Edward C

2017-06-01

Enrofloxacin is known to cause retinal toxicity in domestic cats. The hallmark lesion of enrofloxacin-associated retinal toxicity in domestic cats is thinning of the outer nuclear layer of the retina. Enrofloxacin is commonly used to treat bacterial infections in nondomestic felids because of its action against a wide spectrum of bacteria and the ability for it to be given orally. No previous studies have investigated the potential retinal toxicity of enrofloxacin in nondomestic felids. This retrospective study evaluated 81 eyes from 14 lions ( Panthera leo ) and 33 tigers ( Panthera tigris ) that had been enucleated or collected postmortem. The thickness of the outer nuclear retina was assessed in two separate sites in each eye by counting the rows of nuclei and by using digital image analysis software to determine the area of the nuclei at each site. Medical records were reviewed to determine the enrofloxacin dose for each cat. Cats that had not received enrofloxacin (n = 11) were compared with treated animals (n = 36). The outer nuclear layer thickness or area in treated versus untreated cats was not significantly different. Additionally, no clinical blindness was reported in any of the cats. This study showed no evidence of enrofloxacin-associated thinning of the outer nuclear layer in the lions and tigers evaluated, suggesting that enrofloxacin can be used safely in these animals.

Profile and Determinants of Retinal Optical Intensity in Normal Eyes with Spectral Domain Optical Coherence Tomography.

PubMed

Chen, Binyao; Gao, Enting; Chen, Haoyu; Yang, Jianling; Shi, Fei; Zheng, Ce; Zhu, Weifang; Xiang, Dehui; Chen, Xinjian; Zhang, Mingzhi

2016-01-01

To investigate the profile and determinants of retinal optical intensity in normal subjects using 3D spectral domain optical coherence tomography (SD OCT). A total of 231 eyes from 231 healthy subjects ranging in age from 18 to 80 years were included and underwent a 3D OCT scan. Forty-four eyes were randomly chosen to be scanned by two operators for reproducibility analysis. Distribution of optical intensity of each layer and regions specified by the Early Treatment of Diabetic Retinopathy Study (ETDRS) were investigated by analyzing the OCT raw data with our automatic graph-based algorithm. Univariate and multivariate analyses were performed between retinal optical intensity and sex, age, height, weight, spherical equivalent (SE), axial length, image quality, disc area and rim/disc area ratio (R/D area ratio). For optical intensity measurements, the intraclass correlation coefficient of each layer ranged from 0.815 to 0.941, indicating good reproducibility. Optical intensity was lowest in the central area of retinal nerve fiber layer, ganglion cell layer, inner plexiform layer, inner nuclear layer, outer plexiform layer and photoreceptor layer, except for the retinal pigment epithelium (RPE). Optical intensity was positively correlated with image quality in all retinal layers (0.553<β<0.851, p<0.01), and negatively correlated with age in most retinal layers (-0.362<β<-0.179, p<0.01), except for the RPE (β = 0.456, p<0.01), outer nuclear layer and photoreceptor layer (p>0.05). There was no relationship between retinal optical intensity and sex, height, weight, SE, axial length, disc area and R/D area ratio. There was a specific pattern of distribution of retinal optical intensity in different regions. The optical intensity was affected by image quality and age. Image quality can be used as a reference for normalization. The effect of age needs to be taken into consideration when using OCT for diagnosis.

Denoising and segmentation of retinal layers in optical coherence tomography images

NASA Astrophysics Data System (ADS)

Dash, Puspita; Sigappi, A. N.

2018-04-01

Optical Coherence Tomography (OCT) is an imaging technique used to localize the intra-retinal boundaries for the diagnostics of macular diseases. Due to speckle noise, low image contrast and accurate segmentation of individual retinal layers is difficult. Due to this, a method for retinal layer segmentation from OCT images is presented. This paper proposes a pre-processing filtering approach for denoising and segmentation methods for segmenting retinal layers OCT images using graph based segmentation technique. These techniques are used for segmentation of retinal layers for normal as well as patients with Diabetic Macular Edema. The algorithm based on gradient information and shortest path search is applied to optimize the edge selection. In this paper the four main layers of the retina are segmented namely Internal limiting membrane (ILM), Retinal pigment epithelium (RPE), Inner nuclear layer (INL) and Outer nuclear layer (ONL). The proposed method is applied on a database of OCT images of both ten normal and twenty DME affected patients and the results are found to be promising.

Restoration of Outer Retinal Layers After Aflibercept Therapy in Exudative AMD: Prognostic Value.

PubMed

Coscas, Florence; Coscas, Gabriel; Lupidi, Marco; Dirani, Ali; Srour, Mayer; Semoun, Oudy; Français, Catherine; Souied, Eric H

2015-06-01

To evaluate the outer retinal layer (ellipsoid zone [EZ] and external limiting membrane [ELM]) changes following intravitreal aflibercept injections in eyes with treatment-naïve exudative age-related macular degeneration (eAMD) and to correlate these changes with fluid response and visual improvement. A retrospective case series of 50 treatment-naïve eAMD eyes followed-up for 18 months. All patients underwent regular comprehensive ophthalmic examinations. The presence of EZ disruption, ELM disruption, EZ swelling, subretinal hyper-reflective exudation (SHE), central macular thickness (CMT), cystoid spaces, subretinal fluid, and pigmented epithelium detachment were evaluated by two different retinal specialists at baseline and final visits, and correlated with best corrected visual acuity (BCVA) improvement. At 18 months, BCVA, EZ disruption, ELM disruption, EZ swelling and SHE improved significantly (P = 0.001) at 18 months. Improvement of BCVA showed a statistically significant correlation with ELM restoration (P = 0.018), but not with EZ restoration (P = 0.581). Swelling of the EZ decreased from 72% of the cases at baseline to 30% in 18 months while SHE decreased from 52% to 6% in 18 months (P = 0.001). We observed a statistically significant (P = 0.001) reduction between the baseline and final value of CMT. Aflibercept is safe and effective in treating exudative AMD with the restoration of the outer retinal layers. Restoration of the EZ is not statistically correlated with the final BCVA, even though persistent EZ changes could be associated with irreversible decrease in vision. On the contrary, the final status of the ELM is directly correlated with final BCVA. Also, baseline changes in outer retinal layers, especially the ELM, appear to predict photoreceptor restoration and final BCVA, and must be comprehensively analyzed to enable and determine a future prognosis.

Expression and Characterization of Insulin-Like Growth Factor Binding Proteins (IGFBPs) and IGFBP-2 mRNA in the Developing Chicken Eye

DTIC Science & Technology

1995-03-30

family with autosomal dominant retinitis pigmentosa . American Journal of Human Genetics 48: 26-30. Johnston, M.C., Noden, D.M., Hazelton, R. D...create a double-layered optic cup, with the outer layer forming the retinal pigmented epithelium (RPE) and the inner layer forming the neural retina...the lens, sclera, retina and retinal pigmented epithelium (Bassas et 19 al., 1987; Zick et al., 1987; Ocrant et al., 1989; Waldbillig et al. 1990

Cytologic appearance of retinal cells included in a fine-needle aspirate of a meningioma around the optic nerve of a dog.

PubMed

Tvedten, Harold; Hillström, Anna

2013-06-01

A 6-year-old Wirehair Dachshund had a meningioma around the optic nerve that caused exophthalmos. A benign mesenchymal tumor was suspected based on the cytologic pattern of a fine-needle aspirate, and a meningioma was diagnosed by histopathologic examination. In addition to the meningioma cells, the cytologic smears included groups of cells from apparently 4 layers of normal retina. In particular, uniform rod-shaped structures in the cytologic sample could suggest rod-shaped bacteria, but these structures were identified as cylindrical outer segments of photoreceptor rod cells. Other retinal structures recognized included pigmented epithelial layer cells with their uniquely formed pigment granules, the characteristic bi-lobed, cleaved nuclei from the outer nuclear layer, and nerve tissue likely from the outer plexiform layer of the retina. © 2013 American Society for Veterinary Clinical Pathology.

Analysis of the chicken retina with an adaptive optics multiphoton microscope.

PubMed

Bueno, Juan M; Giakoumaki, Anastasia; Gualda, Emilio J; Schaeffel, Frank; Artal, Pablo

2011-06-01

The structure and organization of the chicken retina has been investigated with an adaptive optics multiphoton imaging microscope in a backward configuration. Non-stained flat-mounted retinal tissues were imaged at different depths, from the retinal nerve fiber layer to the outer segment, by detecting the intrinsic nonlinear fluorescent signal. From the stacks of images corresponding to the different retinal layers, volume renderings of the entire retina were reconstructed. The density of photoreceptors and ganglion cells layer were directly estimated from the images as a function of the retinal eccentricity. The maximum anatomical resolving power at different retinal eccentricities was also calculated. This technique could be used for a better characterization of retinal alterations during myopia development, and may be useful for visualization of retinal pathologies and intoxication during pharmacological studies.

Retinal Structure Measurements as Inclusion Criteria for Stem Cell-Based Therapies of Retinal Degenerations.

PubMed

Jacobson, Samuel G; Matsui, Rodrigo; Sumaroka, Alexander; Cideciyan, Artur V

2016-04-01

We reviewed and illustrated the most optimal retinal structural measurements to make in stem cell clinical trials. Optical coherence tomography (OCT) and autofluorescence (AF) imaging were used to evaluate patients with severe visual loss from nonsyndromic and syndromic retinitis pigmentosa (RP), ABCA4-Stargardt disease, and nonneovascular age-related macular degeneration (AMD). Outer nuclear layer (ONL), rod outer segment (ROS) layer, inner retina, ganglion cell layer (GCL), and nerve fiber layer (NFL) thicknesses were quantified. All patients had severely reduced visual acuities. Retinitis pigmentosa patients had limited visual fields; maculopathy patients had central scotomas with retained peripheral function. For the forms of RP illustrated, there was detectable albeit severely reduced ONL across the scanned retina, and normal or hyperthick GCL and NFL. Maculopathy patients had no measurable ONL centrally; it became detectable with eccentricity. Some maculopathy patients showed unexpected GCL losses. Autofluorescence imaging illustrated central losses of RPE integrity. A hypothetical scheme to relate patient data with different phases of retinal remodeling in animal models of retinal degeneration was presented. Stem cell science is advancing, but it is not too early to open the discussion of criteria for patient selection and monitoring. Available clinical tools, such as OCT and AF imaging, can provide inclusion/exclusion criteria and robust objective outcomes. Accepting that early trials may not lead to miraculous cures, we should be prepared to know why-scientifically and clinically-so we can improve subsequent trials. We also must determine if retinal remodeling is an impediment to efficacy.

Staging of Macular Telangiectasia: Power-Doppler Optical Coherence Tomography and Macular Pigment Optical Density

PubMed Central

Chin, Eric K.; Kim, Dae Yu; Hunter, Allan A.; Pilli, Suman; Wilson, Machelle; Zawadzki, Robert J.; Werner, John S.; Park, Susanna S.

2013-01-01

Purpose. Two methods were used to study the stages of macular telangiectasia (MacTel): Power-Doppler optical coherence tomography (PD-OCT), which allows imaging of the retinal circulation in three dimensions, and macular pigment optical density (MPOD), which quantifies the distribution of macular carotenoids. Methods. Among 49 patients with MacTel identified, 12 eyes (6 patients) with MacTel and 7 age-matched control eyes (7 patients) were imaged with a custom-built Fourier-domain OCT instrument to acquire PD-OCT images. MPOD was measured using heterochromatic flicker photometry in 10 eyes (5 patients) with MacTel and compared with 44 age-matched control eyes (44 patients). Clinical staging of MacTel was based on best-corrected visual acuity, fundus biomicroscopy, fluorescein angiography, and OCT. Results. Stage 1 eyes (n = 2) had subtle punctate vascular signal confined to the inner portion of the outer plexiform layer (OPL) on PD-OCT. Stage 2 (n = 2) showed larger oblique vascular signal extending into deeper OPL. Stage 3 (n = 5) had disruption of outer retinal layers with abnormal vasculature extending into the outer nuclear layer. Stage 4 (n = 3) showed diffuse blurring of the retinal layers with vascular channels extending the full thickness of the retina. MPOD values in four eyes with stage 1 or 2 MacTel correlated well with age-matched controls. Six eyes with stage 3 or 4 MacTel had loss of MPOD especially at the fovea. Conclusions. PD-OCT shows penetration of the retinal capillaries into the deeper retinal layers in early stages of MacTel, with full thickness vascular proliferation in advanced disease. MPOD is commonly depleted but may appear normal in early stage MacTel. PMID:23716628

LONG-TERM SD-OCT/SLO IMAGING OF NEURORETINA AND RETINAL PIGMENT EPITHELIUM AFTER SUB-THRESHOLD INFRARED LASER TREATMENT OF DRUSEN

PubMed Central

MOJANA, FRANCESCA; BRAR, MANPREET; CHENG, LINGYUN; BARTSCH, DIRK-UWE G.; FREEMAN, WILLIAM R.

2012-01-01

PURPOSE To determine the long-term effect of sub-threshold diode laser treatment for drusen in patients with non-exudative age-related macular degeneration (AMD) with spectral domain optical coherence tomography combined with simultaneous scanning laser ophthalmoscope (SD-OCT/SLO). METHODS 8 eyes of 4 consecutive AMD patients with bilateral drusen previously treated with sub-threshold diode laser were imaged with SD-OCT/SLO. Abnormalities in the outer retina layers reflectivity as seen with SD-OCT/SLO were retrospectively analyzed and compared with color fundus pictures and autofluorescence images (AF) acquired immediately before and after the laser treatment. RESULTS A focal discrete disruptions in the reflectivity of the outer retinal layers was noted in 29% of the laser lesions. The junction in between the inner and outer segment of the photoreceptor was more frequently affected, with associated focal damage of the outer nuclear layer. Defects of the RPE were occasionally detected. These changes did not correspond to threshold burns on color fundus photography, but corresponded to focal areas of increased AF in the majority of the cases. CONCLUSIONS Sub-threshold diode laser treatment causes long-term disruption of the retinal photoreceptor layer as analyzed by SD-OCT/SLO. The concept that sub-threshold laser treatment can achieve a selected RPE effect without damage to rods and cones may be flawed. PMID:21157398

Analysis of the chicken retina with an adaptive optics multiphoton microscope

PubMed Central

Bueno, Juan M.; Giakoumaki, Anastasia; Gualda, Emilio J.; Schaeffel, Frank; Artal, Pablo

2011-01-01

The structure and organization of the chicken retina has been investigated with an adaptive optics multiphoton imaging microscope in a backward configuration. Non-stained flat-mounted retinal tissues were imaged at different depths, from the retinal nerve fiber layer to the outer segment, by detecting the intrinsic nonlinear fluorescent signal. From the stacks of images corresponding to the different retinal layers, volume renderings of the entire retina were reconstructed. The density of photoreceptors and ganglion cells layer were directly estimated from the images as a function of the retinal eccentricity. The maximum anatomical resolving power at different retinal eccentricities was also calculated. This technique could be used for a better characterization of retinal alterations during myopia development, and may be useful for visualization of retinal pathologies and intoxication during pharmacological studies. PMID:21698025

HISTOLOGY OF GEOGRAPHIC ATROPHY SECONDARY TO AGE-RELATED MACULAR DEGENERATION: A Multilayer Approach.

PubMed

Li, Miaoling; Huisingh, Carrie; Messinger, Jeffrey; Dolz-Marco, Rosa; Ferrara, Daniela; Freund, K Bailey; Curcio, Christine A

2018-05-03

To systematically characterize histologic features of multiple chorioretinal layers in eyes with geographic atrophy, or complete retinal pigment epithelium (RPE) and outer retinal atrophy, secondary to age-related macular degeneration, including Henle fiber layer and outer nuclear layer; and to compare these changes to those in the underlying RPE-Bruch membrane-choriocapillaris complex and associated extracellular deposits. Geographic atrophy was delimited by the external limiting membrane (ELM) descent towards Bruch membrane. In 13 eyes, histologic phenotypes and/or thicknesses of Henle fiber layer, outer nuclear layer, underlying supporting tissues, and extracellular deposits at four defined locations on the non-atrophic and atrophic sides of the ELM descent were assessed and compared across other tissue layers, with generalized estimating equations and logit models. On the non-atrophic side of the ELM descent, distinct Henle fiber layer and outer nuclear layer became dyslaminated, cone photoreceptor inner segment myoids shortened, photoreceptor nuclei and mitochondria translocated inward, and RPE was dysmorphic. On the atrophic side of the ELM descent, all measures of photoreceptor health declined to zero. Henle fiber layer/outer nuclear layer thickness halved, and only Müller cells remained, in the absence of photoreceptors. Sub-RPE deposits remained, Bruch membrane thinned, and choriocapillaris density decreased. The ELM descent sharply delimits an area of marked gliosis and near-total photoreceptor depletion clinically defined as Geographic atrophy (or outer retinal atrophy), indicating severe and potentially irreversible tissue damage. Degeneration of supporting tissues across this boundary is gradual, consistent with steady age-related change and suggesting that RPE and Müller cells subsequently respond to a threshold of stress. Novel clinical trial endpoints should be sought at age-related macular degeneration stages before intense gliosis and thick deposits impede therapeutic intervention.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Early photoreceptor outer segment loss and retinoschisis in Cohen syndrome.

PubMed

Uyhazi, Katherine E; Binenbaum, Gil; Carducci, Nicholas; Zackai, Elaine H; Aleman, Tomas S

2018-06-01

To describe early structural and functional retinal changes in a patient with Cohen syndrome. A 13-month-old Caucasian girl of Irish and Spanish ancestry was noted to have micrognathia and laryngomalacia at birth, which prompted a genetic evaluation that revealed biallelic deletions in COH1 (VPS13B) (a maternally inherited 60-kb deletion involving exons 26-32 and a paternally inherited 3.5-kb deletion within exon 17) consistent with Cohen syndrome. She underwent a complete ophthalmic examination, full-field flash electroretinography and retinal imaging with spectral domain optical coherence tomography. Central vision was central, steady, and maintained. There was bilateral myopic astigmatic refractive error. Fundus exam was notable for dark foveolar pigmentation, but no obvious abnormalities of either eye. Spectral domain optical coherence tomography cross sections through the fovea revealed a normal appearing photoreceptor outer nuclear layer but loss of the interdigitation signal between the photoreceptor outer segments and the apical retinal pigment epithelium. Retinoschisis involving the inner nuclear layer of both eyes and possible ganglion cell layer thinning were also noted. There was a detectable electroretinogram with similarly reduced amplitudes of rod- (white, 0.01 cd.s.m -2 ) and cone-mediated (3 cd.s.m -2 , 30 Hz) responses. Photoreceptor outer segment abnormalities and retinoschisis may represent the earliest structural retinal change detected by spectral domain optical coherence tomography in patients with Cohen syndrome, suggesting a complex pathophysiology with primary involvement of the photoreceptor cilium and disorganization of the structural integrity of the inner retina.

Retinal Layer Abnormalities as Biomarkers of Schizophrenia.

PubMed

Samani, Niraj N; Proudlock, Frank A; Siram, Vasantha; Suraweera, Chathurie; Hutchinson, Claire; Nelson, Christopher P; Al-Uzri, Mohammed; Gottlob, Irene

2018-06-06

Schizophrenia is associated with several brain deficits, as well as visual processing deficits, but clinically useful biomarkers are elusive. We hypothesized that retinal layer changes, noninvasively visualized using spectral-domain optical coherence tomography (SD-OCT), may represent a possible "window" to these abnormalities. A Leica EnvisuTM SD-OCT device was used to obtain high-resolution central foveal B-scans in both eyes of 35 patients with schizophrenia and 50 demographically matched controls. Manual retinal layer segmentation was performed to acquire individual and combined layer thickness measurements in 3 macular regions. Contrast sensitivity was measured at 3 spatial frequencies in a subgroup of each cohort. Differences were compared using adjusted linear models and significantly different layer measures in patients underwent Spearman Rank correlations with contrast sensitivity, quantified symptoms severity, disease duration, and antipsychotic medication dose. Total retinal and photoreceptor complex thickness was reduced in all regions in patients (P < .0001). Segmentation revealed consistent thinning of the outer nuclear layer (P < .001) and inner segment layer (P < .05), as well as a pattern of parafoveal ganglion cell changes. Low spatial frequency contrast sensitivity was reduced in patients (P = .002) and correlated with temporal parafoveal ganglion cell complex thinning (R = .48, P = .01). Negative symptom severity was inversely correlated with foveal photoreceptor complex thickness (R = -.54, P = .001) and outer nuclear layer thickness (R = -.47, P = .005). Our novel findings demonstrate considerable retinal layer abnormalities in schizophrenia that are related to clinical features and visual function. With time, SD-OCT could provide easily-measurable biomarkers to facilitate clinical assessment and further our understanding of the disease.

Structural and functional changes associated with normal and abnormal fundus autofluorescence in patients with retinitis pigmentosa.

PubMed

Greenstein, Vivienne C; Duncker, Tobias; Holopigian, Karen; Carr, Ronald E; Greenberg, Jonathan P; Tsang, Stephen H; Hood, Donald C

2012-02-01

To analyze the structure and visual function of regions bordering the hyperautofluorescent ring/arcs in retinitis pigmentosa. Twenty-one retinitis pigmentosa patients (21 eyes) with rings/arcs and 21 normal individuals (21 eyes) were studied. Visual sensitivity in the central 10° was measured with microperimetry. Retinal structure was evaluated with spectral-domain optical coherence tomography. The distance from the fovea to disruption/loss of the inner outer segment (IS/OS) junction and thicknesses of the total receptor plus retinal pigment epithelial complex and outer segment plus retinal pigment epithelial complex layers were measured. Results were compared with measurements of the distance from the fovea to the inner and outer borders of the ring/arc seen on fundus autofluorescence. Disruption/loss of the inner outer segment junction occurred closer to the inner border of the ring/arc and it was closer to the fovea in eight eyes. For 19 eyes, outer segment plus and receptor plus RPE complex thicknesses were significantly decreased at locations closer to the fovea than the appearance of the inner border of hyperautofluorescence. Mean visual sensitivity was decreased inside, across, and outside the ring/arc by 3.5 ± 3.8, 8.9 ± 4.8, and 17.0 ± 2.4 dB, respectively. Structural and functional changes can occur inside the hyperfluorescent ring/arc in retinitis pigmentosa.

MRI of Retinal Free Radical Production With Laminar Resolution In Vivo

PubMed Central

Berkowitz, Bruce A.; Lewin, Alfred S.; Biswal, Manas R.; Bredell, Bryce X.; Davis, Christopher; Roberts, Robin

2016-01-01

Purpose Recent studies have suggested the hypothesis that quench-assisted 1/T1 magnetic resonance imaging (MRI) measures free radical production with laminar resolution in vivo without the need of a contrast agent. Here, we test this hypothesis further by examining the spatial and detection sensitivity of quench-assisted 1/T1 MRI to strain, age, or retinal cell layer-specific genetic manipulations. Methods We studied: adult wild-type mice; mice at postnatal day 7 (P7); cre dependent retinal pigment epithelium (RPE)-specific MnSOD knockout mice; doxycycline-treated Sod2flox/flox mice lacking the cre transgene; and α-transducin knockout (Gnat1−/−) mice on a C57Bl/6 background. Transretinal 1/T1 profiles were mapped in vivo in the dark without or with antioxidant treatment, or followed by light exposure. We calibrated profiles spatially using optical coherence tomography. Results Dark-adapted RPE-specific MnSOD knockout mice had greater than normal 1/T1 in the RPE and outer nuclear layers that was corrected to wild-type levels by antioxidant treatment. Dark and light Gnat1−/− mice also had greater than normal outer retinal 1/T1 values. In adult wild-type mice, dark values of 1/T1 in the ellipsoid region and in the outer segment were suppressed by 13 minutes of light. By 29 minutes of light, 1/T1 reduction extended to the outer nuclear layer. Gnat1−/− mice demonstrated a faster light-evoked suppression of 1/T1 values in the outer retina. In P7 mice, transretinal 1/T1 profiles were the same in dark and light. Conclusions Quench-assisted MRI has the laminar resolution and detection sensitivity to evaluate normal and pathologic production of free radicals in vivo. PMID:26886890

TUDCA Slows Retinal Degeneration in Two Different Mouse Models of Retinitis Pigmentosa and Prevents Obesity in Bardet-Biedl Syndrome Type 1 Mice

PubMed Central

Drack, Arlene V.; Dumitrescu, Alina V.; Bhattarai, Sajag; Gratie, Daniel; Stone, Edwin M.; Mullins, Robert

2012-01-01

Purpose. To evaluate and compare the protective effect of tauroursodeoxycholic acid (TUDCA) on photoreceptor degeneration in different models of retinal degeneration (RD) in mice. Methods. BbsM390R/M390R mice were injected subcutaneously twice a week, from P40 to P120, and rd10 mice were injected every 3 days from P6 to P38 with TUDCA or vehicle (0.15 M NaHCO3). Rd1 and rd16 mice were injected daily from P6 to P30 with TUDCA or vehicle. Retinal structure and function were determined at multiple time points by electroretinography (ERG), optical coherence tomography (OCT), and histology. Results. The amplitude of ERG b-waves was significantly higher in TUDCA-treated Bbs1 and rd10 animals than in controls. Retinal thickness on OCT was slightly greater in treated Bbs1 animals than in the controls. Histologically, outer segments were preserved, and the outer nuclear layer was significantly thicker in the treated Bbs1 and rd10 mice than in the controls. Bbs1M390R/M390R mice developed less obesity than the control Bbs1M390R/M390R while receiving TUDCA. The Rd1 and rd16 mice showed no improvement with TUDCA treatment, and the rd1 mice did not have normal weight gain during treatment. Conclusions. TUDCA treatment preserved ERG b-waves and the outer nuclear layer in Bbs1M390R/M390R mice, and prevented obesity assessed at P120. TUDCA treatment preserved ERG b-waves and the outer nuclear layer in the rd10 mice to P30. TUDCA is a prime candidate for treatment of humans with retinal degeneration, especially those with Bardet-Biedl syndrome, whom it may help not only with the vision loss, but with the debilitating obesity as well. PMID:22110077

Diagnostic Accuracy of Spectralis SD OCT Automated Macular Layers Segmentation to Discriminate Normal from Early Glaucomatous Eyes.

PubMed

Pazos, Marta; Dyrda, Agnieszka Anna; Biarnés, Marc; Gómez, Alicia; Martín, Carlos; Mora, Clara; Fatti, Gianluca; Antón, Alfonso

2017-08-01

To evaluate the accuracy of the macular retinal layer segmentation software of the Spectralis spectral-domain (SD) optical coherence tomography (OCT) device (Heidelberg Engineering, Inc., Heidelberg, Germany) to discriminate between healthy and early glaucoma (EG) eyes. Prospective, cross-sectional study. Forty EG eyes and 40 healthy controls were included. All participants were examined using the standard posterior pole and the peripapillary retinal nerve fiber layer (pRNFL) protocols of the Spectralis OCT device. Using an Early Treatment Diagnostic Retinopathy Study circle at the macular level, the automated retinal segmentation software was applied to determine thicknesses of the following parameters: total retinal thickness, inner retinal layer (IRL), macular retinal nerve fiber layer (mRNFL), macular ganglion cell layer (mGCL), macular inner plexiform layer (mIPL), macular inner nuclear layer (mINL), macular outer plexiform layer (mOPL), macular outer nuclear layer (mONL), photoreceptors (PR), and retinal pigmentary epithelium (RPE). The ganglion cell complex (GCC) was determined by adding the mRNFL, mGCL, and mIPL parameters and the ganglion cell layer-inner plexiform layer (mGCL-IPL) was determined by combining the mGCL and mIPL parameters. Thickness of each layer was compared between the groups, and the layer and sector with the best area under the receiver operating characteristic curve (AUC) were identified. Comparison of pRNFL, IRL, mRNFL, mGCL, mIPL, mGCC, mGCL-IPL, mINL, mOPL, mONL, PR, and RPE parameters and total retinal thicknesses between groups for the different areas and their corresponding AUCs. Peripapillary RNFL was significantly thinner in the EG group globally and in all 6 sectors assessed (P < 0.0005). For the macular variables, retinal thickness was significantly reduced in the EG group for total retinal thickness, mIRL, mRNFL, mGCL, and mIPL. The 2 best isolated parameters to discriminate between the 2 groups were pRNFL (AUC, 0.956) and mRNFL (AUC, 0.906). When mRNFL, mGCL, and mIPL measurements were combined (mGCC and mGCL plus mIPL), then its diagnostic performance improved (AUC, 0.940 and 0.952, respectively). Macular RNFL, mGCL-IPL, and mGCC measurements showed a high diagnostic capability to discriminate between healthy and EG participants. However, macular intraretinal measurements still have not overcome standard pRNFL parameters. Copyright © 2017 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Two-photon excited autofluorescence imaging of freshly isolated frog retinas.

PubMed

Lu, Rong-Wen; Li, Yi-Chao; Ye, Tong; Strang, Christianne; Keyser, Kent; Curcio, Christine A; Yao, Xin-Cheng

2011-06-01

The purpose of this study was to investigate cellular sources of autofluorescence signals in freshly isolated frog (Rana pipiens) retinas. Equipped with an ultrafast laser, a laser scanning two-photon excitation fluorescence microscope was employed for sub-cellular resolution examination of both sliced and flat-mounted retinas. Two-photon imaging of retinal slices revealed autofluorescence signals over multiple functional layers, including the photoreceptor layer (PRL), outer nuclear layer (ONL), outer plexiform layer (OPL), inner nuclear layer (INL), inner plexiform layer (IPL), and ganglion cell layer (GCL). Using flat-mounted retinas, depth-resolved imaging of individual retinal layers further confirmed multiple sources of autofluorescence signals. Cellular structures were clearly observed at the PRL, ONL, INL, and GCL. At the PRL, the autofluorescence was dominantly recorded from the intracellular compartment of the photoreceptors; while mixed intracellular and extracellular autofluorescence signals were observed at the ONL, INL, and GCL. High resolution autofluorescence imaging clearly revealed mosaic organization of rod and cone photoreceptors; and sub-cellular bright autofluorescence spots, which might relate to connecting cilium, was observed in the cone photoreceptors only. Moreover, single-cone and double-cone outer segments could be directly differentiated.

Outer Retinal Assessment Using Spectral-Domain Optical Coherence Tomography in Patients With Alzheimer's and Parkinson's Disease.

PubMed

Uchida, Atsuro; Pillai, Jagan A; Bermel, Robert; Bonner-Jackson, Aaron; Rae-Grant, Alexander; Fernandez, Hubert; Bena, James; Jones, Stephen E; Leverenz, James B; Srivastava, Sunil K; Ehlers, Justis P

2018-06-01

To investigate outer retinal parameters among patients with various chronic neurodegenerative disorders by using spectral-domain coherence tomography (OCT) in a prospective cross-sectional cohort study. A total of 132 participants were enrolled following a comprehensive diagnostic evaluation with neurologic, neuropsychology, and magnetic resonance imaging volumetric evaluations. Participants were 50 years or older, either diagnosed with Alzheimer's disease (AD) dementia, amnestic mild cognitive impairment (MCI), non-AD dementia, Parkinson's disease (PD), or age- and sex-matched controls. All participants underwent a macular cube scan for both eyes by using the Cirrus 4000 HD-OCT (Zeiss, Oberkochen, Germany). The OCT image with the best quality was selected for further analysis. Outer retinal parameters including ellipsoid zone mapping and outer nuclear layer metrics were evaluated with a novel software platform. One hundred twenty-four eyes of 124 participants with AD dementia (24 eyes), amnestic MCI (22 eyes), non-AD dementia (20 eyes), PD (22 eyes), and age- and sex-matched controls (36 eyes) were included in the analysis. Eight eyes were excluded either due to the presence of macular disease or poor quality of the OCT image. The mean ages of participants were 65.9 ± 8.9 years. The outer retinal thickness measures did not show any statistical significance between the groups. However, ellipsoid zone to retinal pigment epithelium volume correlated with cognitive testing scores in all study participants. There were no identifiable differences in the outer retinal metrics across neurodegenerative disease groups and controls. The relationship between the degree of cognitive impairment and ellipsoid zone to retinal pigment epithelium volume warrants further study.

Investigation of changes in fractal dimension from layered retinal structures of healthy and diabetic eyes with optical coherence tomography

NASA Astrophysics Data System (ADS)

Gao, Wei; Zakharov, Valery P.; Myakinin, Oleg O.; Bratchenko, Ivan A.; Artemyev, Dmitry N.; Kornilin, Dmitry V.

2015-07-01

Optical coherence tomography (OCT) is usually employed for the measurement of retinal thickness characterizing the structural changes of tissue. However, fractal dimension (FD) could also character the structural changes of tissue. Therefore, fractal dimension changes may provide further information regarding cellular layers and early damage in ocular diseases. We investigated the possibility of OCT in detecting changes in fractal dimension from layered retinal structures. OCT images were obtained from diabetic patients without retinopathy (DM, n = 38 eyes) or mild diabetic retinopathy (MDR, n = 43 eyes) and normal healthy subjects (Controls, n = 74 eyes). Fractal dimension was calculated using the differentiate box counting methodology. We evaluated the usefulness of quantifying fractal dimension of layered structures in the detection of retinal damage. Generalized estimating equations considering within-subject intereye relations were used to test for differences between the groups. A modified p value of <0.001 was considered statistically significant. Receiver operating characteristic (ROC) curves were constructed to describe the ability of fractal dimension to discriminate between the eyes of DM, MDR and healthy eyes. Significant decreases of fractal dimension were observed in all layers in the MDR eyes compared with controls except in the inner nuclear layer (INL). Significant decreases of fractal dimension were also observed in all layers in the MDR eyes compared with DM eyes. The highest area under receiver operating characteristic curve (AUROC) values estimated for fractal dimension were observed for the outer plexiform layer (OPL) and outer segment photoreceptors (OS) when comparing MDR eyes with controls. The highest AUROC value estimated for fractal dimension were also observed for the retinal nerve fiber layer (RNFL) and OS when comparing MDR eyes with DM eyes. Our results suggest that fractal dimension of the intraretinal layers may provide useful information to differentiate pathological from healthy eyes. Further research is warranted to determine how this approach may be used to improve diagnosis of early retinal neurodegeneration.

Diabetic retinal pigment epitheliopathy: fundus autofluorescence and spectral-domain optical coherence tomography findings.

PubMed

Kang, Eui Chun; Seo, Yuri; Byeon, Suk Ho

2016-10-01

To describe the characteristics of an unfamiliar disease entity, diabetic retinal pigment epitheliopathy (DRPE), using fundus autofluorescence (FAF) and spectral-domain optical coherence tomography (SD-OCT). This retrospective study included 17 eyes from 10 proliferative diabetic retinopathy (PDR) patients with granular hypo-autofluorescence and/or variable hyper-autofluorescence on FAF (DRPE group) and 17 eyes from 10 age- and sex-matched PDR patients without abnormal autofluorescence (PDR group). Eyes with diabetic macular edema were excluded. Visual acuity (VA), retinal thickness (RT), and choroidal thickness (CT) were compared between the groups. Eyes in the DRPE group had worse logMAR VA than eyes in the PDR group (0.369 ± 0.266 vs. 0.185 ± 0.119; P = 0.026). The thickness of the retinal pigment epithelium plus the inner segment/outer segment of the photoreceptors was reduced to a greater degree in the DRPE group than the PDR group (P < 0.001). Moreover, the thickness of the outer nuclear layer plus the outer plexiform layer was thinner in the DRPE group than in the PDR (P = 0.013). However, the thickness of the inner retina showed no differences between the two groups. CT was significantly thicker in the DRPE group than in the PDR group (329.00 ± 33.76 vs. 225.62 ± 37.47 μm; P < 0.001). Eyes with DRPE showed reduced VA, a thinner outer retina, and thicker choroid in comparison with eyes with PDR. Alterations of autofluorescence on FAF and changes in the outer retinal thickness and CT on SD-OCT can be helpful for differentiating DRPE in patients with PDR.

Age-Related Alterations in the Retinal Microvasculature, Microcirculation, and Microstructure.

PubMed

Wei, Yantao; Jiang, Hong; Shi, Yingying; Qu, Dongyi; Gregori, Giovanni; Zheng, Fang; Rundek, Tatjana; Wang, Jianhua

2017-07-01

To characterize age-related alterations in the retinal microcirculation, microvascular network, and microstructure in healthy subjects. Seventy-four healthy subjects aged from 18 to 82 years were recruited and divided into four age groups (G1 with age <35 years, G2 with age 35 ∼ 49 years, G3 with age 50 ∼ 64 years, and G4 with age ≥65 years). Custom ultra-high resolution optical coherence tomography (UHR-OCT) was used to acquire six intraretinal layers of the macula. OCT angiography (OCTA) was used to image the retinal microvascular network. The retinal blood flow velocity (BFV) was measured using a Retinal Function Imager (RFI). Compared to G1, G2 had significant thinning of the retinal nerve fiber layer (RNFL) (P < 0.05), while G3 had thinning of the RNFL and ganglion cell and inner plexiform layer (GCIPL) (P < 0.05), in addition to thickening of the outer plexiform layer (OPL) and photoreceptor layer (PR) (P < 0.05). G4 had loss in retinal vessel density, thinning in RNFL and GCIPL, and decrease in venular BFV, in addition to thickening of the OPL and PR (P < 0.05). Age was negatively related to retinal vessel densities, the inner retinal layers, and venular BFV (P < 0.05). By contrast, age was positively related to OPL and PR (P < 0.05). During aging, decreases in retinal vessel density, inner retinal layer thickness, and venular BFV were evident and impacted each other as observed by simultaneous changes in multiple retinal components.

Optical Coherence Tomography of Retinal Degeneration in Royal College of Surgeons Rats and Its Correlation with Morphology and Electroretinography

PubMed Central

Yamauchi, Kodai; Mounai, Natsuki; Tanabu, Reiko; Nakazawa, Mitsuru

2016-01-01

Purpose To evaluate the correlation between optical coherence tomography (OCT) and the histological, ultrastructural and electroretinography (ERG) findings of retinal degeneration in Royal College of Surgeons (RCS-/-) rats. Materials and Methods Using OCT, we qualitatively and quantitatively observed the continual retinal degeneration in RCS-/- rats, from postnatal (PN) day 17 until PN day 111. These findings were compared with the corresponding histological, electron microscopic, and ERG findings. We also compared them to OCT findings in wild type RCS+/+ rats, which were used as controls. Results After PN day 17, the hyperreflective band at the apical side of the photoreceptor layer became blurred. The inner segment (IS) ellipsoid zone then became obscured, and the photoreceptor IS and outer segment (OS) layers became diffusely hyperreflective after PN day 21. These changes correlated with histological and electron microscopic findings showing extracellular lamellar material that accumulated in the photoreceptor OS layer. After PN day 26, the outer nuclear layer became significantly thinner (P < 0.01) and hyperreflective compared with that in the controls; conversely, the photoreceptor IS and OS layers, as well as the inner retinal layers, became significantly thicker (P < 0.001 and P = 0.05, respectively). The apical hyperreflective band, as well as the IS ellipsoid zone, gradually disappeared between PN day 20 and PN day 30; concurrently, the ERG a- and b-wave amplitudes deteriorated. In contrast, the thicknesses of the combined retinal pigment epithelium and choroid did not differ significantly between RCS-/- and RCS+/+ rats. Conclusion Our results suggest that OCT demonstrates histologically validated photoreceptor degeneration in RCS rats, and that OCT findings partly correlate with ERG findings. We propose that OCT is a less invasive and useful method for evaluating photoreceptor degeneration in animal models of retinitis pigmentosa. PMID:27644042

Structural and functional correlates in color vision deficiency

PubMed Central

Gupta, A; Laxmi, G; Nittala, M G; Raman, R

2011-01-01

Purpose The aim of this study is to assess the photoreceptor integrity, using spectral domain optical coherence tomography (SD-OCT), and to measure the retinal sensitivity of patients with congenital red–green color vision deficiency (CVD). Methods In all, 14 eyes from 7 patients with congenital red–green CVD (diagnosed by Farnsworth Munsell 100 hue test), and 14 eyes from 7 control subjects were examined by SD-OCT and microperimetry. Radial scans (7-mm) were taken of the macula. The center of the fovea was defined. The thickness of different retinal layers, at the foveal center, and at multiple defined points along all six radial scans, was measured. The median readings were compared between the two groups using Mann–Whitney U-test. Results SD-OCT demonstrated normal total retinal thickness, normal thickness of the photoreceptor layer, normal thickness of the outer nuclear layer, normal vertical thickness of the outer segments (OSs), and normal vertical thickness of the inner segments. OS horizontal diameter was less in left eye in cases with CVD when compared with controls. The mean retinal and foveal sensitivity was similar between cases and controls. Conclusions In subjects with congenital red–green CVD, there are no discernible anatomical abnormalities seen on SD-OCT in various retinal layers, except for a narrower foveal pit. However, further studies with larger sample size are required. PMID:21494280

Retinal profile and structural differences between myopes and emmetropes

NASA Astrophysics Data System (ADS)

Clark, Christopher Anderson

Refractive development has been shown to be influenced by optical defocus in the eye and the interpretation of this signal appears to be localized in the retina. Optical defocus is not uniform across the retina and has been suggested as a potential cause of myopia development. Specifically hyperopic focus, i.e. focusing light behind the retina, may signal the eye to elongate, causing myopia. This non-uniform hyperopic signal appears to be due to the retinal shape. Ultimately, these signals are detected by the retina in an as yet undetermined manner. The purpose of this thesis is to examine the retinal profile using a novel method developed at Indiana University and then to examine retinal structural changes across the retina associated with myopia. Myopes exhibited more prolate retinas than hyperopes/emmetropes using the SD OCT. Using the SD OCT, this profile difference was detectable starting at 5 degrees from the fovea, which was closer than previously reported in the literature. These results agreed significantly with results found from peripheral refraction and peripheral axial length at 10 degrees. Overall, the total retina was thinner for myopes than hyperopes/emmetropes. It was also statistically significantly thinner for the Outer Nuclear Layer (ONL), Inner Nuclear Layer (INL) and Outer Plexiform Layer (OPL) but not for other retinal layers such as the Ganglion Layer. Thinning generally occurred outside of 5 degrees. The SD OCT method provided a nearly 10 fold increase in sensitivity which allowed for detection of profile changes closer to the fovea. The location of the retinal changes may be interesting as the layers that showed significant differences in thickness are also layers that contain cells believed to be associated with refractive development (amacrine, bipolar, and photoreceptor cells.) The reason for the retinal changes cannot be determined with this study, but possible theories include stretch due to axial elongation, neural remodeling due to blur, and/or direct influence on refractive development due to neural cell densities.

Multicenter reliability of semiautomatic retinal layer segmentation using OCT

PubMed Central

Oberwahrenbrock, Timm; Traber, Ghislaine L.; Lukas, Sebastian; Gabilondo, Iñigo; Nolan, Rachel; Songster, Christopher; Balk, Lisanne; Petzold, Axel; Paul, Friedemann; Villoslada, Pablo; Brandt, Alexander U.; Green, Ari J.

2018-01-01

Objective To evaluate the inter-rater reliability of semiautomated segmentation of spectral domain optical coherence tomography (OCT) macular volume scans. Methods Macular OCT volume scans of left eyes from 17 subjects (8 patients with MS and 9 healthy controls) were automatically segmented by Heidelberg Eye Explorer (v1.9.3.0) beta-software (Spectralis Viewing Module v6.0.0.7), followed by manual correction by 5 experienced operators from 5 different academic centers. The mean thicknesses within a 6-mm area around the fovea were computed for the retinal nerve fiber layer, ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer, outer plexiform layer (OPL), and outer nuclear layer (ONL). Intraclass correlation coefficients (ICCs) were calculated for mean layer thickness values. Spatial distribution of ICC values for the segmented volume scans was investigated using heat maps. Results Agreement between raters was good (ICC > 0.84) for all retinal layers, particularly inner retinal layers showed excellent agreement across raters (ICC > 0.96). Spatial distribution of ICC showed highest values in the perimacular area, whereas the ICCs were poorer for the foveola and the more peripheral macular area. The automated segmentation of the OPL and ONL required the most correction and showed the least agreement, whereas differences were less prominent for the remaining layers. Conclusions Automated segmentation with manual correction of macular OCT scans is highly reliable when performed by experienced raters and can thus be applied in multicenter settings. Reliability can be improved by restricting analysis to the perimacular area and compound segmentation of GCL and IPL. PMID:29552598

The New Pretender: A Large UK Case Series of Retinal Injuries in Children Secondary to Handheld Lasers.

PubMed

Raoof, Naz; Bradley, Patrick; Theodorou, Maria; Moore, Anthony T; Michaelides, Michel

2016-11-01

To characterize a large single-center series of retinal injuries in children secondary to handheld laser devices, with emphasis on potential prognostic factors. Retrospective case series. Sixteen children (24 eyes) with retinal injuries secondary to handheld lasers were identified from our electronic patient record system. Case notes, digital fundus photography, and spectral-domain optical coherence tomography images were reviewed. The mean age of affected children was 12.7 years (range 9-16 years), with 12 male and 4 female subjects. Mean follow up was 5.4 months (range 1-23 months). Five children (31%) were referred as suspected retinal dystrophies. The mean logMAR visual acuity at presentation was 0.30 (20/40) (range -0.20 [20/12.5] to 1.6 [20/800]). Eleven children (69%; 15 eyes) had "mild" injuries with focal retinal disruption confined to the photoreceptor and ellipsoid layers; such injuries were associated with a better prognosis, the mean visual acuity at presentation being 0.10 (20/25). "Moderate" injuries were seen in 3 eyes of 2 children, with retinal disruption confined to the outer retinal layer but diffuse rather than focal in nature. Three patients (4 eyes) had "severe" injuries, with subfoveal outer retinal architecture loss and overlying hyperreflective material in inner retinal layers. Retinal injuries secondary to handheld laser devices may be difficult to diagnose and are likely underreported. It is important that such data are in the public domain, so regulatory authorities recognize the importance of laser retinopathy as an avoidable cause of childhood visual impairment and take steps to minimize the incidence and impact of laser injuries. Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.

Predictive value of spectral-domain optical coherence tomography features in assessment of visual prognosis in eyes with acute welding arc maculopathy.

PubMed

Zhang, Chunxia; Dang, Guangfu; Zhao, Tianmei; Wang, DongLin; Su, Yan; Qu, Yi

2018-04-12

To observe spectral-domain optical coherence tomography (SD-OCT) features and to determine whether baseline OCT features can be used as predictors of visual acuity outcome in eyes with acute welding arc maculopathy. This retrospective study enrolled twenty-two eyes of eleven subjects with acute welding arc maculopathy. All subjects were evaluated by SD-OCT at baseline and final visit. The involved parameters included best-corrected visual acuity (BCVA), central macular thickness (CMT), the length of ellipsoid zone (EZ) defects, the greatest linear dimension (GLD) of outer retinal lesions, EZ reflectivity and relative EZ reflectivity (defined as the ratio of EZ reflectivity to retinal pigment epithelium reflectivity on OCT). Acute welding arc maculopathy was presented as abnormal hyperreflectivity, hyporeflectivity and defects of outer retinal layer in fovea on OCT. Compared with baseline, BCVA improved significantly accompanied by decreased GLD of outer retinal lesions and the length of EZ defects at final visit (P = 0.0004, P < 0.0001 and P < 0.0001, respectively). No significant changes were shown on CMT (P = 0.248). In multivariate regression analysis, final BCVA was associated with baseline BCVA and the length of EZ defects (P = 0.012 and P = 0.045, respectively). However, EZ reflectivity and relative EZ reflectivity were not associated with final BCVA (P > 0.05). In conclusion, SD-OCT images clearly reveal morphological changes in outer retinal layer in acute welding arc maculopathy. The baseline BCVA and length of EZ defects are the strongest predictors of final BCVA.

Internal retinal layer thickness and macular migration after internal limiting membrane peeling in macular hole surgery.

PubMed

Faria, Mun Y; Ferreira, Nuno P; Mano, Sofia; Cristóvao, Diana M; Sousa, David C; Monteiro-Grillo, Manuel E

2018-05-01

To provide a spectral-domain optical coherence tomography (SD-OCT)-based analysis of retinal layers thickness and nasal displacement of closed macular hole after internal limiting membrane peeling in macular hole surgery. In this nonrandomized prospective interventional study, 36 eyes of 32 patients were subjected to pars plana vitrectomy and 3.5 mm diameter internal limiting membrane (ILM) peeling for idiopathic macular hole (IMH). Nasal and temporal internal retinal layer thickness were assessed with SD-OCT. Each scan included optic disc border so that distance between optic disc border and fovea were measured. Thirty-six eyes had a successful surgery with macular hole closure. Total nasal retinal thickening (p<0.001) and total temporal retinal thinning (p<0.0001) were observed. Outer retinal layers increased thickness after surgery (nasal p<0.05 and temporal p<0.01). Middle part of inner retinal layers (mIRL) had nasal thickening (p<0.001) and temporal thinning (p<0.05). The mIRL was obtained by deducting ganglion cell layer (GCL) and retinal nerve fiber layer (RNFL) thickness from overall thickness of the inner retinal layer. Papillofoveal distance was shorter after ILM peeling in macular hole surgery (3,651 ± 323 μm preoperatively and 3,361 ± 279 μm at 6 months; p<0.0001). Internal limiting membrane peel is associated with important alteration in inner retinal layer architecture, with thickening of mIRL and shortening of papillofoveal distance. These factors may contribute to recovery of disrupted foveal photoreceptor and vision improvement after IMH closure.

Age-Related Alterations in the Retinal Microvasculature, Microcirculation, and Microstructure

PubMed Central

Wei, Yantao; Jiang, Hong; Shi, Yingying; Qu, Dongyi; Gregori, Giovanni; Zheng, Fang; Rundek, Tatjana; Wang, Jianhua

2017-01-01

Purpose To characterize age-related alterations in the retinal microcirculation, microvascular network, and microstructure in healthy subjects. Methods Seventy-four healthy subjects aged from 18 to 82 years were recruited and divided into four age groups (G1 with age <35 years, G2 with age 35 ∼ 49 years, G3 with age 50 ∼ 64 years, and G4 with age ≥65 years). Custom ultra-high resolution optical coherence tomography (UHR-OCT) was used to acquire six intraretinal layers of the macula. OCT angiography (OCTA) was used to image the retinal microvascular network. The retinal blood flow velocity (BFV) was measured using a Retinal Function Imager (RFI). Results Compared to G1, G2 had significant thinning of the retinal nerve fiber layer (RNFL) (P < 0.05), while G3 had thinning of the RNFL and ganglion cell and inner plexiform layer (GCIPL) (P < 0.05), in addition to thickening of the outer plexiform layer (OPL) and photoreceptor layer (PR) (P < 0.05). G4 had loss in retinal vessel density, thinning in RNFL and GCIPL, and decrease in venular BFV, in addition to thickening of the OPL and PR (P < 0.05). Age was negatively related to retinal vessel densities, the inner retinal layers, and venular BFV (P < 0.05). By contrast, age was positively related to OPL and PR (P < 0.05). Conclusions During aging, decreases in retinal vessel density, inner retinal layer thickness, and venular BFV were evident and impacted each other as observed by simultaneous changes in multiple retinal components. PMID:28744554

Long-term Characterization of Retinal Degeneration in Royal College of Surgeons Rats Using Spectral-Domain Optical Coherence Tomography

PubMed Central

Ryals, Renee C.; Andrews, Michael D.; Datta, Shreya; Coyner, Aaron S.; Fischer, Cody M.; Wen, Yuquan; Pennesi, Mark E.; McGill, Trevor J.

2017-01-01

Purpose Prospective treatments for age-related macular degeneration and inherited retinal degenerations are commonly evaluated in the Royal College of Surgeons (RCS) rat before translation into clinical application. Historically, retinal thickness obtained through postmortem anatomic assessments has been a key outcome measure; however, utility of this measurement is limited because it precludes the ability to perform longitudinal studies. To overcome this limitation, the present study was designed to provide a baseline longitudinal quantification of retinal thickness in the RCS rat by using spectral-domain optical coherence tomography (SD-OCT). Methods Horizontal and vertical linear SD-OCT scans centered on the optic nerve were captured from Long-Evans control rats at P30, P60, P90 and from RCS rats between P17 and P90. Total retina (TR), outer nuclear layer+ (ONL+), inner nuclear layer (INL), and retinal pigment epithelium (RPE) thicknesses were quantified. Histologic sections of RCS retina obtained from P21 to P60 were compared to SD-OCT images. Results In RCS rats, TR and ONL+ thickness decreased significantly as compared to Long-Evans controls. Changes in INL and RPE thickness were not significantly different between control and RCS retinas. From P30 to P90 a subretinal hyperreflective layer (HRL) was observed and quantified in RCS rats. After correlation with histology, the HRL was identified as disorganized outer segments and the location of accumulated debris. Conclusions Retinal layer thickness can be quantified longitudinally throughout the course of retinal degeneration in the RCS rat by using SD-OCT. Thickness measurements obtained with SD-OCT were consistent with previous anatomic thickness assessments. This study provides baseline data for future longitudinal assessment of therapeutic agents in the RCS rat. PMID:28253400

Long-term Characterization of Retinal Degeneration in Royal College of Surgeons Rats Using Spectral-Domain Optical Coherence Tomography.

PubMed

Ryals, Renee C; Andrews, Michael D; Datta, Shreya; Coyner, Aaron S; Fischer, Cody M; Wen, Yuquan; Pennesi, Mark E; McGill, Trevor J

2017-03-01

Prospective treatments for age-related macular degeneration and inherited retinal degenerations are commonly evaluated in the Royal College of Surgeons (RCS) rat before translation into clinical application. Historically, retinal thickness obtained through postmortem anatomic assessments has been a key outcome measure; however, utility of this measurement is limited because it precludes the ability to perform longitudinal studies. To overcome this limitation, the present study was designed to provide a baseline longitudinal quantification of retinal thickness in the RCS rat by using spectral-domain optical coherence tomography (SD-OCT). Horizontal and vertical linear SD-OCT scans centered on the optic nerve were captured from Long-Evans control rats at P30, P60, P90 and from RCS rats between P17 and P90. Total retina (TR), outer nuclear layer+ (ONL+), inner nuclear layer (INL), and retinal pigment epithelium (RPE) thicknesses were quantified. Histologic sections of RCS retina obtained from P21 to P60 were compared to SD-OCT images. In RCS rats, TR and ONL+ thickness decreased significantly as compared to Long-Evans controls. Changes in INL and RPE thickness were not significantly different between control and RCS retinas. From P30 to P90 a subretinal hyperreflective layer (HRL) was observed and quantified in RCS rats. After correlation with histology, the HRL was identified as disorganized outer segments and the location of accumulated debris. Retinal layer thickness can be quantified longitudinally throughout the course of retinal degeneration in the RCS rat by using SD-OCT. Thickness measurements obtained with SD-OCT were consistent with previous anatomic thickness assessments. This study provides baseline data for future longitudinal assessment of therapeutic agents in the RCS rat.

Retinal Structure in Cobalamin C Disease: Mechanistic and Therapeutic Implications.

PubMed

Aleman, Tomas S; Brodie, Frank; Garvin, Christopher; Gewaily, Dina Y; Ficicioglu, Can H; Mills, Monte D; Forbes, Brian J; Maguire, Albert M; Davidson, Stefanie L

2015-01-01

To describe the retinal structure in a patient with cobalamin C (cblC) disease. A 13-year-old male patient diagnosed with cblC disease during a perinatal metabolic screening prompted by jaundice and hypotony underwent ophthalmic examinations, electroretinography (ERG) and spectral domain optical coherence tomography (SD-OCT). The patient carried a homozygous (c.271dupA) mutation in the methylmalonic aciduria and homocystinuria type C (MMACHC) gene. At age 3 months he had a normal eye exam. A pigmentary maculopathy progressed to chorioretinal atrophy from 5-10 months. ERG at 7 months was normal. A nystagmus remained stable since the age of 2 years. At age 13, visual acuity was 20/250 (right eye) and 20/400 (left eye), with a +5.00 D correction, a level of vision maintained since first measurable at age 5 years. SD-OCT showed bilateral macular coloboma-like lesions; there was also a thickened surface layer with ganglion cell layer thinning. Photoreceptor outer segment loss and thinning of the outer nuclear layer (ONL) transitioned to regions with no discernible ONL with a delaminated, thickened, inner retina. A thick surface layer near the optic nerve resembling an immature retina and an initially normal macula that rapidly developed coloboma-like lesions suggest there may be an interference with retinal/foveal development in cblC, a mechanism of maculopathy that may be shared by other early onset retinal degenerations. Photoreceptor loss and inner retinal remodeling confirm associated photoreceptor degeneration.

Discovery of a Cynomolgus Monkey Family With Retinitis Pigmentosa.

PubMed

Ikeda, Yasuhiro; Nishiguchi, Koji M; Miya, Fuyuki; Shimozawa, Nobuhiro; Funatsu, Jun; Nakatake, Shunji; Fujiwara, Kohta; Tachibana, Takashi; Murakami, Yusuke; Hisatomi, Toshio; Yoshida, Shigeo; Yasutomi, Yasuhiro; Tsunoda, Tatsuhiko; Nakazawa, Toru; Ishibashi, Tatsuro; Sonoda, Koh-Hei

2018-02-01

To accelerate the development of new therapies, an inherited retinal degeneration model in a nonhuman primate would be useful to confirm the efficacy in preclinical studies. In this study, we describe the discovery of retinitis pigmentosa in a cynomolgus monkey (Macaca fascicularis) pedigree. First, screening with fundus photography was performed on 1443 monkeys at the Tsukuba Primate Research Center. Ophthalmic examinations, such as indirect ophthalmoscopy, ERGs using RETeval, and optic coherent tomography (OCT) measurement, were then performed to confirm diagnosis. Retinal degeneration with cystoid macular edema was observed in both eyes of one 14-year-old female monkey. In her examinations, the full-field ERGs were nonrecordable and the outer layer of the retina in the parafoveal area was not visible on OCT imaging. Moreover, less frequent pigmentary retinal anomalies also were observed in her 3-year-old nephew. His full-field ERGs were almost nonrecordable and the outer layer was not visible in the peripheral retina. His father was her cousin (the son of her mother's older brother) and his mother was her younger half-sibling sister with a different father. The hereditary nature is highly probable (autosomal recessive inheritance suspected). However, whole-exome analysis performed identified no pathogenic mutations in these monkeys.

Type 3 Neovascularization Associated with Retinitis Pigmentosa.

PubMed

Sayadi, Jihene; Miere, Alexandra; Souied, Eric H; Cohen, Salomon Y

2017-01-01

To report a case of type 3 neovascular lesion in a patient with retinitis pigmentosa (RP) complicated by macular edema. A 78-year-old man with a long follow-up for RP was referred for painless visual acuity decrease in the right eye. Best-corrected visual acuity was 20/125 in the right eye and 20/40 in the left. Fundus examination showed typical RP and macular edema in both eyes. In the right eye, spectral domain optical coherence tomography revealed a marked cystic macular edema associated with disruption of the Bruch membrane/retinal pigment epithelium complex overlying a pigmentary epithelium detachment, with a vascular structure which appeared to originate from the deep capillary plexus and to be connected with the subretinal pigment epithelium space. Optical coherence tomography angiography showed a high-flow vessel infiltrating the outer retinal layers in the deep capillary plexus segmentation, and a tuft-shaped, bright, high-flow network that seemed to be connected with the subretinal pigment epithelium space in the outer retinal layer segmentation. This presentation was consistent with an early type 3 neovascular lesion in the right eye. Type 3 neovascularization may be considered a possible complication of RP.

Intraocular gene transfer of ciliary neurotrophic factor rescues photoreceptor degeneration in RCS rats.

PubMed

Huang, Shun-Ping; Lin, Po-Kang; Liu, Jorn-Hon; Khor, Chin-Ni; Lee, Yih-Jing

2004-01-01

Ciliary neurotrophic factor (CNTF) is known as an important factor in the regulation of retinal cell growth. We used both recombinant CNTF and an adenovirus carrying the CNTF gene to regulate retinal photoreceptor expression in a retinal degenerative animal, Royal College of Surgeons (RCS) rats. Cells in the outer nuclear layer of the retinae from recombinant-CNTF-treated, adenoviral-CNTF-treated, saline-operated, and contralateral untreated preparations were examined for those exhibiting CNTF photoreceptor protective effects. Cell apoptosis in the outer nuclear layer of the retinae was also detected. It was found that CNTF had a potent effect on delaying the photoreceptor degeneration process in RCS rats. Furthermore, adenovirus CNTF gene transfer was proven to be better at rescuing photoreceptors than that when using recombinant CNTF, since adenoviral CNTF prolonged the photoreceptor protection effect. The function of the photoreceptors was also examined by taking electroretinograms of different animals. Adenoviral-CNTF-treated eyes showed better retinal function than did the contralateral control eyes. This study indicates that adenoviral CNTF effectively rescues degenerating photoreceptors in RCS rats. Copyright 2004 National Science Council, ROC and S. Karger AG, Basel

Meckelin 3 Is Necessary for Photoreceptor Outer Segment Development in Rat Meckel Syndrome

PubMed Central

Tiwari, Sarika; Hudson, Scott; Gattone, Vincent H.; Miller, Caroline; Chernoff, Ellen A. G.; Belecky-Adams, Teri L.

2013-01-01

Ciliopathies lead to multiorgan pathologies that include renal cysts, deafness, obesity and retinal degeneration. Retinal photoreceptors have connecting cilia joining the inner and outer segment that are responsible for transport of molecules to develop and maintain the outer segment process. The present study evaluated meckelin (MKS3) expression during outer segment genesis and determined the consequences of mutant meckelin on photoreceptor development and survival in Wistar polycystic kidney disease Wpk/Wpk rat using immunohistochemistry, analysis of cell death and electron microscopy. MKS3 was ubiquitously expressed throughout the retina at postnatal day 10 (P10) and P21. However, in the mature retina, MKS3 expression was restricted to photoreceptors and the retinal ganglion cell layer. At P10, both the wild type and homozygous Wpk mutant retina had all retinal cell types. In contrast, by P21, cells expressing rod- and cone-specific markers were fewer in number and expression of opsins appeared to be abnormally localized to the cell body. Cell death analyses were consistent with the disappearance of photoreceptor-specific markers and showed that the cells were undergoing caspase-dependent cell death. By electron microscopy, P10 photoreceptors showed rudimentary outer segments with an axoneme, but did not develop outer segment discs that were clearly present in the wild type counterpart. At p21 the mutant outer segments appeared much the same as the P10 mutant outer segments with only a short axoneme, while the wild-type controls had developed outer segments with many well-organized discs. We conclude that MKS3 is not important for formation of connecting cilium and rudimentary outer segments, but is critical for the maturation of outer segment processes. PMID:23516626

Investigation of Retinal Morphology Alterations Using Spectral Domain Optical Coherence Tomography in a Mouse Model of Retinal Branch and Central Retinal Vein Occlusion

PubMed Central

Ebneter, Andreas; Agca, Cavit; Dysli, Chantal; Zinkernagel, Martin S.

2015-01-01

Retinal vein occlusion is a leading cause of visual impairment. Experimental models of this condition based on laser photocoagulation of retinal veins have been described and extensively exploited in mammals and larger rodents such as the rat. However, few reports exist on the use of this paradigm in the mouse. The objective of this study was to investigate a model of branch and central retinal vein occlusion in the mouse and characterize in vivo longitudinal retinal morphology alterations using spectral domain optical coherence tomography. Retinal veins were experimentally occluded using laser photocoagulation after intravenous application of Rose Bengal, a photo-activator dye enhancing thrombus formation. Depending on the number of veins occluded, variable amounts of capillary dropout were seen on fluorescein angiography. Vascular endothelial growth factor levels were markedly elevated early and peaked at day one. Retinal thickness measurements with spectral domain optical coherence tomography showed significant swelling (p<0.001) compared to baseline, followed by gradual thinning plateauing two weeks after the experimental intervention (p<0.001). Histological findings at day seven correlated with spectral domain optical coherence tomography imaging. The inner layers were predominantly affected by degeneration with the outer nuclear layer and the photoreceptor outer segments largely preserved. The application of this retinal vein occlusion model in the mouse carries several advantages over its use in other larger species, such as access to a vast range of genetically modified animals. Retinal changes after experimental retinal vein occlusion in this mouse model can be non-invasively quantified by spectral domain optical coherence tomography, and may be used to monitor effects of potential therapeutic interventions. PMID:25775456

Pars Plana Vitrectomy with Internal Limiting Membrane Peeling for Nontractional Diabetic Macular Edema.

PubMed

Ulrich, Jan Niklas

2017-01-01

Diabetes mellitus remains the leading cause of blindness among working age Americans with diabetic macular edema being the most common cause for moderate and severe vision loss. To investigate the anatomical and visual benefits of pars plana vitrectomy with inner limiting membrane peeling in patients with nontractional diabetic macular edema as well as correlation of integrity of outer retinal layers on spectral domain optical coherence tomography to visual outcomes. We retrospectively reviewed the charts of 42 diabetic patients that underwent vitrectomy with internal limiting membrane peeling for nontractional diabetic macula edema. The integrity of outer retinal layers was evaluated and preoperative central macular thickness and visual acuity were compared with data at 1 month, 3 months and 6 months postoperatively. The student t-test was used to compare the groups. 31 eyes were included. While no differences were seen at 1 and 3 months, there was significant improvement of both central macular thickness and visual acuity at the 6 months follow up visit compared to preoperatively (357, 427 microns; p=0.03. 20/49, 20/82; p=0.03) . Patients with intact external limiting membrane and ellipsoid zone had better preoperative vision than patients with outer retinal layer irregularities (20/54, 20/100; p=0.03) and greater visual gains postoperatively (20/33, p<0.001 versus 20/81; p=non-significant). Pars plana vitrectomy with internal limiting membrane peeling can improve retinal anatomy and visual acuity in patients with nontractional diabetic macular edema. Spectral domain optical coherence tomography may help identify patients with potential for visual improvement.

Automated classifiers for early detection and diagnosis of retinopathy in diabetic eyes.

PubMed

Somfai, Gábor Márk; Tátrai, Erika; Laurik, Lenke; Varga, Boglárka; Ölvedy, Veronika; Jiang, Hong; Wang, Jianhua; Smiddy, William E; Somogyi, Anikó; DeBuc, Delia Cabrera

2014-04-12

Artificial neural networks (ANNs) have been used to classify eye diseases, such as diabetic retinopathy (DR) and glaucoma. DR is the leading cause of blindness in working-age adults in the developed world. The implementation of DR diagnostic routines could be feasibly improved by the integration of structural and optical property test measurements of the retinal structure that provide important and complementary information for reaching a diagnosis. In this study, we evaluate the capability of several structural and optical features (thickness, total reflectance and fractal dimension) of various intraretinal layers extracted from optical coherence tomography images to train a Bayesian ANN to discriminate between healthy and diabetic eyes with and with no mild retinopathy. When exploring the probability as to whether the subject's eye was healthy (diagnostic condition, Test 1), we found that the structural and optical property features of the outer plexiform layer (OPL) and the complex formed by the ganglion cell and inner plexiform layers (GCL + IPL) provided the highest probability (positive predictive value (PPV) of 91% and 89%, respectively) for the proportion of patients with positive test results (healthy condition) who were correctly diagnosed (Test 1). The true negative, TP and PPV values remained stable despite the different sizes of training data sets (Test 2). The sensitivity, specificity and PPV were greater or close to 0.70 for the retinal nerve fiber layer's features, photoreceptor outer segments and retinal pigment epithelium when 23 diabetic eyes with mild retinopathy were mixed with 38 diabetic eyes with no retinopathy (Test 3). A Bayesian ANN trained on structural and optical features from optical coherence tomography data can successfully discriminate between healthy and diabetic eyes with and with no retinopathy. The fractal dimension of the OPL and the GCL + IPL complex predicted by the Bayesian radial basis function network provides better diagnostic utility to classify diabetic eyes with mild retinopathy. Moreover, the thickness and fractal dimension parameters of the retinal nerve fiber layer, photoreceptor outer segments and retinal pigment epithelium show promise for the diagnostic classification between diabetic eyes with and with no mild retinopathy.

Relationship between macular ganglion cell complex thickness and macular outer retinal thickness: a spectral-domain optical coherence tomography study.

PubMed

Kita, Yoshiyuki; Kita, Ritsuko; Takeyama, Asuka; Anraku, Ayako; Tomita, Goji; Goldberg, Ivan

2013-01-01

To assess the relationship between macular ganglion cell complex and macular outer retinal thicknesses. Case-control study. Forty-two normal eyes and 91 eyes with primary open-angle glaucoma were studied. Spectral-domain optical coherence tomography (RTVue-100) was used to measure the macular ganglion cell complex and macular outer retinal thickness. Ganglion cell complex to outer retinal thickness ratio was also calculated. The relationships between the ganglion cell complex and outer retinal thicknesses and between the ganglion cell complex to outer retinal thickness ratio and outer retinal thickness were evaluated. There was a positive correlation between ganglion cell complex and outer retinal thicknesses in the normal group and the glaucoma group (r = 0.53, P < 0.001 and r = 0.42, P < 0.001, respectively). In that respect, there was no correlation between ganglion cell complex to outer retinal thickness ratio and outer retinal thickness in the both groups (r = -0.07, P = 0.657, and r = 0.04, P = 0.677, respectively). The ganglion cell complex to outer retinal thickness ratio was 55.65% in the normal group, 45.07% in the glaucoma group. This difference was statistically significant. The ganglion cell complex thickness may be affected by outer retinal thickness, and there is individual variation in the outer retinal thickness. Therefore, when determining the ganglion cell complex, it seems necessary to consider the outer retinal thickness as well. We propose the ratio as a suitable parameter to account for individual variations in outer retinal thickness. © 2013 The Authors. Clinical and Experimental Ophthalmology © 2013 Royal Australian and New Zealand College of Ophthalmologists.

FREQUENT SUBCLINICAL MACULAR CHANGES IN COMBINED BRAF/MEK INHIBITION WITH HIGH-DOSE HYDROXYCHLOROQUINE AS TREATMENT FOR ADVANCED METASTATIC BRAF MUTANT MELANOMA: Preliminary Results From a Phase I/II Clinical Treatment Trial.

PubMed

Nti, Akosua A; Serrano, Leona W; Sandhu, Harpal S; Uyhazi, Katherine E; Edelstein, Ilaina D; Zhou, Elaine J; Bowman, Scott; Song, Delu; Gangadhar, Tara C; Schuchter, Lynn M; Mitnick, Sheryl; Huang, Alexander; Nichols, Charles W; Amaravadi, Ravi K; Kim, Benjamin J; Aleman, Tomas S

2018-01-10

To assess the potential ocular toxicity of a combined BRAF inhibition (BRAFi) + MEK inhibition (MEKi) + hydroxychloroquine (HCQ) regime used to treat metastatic BRAF mutant melanoma. Patients with stage IV metastatic melanoma and BRAF V600E mutations (n = 11, 31-68 years of age) were included. Treatment was with oral dabrafenib, 150 mg bid, trametinib, 2 mg/day, and HCQ, 400 mg to 600 mg bid. An ophthalmic examination, spectral domain optical coherence tomography, near-infrared and short-wavelength fundus autofluorescence, and static perimetry were performed at baseline, 1 month, and q/6 months after treatment. There were no clinically significant ocular events; there was no ocular inflammation. The only medication-related change was a separation of the photoreceptor outer segment tip from the apical retinal pigment epithelium that could be traced from the fovea to the perifoveal retina noted in 9/11 (82%) of the patients. There were no changes in retinal pigment epithelium melanization or lipofuscin content by near-infrared fundus autofluorescence and short-wavelength fundus autofluorescence, respectively. There were no inner retinal or outer nuclear layer changes. Visual acuities and sensitivities were unchanged. BRAFi (trametinib) + MEKi (dabrafenib) + HCQ causes very frequent, subclinical separation of the photoreceptor outer segment from the apical retinal pigment epithelium without inner retinal changes or signs of inflammation. The changes suggest interference with the maintenance of the outer retinal barrier and/or phagocytic/pump functions of the retinal pigment epithelium by effective MEK inhibition.

Aldose reductase mediates retinal microglia activation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chang, Kun-Che; Shieh, Biehuoy; Petrash, J. Mark, E-mail: mark.petrash@ucdenver.edu

Retinal microglia (RMG) are one of the major immune cells in charge of surveillance of inflammatory responses in the eye. In the absence of an inflammatory stimulus, RMG reside predominately in the ganglion layer and inner or outer plexiform layers. However, under stress RMG become activated and migrate into the inner nuclear layer (INL) or outer nuclear layer (ONL). Activated RMG in cell culture secrete pro-inflammatory cytokines in a manner sensitive to downregulation by aldose reductase inhibitors. In this study, we utilized CX3CR1{sup GFP} mice carrying AR mutant alleles to evaluate the role of AR on RMG activation and migrationmore » in vivo. When tested on an AR{sup WT} background, IP injection of LPS induced RMG activation and migration into the INL and ONL. However, this phenomenon was largely prevented by AR inhibitors or in AR null mice, or was exacerbated in transgenic mice that over-express AR. LPS-induced increases in ocular levels of TNF-α and CX3CL-1 in WT mice were substantially lower in AR null mice or were reduced by AR inhibitor treatment. These studies demonstrate that AR expression in RMG may contribute to the proinflammatory phenotypes common to various eye diseases such as uveitis and diabetic retinopathy. - Highlights: • AR inhibition prevents retinal microglial activation. • Endotoxin-induced ocular cytokine production is reduced in AR null mice. • Overexpression of AR spontaneously induces retinal microglial activation.« less

Autofluorescence Imaging and Spectral-Domain Optical Coherence Tomography in Incomplete Congenital Stationary Night Blindness and Comparison with Retinitis Pigmentosa

PubMed Central

CHEN, ROYCE W. S.; GREENBERG, JONATHAN P.; LAZOW, MARGOT A.; RAMACHANDRAN, RITHU; LIMA, LUIZ H.; HWANG, JOHN C.; SCHUBERT, CARL; BRAUNSTEIN, ALEXANDRA; ALLIKMETS, RANDO; TSANG, STEPHEN H.

2015-01-01

PURPOSE To test the hypothesis that the evaluation of retinal structure can have diagnostic value in differentiating between incomplete congenital stationary night blindness (CSNB2) and retinitis pigmentosa (RP). To compare retinal thickness differences between patients with CSNB2 and myopic controls. DESIGN Prospective cross-sectional study. METHODS Ten eyes of 5 patients diagnosed with CSNB2 (4 X-linked recessive, 1 autosomal recessive) and 6 eyes of 3 patients with RP (2 autosomal dominant, 1 autosomal recessive) were evaluated with spectral-domain optical coherence tomography (SD OCT) and fundus autofluorescence (FAF). Diagnoses of CSNB2 and RP were confirmed by full-field electroretinography (ERG). Manual segmentation of retinal layers, aided by a computer program, was performed by 2 professional segmenters on SD OCT images of all CSNB2 patients and 4 age-similar, normal myopic controls. Seven patients were screened for mutations with congenital stationary night blindness and RP genotyping arrays. RESULTS Patients with CSNB2 had specific findings on SD OCT and FAF that were distinct from those found in RP. CSNB2 patients showed qualitatively normal SD OCT results with preserved photoreceptor inner segment/outer segment junction, whereas this junction was lost in RP patients. In addition, CSNB2 patients had normal FAF images, whereas patients with RP demonstrated a ring of increased autofluorescence around the macula. On SD OCT segmentation, the inner and outer retinal layers of both X-linked recessive and autosomal recessive CSNB2 patients were thinner compared with those of normal myopic controls, with means generally outside of normal 95% confidence intervals. The only layers that demonstrated similar thickness between CSNB2 patients and the controls were the retinal nerve fiber layer and, temporal to the fovea, the combined outer segment layer and retinal pigment epithelium. A proband and his 2 affected brothers from a family segregating X-linked recessive CSNB2 had a mutation, p.R614X, in the gene encoding calcium channel, α 1F subunit. CONCLUSIONS CSNB2 patients (X-linked recessive and autosomal recessive) had significantly thinner retinas than myopic controls. However, they demonstrated qualitatively normal SD OCT and FAF images, and therefore can be differentiated from RP patients with these techniques. Although ERG testing remains the gold standard for the diagnosis of these conditions, FAF and SD OCT systems are more widely available to community ophthalmologists, offer shorter acquisition times, and, unlike ERG, can be performed on the same day as the initial clinic visit. Therefore, as a supplement to ERG and genetic testing, we advocate the use of FAF and SD OCT in the examination of patients with CSNB2 and RP. PMID:21920492

Structural analysis of retinal photoreceptor ellipsoid zone and postreceptor retinal layer associated with visual acuity in patients with retinitis pigmentosa by ganglion cell analysis combined with OCT imaging

PubMed Central

Liu, Guodong; Li, Hui; Liu, Xiaoqiang; Xu, Ding; Wang, Fang

2016-01-01

Abstract The aim of this study was to examine changes in photoreceptor ellipsoid zone (EZ) and postreceptor retinal layer in retinitis pigmentosa (RP) patients by ganglion cell analysis (GCA) combined with optical coherence tomography (OCT) imaging to evaluate the structure–function relationships between retinal layer changes and best corrected visual acuity (BCVA). Sixty-eight eyes of 35 patients with RP and 65 eyes of 35 normal controls were analyzed in the study. The average length of EZ was 911.1 ± 208.8 μm in RP patients, which was shortened with the progression of the disease on the OCT images. The average ganglion cell–inner plexiform layer thickness (GCIPLT) was 54.7 ± 18.9 μm in RP patients, while in normal controls it was 85.6 ± 6.8 μm. The GCIPLT in all quarters became significantly thinner along with outer retinal thinning. There was a significantly positive correlation between BCVA and EZ (r = −0.7622, P < 0.001) and GCIPLT (r = −0.452, P < 0.001). Therefore, we assess the retinal layer changes from a new perspective in RP patients, which suggests that EZ and GCIPLT obtained by GCA combined with OCT imaging are the direct and valid indicators to diagnosis and predict the pathological process of RP. PMID:28033301

SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY FINDINGS IN MACULA-INVOLVING CYTOMEGALOVIRUS RETINITIS.

PubMed

Gupta, Mrinali P; Patel, Sarju; Orlin, Anton; Marlow, Elizabeth; Chee, Ru-Ik; Nadelmann, Jennifer; Chan, R V Paul; DʼAmico, Donald J; Kiss, Szilard

2018-05-01

To evaluate the microstructural features of cytomegalovirus (CMV) retinitis by spectral domain optical coherence tomography (OCT). Subjects were patients with macula-involving CMV retinitis with OCT imaging. The leading edge of retinitis in the macula was identified based on fundus imaging, and OCT findings were longitudinally evaluated in three areas: within the area of active retinitis, at the leading edge of retinitis, and just beyond the leading edge of retinitis. Optical coherence tomography imaging of macular CMV retinitis identified vitreous cells in 10 eyes (100%), posterior vitreous detachment in four eyes (40%), broad-based vitreomacular traction in one eye (10%), epiretinal membrane in eight eyes (80%), and lamellar hole-associated epiretinal proliferation associated with an atrophic hole in one eye (10%). Retinal architectural disruption, disruption of inner retinal layers, disruption of the external limiting membrane, and ellipsoid zone abnormalities were noted within the area of retinitis in all eyes and decreased in frequency and severity at and beyond the leading edge of retinitis, although all 10 eyes (100%) exhibited one of these abnormalities, especially outer retinal microabnormalities, beyond the leading edge of retinitis. Microstructural abnormalities were frequently noted on OCT of CMV retinitis, including within the retina beyond the leading edge of retinitis identified by corresponding fundus imaging. Outer retinal abnormalities were noted more frequently than inner retinal abnormalities beyond the leading edge of retinitis. These findings provide insight into the effects of CMV retinitis on retinal microstructure and potentially on vision and highlight the potential utility of OCT for monitoring microprogression of macula-involving CMV retinitis.

Biological effects of blocking blue and other visible light on the mouse retina.

PubMed

Narimatsu, Toshio; Ozawa, Yoko; Miyake, Seiji; Kubota, Shunsuke; Yuki, Kenya; Nagai, Norihiro; Tsubota, Kazuo

2014-08-01

To elucidate the biological effects of blocking fluorescent light on the retina using specific blocking materials. Seven- to 8-week-old BALB/c mice were divided into three groups and placed in one of the three boxes: one blocked ultraviolet and violet wavelengths of light (violet blockade), one blocked ultraviolet, violet, blue and some other visible wavelengths (blue-plus blockade), and one allowed most visible light to pass through (control). They were then exposed to a white fluorescent lamp for 1 h at 5.65E-05 mW/cm(2) /s. After treatment, the electroretinogram, retinal outer nuclear layer thickness and retinal outer segment length were measured. In addition, retinal apoptotic cells were quantified by TdT-mediated dUTP nick-end labelling assay and c-Fos messenger RNA, and protein levels were measured by real-time reverse-transcription polymerase chain reaction and immunoblot analyses, respectively. The blue-plus blockade group retained a significantly better electroretinogram response following light exposure than the control or violet blockade groups. The blue-plus blockade group also exhibited greater outer nuclear layer thickness and greater outer-segment length, and fewer apoptotic cells after light exposure than the other groups. The c-Fos messenger RNA and protein levels were substantially reduced in the blue-plus blockade group and reduced to a lesser extent in the violet blockade group. The blockade of blue plus additional visible wavelengths of light was most effective in protecting the retina from light-induced damage. The blockade of violet light alone was also effective in reducing intracellular molecular responses, but these effects were not sufficient for attenuating retinal degeneration. © 2013 Royal Australian and New Zealand College of Ophthalmologists.

Fundus autofluorescence and optical coherence tomographic findings in acute zonal occult outer retinopathy.

PubMed

Fujiwara, Takamitsu; Imamura, Yutaka; Giovinazzo, Vincent J; Spaide, Richard F

2010-09-01

The purpose of this study was to investigate the fundus autofluorescence and optical coherence tomography findings in eyes with acute zonal occult outer retinopathy (AZOOR). A retrospective observational case series of the fundus autofluorescence and spectral domain optical coherence tomography in a series of patients with AZOOR. There were 19 eyes of 11 patients (10 women), who had a mean age of 49.1 +/- 13.9 years. Fundus autofluorescence abnormalities were seen in 17 of the 19 eyes, were more common in the peripapillary area, and were smaller in extent than the optical coherence tomography abnormalities. Nine eyes showed progression of hypoautofluorescence area during the mean follow-up of 69.7 months. The mean thickness of the photoreceptor layer at fovea was 177 microm in eyes with AZOOR, which was significantly thinner than controls (193 microm, P = 0.049). Abnormal retinal laminations were found in 12 eyes and were located over areas of loss of the photoreceptors. The subfoveal choroidal thickness was 243 microm, which is normal. Fundus autofluorescence abnormalities in AZOOR showed distinct patterns of retinal pigment epithelial involvement, which may be progressive. Thinning of photoreceptor cell layer with loss of the outer segments and abnormal inner retinal lamination in the context of a normal choroid are commonly found in AZOOR.

Comparison of spectral-domain optical coherence tomography for intra-retinal layers thickness measurements between healthy and diabetic eyes among Chinese adults

PubMed Central

Li, Shu-ting; Wang, Xiang-ning; Du, Xin-hua; Wu, Qiang

2017-01-01

Purpose To compare intra-retinal layer thickness measurements between eyes with no or mild diabetic retinopathy (DR) and age-matched controls using Spectralis spectral-domain optical coherence tomography (SD-OCT). Methods Cross-sectional observational analysis study. High-resolution macular volume scans (30° * 25°) were obtained for 133 type 2 diabetes mellitus (T2DM) patients with no DR, 42 T2DM patients with mild DR and 115 healthy controls. The mean thickness was measured in all 9 Early Treatment Diabetic Retinopathy Study (ETDRS) sectors for 8 separate layers, inner retinal layer (IRL), outer retinal layer (ORL) and total retina (TR), after automated segmentation. The ETDRS grid consisted of three concentric circles of 1-, 3-, and 6-mm diameter. The superior, inferior, temporal, and nasal sectors of the 3- and 6-mm circles were respectively designated as S3, I3, T3, and N3 and S6, I6, T6, and N6. Linear regression analyses were conducted to evaluate the associations between the intra-retinal layer thicknesses, age, diabetes duration, fasting blood glucose and HbA1c. Results The mean age and duration of T2DM were 61.1 and 13.7 years, respectively. Although no significant differences in the average TR and ORL volumes were observed among the groups, significant differences were found in the volume and sectorial thicknesses of the inner plexiform layer (IPL), outer plexiform layer (OPL) and IRL among the groups. In particular, the thicknesses of the IPL (S3, T3, S6, I6 and T6 sectors) and the IRL (S6 sector) were decreased in the no-DR group compared with the controls (P < 0.05). The thickness of the OPL (S3, N3, S6 and N6 sectors) was thinner in the no-DR group than in mild DR (P < 0.05). The average IPL thickness was significantly negatively correlated with age and the duration of diabetes. Conclusion The assessment of the intra-retinal layer thickness showed a significant decrease in the IPL and IRL thicknesses in Chinese adults with T2DM, even in the absence of visible microvascular signs of DR. PMID:28493982

Correlation of outer nuclear layer thickness with cone density values in patients with retinitis pigmentosa and healthy subjects.

PubMed

Menghini, Moreno; Lujan, Brandon J; Zayit-Soudry, Shiri; Syed, Reema; Porco, Travis C; Bayabo, Kristine; Carroll, Joseph; Roorda, Austin; Duncan, Jacque L

2014-12-16

We studied the correlation between outer nuclear layer (ONL) thickness and cone density in normal eyes and eyes with retinitis pigmentosa (RP). Spectral-domain optical coherence tomography (SD-OCT) scans were acquired using a displaced pupil entry position of the scanning beam to distinguish Henle's fiber layer from the ONL in 20 normal eyes (10 subjects) and 12 eyes with RP (7 patients). Cone photoreceptors were imaged using adaptive optics scanning laser ophthalmoscopy. The ONL thickness and cone density were measured at 0.5° intervals along the horizontal meridian through the fovea nasally and temporally. The ONL thickness and cone density were correlated using Spearman's rank correlation coefficient r. Cone densities averaged over the central 6° were lower in eyes with RP than normal, but showed high variability in both groups. The ONL thickness and cone density were significantly correlated when all retinal eccentricities were combined (r = 0.74); the correlation for regions within 0.5° to 1.5° eccentricity was stronger (r = 0.67) than between 1.5° and 3.0° eccentricity (r = 0.23). Although cone densities were lower between 0.5° and 1.5° in eyes with RP, ONL thickness measures at identical retinal locations were similar in the two groups (P = 0.31), and interindividual variation was high for ONL and cone density measures. Although ONL thickness and retinal eccentricity were important predictors of cone density, eccentricity was over 3 times more important. The ONL thickness and cone density were correlated in normal eyes and eyes with RP, but both were strongly correlated with retinal eccentricity, precluding estimation of cone density from ONL thickness. (ClinicalTrials.gov number, NCT00254605.). Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc.

Correlation of Outer Nuclear Layer Thickness With Cone Density Values in Patients With Retinitis Pigmentosa and Healthy Subjects

PubMed Central

Menghini, Moreno; Lujan, Brandon J.; Zayit-Soudry, Shiri; Syed, Reema; Porco, Travis C.; Bayabo, Kristine; Carroll, Joseph; Roorda, Austin; Duncan, Jacque L.

2015-01-01

Purpose. We studied the correlation between outer nuclear layer (ONL) thickness and cone density in normal eyes and eyes with retinitis pigmentosa (RP). Methods. Spectral-domain optical coherence tomography (SD-OCT) scans were acquired using a displaced pupil entry position of the scanning beam to distinguish Henle's fiber layer from the ONL in 20 normal eyes (10 subjects) and 12 eyes with RP (7 patients). Cone photoreceptors were imaged using adaptive optics scanning laser ophthalmoscopy. The ONL thickness and cone density were measured at 0.5° intervals along the horizontal meridian through the fovea nasally and temporally. The ONL thickness and cone density were correlated using Spearman's rank correlation coefficient r. Results. Cone densities averaged over the central 6° were lower in eyes with RP than normal, but showed high variability in both groups. The ONL thickness and cone density were significantly correlated when all retinal eccentricities were combined (r = 0.74); the correlation for regions within 0.5° to 1.5° eccentricity was stronger (r = 0.67) than between 1.5° and 3.0° eccentricity (r = 0.23). Although cone densities were lower between 0.5° and 1.5° in eyes with RP, ONL thickness measures at identical retinal locations were similar in the two groups (P = 0.31), and interindividual variation was high for ONL and cone density measures. Although ONL thickness and retinal eccentricity were important predictors of cone density, eccentricity was over 3 times more important. Conclusions. The ONL thickness and cone density were correlated in normal eyes and eyes with RP, but both were strongly correlated with retinal eccentricity, precluding estimation of cone density from ONL thickness. (ClinicalTrials.gov number, NCT00254605.) PMID:25515570

Spectral domain optical coherence tomography findings in tamoxifen retinopathy--a case report.

PubMed

Nair, Sandhya Narayanan; Anantharaman, Giridhar; Gopalakrishnan, Mahesh; Vyas, Jyothiprakash

2013-01-01

To report spectral domain optical coherence tomography findings in a case of typical tamoxifen retinopathy. In this observational case report, a patient with tamoxifen retinopathy was imaged with spectral domain optical coherence tomography and fundus auto fluorescence. Spectral domain optical coherence tomography showed numerous hyperreflective spots within the retina, mainly in the inner retinal layers in both the eyes. The external limiting membrane, the Inner Segment-Outer Segment junction, and the photoreceptors were not discernable at the fovea in the right eye. In the left eye, there was foveal atrophy with total loss of photoreceptors. The autofluorescent images showed macular hypofluorescence with foveal hyperfluorescence. Spectral domain optical coherence tomography demonstrated abnormalities in the outer retinal layers in tamoxifen retinopathy. There were also characteristic alterations in the autofluorescence pattern at the macula in tamoxifen retinopathy.

The Involvement of the Oxidative Stress in Murine Blue LED Light-Induced Retinal Damage Model.

PubMed

Nakamura, Maho; Kuse, Yoshiki; Tsuruma, Kazuhiro; Shimazawa, Masamitsu; Hara, Hideaki

2017-01-01

The aim of study was to establish a mouse model of blue light emitting diode (LED) light-induced retinal damage and to evaluate the effects of the antioxidant N-acetylcysteine (NAC). Mice were exposed to 400 or 800 lx blue LED light for 2 h, and were evaluated for retinal damage 5 d later by electroretinogram amplitude and outer nuclear layer (ONL) thickness. Additionally, we investigated the effect of blue LED light exposure on shorts-wave-sensitive opsin (S-opsin), and rhodopsin expression by immunohistochemistry. Blue LED light induced light intensity dependent retinal damage and led to collapse of S-opsin and altered rhodopsin localization from inner and outer segments to ONL. Conversely, NAC administered at 100 or 250 mg/kg intraperitoneally twice a day, before dark adaptation and before light exposure. NAC protected the blue LED light-induced retinal damage in a dose-dependent manner. Further, blue LED light-induced decreasing of S-opsin levels and altered rhodopsin localization, which were suppressed by NAC. We established a mouse model of blue LED light-induced retinal damage and these findings indicated that oxidative stress was partially involved in blue LED light-induced retinal damage.

Progranulin, a Major Secreted Protein of Mouse Adipose-Derived Stem Cells, Inhibits Light-Induced Retinal Degeneration

PubMed Central

Tsuruma, Kazuhiro; Yamauchi, Mika; Sugitani, Sou; Otsuka, Tomohiro; Ohno, Yuta; Nagahara, Yuki; Ikegame, Yuka; Shimazawa, Masamitsu; Yoshimura, Shinichi; Iwama, Toru

2014-01-01

Adipose tissue stromal vascular fraction contains mesenchymal stem cells, which show protective effects when administered to damaged tissues, mainly through secreted trophic factors. We examined the protective effects of adipose-derived stem cells (ASCs) and ASC-conditioned medium (ASC-CM) against retinal damage and identified the neuroprotective factors in ASC-CM. ASCs and mature adipocytes were isolated from mouse subcutaneous tissue. ASCs were injected intravitreally in a mouse model of light-induced retinal damage, and ASC injection recovered retinal function as measured by electroretinogram and inhibited outer nuclear layer, thinning, without engraftment of ASCs. ASC-CM and mature adipocyte-conditioned medium were collected after 72 hours of culture. In vitro, H2O2- and light-induced cell death was reduced in a photoreceptor cell line with ASC-CM but not with mature adipocyte-conditioned medium. In vivo, light-induced photoreceptor damage was evaluated by measurement of outer nuclear layer thickness at 5 days after light exposure and by electroretinogram recording. ASC-CM significantly inhibited photoreceptor degeneration and retinal dysfunction after light exposure. Progranulin was identified as a major secreted protein of ASCs that showed protective effects against retinal damage in vitro and in vivo. Furthermore, progranulin phosphorylated extracellular signal-regulated kinase, cAMP response element binding protein, and hepatocyte growth factor receptor, and protein kinase C signaling pathways were involved in the protective effects of progranulin. These findings suggest that ASC-CM and progranulin have neuroprotective effects in the light-induced retinal-damage model. Progranulin may be a potential target for the treatment of the degenerative diseases of the retina. PMID:24233842

Progranulin, a major secreted protein of mouse adipose-derived stem cells, inhibits light-induced retinal degeneration.

PubMed

Tsuruma, Kazuhiro; Yamauchi, Mika; Sugitani, Sou; Otsuka, Tomohiro; Ohno, Yuta; Nagahara, Yuki; Ikegame, Yuka; Shimazawa, Masamitsu; Yoshimura, Shinichi; Iwama, Toru; Hara, Hideaki

2014-01-01

Adipose tissue stromal vascular fraction contains mesenchymal stem cells, which show protective effects when administered to damaged tissues, mainly through secreted trophic factors. We examined the protective effects of adipose-derived stem cells (ASCs) and ASC-conditioned medium (ASC-CM) against retinal damage and identified the neuroprotective factors in ASC-CM. ASCs and mature adipocytes were isolated from mouse subcutaneous tissue. ASCs were injected intravitreally in a mouse model of light-induced retinal damage, and ASC injection recovered retinal function as measured by electroretinogram and inhibited outer nuclear layer, thinning, without engraftment of ASCs. ASC-CM and mature adipocyte-conditioned medium were collected after 72 hours of culture. In vitro, H2O2- and light-induced cell death was reduced in a photoreceptor cell line with ASC-CM but not with mature adipocyte-conditioned medium. In vivo, light-induced photoreceptor damage was evaluated by measurement of outer nuclear layer thickness at 5 days after light exposure and by electroretinogram recording. ASC-CM significantly inhibited photoreceptor degeneration and retinal dysfunction after light exposure. Progranulin was identified as a major secreted protein of ASCs that showed protective effects against retinal damage in vitro and in vivo. Furthermore, progranulin phosphorylated extracellular signal-regulated kinase, cAMP response element binding protein, and hepatocyte growth factor receptor, and protein kinase C signaling pathways were involved in the protective effects of progranulin. These findings suggest that ASC-CM and progranulin have neuroprotective effects in the light-induced retinal-damage model. Progranulin may be a potential target for the treatment of the degenerative diseases of the retina.

Mapping of photoreceptor dysfunction using high resolution three-dimensional spectral optical coherence tomography

NASA Astrophysics Data System (ADS)

Sikorski, B. L.; Szkulmowski, M.; Kałużny, J. J.; Bajraszewski, T.; Kowalczyk, A.; Wojtkowski, M.

2008-02-01

The ability to obtain reliable information on functional status of photoreceptor layer is essential for assessing vision impairment in patients with macular diseases. The reconstruction of three-dimensional retinal structure in vivo using Spectral Optical Coherence Tomography (Spectral OCT) became possible with a recent progress of the OCT field. Three-dimensional data collected by Spectral OCT devices comprise information on light intensity back-reflected from the junction between photoreceptor outer and inner segments (IS/OS) and thus can be used for evaluating photoreceptors impairment. In this paper, we introduced so called Spectral OCT reflectivity maps - a new method of selecting and displaying the spatial distribution of reflectivity of individual retinal layers. We analyzed the reflectivity of the IS/OS layer in various macular diseases. We have measured eyes of 49 patients with photoreceptor dysfunction in course of age-related macular degeneration, macular holes, central serous chorioretinopathy, acute zonal occult outer retinopathy, multiple evanescent white dot syndrome, acute posterior multifocal placoid pigment epitheliopathy, drug-induced retinopathy and congenital disorders.

Bilateral foveal retinoschisis accompanying unilateral peripheral retinoschisis.

PubMed

Kocak, Nilufer; Ozturk, Taylan A; Kaynak, Suleyman

2014-04-01

X-linked juvenile retinoschisis is a rare hereditary retinal disease characterized by a tangential splitting of the neurosensory retina which may cause early-onset visual impairment. Existence of the retinal neurosensory layer splitting on cross-sectional images of optical coherance tomography (OCT) and the absence of leakage on fluorescein angiography (FA) help confirming the diagnosis. Such diagnostic tests are also helpful in determining the management of the disease. However, most of the retinoschisis cavities remain stable and rarely extend to the posterior pole, many authors suggest laser prophylaxis to avoid the potential risk of retinal detachment due to holes in the outer retinal layer. Herein, we report a case with bilateral foveal retinoschisis accompanying unilateral peripheral retinoschisis who was evaluated with detailed ophthalmologic examination. Visual acuity, fundoscopy, OCT, and FA remained stable in the second year of follow-up after prophylactic argon laser treatment.

SD-OCT stages of progression of type 2 macular telangiectasia in a patient followed for 3 years.

PubMed

Coscas, Gabriel; Coscas, Florence; Zucchiatti, Ilaria; Bandello, Francesco; Soubrane, Gisele; SouÏed, Eric

2013-01-01

To describe the natural course of type 2 idiopathic macular telangiectasia (MT) using spectral-domain optical coherence tomography (SD-OCT). Analysis of the different stages of progression of type 2 MT during a period of 3 years using multimodal imaging, including SD-OCT correlated with angiographic and autofluorescence images. The analysis of the different steps was obtained initially from the first eye, then successively from the fellow eye when progressive changes appeared. The earliest visible alteration at SD-OCT was the interruption of the interface between inner segment and ellipsoid (IS/EL) (stage 1). The second stage was characterized by the complete interruption of both IS/EL interface and external limiting membrane (stage 2). At the next step, a wide disruption of the outer nuclear layer was noted (stage 3). The fourth stage showed a complete disorganization of the inner layers with aspect of fusion of the inner retinal layers associated with progressive atrophy of the outer layers (stage 4). Hyper-reflective deposits were found in both the internal and external retinal layers (stage 5). Small intraretinal cystoid spaces appeared in the different retinal layers (stage 6). This last feature was an earlier manifestation of the typical intraretinal cysts that are the well-known OCT appearance of type 2 MT. We describe the 6 steps of progression from earlier SD-OCT findings that led to a complete disorganization and fusion of the inner layers (probably due to changes in the Müller cells) to the typical intraretinal cysts.

Quantification of Peripapillary Sparing and Macular Involvement in Stargardt Disease (STGD1)

PubMed Central

Rhee, David W.; Smith, R. Theodore; Tsang, Stephen H.; Allikmets, Rando; Chang, Stanley; Lazow, Margot A.; Hood, Donald C.; Greenstein, Vivienne C.

2011-01-01

Purpose. To quantify and compare structure and function across the macula and peripapillary area in Stargardt disease (STGD1). Methods. Twenty-seven patients (27 eyes) and 12 age-similar controls (12 eyes) were studied. Patients were classified on the basis of full-field electroretinogram (ERG) results. Fundus autofluorescence (FAF) and spectral domain-optical coherence tomography (SD-OCT) horizontal line scans were obtained through the fovea and peripapillary area. The thicknesses of the outer nuclear layer plus outer plexiform layer (ONL+), outer segment (OS), and retinal pigment epithelium (RPE) were measured through the fovea, and peripapillary areas from 1° to 4° temporal to the optic disc edge using a computer-aided, manual segmentation technique. Visual sensitivities in the central 10° were assessed using microperimetry and related to retinal layer thicknesses. Results. Compared to the central macula, the differences between controls and patients in ONL+, OS, and RPE layer thicknesses were less in the nasal and temporal macula. Relative sparing of the ONL+ and/or OS layers was detected in the nasal (i.e., peripapillary) macula in 8 of 13 patients with extramacular disease on FAF; relative functional sparing was also detected in this subgroup. All 14 patients with disease confined to the central macula, as detected on FAF, showed ONL+ and OS layer thinning in regions of normal RPE thickness. Conclusions. Relative peripapillary sparing was detected in STGD1 patients with extramacular disease on FAF. Photoreceptor thinning may precede RPE degeneration in STGD1. PMID:21873672

Stimulus-evoked outer segment changes in rod photoreceptors

NASA Astrophysics Data System (ADS)

Zhao, Xiaohui; Thapa, Damber; Wang, Benquan; Lu, Yiming; Gai, Shaoyan; Yao, Xincheng

2016-06-01

Rod-dominated transient retinal phototropism (TRP) has been recently observed in freshly isolated mouse and frog retinas. Comparative confocal microscopy and optical coherence tomography revealed that the TRP was predominantly elicited from the rod outer segment (OS). However, the biophysical mechanism of rod OS dynamics is still unknown. Mouse and frog retinal slices, which displayed a cross-section of retinal photoreceptors and other functional layers, were used to test the effect of light stimulation on rod OSs. Time-lapse microscopy revealed stimulus-evoked conformational changes of rod OSs. In the center of the stimulated region, the length of the rod OS shrunk, while in the peripheral region, the rod OS swung toward the center region. Our experimental observation and theoretical analysis suggest that the TRP may reflect unbalanced rod disc-shape changes due to localized visible light stimulation.

Stimulus-evoked outer segment changes in rod photoreceptors

PubMed Central

Zhao, Xiaohui; Thapa, Damber; Wang, Benquan; Lu, Yiming; Gai, Shaoyan; Yao, Xincheng

2016-01-01

Abstract. Rod-dominated transient retinal phototropism (TRP) has been recently observed in freshly isolated mouse and frog retinas. Comparative confocal microscopy and optical coherence tomography revealed that the TRP was predominantly elicited from the rod outer segment (OS). However, the biophysical mechanism of rod OS dynamics is still unknown. Mouse and frog retinal slices, which displayed a cross-section of retinal photoreceptors and other functional layers, were used to test the effect of light stimulation on rod OSs. Time-lapse microscopy revealed stimulus-evoked conformational changes of rod OSs. In the center of the stimulated region, the length of the rod OS shrunk, while in the peripheral region, the rod OS swung toward the center region. Our experimental observation and theoretical analysis suggest that the TRP may reflect unbalanced rod disc-shape changes due to localized visible light stimulation. PMID:27334933

Progression of neuronal and synaptic remodeling in the rd10 mouse model of retinitis pigmentosa.

PubMed

Phillips, M Joseph; Otteson, Deborah C; Sherry, David M

2010-06-01

The Pde6b(rd10) (rd10) mouse has a moderate rate of photoreceptor degeneration and serves as a valuable model for human autosomal recessive retinitis pigmentosa (RP). We evaluated the progression of neuronal remodeling of second- and third-order retinal cells and their synaptic terminals in retinas from Pde6b(rd10) (rd10) mice at varying stages of degeneration ranging from postnatal day 30 (P30) to postnatal month 9.5 (PNM9.5) using immunolabeling for well-known cell- and synapse-specific markers. Following photoreceptor loss, changes occurred progressively from outer to inner retina. Horizontal cells and rod and cone bipolar cells underwent morphological remodeling that included loss of dendrites, cell body migration, and the sprouting of ectopic processes. Gliosis, characterized by translocation of Müller cell bodies to the outer retina and thickening of their processes, was evident by P30 and became more pronounced as degeneration progressed. Following rod degeneration, continued expression of VGluT1 in the outer retina was associated with survival and expression of synaptic proteins by nearby second-order neurons. Rod bipolar cell terminals showed a progressive reduction in size and ectopic bipolar cell processes extended into the inner nuclear layer and ganglion cell layer by PNM3.5. Putative ectopic conventional synapses, likely arising from amacrine cells, were present in the inner nuclear layer by PNM9.5. Despite these changes, the laminar organization of bipolar and amacrine cells and the ON-OFF organization in the inner plexiform layer was largely preserved. Surviving cone and bipolar cell terminals continued to express the appropriate cell-specific presynaptic proteins needed for synaptic function up to PNM9.5. (c) 2010 Wiley-Liss, Inc.

Progression of Neuronal and Synaptic Remodeling in the rd10 Mouse Model of Retinitis Pigmentosa

PubMed Central

Phillips, M. Joseph; Otteson, Deborah C.; Sherry, David M.

2010-01-01

The Pde6brd10 (rd10) mouse has a moderate rate of photoreceptor degeneration and serves as a valuable model for human autosomal recessive retinitis pigmentosa (RP). We evaluated the progression of neuronal remodeling of second- and third-order retinal cells and their synaptic terminals in retinas from Pde6brd10 (rd10) mice at varying stages of degeneration ranging from postnatal day 30 (P30) to postnatal month 9.5 (PNM9.5) using immunolabeling for well known cell- and synapse-specific markers. Following photoreceptor loss, changes occurred progressively from outer to inner retina. Horizontal cells and rod and cone bipolar cells underwent morphological remodeling that included loss of dendrites, cell body migration, and the sprouting of ectopic processes. Gliosis, characterized by translocation of Müller cell bodies to the outer retina and thickening of their processes, was evident by P30 and became more pronounced as degeneration progressed. Following rod degeneration, continued expression of VGluT1 in the outer retina was associated with survival and expression of synaptic proteins by nearby second-order neurons. Rod bipolar cell terminals showed a progressive reduction in size and ectopic bipolar cell processes extended into the inner nuclear layer and ganglion cell layer by PNM3.5. Putative ectopic conventional synapses, likely arising from amacrine cells, were present in the inner nuclear layer by PNM9.5. Despite these changes, the laminar organization of bipolar and amacrine cells and the ON-OFF organization in the inner plexiform layer was largely preserved. Surviving cone and bipolar cell terminals continued to express the appropriate cell-specific presynaptic proteins needed for synaptic function up to PNM9.5. PMID:20394059

Communications between intraretinal and subretinal space on optical coherence tomography of neurosensory retinal detachment in diabetic macular edema

PubMed Central

Gupta, Aditi; Raman, Rajiv; Mohana, KP; Kulothungan, Vaitheeswaran; Sharma, Tarun

2013-01-01

Background: The pathogenesis of development and progression of neurosensory retinal detachment (NSD) in diabetic macular edema (DME) is not yet fully understood. The purpose of this study is to describe the spectral domain optical coherence tomography (SD-OCT) morphological characteristics of NSD associated with DME in the form of outer retinal communications and to assess the correlation between the size of communications and various factors. Materials and Methods: This was an observational retrospective nonconsecutive case series in a tertiary care eye institute. We imaged NSD and outer retinal communications in 17 eyes of 16 patients having NSD associated with DME using SD-OCT. We measured manually the size of the outer openings of these communications and studied its correlation with various factors. Statistical analysis (correlation test) was performed using the Statistical Package for Social Sciences (SPSS) software (version 14.0). The main outcome measures were correlation of the size of communications with dimensions of NSD, presence of subretinal hyper-reflective dots, and best-corrected visual acuity (BCVA). Results: The communications were seen as focal defects of the outer layers of elevated retina. With increasing size of communication, there was increase in height of NSD (r = 0.701, P = 0.002), horizontal diameter of NSD (r = 0.695, P = 0.002), and the number of hyper-reflective dots in the subretinal space (r = 0.729, P = 0.002). The minimum angle of resolution (logMAR) BCVA increased with the increasing size of communications (r = 0.827, P < 0.0001). Conclusions: Outer retinal communications between intra and subretinal space were noted in eyes having NSD associated with DME. The size of communications correlated positively with the size of NSD and subretinal detachment space hyper-reflective dots, and inversely with BCVA. PMID:24379554

Communications between intraretinal and subretinal space on optical coherence tomography of neurosensory retinal detachment in diabetic macular edema.

PubMed

Gupta, Aditi; Raman, Rajiv; Mohana, Kp; Kulothungan, Vaitheeswaran; Sharma, Tarun

2013-09-01

The pathogenesis of development and progression of neurosensory retinal detachment (NSD) in diabetic macular edema (DME) is not yet fully understood. The purpose of this study is to describe the spectral domain optical coherence tomography (SD-OCT) morphological characteristics of NSD associated with DME in the form of outer retinal communications and to assess the correlation between the size of communications and various factors. This was an observational retrospective nonconsecutive case series in a tertiary care eye institute. We imaged NSD and outer retinal communications in 17 eyes of 16 patients having NSD associated with DME using SD-OCT. We measured manually the size of the outer openings of these communications and studied its correlation with various factors. Statistical analysis (correlation test) was performed using the Statistical Package for Social Sciences (SPSS) software (version 14.0). The main outcome measures were correlation of the size of communications with dimensions of NSD, presence of subretinal hyper-reflective dots, and best-corrected visual acuity (BCVA). The communications were seen as focal defects of the outer layers of elevated retina. With increasing size of communication, there was increase in height of NSD (r = 0.701, P = 0.002), horizontal diameter of NSD (r = 0.695, P = 0.002), and the number of hyper-reflective dots in the subretinal space (r = 0.729, P = 0.002). The minimum angle of resolution (logMAR) BCVA increased with the increasing size of communications (r = 0.827, P < 0.0001). Outer retinal communications between intra and subretinal space were noted in eyes having NSD associated with DME. The size of communications correlated positively with the size of NSD and subretinal detachment space hyper-reflective dots, and inversely with BCVA.

Mechanisms of Retinal Damage from Chronic Laser Radiation.

DTIC Science & Technology

1981-07-01

culture. The pigment epithelium is deter- mined to be almost equally susceptible to damage in vitro as in vivo and the same action spectrum is similar in...92 -97 D. Experiment III. Light Damage in Culture of Bovine Retinal Pigment Epithelium 1. Methodology a. Collection of Cells... epithelium : Mild form of damage. Figure 18 Inner segments severely damaged. Figure 19 : Cone pedicle after exposure. Figure 20 Outer plexiform layer

Subretinally transplanted embryonic stem cells rescue photoreceptor cells from degeneration in the RCS rats.

PubMed

Schraermeyer, U; Thumann, G; Luther, T; Kociok, N; Armhold, S; Kruttwig, K; Andressen, C; Addicks, K; Bartz-Schmidt, K U

2001-01-01

The Royal College of Surgeons (RCS) rat is an animal model for retinal degeneration such as the age-related macular degeneration. The RCS rat undergoes a progressive retinal degeneration during the early postnatal period. A potential treatment to prevent this retinal degeneration is the transplantation into the subretinal space of cells that would replace functions of the degenerating retinal pigment epithelium (RPE) cells or may form neurotrophic factors. In this study we have investigated the potential of subretinally transplanted embryonic stem cells to prevent the genetically determined photoreceptor cell degeneration in the RCS rat. Embryonic stem cells from the inner cell mass of the mouse blastocyst were allowed to differentiate to neural precursor cells in vitro and were then transplanted into the subretinal space of 20-day-old RCS rats. Transplanted and sham-operated rats were sacrificed 2 months following cell transplantation. The eyes were enucleated and photoreceptor degeneration was quantified by analyzing and determining the thickness of the outer nuclear layer by light and electron microscopy. In the eyes transplanted with embryonic cells up to 8 rows of photoreceptor cell nuclei were observed, whereas in nontreated control eyes the outer nuclear layer had degenerated completely. Transplantation of embryonic stem cells appears to delay photoreceptor cell degeneration in RCS rats.

Outer Retinal Tubulation in Degenerative Retinal Disorders

PubMed Central

Goldberg, Naomi R.; Greenberg, Jonathan P.; Laud, Ketan; Tsang, Stephen; Freund, K. Bailey

2013-01-01

Objective To demonstrate outer retinal tubulation (ORT) in various degenerative retinal disorders. Methods This was a retrospective review of the multimodal imaging of 29 eyes of 15 patients with various retinal dystrophies and inflammatory maculopathies manifesting ORT. The morphologic features of ORT and its evolution over time were analyzed using spectral-domain optical coherence tomography (SD-OCT) data. Results Outer retinal tubulation was identified as round or ovoid structures with hyper-reflective borders in pattern dystrophy (6 eyes), acute zonal occult outer retinopathy (5 eyes), retinitis pigmentosa (4 eyes), Stargardt disease (4 eyes), gyrate atrophy (2 eyes), choroideremia (2 eyes), and various other degenerative conditions. These structures appeared to develop from the invagination of photoreceptors at the junction of intact and atrophic outer retina. During follow-up, the number and distribution of ORT largely remained stable. As zones of atrophy enlarged, the frequency of ORT appeared to increase. The ORT structures were found in fewer than 10% of patients with retinitis pigmentosa, Stargardt, or pattern dystrophy. Conclusion Outer retinal tubulation is found in various degenerative retinal disorders that share in common damage to the outer retina and/or retinal pigment epithelium. The presence of ORT may be in an indicator of underlying disease stage and severity. PMID:23676993

Bilateral foveal retinoschisis accompanying unilateral peripheral retinoschisis

PubMed Central

Kocak, Nilufer; Ozturk, Taylan A; Kaynak, Suleyman

2014-01-01

X-linked juvenile retinoschisis is a rare hereditary retinal disease characterized by a tangential splitting of the neurosensory retina which may cause early-onset visual impairment. Existence of the retinal neurosensory layer splitting on cross-sectional images of optical coherance tomography (OCT) and the absence of leakage on fluorescein angiography (FA) help confirming the diagnosis. Such diagnostic tests are also helpful in determining the management of the disease. However, most of the retinoschisis cavities remain stable and rarely extend to the posterior pole, many authors suggest laser prophylaxis to avoid the potential risk of retinal detachment due to holes in the outer retinal layer. Herein, we report a case with bilateral foveal retinoschisis accompanying unilateral peripheral retinoschisis who was evaluated with detailed ophthalmologic examination. Visual acuity, fundoscopy, OCT, and FA remained stable in the second year of follow-up after prophylactic argon laser treatment. PMID:23571248

Ultrahigh-Resolution Optical Coherence Tomography of Surgically Closed Macular Holes

PubMed Central

Ko, Tony H.; Witkin, Andre J.; Fujimoto, James G.; Chan, Annie; Rogers, Adam H.; Baumal, Caroline R.; Schuman, Joel S.; Drexler, Wolfgang; Reichel, Elias; Duker, Jay S.

2007-01-01

Objective To evaluate retinal anatomy using ultrahigh-resolution optical coherence tomography (OCT) in eyes after successful surgical repair of full-thickness macular hole. Methods Twenty-two eyes of 22 patients were diagnosed as having macular hole, underwent pars plana vitrectomy, and had flat/closed macular anatomy after surgery, as confirmed with biomicroscopic and OCT examination findings. An ultrahigh-resolution–OCT system developed for retinal imaging, with the capability to achieve approximately 3-μm axial resolution, was used to evaluate retinal anatomy after hole repair. Results Despite successful closure of the macular hole, all 22 eyes had macular abnormalities on ultrahigh-resolution–OCT images after surgery. These abnormalities were separated into the following 5 categories: (1) outer foveal defects in 14 eyes (64%), (2) persistent foveal detachment in 4 (18%), (3) moderately reflective foveal lesions in 12 (55%), (4) epiretinal membranes in 14 (64%), and (5) nerve fiber layer defects in 3 (14%). Conclusions With improved visualization of fine retinal architectural features, ultrahigh-resolution OCT can visualize persistent retinal abnormalities despite anatomically successful macular hole surgery. Outer foveal hyporeflective disruptions of the junction between the inner and outer segments of the photoreceptors likely represent areas of foveal photoreceptor degeneration. Moderately reflective lesions likely represent glial cell proliferation at the site of hole reapproximation. Thin epiretinal membranes do not seem to decrease visual acuity and may play a role in reestablishing foveal anatomy after surgery. PMID:16769836

High-Resolution Images of Retinal Structure in Patients with Choroideremia

PubMed Central

Syed, Reema; Sundquist, Sanna M.; Ratnam, Kavitha; Zayit-Soudry, Shiri; Zhang, Yuhua; Crawford, J. Brooks; MacDonald, Ian M.; Godara, Pooja; Rha, Jungtae; Carroll, Joseph; Roorda, Austin; Stepien, Kimberly E.; Duncan, Jacque L.

2013-01-01

Purpose. To study retinal structure in choroideremia patients and carriers using high-resolution imaging techniques. Methods. Subjects from four families (six female carriers and five affected males) with choroideremia (CHM) were characterized with best-corrected visual acuity (BCVA), kinetic and static perimetry, full-field electroretinography, and fundus autofluorescence (FAF). High-resolution macular images were obtained with adaptive optics scanning laser ophthalmoscopy (AOSLO) and spectral domain optical coherence tomography (SD-OCT). Coding regions of the CHM gene were sequenced. Results. Molecular analysis of the CHM gene identified a deletion of exons 9 to 15 in family A, a splice site mutation at position 79+1 of exon 1 in family B, deletion of exons 6 to 8 in family C, and a substitution at position 106 causing a premature stop in family D. BCVA ranged from 20/16 to 20/63 in carriers and from 20/25 to 5/63 in affected males. FAF showed abnormalities in all subjects. SD-OCT showed outer retinal layer loss, outer retinal tubulations at the margin of outer retinal loss, and inner retinal microcysts. Patchy cone loss was present in two symptomatic carriers. In two affected males, cone mosaics were disrupted with increased cone spacing near the fovea but more normal cone spacing near the edge of atrophy. Conclusions. High-resolution retinal images in CHM carriers and affected males demonstrated RPE and photoreceptor cell degeneration. As both RPE and photoreceptor cells were affected, these cell types may degenerate simultaneously in CHM. These findings provide insight into the effect of CHM mutations on macular retinal structure, with implications for the development of treatments for CHM. (ClinicalTrials.gov number, NCT00254605.) PMID:23299470

High-resolution images of retinal structure in patients with choroideremia.

PubMed

Syed, Reema; Sundquist, Sanna M; Ratnam, Kavitha; Zayit-Soudry, Shiri; Zhang, Yuhua; Crawford, J Brooks; MacDonald, Ian M; Godara, Pooja; Rha, Jungtae; Carroll, Joseph; Roorda, Austin; Stepien, Kimberly E; Duncan, Jacque L

2013-02-01

To study retinal structure in choroideremia patients and carriers using high-resolution imaging techniques. Subjects from four families (six female carriers and five affected males) with choroideremia (CHM) were characterized with best-corrected visual acuity (BCVA), kinetic and static perimetry, full-field electroretinography, and fundus autofluorescence (FAF). High-resolution macular images were obtained with adaptive optics scanning laser ophthalmoscopy (AOSLO) and spectral domain optical coherence tomography (SD-OCT). Coding regions of the CHM gene were sequenced. Molecular analysis of the CHM gene identified a deletion of exons 9 to 15 in family A, a splice site mutation at position 79+1 of exon 1 in family B, deletion of exons 6 to 8 in family C, and a substitution at position 106 causing a premature stop in family D. BCVA ranged from 20/16 to 20/63 in carriers and from 20/25 to 5/63 in affected males. FAF showed abnormalities in all subjects. SD-OCT showed outer retinal layer loss, outer retinal tubulations at the margin of outer retinal loss, and inner retinal microcysts. Patchy cone loss was present in two symptomatic carriers. In two affected males, cone mosaics were disrupted with increased cone spacing near the fovea but more normal cone spacing near the edge of atrophy. High-resolution retinal images in CHM carriers and affected males demonstrated RPE and photoreceptor cell degeneration. As both RPE and photoreceptor cells were affected, these cell types may degenerate simultaneously in CHM. These findings provide insight into the effect of CHM mutations on macular retinal structure, with implications for the development of treatments for CHM. (ClinicalTrials.gov number, NCT00254605.).

Disease expression in Usher syndrome caused by VLGR1 gene mutation (USH2C) and comparison with USH2A phenotype.

PubMed

Schwartz, Sharon B; Aleman, Tomas S; Cideciyan, Artur V; Windsor, Elizabeth A M; Sumaroka, Alexander; Roman, Alejandro J; Rane, Tej; Smilko, Elaine E; Bennett, Jean; Stone, Edwin M; Kimberling, William J; Liu, Xue-Zhong; Jacobson, Samuel G

2005-02-01

To investigate the retinal disease expression in USH2C, the subtype of Usher syndrome type 2 recently shown to be caused by mutation in the VLGR1 gene, and compare results with those from USH2A, a more common cause of Usher syndrome. Three siblings with USH2C and 14 patients with USH2A were studied. Visual function was measured by kinetic perimetry, static chromatic perimetry, and electroretinography (ERG). Central retinal microstructure was studied with optical coherence tomography (OCT). The siblings with VLGR1 mutation showed abnormal photoreceptor-mediated function in all retinal regions, and there was greater rod than cone dysfunction. USH2A had a wider spectrum of disease expression and included patients with normal function in some retinal regions. When abnormalities were detected, there was more rod than cone dysfunction. Retinal microstructure in both USH2C and USH2A shared the abnormality of loss of outer nuclear layer thickness. Central retinal structure in both genotypes was complicated by cystic macular lesions. A coincidental finding in an USH2C patient was that oral intake of antihistamines was associated with temporary resolution of the macular cystic change. USH2C and USH2A manifest photoreceptor disease with rod- and cone-mediated visual losses and thinning of the outer nuclear layer. An orderly progression through disease stages was estimated from cross-sectional and limited longitudinal data. Intrafamilial and interfamilial variation in retinal severity in USH2A, however, suggests that genetic or nongenetic modifiers may be involved in the disease expression.

MULTIMODAL IMAGING OF MOSAIC RETINOPATHY IN CARRIERS OF HEREDITARY X-LINKED RECESSIVE DISEASES.

PubMed

Wu, An-Lun; Wang, Jung-Pan; Tseng, Yun-Ju; Liu, Laura; Kang, Yu-Chuan; Chen, Kuan-Jen; Chao, An-Ning; Yeh, Lung-Kun; Chen, Tun-Lu; Hwang, Yih-Shiou; Wu, Wei-Chi; Lai, Chi-Chun; Wang, Nan-Kai

2018-05-01

To investigate the clinical features in carriers of X-linked retinitis pigmentosa, X-linked ocular albinism, and choroideremia (CHM) using multimodal imaging and to assess their diagnostic value in these three mosaic retinopathies. We prospectively examined 14 carriers of 3 X-linked recessive disorders (X-linked retinitis pigmentosa, X-linked ocular albinism, and CHM). Details of abnormalities of retinal morphology were evaluated using fundus photography, fundus autofluorescence (FAF) imaging, and spectral domain optical coherence tomography. In six X-linked retinitis pigmentosa carriers, fundus appearance varied from unremarkable to the presence of tapetal-like reflex and pigmentary changes. On FAF imaging, all carriers exhibited a bright radial reflex against a dark background. By spectral domain optical coherence tomography, loss of the ellipsoid zone in the macula was observed in 3 carriers (50%). Regarding the retinal laminar architecture, 4 carriers (66.7%) showed thinning of the outer nuclear layer and a dentate appearance of the outer plexiform layer. All five X-linked ocular albinism carriers showed a characteristic mud-splatter patterned fundus, dark radial streaks against a bright background on FAF imaging, and a normal-appearing retinal structure by spectral domain optical coherence tomography imaging. Two of the 3 CHM carriers (66.7%) showed a diffuse moth-eaten appearance of the fundus, and all 3 showed irregular hyper-FAF and hypo-FAF spots throughout the affected area. In the CHM carriers, the structural changes observed by spectral domain optical coherence tomography imaging were variable. Our findings in an Asian cohort suggest that FAF imaging is a practical diagnostic test for differentiating X-linked retinitis pigmentosa, X-linked ocular albinism, and CHM carriers. Wide-field FAF is an easy and helpful adjunct to testing for the correct diagnosis and identification of lyonization in carriers of these three mosaic retinopathies.

Human organotypic retinal flat-mount culture (HORFC) as a model for retinitis pigmentosa11.

PubMed

Azizzadeh Pormehr, Leila; Daftarian, Narsis; Ahmadian, Shahin; Rezaei Kanavi, Mozhgan; Ahmadieh, Hamid; Shafiezadeh, Mahshid

2018-05-10

The splicing factor PRPF31 is the most commonly mutated general splicing factor in the retinitis pigmentosa. We used a rapid, convenient and cost effective transfection method with an efficient PRPF31 knockdown in HORFC in order to study the effect of PRPF31 downregulation on retinal gene expressions in an ex vivo model. Modified calcium phosphate method was used to transfect HORFC by PRPF31 siRNA. Different times and doses of siRNA for transfection were assayed and optimum condition was obtained. PRPF31 mRNA and protein downregulation were assessed by qRTPCR and Western blot. The tissue viability of HORFC was measured using the MTT. ImageJ analysis on stained retinal sections by immunohistochemistry was used for thickness measurement of outer nuclear photoreceptor layer. The PRPF31 gene downregulation effects on retinal specific gene expression were analyzed by qRTPCR. A total of 50 nM of PRPF31 siRNA transfection after 63 h in HORFC, showed the optimum reduction in the level of PRPF31 mRNA and protein as shown by qRTPCR and Western blot (over 90% and 50% respectively). The PRPF31 mRNA silencing with calcium phosphate had no effect on cell viability in the period of the experiment. Thickness measurement of outer nuclear photoreceptor layer with IHC showed the significant reduction after 63 h of study (P value = 0.02). siRNA induced PRPF31 knockdown, led to reduction of retinal specific mRNA gene expression involved in phototransduction (RHO, GNAT1, RP1), photoreceptor structure (ROM1, FSCN2, CA4, SEMA4) and transcription factor (CRX) (fold change >5), after 63 h. © 2018 Wiley Periodicals, Inc.

Effects of alpha-lipoic acid on retinal ganglion cells, retinal thicknesses, and VEGF production in an experimental model of diabetes.

PubMed

Kan, Emrah; Alici, Ömer; Kan, Elif Kılıç; Ayar, Ahmet

2017-12-01

The purpose of the present study was to investigate the effect of alpha-lipoic acid (ALA) on the thicknesses of various retinal layers and on the numbers of retinal ganglion cells and vascular endothelial growth factor levels in experimental diabetic mouse retinas. Twenty-one male BALB/C mice were made diabetic by the intraperitoneal administration of streptozotocin (200 mg/kg). One week after the induction of diabetes, the mice were divided randomly into three groups: control group (non-diabetic mice treated with alpha-lipoic acid, n = 7), diabetic group (diabetic mice without treatment, n = 7), and alpha-lipoic acid treatment group (diabetic mice with alpha-lipoic acid treatment, n = 7). At the end of the 8th week, the thicknesses of the inner nuclear layer (INL), outer nuclear layer (ONL), and full-length retina were measured; also retinal ganglion cells and VEGF expressions were counted on the histological sections of the mouse retinas and compared with each other. The thicknesses of the full-length retina, ONL, and INL were significantly reduced in the diabetic group compared to the control and ALA treatment groups (p = 0.001), whereas the thicknesses of these layers did not show a significant difference between ALA treatment and control groups. The number of ganglion cells in the diabetic group was significantly lower than those in the control and ALA treatment groups (p = 0.001). The VEGF expression was significantly higher in the diabetic group and mostly observed in the ganglion cell and inner nuclear layers compared to the control and ALA treatment groups (p = 0.001). Therefore, the number of ganglion cells and VEGF levels did not show significant differences between the ALA treatment and control groups (p = 0.7). Our results show that alpha-lipoic acid treatment may have an impact on reducing VEGF levels, protecting ganglion cells, and preserving the thicknesses of the inner and outer layers in diabetic mouse retinas.

Enface Thickness Mapping and Reflectance Imaging of Retinal Layers in Diabetic Retinopathy.

PubMed

Francis, Andrew W; Wanek, Justin; Lim, Jennifer I; Shahidi, Mahnaz

2015-01-01

To present a method for image segmentation and generation of enface thickness maps and reflectance images of retinal layers in healthy and diabetic retinopathy (DR) subjects. High density spectral domain optical coherence tomography (SDOCT) images were acquired in 10 healthy and 4 DR subjects. Customized image analysis software identified 5 retinal cell layer interfaces and generated thickness maps and reflectance images of the total retina (TR), inner retina (IR), outer retina (OR), and the inner segment ellipsoid (ISe) band. Thickness maps in DR subjects were compared to those of healthy subjects by generating deviation maps which displayed retinal locations with thickness below, within, and above the normal 95% confidence interval. In healthy subjects, TR and IR thickness maps displayed the foveal depression and increased thickness in the parafoveal region. OR and ISe thickness maps showed increased thickness at the fovea, consistent with normal retinal anatomy. In DR subjects, thickening and thinning in localized regions were demonstrated on TR, IR, OR, and ISe thickness maps, corresponding to retinal edema and atrophy, respectively. TR and OR reflectance images showed reduced reflectivity in regions of increased thickness. Hard exudates appeared as hyper-reflective spots in IR reflectance images and casted shadows on the deeper OR and ISe reflectance images. The ISe reflectance image clearly showed the presence of focal laser scars. Enface thickness mapping and reflectance imaging of retinal layers is a potentially useful method for quantifying the spatial and axial extent of pathologies due to DR.

Enface Thickness Mapping and Reflectance Imaging of Retinal Layers in Diabetic Retinopathy

PubMed Central

Francis, Andrew W.; Wanek, Justin; Lim, Jennifer I.; Shahidi, Mahnaz

2015-01-01

Purpose To present a method for image segmentation and generation of enface thickness maps and reflectance images of retinal layers in healthy and diabetic retinopathy (DR) subjects. Methods High density spectral domain optical coherence tomography (SDOCT) images were acquired in 10 healthy and 4 DR subjects. Customized image analysis software identified 5 retinal cell layer interfaces and generated thickness maps and reflectance images of the total retina (TR), inner retina (IR), outer retina (OR), and the inner segment ellipsoid (ISe) band. Thickness maps in DR subjects were compared to those of healthy subjects by generating deviation maps which displayed retinal locations with thickness below, within, and above the normal 95% confidence interval. Results In healthy subjects, TR and IR thickness maps displayed the foveal depression and increased thickness in the parafoveal region. OR and ISe thickness maps showed increased thickness at the fovea, consistent with normal retinal anatomy. In DR subjects, thickening and thinning in localized regions were demonstrated on TR, IR, OR, and ISe thickness maps, corresponding to retinal edema and atrophy, respectively. TR and OR reflectance images showed reduced reflectivity in regions of increased thickness. Hard exudates appeared as hyper-reflective spots in IR reflectance images and casted shadows on the deeper OR and ISe reflectance images. The ISe reflectance image clearly showed the presence of focal laser scars. Conclusions Enface thickness mapping and reflectance imaging of retinal layers is a potentially useful method for quantifying the spatial and axial extent of pathologies due to DR. PMID:26699878

Natural History of the Central Structural Abnormalities in Choroideremia: A Prospective Cross-Sectional Study.

PubMed

Aleman, Tomas S; Han, Grace; Serrano, Leona W; Fuerst, Nicole M; Charlson, Emily S; Pearson, Denise J; Chung, Daniel C; Traband, Anastasia; Pan, Wei; Ying, Gui-Shuang; Bennett, Jean; Maguire, Albert M; Morgan, Jessica I W

2017-03-01

To describe in detail the central retinal structure of a large group of patients with choroideremia (CHM). A prospective, cross-sectional, descriptive study. Patients (n = 97, age 6-71 years) with CHM and subjects with normal vision (n = 44; ages 10-50 years) were included. Subjects were examined with spectral-domain optical coherence tomography (SD OCT) and near-infrared reflectance imaging. Visual acuity (VA) was measured during their encounter or obtained from recent ophthalmic examinations. Visual thresholds were measured in a subset of patients (n = 24) with automated static perimetry within the central regions (±15°) examined with SD OCT. Visual acuity and visual thresholds; total nuclear layer, inner nuclear layer (INL), and outer nuclear layer (ONL) thicknesses; and horizontal extent of the ONL and the photoreceptor outer segment (POS) interdigitation zone (IZ). Earliest abnormalities in regions with normally appearing retinal pigment epithelium (RPE) were the loss of the POS and ellipsoid zone associated with rod dysfunction. Transition zones (TZs) from relatively preserved retina to severe ONL thinning and inner retinal thickening moved centripetally with age. Most patients (88%) retained VAs better than 20/40 until their fifth decade of life. The VA decline coincided with migration of the TZ near the foveal center. There were outer retinal tubulations in degenerated, nonatrophic retina in the majority (69%) of patients. In general, RPE abnormalities paralleled photoreceptor degeneration, although there were regions with detectable but abnormally thin ONL co-localizing with severe RPE depigmentation and choroidal thinning. Abnormalities of the POS and rod dysfunction are the earliest central abnormalities observed in CHM. Foveal function is relatively preserved until the fifth decade of life. Migration of the TZs to the foveal center with foveal thinning and structural disorganization heralded central VA loss. The relationships established may help outline the eligibility criteria and outcome measures for clinical trials for CHM. Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Human Chorioretinal Layer Thicknesses Measured in Macula-wide, High-Resolution Histologic Sections

PubMed Central

Messinger, Jeffrey D.; Sloan, Kenneth R.; Mitra, Arnab; McGwin, Gerald; Spaide, Richard F.

2011-01-01

Purpose. To provide a comprehensive description of chorioretinal layer thicknesses in the normal human macula, including two-layer pairs that can produce a combined signal in some optical coherence tomography (OCT) devices (ganglion cell [GCL] and inner plexiform [IPL] layers and outer plexiform [OPL] and outer nuclear [ONL] layers). Methods. In 0.8-μm-thick, macula-wide sections through the foveola of 18 donors (age range, 40–92 years), 21 layers were measured at 25 locations by a trained observer and validated by a second observer. Tissue volume changes were assessed by comparing total retinal thickness in ex vivo OCT and in sections. Results. Median tissue shrinkage was 14.5% overall and 29% in the fovea. Histologic laminar boundaries resembled those in SD-OCT scans, but the shapes of the foveolar OPL and ONL differed. Histologic GCL, IPL, and OPLHenle were thickest at 0.8. to 1, 1.5, and 0.4 mm eccentricity, respectively. ONL was thickest in an inward bulge at the foveal center. At 1 mm eccentricity, GCL, INL, and OPLHenle represented 17.3% to 21.1%, 18.0% to 18.5%, and 14.2% to 16.6% of total retinal thickness, respectively. In donors ≥70 years of age, the RPE and choroid were 17.1% and 29.6% thinner and OPLHenle was 20.8% thicker than in donors <70 years. Conclusions. In this study, the first graphic representation and thickness database of chorioretinal layers in normal macula were generated. Newer OCT systems can separate GCL from IPL and OPLHenle from ONL, with good agreement for the proportion of retinal thickness occupied by OPLHenle in OCT and histology. The thickening of OPLHenle in older eyes may reflect Müller cell hypertrophy associated with rod loss. PMID:21421869

Light-Induced Thickening of Photoreceptor Outer Segment Layer Detected by Ultra-High Resolution OCT Imaging.

PubMed

Li, Yichao; Fariss, Robert N; Qian, Jennifer W; Cohen, Ethan D; Qian, Haohua

2016-07-01

We examined if light induces changes in the retinal structure that can be observed using optical coherence tomography (OCT). Normal C57BL/6J mice (age 3-6 months) adapted to either room light (15 minutes to ∼5 hours, 50-500 lux) or darkness (overnight) were imaged using a Bioptigen UHR-OCT system. Confocal histologic images were obtained from mice killed under light- or dark-adapted conditions. The OCT image of eyes adapted to room light exhibited significant increases (6.1 ± 0.8 μm, n = 13) in total retina thickness compared to the same eyes after overnight dark adaptation. These light-adapted retinal thickness changes occurred mainly in the outer retina, with the development of a hyporeflective band between the RPE and photoreceptor-tip layers. Histologic analysis revealed a light-evoked elongation between the outer limiting membrane and Bruch's membrane from 45.8 ± 1.7 μm in the dark (n = 5) to 52.1 ± 3.7 μm (n = 5) in the light. Light-adapted retinas showed an increase of actin staining in RPE apical microvilli at the same location as the hyporeflective band observed in OCT images. Elongation of the outer retina could be detected even with brief light exposures, increasing 2.1 ± 0.3 μm after 15 minutes (n = 9), and 4.1 ± 1.0 μm after 2 hours (n = 6). Conversely, dark-adaptation caused outer retinal shortening of 1.4 ± 0.4 μm (n = 7) and 3.0 ± 0.5 μm (n = 8) after 15 minutes and 2 hours, respectively. Light-adaption induces an increase in the thickness of the outer retina and the appearance of a hyporeflective band in the OCT image. This is consistent with previous reports of light-induced fluid accumulation in the subretinal space.

Retinal pigment epithelial dystrophy in Briard dogs.

PubMed

Lightfoot, R M; Cabral, L; Gooch, L; Bedford, P G; Boulton, M E

1996-01-01

The eyes of normal Briard dogs, Briards affected with inherited retinal pigment epithelial dystrophy (RPED) and a range of normal crossbred and beagle dogs were examined and the histopathology of RPED in the Briard was compared with the histopathological features of ageing in the normal canine retina. RPED was characterised by the accumulation of auto-fluorescent lipofuscin-like inclusions in the retinal pigment epithelium (RPE), which initially involved only non-pigmented RPE cells overlying the tapetum but subsequently spread to all pigmented RPE cells. Secondary neuro-retinal degeneration was characterised by a gradual loss of the outer nuclear layer and the subsequent atrophy and degeneration of the inner retina. The loss of primary photoreceptors in the peripheral retina was accompanied by the migration of photoreceptor nuclei and appeared to resemble severe changes due to ageing. Intra-vitreal radiolabelled leucine was used to examine the rate of turnover of the outer segments of the rods in some Briards, but no significant variations were found. The activity of acid phosphatase in RPE was assayed in vitro and showed comparable regional variations in Briard and crossbred dogs. The results suggest that RPED in the Briard is unlikely to be due either to an increased rate of turnover of rod outer segments (and thus an increased phagocytic load) or to a primary insufficiency of lysosomal enzyme.

KCNQ5/Kv7.5 potassium channel expression and subcellular localization in primate retinal pigment epithelium and neural retina

PubMed Central

Zhang, Xiaoming; Yang, Dongli

2011-01-01

Previous studies identified in retinal pigment epithelial (RPE) cells an M-type K+ current, which in many other cell types is mediated by channels encoded by KCNQ genes. The aim of this study was to assess the expression of KCNQ genes in the monkey RPE and neural retina. Application of the specific KCNQ channel blocker XE991 eliminated the M-type current in freshly isolated monkey RPE cells, indicating that KCNQ subunits contribute to the underlying channels. RT-PCR analysis revealed the expression of KCNQ1, KCNQ4, and KCNQ5 transcripts in the RPE and all five KCNQ transcripts in the neural retina. At the protein level, KCNQ5 was detected in the RPE, whereas both KCNQ4 and KCNQ5 were found in neural retina. In situ hybridization in frozen monkey retinal sections revealed KCNQ5 gene expression in the ganglion cell layer and the inner and outer nuclear layers of the neural retina, but results in the RPE were inconclusive due to the presence of melanin. Immunohistochemistry revealed KCNQ5 in the inner and outer plexiform layers, in cone and rod photoreceptor inner segments, and near the basal membrane of the RPE. The data suggest that KCNQ5 channels contribute to the RPE basal membrane K+ conductance and, thus, likely play an important role in active K+ absorption. The distribution of KCNQ5 in neural retina suggests that these channels may function in the shaping of the photoresponses of cone and rod photoreceptors and the processing of visual information by retinal neurons. PMID:21795522

Development of Choroidal Neovascularization in rats with Advanced Intense Cyclic Light-induced Retinal Degeneration

PubMed Central

Albert, Daniel M.; Neekhra, Aneesh; Wang, Shoujian; Darjatmoko, Soesiawati R.; Sorenson, Christine M.; Dubielzig, Richard R.; Sheibani, Nader

2010-01-01

Objective To study the progressive changes of intense cyclic light-induced retinal degeneration and determine whether it results in choroidal neovascularization (CNV). Methods Albino rats were exposed to 12 h of 3000 lux cyclic light for 1, 3, or 6 months. Prior to euthanization, fundus examination, fundus photographs, fluorescein and indocyanine green angiography, and Optical Coherence Tomography (OCT) evaluations were performed. Light exposed animals were euthanized after 1, 3, or 6 months for histopathological evaluation. Retinas were examined for the presence of 4-hydroxy-2-nonenal (HNE) and nitrotyrosine modified proteins by immunofluorescence staining. Results Chronic intense cyclic light exposure resulted in retinal degeneration with loss of the outer segments of photoreceptors and approximately two-thirds of the outer nuclear layer (ONL) and development of sub-retinal pigment epithelium (RPE) neovascularization after 1 month. Almost the entire ONL was absent with the presence of CNV, which penetrated Bruch’s membrane and extended into the outer retina after 3 months. Absence of the ONL, multiple foci of CNV, RPE fibrous metaplasia, and connective tissue bands containing blood vessels extending into the retina were observed after 6 months. All intense light exposed animals showed an increased presence of HNE and nitrotyrosine staining. OCT and angiographic studies confirmed retinal thinning and leakiness of the newly fromed blood vessels. Conclusions Our results suggest albino rats develop progressive stages of retinal degeneration and CNV after chronic intense cyclic light exposure allowing the detailed study of the pathogenesis and treatment of age-related macular degeneration. PMID:20142545

The BALB/c mouse: Effect of standard vivarium lighting on retinal pathology during aging

PubMed Central

Bell, Brent A.; Kaul, Charles; Bonilha, Vera L.; Rayborn, Mary E.; Shadrach, Karen; Hollyfield, Joe G.

2015-01-01

BALB/cJ mice housed under normal vivarium lighting conditions can exhibit profound retinal abnormalities, including retinal infoldings, autofluorescent inflammatory cells, and photoreceptor degeneration. To explore the sensitivity of the outer retina to cyclic lighting during aging, a cohort of BALB/cJ mice was evaluated with Scanning Laser Ophthalmoscopy (SLO), Spectral-Domain Optical Coherence Tomography (OCT) and conventional histopathology. Mice were bred and reared in a low-illuminance (extracage/intracage: 13 lx/1 lx) vivarium under cyclic light (14 h light: 10 h dark). Retinal imaging (around postnatal day 70) was performed to screen for any pre-existing abnormalities and to establish a baseline. Mice with normal retinas were separated into groups (A, B, C) and placed on bottom (Groups A & B) or top (Group C) of the cage racks where cage illumination was <10 & 150 lx respectively. Experimental groups B & C were imaged multiple times over a 17 month period. Mice from group A (controls) were imaged only once post-baseline at various times for comparison to groups B & C. Mice were assessed by histology at 8, 15, 20, 36, and 56 weeks and immunohistochemistry at 15 weeks post-baseline. SLO and OCT retinal images were measured and the resulting trends displayed as a function of age and light exposure. Retinal lesions (RL) and autofluorescent foci (AFF) were identified with histology as photoreceptor layer infoldings (IF) and localized microglia/macrophages (MM), respectively. Few RL and AFF were evident at baseline. Retinal infoldings were the earliest changes followed by subjacent punctate autofluorescent MM. The colocalization of IF and MM suggests a causal relationship. The incidence of these pathological features increased in all groups relative to baseline. OCT imaging revealed thinning of the outer nuclear layer (ONL) in all groups at 1 year relative to baseline. ONL thinning followed an exponential rate of change but the decay constant varied depending on intensity of illumination of the groups. Advanced age and top row illuminance conditions resulted in significant photoreceptor cell loss as judged by decreased thickness of the ONL. Photoreceptor loss was preceded by both retinal infoldings and the presence of autofluorescent inflammatory cells in the outer retina, suggesting that these changes are early indicators of light toxicity in the BALB/cJ mouse. PMID:25895728

The BALB/c mouse: Effect of standard vivarium lighting on retinal pathology during aging.

PubMed

Bell, Brent A; Kaul, Charles; Bonilha, Vera L; Rayborn, Mary E; Shadrach, Karen; Hollyfield, Joe G

2015-06-01

BALB/cJ mice housed under normal vivarium lighting conditions can exhibit profound retinal abnormalities, including retinal infoldings, autofluorescent inflammatory cells, and photoreceptor degeneration. To explore the sensitivity of the outer retina to cyclic lighting during aging, a cohort of BALB/cJ mice was evaluated with Scanning Laser Ophthalmoscopy (SLO), Spectral-Domain Optical Coherence Tomography (OCT) and conventional histopathology. Mice were bred and reared in a low-illuminance (extracage/intracage: 13 lx/1 lx) vivarium under cyclic light (14 h light: 10 h dark). Retinal imaging (around postnatal day 70) was performed to screen for any pre-existing abnormalities and to establish a baseline. Mice with normal retinas were separated into groups (A, B, C) and placed on bottom (Groups A & B) or top (Group C) of the cage racks where cage illumination was <10 & 150 lx respectively. Experimental groups B & C were imaged multiple times over a 17 month period. Mice from group A (controls) were imaged only once post-baseline at various times for comparison to groups B & C. Mice were assessed by histology at 8, 15, 20, 36, and 56 weeks and immunohistochemistry at 15 weeks post-baseline. SLO and OCT retinal images were measured and the resulting trends displayed as a function of age and light exposure. Retinal lesions (RL) and autofluorescent foci (AFF) were identified with histology as photoreceptor layer infoldings (IF) and localized microglia/macrophages (MM), respectively. Few RL and AFF were evident at baseline. Retinal infoldings were the earliest changes followed by subjacent punctate autofluorescent MM. The colocalization of IF and MM suggests a causal relationship. The incidence of these pathological features increased in all groups relative to baseline. OCT imaging revealed thinning of the outer nuclear layer (ONL) in all groups at 1 year relative to baseline. ONL thinning followed an exponential rate of change but the decay constant varied depending on intensity of illumination of the groups. Advanced age and top row illuminance conditions resulted in significant photoreceptor cell loss as judged by decreased thickness of the ONL. Photoreceptor loss was preceded by both retinal infoldings and the presence of autofluorescent inflammatory cells in the outer retina, suggesting that these changes are early indicators of light toxicity in the BALB/cJ mouse. Copyright © 2015 Elsevier Ltd. All rights reserved.

Early Events in Retinal Degeneration Caused by Rhodopsin Mutation or Pigment Epithelium Malfunction: Differences and Similarities

PubMed Central

Di Pierdomenico, Johnny; García-Ayuso, Diego; Pinilla, Isabel; Cuenca, Nicolás; Vidal-Sanz, Manuel; Agudo-Barriuso, Marta; Villegas-Pérez, María P.

2017-01-01

To study the course of photoreceptor cell death and macro and microglial reactivity in two rat models of retinal degeneration with different etiologies. Retinas from P23H-1 (rhodopsin mutation) and Royal College of Surgeon (RCS, pigment epithelium malfunction) rats and age-matched control animals (Sprague-Dawley and Pievald Viro Glaxo, respectively) were cross-sectioned at different postnatal ages (from P10 to P60) and rhodopsin, L/M- and S-opsin, ionized calcium-binding adapter molecule 1 (Iba1), glial fibrillary acid protein (GFAP), and proliferating cell nuclear antigen (PCNA) proteins were immunodetected. Photoreceptor nuclei rows and microglial cells in the different retinal layers were quantified. Photoreceptor degeneration starts earlier and progresses quicker in P23H-1 than in RCS rats. In both models, microglial cell activation occurs simultaneously with the initiation of photoreceptor death while GFAP over-expression starts later. As degeneration progresses, the numbers of microglial cells increase in the retina, but decreasing in the inner retina and increasing in the outer retina, more markedly in RCS rats. Interestingly, and in contrast with healthy animals, microglial cells reach the outer nuclei and outer segment layers. The higher number of microglial cells in dystrophic retinas cannot be fully accounted by intraretinal migration and PCNA immunodetection revealed microglial proliferation in both models but more importantly in RCS rats. The etiology of retinal degeneration determines the initiation and pattern of photoreceptor cell death and simultaneously there is microglial activation and migration, while the macroglial response is delayed. The actions of microglial cells in the degeneration cannot be explained only in the basis of photoreceptor death because they participate more actively in the RCS model. Thus, the retinal degeneration caused by pigment epithelium malfunction is more inflammatory and would probably respond better to interventions by inhibiting microglial cells. PMID:28321183

Microperimetric assessment of the two optical coherence tomography subtypes of acute macular neuroretinopathy.

PubMed

Battaglia Parodi, Maurizio; Iacono, Pierluigi; Panico, Daniele; Cascavilla, Marialucia; Bandello, Francesco

2015-01-01

This study evaluates the morpho-functional alterations associated with acute macular neuroretinopathy (AMNR). Prospective observational case series study carried out at the University Vita-Salute, Scientific Institute San Raffaele. Five out of six eyes (three patients) showed the typical features of AMNR. The patients underwent an ophthalmological examination, including best-corrected visual acuity (BCVA) measurement, electroretinogram and electroculogram (ERG/EOG), multifocal electroretinogram (mfERG), infrared reflectance, short wavelength and near-infrared-fundus autofluorescence (SW-FAF/NIR-FAF), spectral-domain optical coherence tomography (SD-OCT) and microperimetry. Microperimetric alterations in the two SD-OCT subtypes of AMNR. The BCVA was 20/20 in all patients. ERG and EOG were normal; mfERG revealed a generally reduced response with a more reduced signal in the areas corresponding to the macular lesions. SD-OCT demonstrated two different patterns of retinal alterations. In case 1, SD-OCT revealed a hyperreflective, plaque-like band at the junction of the outer plexiform layer (OPL) and the inner nuclear layer (INL), extending into the INL (type 1 lesion). In cases 2 and 3, SD-OCT disclosed a hyperreflectivity of the OPL associated with outer nuclear layer thinning and disruption of the outer segment/retinal pigment epithelium junction (type 2 lesion). Microperimetry revealed a wide scotoma involving the entire macular area in all eyes, including the unaffected eye of case 1. The reduction in retinal sensitivity was greatest in type 1. SD-OCT confirms that AMNR may occur in different patterns. Microperimetry demonstrated that functional alterations are also discernible in apparently uninvolved areas. Both examinations are extremely valuable in characterizing the changes associated with AMNR. © 2015 Royal Australian and New Zealand College of Ophthalmologists.

Human retinal gene therapy for Leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement.

PubMed

Cideciyan, Artur V; Jacobson, Samuel G; Beltran, William A; Sumaroka, Alexander; Swider, Malgorzata; Iwabe, Simone; Roman, Alejandro J; Olivares, Melani B; Schwartz, Sharon B; Komáromy, András M; Hauswirth, William W; Aguirre, Gustavo D

2013-02-05

Leber congenital amaurosis (LCA) associated with retinal pigment epithelium-specific protein 65 kDa (RPE65) mutations is a severe hereditary blindness resulting from both dysfunction and degeneration of photoreceptors. Clinical trials with gene augmentation therapy have shown partial reversal of the dysfunction, but the effects on the degeneration are not known. We evaluated the consequences of gene therapy on retinal degeneration in patients with RPE65-LCA and its canine model. In untreated RPE65-LCA patients, there was dysfunction and degeneration of photoreceptors, even at the earliest ages. Examined serially over years, the outer photoreceptor nuclear layer showed progressive thinning. Treated RPE65-LCA showed substantial visual improvement in the short term and no detectable decline from this new level over the long term. However, retinal degeneration continued to progress unabated. In RPE65-mutant dogs, the first one-quarter of their lifespan showed only dysfunction, and there was normal outer photoreceptor nuclear layer thickness retina-wide. Dogs treated during the earlier dysfunction-only stage showed improved visual function and dramatic protection of treated photoreceptors from degeneration when measured 5-11 y later. Dogs treated later during the combined dysfunction and degeneration stage also showed visual function improvement, but photoreceptor loss continued unabated, the same as in human RPE65-LCA. The results suggest that, in RPE65 disease treatment, protection from visual function deterioration cannot be assumed to imply protection from degeneration. The effects of gene augmentation therapy are complex and suggest a need for a combinatorial strategy in RPE65-LCA to not only improve function in the short term but also slow retinal degeneration in the long term.

Gene therapy rescues photoreceptor blindness in dogs and paves the way for treating human X-linked retinitis pigmentosa.

PubMed

Beltran, William A; Cideciyan, Artur V; Lewin, Alfred S; Iwabe, Simone; Khanna, Hemant; Sumaroka, Alexander; Chiodo, Vince A; Fajardo, Diego S; Román, Alejandro J; Deng, Wen-Tao; Swider, Malgorzata; Alemán, Tomas S; Boye, Sanford L; Genini, Sem; Swaroop, Anand; Hauswirth, William W; Jacobson, Samuel G; Aguirre, Gustavo D

2012-02-07

Hereditary retinal blindness is caused by mutations in genes expressed in photoreceptors or retinal pigment epithelium. Gene therapy in mouse and dog models of a primary retinal pigment epithelium disease has already been translated to human clinical trials with encouraging results. Treatment for common primary photoreceptor blindness, however, has not yet moved from proof of concept to the clinic. We evaluated gene augmentation therapy in two blinding canine photoreceptor diseases that model the common X-linked form of retinitis pigmentosa caused by mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene, which encodes a photoreceptor ciliary protein, and provide evidence that the therapy is effective. After subretinal injections of adeno-associated virus-2/5-vectored human RPGR with human IRBP or GRK1 promoters, in vivo imaging showed preserved photoreceptor nuclei and inner/outer segments that were limited to treated areas. Both rod and cone photoreceptor function were greater in treated (three of four) than in control eyes. Histopathology indicated normal photoreceptor structure and reversal of opsin mislocalization in treated areas expressing human RPGR protein in rods and cones. Postreceptoral remodeling was also corrected: there was reversal of bipolar cell dendrite retraction evident with bipolar cell markers and preservation of outer plexiform layer thickness. Efficacy of gene therapy in these large animal models of X-linked retinitis pigmentosa provides a path for translation to human treatment.

High-Resolution Imaging of the Optic Nerve and Retina in Optic Nerve Hypoplasia

PubMed Central

Pilat, Anastasia; Sibley, Daniel; McLean, Rebecca J.; Proudlock, Frank A.; Gottlob, Irene

2015-01-01

Purpose To investigate the optic nerve and macular morphology in patients with optic nerve hypoplasia (ONH) using spectral-domain optical coherence tomography (SD OCT). Design Prospective, cross-sectional, observational study. Subjects A total of 16 participants with ONH (10 female and 6 male; mean age, 17.2 years; 6 bilateral involvement) and 32 gender-, age-, ethnicity-, and refraction-matched healthy controls. Methods High-resolution SD OCT (Copernicus [Optopol Technology S.A., Zawiercie, Poland], 3 μm resolution) and handheld SD OCT (Bioptigen Inc [Research Triangle Park, NC], 2.6 μm resolution) devices were used to acquire horizontal scans through the center of the optic disc and macula. Main Outcome Measures Horizontal optic disc/cup and rim diameters, cup depth, peripapillary retinal nerve fiber layer (RNFL), and thickness of individual retinal layers in participants with ONH and in controls. Results Patients with ONH had significantly smaller discs (P < 0.03 and P < 0.001 compared with unaffected eye and healthy controls, respectively), horizontal cup diameter (P < 0.02 for both), and cup depth (P < 0.02 and P < 0.01, respectively). In the macula, significantly thinner RNFL (nasally), ganglion cell layer (GCL) (nasally and temporally), inner plexiform layer (IPL) (nasally), outer nuclear layer (ONL) (nasally), and inner segment (centrally and temporally) were found in patients with ONH compared with the control group (P < 0.05 for all comparisons). Continuation of significantly thicker GCL, IPL, and outer plexiform layer in the central retinal area (i.e., foveal hypoplasia) was found in more than 80% of patients with ONH. Clinically unaffected fellow eyes of patients with ONH showed mild features of underdevelopment. Visual acuity and presence of septo-optic dysplasia were associated with changes in GCL and IPL. Sensitivity and specificity for the detection of ONH based on disc and retinal optical coherence tomography (OCT) parameters were >80%. Conclusions Our study provides evidence of retinal changes in ONH. In addition to thinning of retina layers mainly involving the RNFL and GCL, signs reminiscent of foveal hypoplasia were observed in patients with ONH. Optic nerve and foveal parameters measured using OCT showed high sensitivity and specificity for detecting ONH, demonstrating their useful for clinical diagnosis. PMID:25939636

Region-specific ischemia, neovascularization and macular oedema in treatment-naïve proliferative diabetic retinopathy.

PubMed

Lange, Jason; Hadziahmetovic, Majda; Zhang, Jingfa; Li, Weiye

2018-02-07

Region-specific pathology in proliferative diabetic retinopathy enhances our understanding and management of this disease. To investigate non-perfusion, neovascularization and macular oedema. A cross-sectional, observational, non-randomized study. Consecutive 43 eyes of 27 treatment-naïve patients. Ultra-widefield fluorescein angiography for studying specific zones, that is, far-peripheral zone, mid-peripheral zone and central retina (cr), and spectral-domain optical coherence tomography for analysing thickness of macular layers. Non-perfusion index (NPI) and neovascularization index (NVI) in different zones, thickness of cr, retinal nerve fibre layer, ganglion cell layer (GCL), inner nuclear layer (INL) and outer plexiform layer in parafoveal regions. The NPI of far-periphery and NVI of mid-periphery were the highest by one-way analysis of variance testing. Ischemic retina defined as high NPI in far-periphery was significantly related to macular oedema via a binary classification approach (P < 0.05). The ischemic retina was correlated with a decreased thickness of both retinal nerve fibre and GCL (P < 0.05); macular oedema was correlated with increased INL thickness (P < 0.0001). The region-specific correlation of NPI of far-periphery and NVI of mid-periphery, but not with central retinal thickness, suggests different pathogeneses of neovascularization and macular oedema. Retinal nerve fibre layer and GCL, both biomarkers of diabetic retinal neuronopathy, are associated with retinal ischemia, but not with macular oedema, suggesting that diabetic microangiopathy and neuronopathy possess distinct pathogenic pathways. The strong correlation between macular oedema and INL indicates that intracellular oedema is a determining factor of diabetic macular oedema. © 2018 Royal Australian and New Zealand College of Ophthalmologists.

Three-dimensional spectral domain optical coherence tomography in X linked foveal retinoschisis

PubMed Central

Saxena, Sandeep; Manisha; Meyer, Carsten H

2013-01-01

Spectral domain optical coherence tomography (SD-OCT) was performed in two cases of bilateral X linked foveal retinoschisis of different age groups. On fundus examination spoke wheel and honeycomb pattern of cysts were observed along with retinal nerve fibre layer (RNFL) defects. On SD-OCT, schisis was observed in the outer plexiform layer. External limiting membrane disruption was observed in the subfoveal area, along with disruption of outer nuclear layer (ONL) and inner–outer segment junction. Elevation of ONL due to tractional pull of central palisade was a novel observation. Retinoschisis extended beyond the optic disc up to the nasal region. Extracted RNFL tomogram presented an unprecedented visualisation of schisis along 360° of the optic disc. Tractional elevation in the foveal area and schisis involving nasal region, not observed upon clinical examination, was highlighted on SD-OCT. This investigative modality is an important adjunct in the assessment of foveal retinoschisis. PMID:23563673

Quercetin protects the retina by reducing apoptosis due to ischemia-reperfusion injury in a rat model.

PubMed

Arikan, Sedat; Ersan, Ismail; Karaca, Turan; Kara, Selcuk; Gencer, Baran; Karaboga, Ihsan; Hasan Ali, Tufan

2015-01-01

This study aimed to investigate the effect of quercetin on apoptotic cell death induced by ischemia-reperfusion (I/R) injury in the rat retina. Twenty-four rats were divided into four equal groups: control, ischemic, solvent, and quercetin. I/R injury was achieved by elevating the intraocular pressure above the perfusion pressure. Intraperitoneal injections of 20 mg/kg of quercetin and dimethyl sulfoxide (DMSO) were performed in the quercetin and solvent groups, respectively, immediately prior to I/R injury, and the researchers allowed for the retinas to be reperfused. Forty-eight hours after injury, the thicknesses of the retinal ganglion cell layer (RGCL), inner nuclear layer (INL), inner plexiform layer (IPL), outer plexiform layer (OPL), and outer nuclear layer (ONL) were measured in all groups. Moreover, the numbers of terminal deoxynucleotidyl transferase dUTP nick-end-labeled [TUNEL (+)] cells and caspase-3 (+) cells in both INL and ONL were evaluated in all groups. The administration of quercetin was found to reduce the thinning of all retinal layers. The mean thickness of INL in the quercetin and ischemic groups was 21 ± 5.6 µm and 16 ± 6.4 µm, respectively (P<0.05). Similarly, the mean thickness of ONL in the quercetin and ischemic groups was 50 ± 12.8 µm and 40 ± 8.7 µm, respectively (P<0.05). The antiapoptotic effect of quercetin in terms of reducing the numbers of both TUNEL (+) cells and caspase-3 (+) cells was significant in INL. The mean number of TUNEL (+) cells in INL in the ischemic and quercetin groups was 476.8 ± 45.6/mm2 and 238.72 ± 251/mm2, respectively (P<0.005). The mean number of caspase-3 (+) cells in INL of ischemic and quercetin groups was 633.6 ± 38.7/mm2 and 342.4 ± 36.1/mm2, respectively (P<0.001). The use of quercetin may be beneficial in the treatment of retinal I/R injury because of its antiapoptotic effect on the retinal layers, particularly in INL.

In vivo imaging of the mouse model of X-linked juvenile retinoschisis with fourier domain optical coherence tomography.

PubMed

Xu, Jing; Molday, Laurie L; Molday, Robert S; Sarunic, Marinko V

2009-06-01

The purpose of this study was to investigate Fourier domain optical coherence tomography (FD OCT) as a noninvasive tool for retinal imaging in the Rs1h-knockout mouse (model for X-linked juvenile retinoschisis). A prototype spectrometer-based FD OCT system was used in combination with a custom optical beam-scanning platform. Images of the retinas from wild-type and Rs1h-knockout mice were acquired noninvasively with FD OCT with the specimen anesthetized. At the completion of the noninvasive FD OCT imaging, invasive retinal cross-sectional images (histology) were acquired from a nearby region for comparison to the FD OCT images. The retinal layers were identifiable in the FD OCT images, permitting delineation and thickness measurement of the outer nuclear layer (ONL). During FD OCT in vivo imaging of the Rs1h-knockout mouse, holes were observed in the inner nuclear layer (INL), and retinal cell disorganization was observed as a change in the backscattering intensity profile. Comparison of the ONL measurements acquired noninvasively with FD OCT to measurements taken using histology at nearby locations showed a degeneration of roughly 30% of the ONL by the age of 2 months in Rs1h-knockout mice relative to wild-type. FD OCT was demonstrated to be effective for noninvasive imaging of retinal degeneration and observation of retinal holes in Rs1h-knockout mice.

Structural and Functional Changes Associated with Normal and Abnormal Fundus Autofluorescence in Patients with Retinitis Pigmentosa

PubMed Central

Greenstein, Vivienne C.; Duncker, Tobias; Holopigian, Karen; Carr, Ronald E.; Greenberg, Jonathan; Tsang, Stephen H.; Hood, Donald C.

2013-01-01

Purpose To analyze the structure and visual function of regions bordering the hyperautofluorescent ring/arcs in retinitis pigmentosa (RP). Methods Twenty -one RP patients (21 eyes) with rings/arcs and 21 normals (21 eyes) were studied. Visual sensitivity in the central 10° was measured with microperimetry. Retinal structure was evaluated with spectral domain optical coherence tomography (SD-OCT). The distance from the fovea to disruption/loss of the inner outer segment (IS/OS) junction and thicknesses of the total receptor plus retinal pigment epithelial (RPE) complex (R+), and outer segment plus RPE complex (OS+) layers were measured. Results were compared to measurements of the distance from the fovea to the inner and outer borders of the ring/arc seen on fundus autofluorescence (FAF). Results Disruption/loss of the IS/OS junction occurred closer to the inner border of the ring/arc and it was closer to the fovea in 8 eyes. For 19 eyes, OS+ and R+ thicknesses were significantly decreased at locations closer to the fovea than the appearance of the inner border of hyperautofluorescence. Mean visual sensitivity was decreased inside, across and outside the ring/arc by 3.5 ± 3.8, 8.9 ± 4.8 and 17.0±2.4 dB respectively. Conclusions Structural and functional changes can occur inside the hyperfluorescent ring/arc in RP. PMID:21909055

Effects of methylprednisolone on laser-induced retinal injuries

NASA Astrophysics Data System (ADS)

Rosner, Mordechai; Tchirkov, Marina; Dubinski, Galina; Solberg, Yoram; Belkin, Michael

1997-05-01

Methylprednisolone have been demonstrated to ameliorate retinal photic injury. In the current study we examined its effect on laser induced retinal injury. Retinal lesions were inflicted by argon laser in 36 pigmented DA rats. The treated groups received intra-peritoneally methylprednisolone in saline, injected 3 times a day for 2 days, starting immediately after exposure. The controls received the vehicle on the same schedule. The rats were sacrificed 3, 20 or 60 days after laser exposure and the lesions were evaluated by light microscopy and morphometric measurements. Laser injuries were associated with disruption of the outer retinal layers. Three and 20 days after exposure, the loss of the photoreceptor-cell nuclei was significantly milder in the treated groups as compared with controls. There was no difference 60 days after exposure. In conclusion, methylprednisolone reduced temporarily the photoreceptor cell loss in argon laser induced retinal injury, when treatment was started immediately after laser exposure. There was no long term effect.

ZIKA virus infection causes persistent chorioretinal lesions.

PubMed

Manangeeswaran, Mohanraj; Kielczewski, Jennifer L; Sen, H Nida; Xu, Biying C; Ireland, Derek D C; McWilliams, Ian L; Chan, Chi-Chao; Caspi, Rachel R; Verthelyi, Daniela

2018-05-25

Zika-infected patients can have eye involvement ranging from mild conjunctivitis to severe chorioretinal lesions, however the possible long-term sequelae of infection and timeline to recovery remain unknown. Here we describe the partial recovery of chorioretinal lesions in an immunocompetent patient diagnosed with bilateral posterior uveitis associated with Zika infection and show that some lesions resolved with focal atrophy evident as pigmentary changes on funduscopy. To better understand the progression of the lesions and correlate the changes in fundus imaging with local viral load, immune responses, and retinal damage, we developed a symptomatic mouse model of ocular Zika virus infection. Imaging of the fundus revealed multiple hypopigmentary patches indicative of chorioretinal degeneration as well as thinning of the retina that mirror the lesions in patients. Microscopically, the virus primarily infected the optic nerve, retinal ganglion cells, and inner nuclear layer cells, showing thinning of the outer plexiform layer. During acute infection, the eyes showed retinal layer disorganization, retinitis, vitritis, and focal choroiditis, with mild cellular infiltration and increased expression of tumor necrosis factor, interferon-γ, granzyme B, and perforin. Focal areas of gliosis and retinal degeneration persisted 60 dpi. The model recapitulates features of ZIKA infections in patients and should help elucidate the mechanisms underlying the damage to the eyes and aid in the development of effective therapeutics.

An animal model for Norrie disease (ND): gene targeting of the mouse ND gene.

PubMed

Berger, W; van de Pol, D; Bächner, D; Oerlemans, F; Winkens, H; Hameister, H; Wieringa, B; Hendriks, W; Ropers, H H

1996-01-01

In order to elucidate the cellular and molecular processes which are involved in Norrie disease (ND), we have used gene targeting technology to generate ND mutant mice. The murine homologue of the ND gene was cloned and shown to encode a polypeptide that shares 94% of the amino acid sequence with its human counterpart. RNA in situ hybridization revealed expression in retina, brain and the olfactory bulb and epithelium of 2 week old mice. Hemizygous mice carrying a replacement mutation in exon 2 of the ND gene developed retrolental structures in the vitreous body and showed an overall disorganization of the retinal ganglion cell layer. The outer plexiform layer disappears occasionally, resulting in a juxtaposed inner and outer nuclear layer. At the same regions, the outer segments of the photoreceptor cell layer are no longer present. These ocular findings are consistent with observations in ND patients and the generated mouse line provides a faithful model for study of early pathogenic events in this severe X-linked recessive neurological disorder.

Developmental origin of the posterior pigmented epithelium of iris.

PubMed

Wang, Xiaobing; Xiong, Kai; Lu, Lei; Gu, Dandan; Wang, Songtao; Chen, Jing; Xiao, Honglei; Zhou, Guomin

2015-03-01

Iris epithelium is a double-layered pigmented cuboidal epithelium. According to the current model, the neural retina and the posterior iris pigment epithelium (IPE) are derived from the inner wall of the optic cup, while the retinal pigment epithelium (RPE) and the anterior IPE are derived from the outer wall of the optic cup during development. Our current study shows evidence, contradicting this model of fetal iris development. We demonstrate that human fetal iris expression patterns of Otx2 and Mitf transcription factors are similar, while the expressions of Otx2 and Sox2 are complementary. Furthermore, IPE and RPE exhibit identical morphologic development during the early embryonic period. Our results suggest that the outer layer of the optic cup forms two layers of the iris epithelium, and the posterior IPE is the inward-curling anterior rim of the outer layer of the optic cup. These findings provide a reasonable explanation of how IPE cells can be used as an appropriate substitute for RPE cells.

Alterations in NMDA receptor expression during retinal degeneration in the RCS rat.

PubMed

Gründer, T; Kohler, K; Guenther, E

2001-01-01

To determine how a progressive loss of photoreceptor cells and the concomitant loss of glutamatergic input to second-order neurons can affect inner-retinal signaling, glutamate receptor expression was analyzed in the Royal College of Surgeons (RCS) rat, an animal model of retinitis pigmentosa. Immunohistochemistry was performed on retinal sections of RCS rats and congenic controls between postnatal (P) day 3 and the aged adult (up to P350) using specific antibodies against N-methyl-D-aspartate (NMDA) subunits. All NMDA subunits (NR1, NR2A-2D) were expressed in control and dystrophic retinas at all ages, and distinct patterns of labeling were found in horizontal cells, subpopulations of amacrine cells and ganglion cells, as well as in the outer and inner plexiform layer (IPL). NRI immunoreactivity in the inner plexiform layer of adult control retinas was concentrated in two distinct bands, indicating a synaptic localization of NMDA receptors in the OFF and ON signal pathways. In the RCS retina, these bands of NRI immunoreactivity in the IPL were much weaker in animals older than P40. In parallel, NR2B immunoreactivity in the outer plexiform layer (OPL) of RCS rats was always reduced compared to controls and vanished between P40 and P120. The most striking alteration observed in the degenerating retina, however, was a strong expression of NRI immunoreactivity in Müller cell processes in the inner retina which was not observed in control animals and which was present prior to any visible sign of photoreceptor degeneration. The results suggest functional changes in glutamatergic receptor signaling in the dystrophic retina and a possible involvement of Müller cells in early processes of this disease.

Outer Retinal and Choroidal Evaluation in Multiple Evanescent White Dot Syndrome (MEWDS): An Enhanced Depth Imaging Optical Coherence Tomography Study.

PubMed

Fiore, Tito; Iaccheri, Barbara; Cerquaglia, Alessio; Lupidi, Marco; Torroni, Giovanni; Fruttini, Daniela; Cagini, Carlo

2018-01-01

To perform an analysis of optical coherence tomography (OCT) abnormalities in patients with MEWDS, during the acute and recovery stages, using enhanced depth imaging-OCT (EDI-OCT). A retrospective case series of five patients with MEWDS was included. EDI-OCT imaging was evaluated to detect retinal and choroidal features. In the acute phase, focal impairment of the ellipsoid zone and external limiting membrane, hyperreflective dots in the inner choroid, and full-thickness increase of the choroidal profile were observed in the affected eye; disappearance of these findings and restoration of the choroidal thickness (p = 0.046) was appreciated in the recovery phase. No OCT abnormalities were assessed in the unaffected eye. EDI-OCT revealed transient outer retinal layer changes and inner choroidal hyperreflective dots. A transient increased thickness of the whole choroid was also identified. This might confirm a short-lasting inflammatory involvement of the whole choroidal tissue in the active phase of MEWDS.

Intraretinal hyperreflective foci on spectral-domain optical coherence tomographic images of patients with retinitis pigmentosa

PubMed Central

Kuroda, Masako; Hirami, Yasuhiko; Hata, Masayuki; Mandai, Michiko; Takahashi, Masayo; Kurimoto, Yasuo

2014-01-01

Background The purpose of this study was to observe the characteristic findings of spectral-domain optical coherence tomography (SD-OCT) images in the retinas of patients with retinitis pigmentosa and to evaluate their distribution patterns in the early and advanced stages of the disease. Methods A total of 184 patients (368 eyes) with retinitis pigmentosa were observed using SD-OCT. We studied the presence or absence of continuous inner/outer segment (IS/OS) lines, presence of thinning of the retinal pigment epithelium-Bruch’s membrane complex, and distribution patterns of hyperreflective foci in the inner and outer nuclear layers (INL and ONL). Results The IS/OS junction had partially disappeared in 275 eyes, which were at the early stage of retinitis pigmentosa (group X), whereas the junction had totally disappeared in 93, which were at the advanced stage of retinitis pigmentosa (group Y). Hyperreflective foci in the INL were observed in a significantly larger proportion of the eyes in group X than in group Y (90% versus 61%, P<0.001), but hyperreflective foci in the ONL were observed in a significantly larger proportion of eyes in group Y than in group X (100% versus 69%, P<0.001). Conclusion Hyperreflective foci in the INL were more frequently observed in retinas with the early stage of retinitis pigmentosa and hyperreflective foci in the ONL were more frequently observed in the advanced stage. Hyperreflective foci may be indicative of changes in the retinal structure at each stage of retinitis pigmentosa. PMID:24591813

[An in vivo study of basic fibroblast growth factor on activation and proliferation of retinal progenitor cell in RCS rats].

PubMed

Xia, Xiaoping; Song, Guoxiang; Liu, Xiangfu; Tang, Xiangchen; Ye, Hui

2010-11-01

To investigate the effect of intravitreal basic fibroblast growth factor(bFGF) on activation and proliferation of endogenous retinal progenitor cells in the Royal College of Surgeons(RCS) rats. Twenty-four rats were studied after the 30th postnatal day(≥30). Eighteen affected rats were randomly divided into 3 groups: bFGF-treated, vehicle-treated and untreated group, and 6 unaffected rats were used as normal controls. Six μl of bFGF (5μg/10 μl) or vehicle was injected into the vitreous on days 31, 33 and 35 after birth (P31, P33, P35) in the bFGF group and vehicle group, and no injection was administered in the untreated and control groups. All the rats were euthanized, and their eyes were enucleated, hemisected and fixed at 50 d after birth for immunohistochemistry and measurement of outer nuclear layer thickness. Nestin and Chx10 were positively expressed in all retinal layers, intravitreous injection of bFGF in retina-dystrophic RCS(RCS-p+/Lav) rats induced intense labeling for the retinal progenitor cell markers Chx10 and Nestin, which were highly colocalized. Fluorescence intensity for both labels was slightly less in the control rats, and much less in the vehicle-injected rats as well as in the untreated RCS rats. The outer nuclear layer (ONL) was significantly thicker in bFGF group than that of vehicle-treated or untreated group(p<0.01), but thinner than that of the control group(p<0.01). No significant difference was observed in the ONL thicknesses between the vehicle group and untreated group(P>0.05). bFGF may contribute to the activation of retinal progenitor cells in RCS rats, thus counteract degeneration by promoting the proliferation of the progenitor cells.

Retinal changes in rats flown on Cosmos 936 - A cosmic ray experiment

NASA Technical Reports Server (NTRS)

Philpott, D. E.; Corbett, R.; Turnbill, C.; Black, S.; Dayhoff, D.; Mcgourty, J.; Lee, R.; Harrison, G.; Savik, L.

1980-01-01

Ten rats, five centrifuged during flight to simulate gravity and five stationary in flight and experiencing hypogravity, orbited the Earth. No differences were noted between flight-stationary and flight-centrifuged animals, but changes were seen between these two groups and ground controls. Morphological alterations were observed comparable to those in the experiment flown on Cosmos 782 and to the retinal cells exposed to high-energy particles at Berkeley. Affected cells in the outer nuclear layer showed swelling, clearing of cytoplasm, and disruption of the membranes. Tissue channels were again found, similar to those seen on 782. After space flight, preliminary data indicated an increase in cell size in montages of the nuclear layer of both groups of flight animals. This experiment shows that weightlessness and environmental conditions other than cosmic radiation do not contribute to the observed damage of retinal cells.

Progressive outer retinal necrosis-like retinitis in immunocompetent hosts.

PubMed

Chawla, Rohan; Tripathy, Koushik; Gogia, Varun; Venkatesh, Pradeep

2016-08-10

We describe two young immunocompetent women presenting with bilateral retinitis with outer retinal necrosis involving posterior pole with centrifugal spread and multifocal lesions simulating progressive outer retinal necrosis (PORN) like retinitis. Serology was negative for HIV and CD4 counts were normal; however, both women were on oral steroids at presentation for suspected autoimmune chorioretinitis. The retinitis in both eyes responded well to oral valaciclovir therapy. However, the eye with the more fulminant involvement developed retinal detachment with a loss of vision. Retinal atrophy was seen in the less involved eye with preservation of vision. Through these cases, we aim to describe a unique evolution of PORN-like retinitis in immunocompetent women, which was probably aggravated by a short-term immunosuppression secondary to oral steroids. 2016 BMJ Publishing Group Ltd.

PARACENTRAL ACUTE MIDDLE MACULOPATHY IN A PERIVENULAR FERN-LIKE DISTRIBUTION WITH EN FACE OPTICAL COHERENCE TOMOGRAPHY.

PubMed

Garrity, Sean T; Tseng, Victoria L; Sarraf, David

2017-11-22

To report a case of central retinal vein occlusion resulting in a perivenular pattern of paracentral acute middle maculopathy lesions best identified with en face optical coherence tomography (OCT). Retrospective case report. Optos ultra-widefield fluorescein angiography, spectral domain OCT, en face OCT, and OCT angiography were performed. A 41-year-old man presented with decreased vision in the right eye for 2 weeks. Funduscopic examination of the affected right eye was notable for subtle retinal whitening in the macula, mild retinal venous dilation and tortuosity, and few scattered retinal dot and blot hemorrhages consistent with an acute central retinal vein occlusion. Widefield fluorescein angiography demonstrated delayed arterial and venous filling but no evidence of significant peripheral retinal vascular ischemia. En face OCT segmented at the inner nuclear layer illustrated a remarkable and precise perivenular distribution of fern-like paracentral acute middle maculopathy with periarterial sparing, whereas en face OCT segmented at the outer nuclear layer demonstrated florid cystoid macular edema. At 6-week follow-up, OCT demonstrated patchy areas of atrophic inner nuclear layer and spontaneous resolution of the cystoid macular edema. Optical coherence tomography angiography at the level of the deep capillary plexus illustrated remarkable flow reduction of the deep capillary plexus in mainly a perivenular distribution. The authors report a case of a central retinal vein occlusion with mild retinal findings associated with a remarkable perivenular pattern of paracentral acute middle maculopathy with en face OCT. Follow-up OCT angiography demonstrated significant flow reduction of the deep capillary plexus in a perivenular pattern. The perivenular pattern of paracentral acute middle maculopathy lesions with en face OCT can be an important finding suggestive of a central retinal vein occlusion.

Protective Effect of Total Flavones from Hippophae rhamnoides L. against Visible Light-Induced Retinal Degeneration in Pigmented Rabbits.

PubMed

Wang, Yong; Huang, Fenghong; Zhao, Liang; Zhang, Di; Wang, Ou; Guo, Xiaoxuan; Lu, Feng; Yang, Xue; Ji, Baoping; Deng, Qianchun

2016-01-13

Sea buckthorn (Hippophae rhamnoides L.) flavones have been used as candidate functional food ingredients because of their bioactivities, such as treating cardiovascular disorders, lowering plasma cholesterol level, and regulating immune function. However, the protective effects of sea buckthorn flavones against retinal degeneration remain unclear to date. This study investigated the protective effects of total flavones from H. rhamnoides (TFH) against visible light-induced retinal damage and explored the related mechanisms in pigmented rabbits. Rabbits were treated with TFH (250 and 500 mg/kg) for 2 weeks pre-illumination and 1 week post-illumination until sacrifice. Retinal function was quantified by performing electroretinography 1 day before and 1, 3, and 7 days after light exposure (18000 lx for 2 h). Retinal degeneration was evaluated by measuring the thickness of the outer nuclear layer (ONL) and performing the TUNEL assay 7 days after light exposure. Enzyme-linked immunosorbent assay, Western blot analysis, and immunohistochemistry were used to explore the antioxidant, anti-inflammatory, and anti-apoptotic mechanisms of TFH during visible light-induced retinal degeneration. Light exposure produced a degenerative effect primarily on the ONL, inner nuclear layer (INL), and ganglion cell layer (GCL). TFH significantly attenuated the destruction of electroretinograms caused by light damage, maintained ONL thickness, and decreased the number of TUNEL-positive cells in the INL and GCL. TFH ameliorated the retinal oxidative stress (GSH-Px, CAT, T-AOC, and MDA), inflammation (IL-1β and IL-6), angiogenesis (VEGF), and apoptosis (Bax, Bcl2, and caspase-3) induced by light exposure. Therefore, TFH exhibited protective effects against light-induced retinal degeneration by increasing the antioxidant defense mechanisms, suppressing pro-inflammatory and angiogenic cytokines, and inhibiting retinal cell apoptosis.

Characterization of photoreceptor degeneration in the rhodopsin P23H transgenic rat line 2 using optical coherence tomography.

PubMed

Monai, Natsuki; Yamauchi, Kodai; Tanabu, Reiko; Gonome, Takayuki; Ishiguro, Sei-Ichi; Nakazawa, Mitsuru

2018-01-01

To characterize the optical coherence tomography (OCT) appearances of photoreceptor degeneration in the rhodopsin P23H transgenic rat (line 2) in relation to the histological, ultrastructural, and electroretinography (ERG) findings. Homozygous rhodopsin P23H transgenic albino rats (line 2, very-slow degeneration model) were employed. Using OCT (Micron IV®; Phoenix Research Labs, Pleasanton, CA, USA), the natural course of photoreceptor degeneration was recorded from postnatal day (P) 15 to P 287. The OCT images were qualitatively observed by comparing them to histological and ultrastructural findings at P 62 and P 169. In addition, each retinal layer was quantitatively analyzed longitudinally during degeneration, compared it to that observed in wild type Sprague-Dawley (SD) rats. The relationships between the ERG (full-field combined rod-cone response, 3.0 cds/m2 stimulation) findings and OCT images were also analyzed. In the qualitative study, the two layers presumably corresponding to the photoreceptor inner segment ellipsoid zone (EZ) and interdigitation zone (IZ) were identified in the P23H rat until PN day 32. However, the photoreceptor inner and outer segment (IS/OS) layer became diffusely hyperreflective on OCT after P 46, and the EZ and IZ zones could no longer be identified on OCT. In contrast, in the SD rats, the EZ and IZ were clearly distinguished until at least P 247. The ultrastructural study showed partial disarrangements of the photoreceptor outer segment discs in the P23H rats at P 62, although a light-microscopic histological study detected almost no abnormality in the outer segment. In the quantitative study, the outer retinal layer including the outer plexiform layer (OPL) and the outer nuclear layer (ONL) became significantly thinner in the P23H rats than in the SD rats after P 71. The thickness of the IS/OS layer was maintained in the P23H rats until P 130, and it became statistically thinner than in the SD rats at P 237. The longitudinal attenuation in the amplitude of the a- and b-waves of ERG was significantly correlated with the thickness of the combined OPL and ONL but not with that of the IS/OS layer. OCT showed the degenerated photoreceptor IS/OS layer in rhodopsin P23H transgenic rats (line 2) as a diffuse hyperreflective zone, even in the early stage, with the partially disarranged and destabilized OS discs recognizable by ultrastructural assessment but not by a histological study. The amplitude of the a- and b-waves mainly depends on the thickness of the OPL and ONL layer rather than the thickness of the photoreceptor IS/OS layer in P23H rats.

Fasudil, a Clinically Used ROCK Inhibitor, Stabilizes Rod Photoreceptor Synapses after Retinal Detachment.

PubMed

Townes-Anderson, Ellen; Wang, Jianfeng; Halász, Éva; Sugino, Ilene; Pitler, Amy; Whitehead, Ian; Zarbin, Marco

2017-06-01

Retinal detachment disrupts the rod-bipolar synapse in the outer plexiform layer by retraction of rod axons. We showed that breakage is due to RhoA activation whereas inhibition of Rho kinase (ROCK), using Y27632, reduces synaptic damage. We test whether the ROCK inhibitor fasudil, used for other clinical applications, can prevent synaptic injury after detachment. Detachments were made in pigs by subretinal injection of balanced salt solution (BSS) or fasudil (1, 10 mM). In some animals, fasudil was injected intravitreally after BSS-induced detachment. After 2 to 4 hours, retinae were fixed for immunocytochemistry and confocal microscopy. Axon retraction was quantified by imaging synaptic vesicle label in the outer nuclear layer. Apoptosis was analyzed using propidium iodide staining. For biochemical analysis by Western blotting, retinal explants, detached from retinal pigmented epithelium, were cultured for 2 hours. Subretinal injection of fasudil (10 mM) reduced retraction of rod spherules by 51.3% compared to control detachments ( n = 3 pigs, P = 0.002). Intravitreal injection of 10 mM fasudil, a more clinically feasible route of administration, also reduced retraction (28.7%, n = 5, P < 0.05). Controls had no photoreceptor degeneration at 2 hours, but by 4 hours apoptosis was evident. Fasudil 10 mM reduced pyknotic nuclei by 55.7% ( n = 4, P < 0.001). Phosphorylation of cofilin and myosin light chain, downstream effectors of ROCK, was decreased with 30 μM fasudil ( n = 8-10 explants, P < 0.05). Inhibition of ROCK signaling with fasudil reduced photoreceptor degeneration and preserved the rod-bipolar synapse after retinal detachment. These results support the possibility, previously tested with Y27632, that ROCK inhibition may attenuate synaptic damage in iatrogenic detachments.

Macular structural characteristics in children with Down syndrome.

PubMed

O'Brien, Scott; Wang, Jingyun; Smith, Heather A; Donaldson, Dana L; Haider, Kathryn M; Roberts, Gavin J; Sprunger, Derek T; Neely, Daniel E; Plager, David A

2015-12-01

This prospective study aimed to investigate macular structural characteristics in children with Down syndrome compared to those in healthy children. Two groups of children (aged 6-16 years) were enrolled: children with Down syndrome (Down syndrome group, N = 17) and age-matched healthy children who were full-term at birth (control group, N = 18). Eligible patients had visual acuity of 20/100 or better and gestational age at birth of ≥ 36 weeks. Fourier domain optical coherence tomography was used for imaging of the macular retinal structure, and retinal volume scans centered on the macula were obtained. Central subfield thickness (CST) and the thickness of the inner and outer retinal layer regions were analyzed using the instrument's segmentation software. The analysis of data is provided for the right eye only, since there was no significant difference between right and left eyes for either the Down syndrome or control groups. Children in the Down syndrome group generally had identifiable retinal structure. The CST for the full retina and inner and outer retinal layers were all significantly greater in the Down syndrome group than the control group (independent t test, all p < 0.05). Despite the significantly thicker macula, only about 29 % (5 of 17) of the right eyes of patients with Down syndrome had macular thickness outside the normal range. Visual acuity in the Down syndrome group was not directly correlated with increased CST (t = 1.288, r = 0.326, p = 0.202). On average, CST in the Down syndrome group was greater than that in the control group, suggesting abnormal macular development in children with Down syndrome.

Multimodal Imaging and Spatial Analysis of Ebola Retinal Lesions in 14 Survivors of Ebola Virus Disease.

PubMed

Steptoe, Paul J; Momorie, Fayiah; Fornah, Alimamy D; Komba, Sahr P; Emsley, Elizabeth; Scott, Janet T; Harding, Simon P; Vandy, Matthew J; Sahr, Foday; Beare, Nicholas A V; Semple, Malcolm G

2018-05-03

Differentiation between Ebola retinal lesions and other retinal pathologies in West Africa is important, and the pathogenesis of Ebola retinal disease remains poorly understood. To describe the appearance of Ebola virus disease (EVD) retinal lesions using multimodal imaging to enable inferences on potential pathogenesis. This prospective case series study was carried out at 34 Military Hospital in Freetown, Sierra Leone. Ophthalmological images were analyzed from 14 consecutively identified survivors of EVD of Sierra Leonean origin who had identified Ebola retinal lesions. Multimodal imaging findings including ultra-widefield scanning laser ophthalmoscopy, fundus autofluorescence, swept-source optical coherence tomography (OCT), Humphrey visual field analysis, and spatial analysis. The 14 study participants had a mean (SD) age of 37.1 (8.8) years; 6 (43%) were women. A total of 141 Ebola retinal lesions were observed in 22 of 27 eyes (81%) of these 14 survivors on ultra-widefield imaging. Of these, 41 lesions (29.1%) were accessible to OCT imaging. Retinal lesions were predominantly nonpigmented with a pale-gray appearance. Peripapillary lesions exhibited variable curvatures in keeping with the retinal nerve fiber layer projections. All lesions respected the horizontal raphe and spared the fovea. The OCT imaging demonstrated a V-shaped hyperreflectivity of the outer nuclear layer overlying discontinuities of the ellipsoid zone and interdigitation zone in the smaller lesions. Larger lesions caused a collapse of the retinal layers and loss of retinal thickness. Lesion shapes were variable, but sharp angulations were characteristic. Perilesional areas of dark without pressure (thinned ellipsoid zone hyporeflectivity) accompanied 125 of the 141 lesions (88.7%) to varying extents. We demonstrate OCT evidence of localized pathological changes at the level of the photoreceptors in small lesions among survivors of EVD with retinal lesions. The relevance of associated areas of dark without pressure remains undetermined.

Phagocytosis of photoreceptor outer segments by transplanted human neural stem cells as a neuroprotective mechanism in retinal degeneration.

PubMed

Cuenca, Nicolás; Fernández-Sánchez, Laura; McGill, Trevor J; Lu, Bin; Wang, Shaomei; Lund, Raymond; Huhn, Stephen; Capela, Alexandra

2013-10-15

Transplantation of human central nervous system stem cells (HuCNS-SC) into the subretinal space of Royal College of Surgeons (RCS) rats preserves photoreceptors and visual function. To explore possible mechanism(s) of action underlying this neuroprotective effect, we performed a detailed morphologic and ultrastructure analysis of HuCNS-SC transplanted retinas. The HuCNS-SC were transplanted into the subretinal space of RCS rats. Histologic examination of the transplanted retinas was performed by light and electron microscopy. Areas of the retina adjacent to HuCNS-SC graft (treated regions) were analyzed and compared to control sections obtained from the same retina, but distant from the transplant site (untreated regions). The HuCNS-SC were detected as a layer of STEM 121 immunopositive cells in the subretinal space. In treated regions, preserved photoreceptor nuclei, as well as inner and outer segments were identified readily. In contrast, classic signs of degeneration were observed in the untreated regions. Interestingly, detailed ultrastructure analysis revealed a striking preservation of the photoreceptor-bipolar-horizontal cell synaptic contacts in the outer plexiform layer (OPL) of treated areas, in stark contrast with untreated areas. Finally, the presence of phagosomes and vesicles exhibiting the lamellar structure of outer segments also was detected within the cytosol of HuCNS-SC, indicating that these cells have phagocytic capacity in vivo. This study reveals the novel finding that preservation of specialized synaptic contacts between photoreceptors and second order neurons, as well as phagocytosis of photoreceptor outer segments, are potential mechanism(s) of HuCNS-SC transplantation, mediating functional rescue in retinal degeneration.

In vivo imaging of the Mouse Model of X-Linked Juvenile Retinoschisis Using Fourier Domain Optical Coherence Tomography

PubMed Central

Xu, Jing; Molday, Laurie L.; Molday, Robert S.; Sarunic, Marinko V.

2009-01-01

Purpose The purpose of this study is to investigate Fourier Domain Optical Coherence Tomography (FD OCT) as a non-invasive tool for retinal imaging in the Rs1h knockout mouse (model for X-linked Juvenile Retinoschisis). Methods A prototype spectrometer based FD OCT system was used in combination with a custom optical beam-scanning platform. Images of the retinas from wild type and Rs1h knockout mice were acquired non-invasively using FD OCT with the specimen anesthetized. At the completion of the non-invasive FD OCT imaging, invasive retinal cross sectional images (histology) were acquired from a nearby region for comparison to the FD OCT images. Results The retinal layers could be identified in the FD OCT images, permitting delineation and thickness measurement of the outer nuclear layer (ONL). During FD OCT in vivo imaging of the Rs1h knockout mouse, holes were observed in the inner nuclear layer (INL) and retinal cell disorganization was observed as a change in the backscattering intensity profile. Comparison of the ONL measurements acquired non-invasively using FD OCT to measurements taken using histology at nearby locations showed a degeneration of roughly thirty percent of the ONL by the age of two months in Rs1h knockout mice relative to wild type. Conclusions FD OCT has been demonstrated for non-invasive imaging of retinal degeneration and observation of retinal holes in Rs1h knockout mice. PMID:19182246

Anatomical correlates to the bands seen in the outer retina by optical coherence tomography: literature review and model.

PubMed

Spaide, Richard F; Curcio, Christine A

2011-09-01

To evaluate the validity of commonly used anatomical designations for the four hyperreflective outer retinal bands seen in current-generation optical coherence tomography, a scale model of outer retinal morphology was created using published information for direct comparison with optical coherence tomography scans. Articles and books concerning histology of the outer retina from 1900 until 2009 were evaluated, and data were used to create a scale model drawing. Boundaries between outer retinal tissue compartments described by the model were compared with intensity variations of representative spectral-domain optical coherence tomography scans using longitudinal reflectance profiles to determine the region of origin of the hyperreflective outer retinal bands. This analysis showed a high likelihood that the spectral-domain optical coherence tomography bands attributed to the external limiting membrane (the first, innermost band) and to the retinal pigment epithelium (the fourth, outermost band) are correctly attributed. Comparative analysis showed that the second band, often attributed to the boundary between inner and outer segments of the photoreceptors, actually aligns with the ellipsoid portion of the inner segments. The third band corresponded to an ensheathment of the cone outer segments by apical processes of the retinal pigment epithelium in a structure known as the contact cylinder. Anatomical attributions and subsequent pathophysiologic assessments pertaining to the second and third outer retinal hyperreflective bands may not be correct. This analysis has identified testable hypotheses for the actual correlates of the second and third bands. Nonretinal pigment epithelium contributions to the fourth band (e.g., Bruch membrane) remain to be determined.

Extracting and compensating dispersion mismatch in ultrahigh-resolution Fourier domain OCT imaging of the retina

PubMed Central

Choi, WooJhon; Baumann, Bernhard; Swanson, Eric A.; Fujimoto, James G.

2012-01-01

We present a numerical approach to extract the dispersion mismatch in ultrahigh-resolution Fourier domain optical coherence tomography (OCT) imaging of the retina. The method draws upon an analogy with a Shack-Hartmann wavefront sensor. By exploiting mathematical similarities between the expressions for aberration in optical imaging and dispersion mismatch in spectral / Fourier domain OCT, Shack-Hartmann principles can be extended from the two-dimensional paraxial wavevector space (or the x-y plane in the spatial domain) to the one-dimensional wavenumber space (or the z-axis in the spatial domain). For OCT imaging of the retina, different retinal layers, such as the retinal nerve fiber layer (RNFL), the photoreceptor inner and outer segment junction (IS/OS), or all the retinal layers near the retinal pigment epithelium (RPE) can be used as point source beacons in the axial direction, analogous to point source beacons used in conventional two-dimensional Shack-Hartman wavefront sensors for aberration characterization. Subtleties regarding speckle phenomena in optical imaging, which affect the Shack-Hartmann wavefront sensor used in adaptive optics, also occur analogously in this application. Using this approach and carefully suppressing speckle, the dispersion mismatch in spectral / Fourier domain OCT retinal imaging can be successfully extracted numerically and used for numerical dispersion compensation to generate sharper, ultrahigh-resolution OCT images. PMID:23187353

Retinal Laminar Architecture in Human Retinitis Pigmentosa Caused by Rhodopsin Gene Mutations

PubMed Central

Aleman, Tomas S.; Cideciyan, Artur V.; Sumaroka, Alexander; Windsor, Elizabeth A. M.; Herrera, Waldo; White, D. Alan; Kaushal, Shalesh; Naidu, Anjani; Roman, Alejandro J.; Schwartz, Sharon B.; Stone, Edwin M.; Jacobson, Samuel G.

2008-01-01

Purpose. To determine the underlying retinal micropathology in subclasses of autosomal dominant retinitis pigmentosa (ADRP) caused by rhodopsin (RHO) mutations. Methods. Patients with RHO-ADRP (n = 17, ages 6–73 years), representing class A (R135W and P347L) and class B (P23H, T58R, and G106R) functional phenotypes, were studied with optical coherence tomography (OCT), and colocalized visual thresholds were determined by dark- and light-adapted chromatic perimetry. Autofluorescence imaging was performed with near-infrared light. Retinal histology in hT17M-rhodopsin mice was compared with the human results. Results. Class A patients had only cone-mediated vision. The outer nuclear layer (ONL) thinned with eccentricity and was not detectable within 3 to 4 mm of the fovea. Scotomatous extracentral retina showed loss of ONL, thickening of the inner retina, and demelanization of RPE. Class B patients had superior–inferior asymmetry in function and structure. The superior retina could have normal rod and cone vision, normal lamination (including ONL) and autofluorescence of the RPE melanin; laminopathy was found in the scotomas. With Fourier-domain-OCT, there was apparent inner nuclear layer (INL) thickening in regions with ONL thinning. Retinal regions without ONL had a thick hyporeflective layer that was continuous with the INL from neighboring regions with normal lamination. Transgenic mice had many of the laminar abnormalities found in patients. Conclusions. Retinal laminar abnormalities were present in both classes of RHO-ADRP and were related to the severity of colocalized vision loss. The results in human class B and the transgenic mice support the following disease sequence: ONL diminution with INL thickening; amalgamation of residual ONL with the thickened INL; and progressive retinal remodeling with eventual thinning. PMID:18385078

Human retinal imaging using visible-light optical coherence tomography guided by scanning laser ophthalmoscopy

PubMed Central

Yi, Ji; Chen, Siyu; Shu, Xiao; Fawzi, Amani A.; Zhang, Hao F.

2015-01-01

We achieved human retinal imaging using visible-light optical coherence tomography (vis-OCT) guided by an integrated scanning laser ophthalmoscopy (SLO). We adapted a spectral domain OCT configuration and used a supercontinuum laser as the illumating source. The center wavelength was 564 nm and the bandwidth was 115 nm, which provided a 0.97 µm axial resolution measured in air. We characterized the sensitivity to be 86 dB with 226 µW incidence power on the pupil. We also integrated an SLO that shared the same optical path of the vis-OCT sample arm for alignment purposes. We demonstrated the retinal imaging from both systems centered at the fovea and optic nerve head with 20° × 20° and 10° × 10° field of view. We observed similar anatomical structures in vis-OCT and NIR-OCT. The contrast appeared different from vis-OCT to NIR-OCT, including slightly weaker signal from intra-retinal layers, and increased visibility and contrast of anatomical layers in the outer retina. PMID:26504622

The effect of a hyperdynamic environment on the development of the rat retina

NASA Technical Reports Server (NTRS)

Murakami, D. M.; Fuller, C. A.

1985-01-01

The effects of a 2 G field on the retinal development of the layers in the rat and central visual system nuclei are investigated. The thickness of the retinal layers, ganglion cells, and brains of male and female Wistar rats suspended from an 18 foot diameter centrifuge creating a 2 G field are evaluated and compared with a control group. A decrease in the thickness of the outer nuclear layer (ONL) of 37.1 percent, of 58.5 percent in the inner nuclear layer (INL), and of 28.8 percent in the inner plexiform layer (IPL), and a reduction in body weight are observed in the 2-G rats. The data reveal that the ganglion cells and visual system nuclei activity correspond well with the control data; however, the medial terminal nucleus (MTN) activity is inhibited in the 2-G rats. It is concluded that the differences in ONL and IPL are attributed to body weight reduction, but the INL and MTN are affected by the 2-G conditions.

Light-induced migration of retinal microglia into the subretinal space.

PubMed

Ng, T F; Streilein, J W

2001-12-01

To explore the effects of light exposure and deprivation on the distribution and function of microglia in the subretinal space of mice. Using a monoclonal antibody, 5D4, that identifies resting, ramified microglia, the distribution and density of microglia in the retina, and the subretinal space were determined by confocal microscopy and by immunohistochemistry of cryopreserved sections of eyes of albino and pigmented mice exposed to diverse levels of light, ranging from complete darkness to intense brightness. Axotomized retinal ganglion cells were retrograde labeled by fluorescent tracer to determine whether the marker colocalizes to 5D4+ cells. Electron microscopy was used to evaluate microglia for evidence of phagocytosis. 5D4+ microglia in pigmented eyes were limited to the inner retinal layers, but in albino eyes 5D4+ cells were found in the outer retinal layers and subretinal space as well. The subretinal space of eyes of albino mice raised from birth in complete darkness contained few 5D4+ cells, but exposure to light caused the rapid accumulation of 5D4+ cells at this site. 5D4+ cell density in the subretinal space correlated directly with intensity of ambient light. Retrograde labeling of axotomized ganglion cells resulted in 5D4+ cells in the subretinal space that contained the retrograde label. Subretinal microglia contained phagocytized rod outer segment discs. On intense light exposure, 5D4+ cells adopted an active morphology, but failed to express class II major histocompatibility complex (MHC) molecules. Light exposure induced retinal microglia migration into the subretinal space in albino mice. Subretinal microglia appeared to augment through phagocytosis the capacity of pigment epithelium to take up the photoreceptor debris of light toxicity. The unexpected presence of these cells in the subretinal space raises questions concerning their potential contribution to immune privilege in this space and to the fate of retinal transplants.

In vivo analysis of the time and spatial activation pattern of microglia in the retina following laser-induced choroidal neovascularization.

PubMed

Crespo-Garcia, Sergio; Reichhart, Nadine; Hernandez-Matas, Carlos; Zabulis, Xenophon; Kociok, Norbert; Brockmann, Claudia; Joussen, Antonia M; Strauss, Olaf

2015-10-01

Microglia play a major role in retinal neovascularization and degeneration and are thus potential targets for therapeutic intervention. In vivo assessment of microglia behavior in disease models can provide important information to understand patho-mechanisms and develop therapeutic strategies. Although scanning laser ophthalmoscope (SLO) permits the monitoring of microglia in transgenic mice with microglia-specific GFP expression, there are fundamental limitations in reliable identification and quantification of activated cells. Therefore, we aimed to improve the SLO-based analysis of microglia using enhanced image processing with subsequent testing in laser-induced neovascularization (CNV). CNV was induced by argon laser in MacGreen mice. Microglia was visualized in vivo by SLO in the fundus auto-fluorescence (FAF) mode and verified ex vivo using retinal preparations. Three image processing algorithms based on different analysis of sequences of images were tested. The amount of recorded frames was limiting the effectiveness of the different algorithms. Best results from short recordings were obtained with a pixel averaging algorithm, further used to quantify spatial and temporal distribution of activated microglia in CNV. Morphologically, different microglia populations were detected in the inner and outer retinal layers. In CNV, the peak of microglia activation occurred in the inner layer at day 4 after laser, lacking an acute reaction. Besides, the spatial distribution of the activation changed by the time over the inner retina. No significant time and spatial changes were observed in the outer layer. An increase in laser power did not increase number of activated microglia. The SLO, in conjunction with enhanced image processing, is suitable for in vivo quantification of microglia activation. This surprisingly revealed that laser damage at the outer retina led to more reactive microglia in the inner retina, shedding light upon a new perspective to approach the immune response in the retina in vivo. Copyright © 2015 Elsevier Ltd. All rights reserved.

Tumor necrosis factor and its receptors in the neuroretina and retinal vasculature after ischemia-reperfusion injury in the pig retina

PubMed Central

Gesslein, Bodil; Håkansson, Gisela; Gustafsson, Lotta; Ekström, Per

2010-01-01

Purpose Numerous studies have been performed aimed at limiting the extent of retinal injury after ischemia, but there is still no effective pharmacological treatment available. The aim of the present study was to examine the role of tumor necrosis factor (TNF)α and its receptors (TNF-R1 and TNF-R2), especially considering the neuroretina and the retinal vasculature since the retinal blood vessels are key organs in circulatory failure. Methods Retinal ischemia was induced in pigs by elevating the intraocular pressure to 80 mmHg in one eye, while the other eye served as a control (sham-operated). One hour of ischemia was followed by 5 or 12 h of reperfusion. Retinal circulation was examined in vivo by fundus imaging and fluorescein angiography. TNF-α levels were measured in the vitreous using an angiogenesis antibody array test. The presence and amounts of TNF-α, TNF-R1, and TNF-R2 were investigated in the neuroretina and in the retinal blood vessels, using immunofluorescence staining and real-time PCR techniques. Results Fundus imaging showed obstructed blood flow when ischemia was induced, and reperfusion was clearly visualized using fluorescein angiography. Ischemia resulted in elevated levels of TNF-α protein in the vitreous and TNF-α mRNA in the neuroretina. TNF-α immunofluorescence staining was localized to the Müller cells and the outer plexiform layer of the neuroretina. The expression of TNF-R1 and TNF-R2 mRNA was increased in both the neuroretina and retinal arteries following ischemia-reperfusion. Immunofluorescence double staining for TNF-R1 and either smooth muscle actin or 4',6-diamidino-2-phenylindole (DAPI) indicated expression in the cell membranes of the vascular smooth muscle cells. Double staining with TNF-R1 and calbindin showed localization to the horizontal cells in the outer plexiform layer of the neuroretina. Conclusions Retinal ischemia results in increased expression of TNF-α and its receptors (TNF-R1 and TNF-R2). Cellular signaling pathways involving TNF may be important in the development of retinal injury following ischemia and thus an interesting target for future development of pharmacological therapeutics. PMID:21152396

Retinal adaptation to dim light vision in spectacled caimans (Caiman crocodilus fuscus): Analysis of retinal ultrastructure.

PubMed

Karl, Anett; Agte, Silke; Zayas-Santiago, Astrid; Makarov, Felix N; Rivera, Yomarie; Benedikt, Jan; Francke, Mike; Reichenbach, Andreas; Skatchkov, Serguei N; Bringmann, Andreas

2018-05-19

It has been shown that mammalian retinal glial (Müller) cells act as living optical fibers that guide the light through the retinal tissue to the photoreceptor cells (Agte et al., 2011; Franze et al., 2007). However, for nonmammalian species it is unclear whether Müller cells also improve the transretinal light transmission. Furthermore, for nonmammalian species there is a lack of ultrastructural data of the retinal cells, which, in general, delivers fundamental information of the retinal function, i.e. the vision of the species. A detailed study of the cellular ultrastructure provides a basic approach of the research. Thus, the aim of the present study was to investigate the retina of the spectacled caimans at electron and light microscopical levels to describe the structural features. For electron microscopy, we used a superfast microwave fixation procedure in order to achieve more precise ultrastructural information than common fixation techniques. As result, our detailed ultrastructural study of all retinal parts shows structural features which strongly indicate that the caiman retina is adapted to dim light and night vision. Various structural characteristics of Müller cells suppose that the Müller cell may increase the light intensity along the path of light through the neuroretina and, thus, increase the sensitivity of the scotopic vision of spectacled caimans. Müller cells traverse the whole thickness of the neuroretina and thus may guide the light from the inner retinal surface to the photoreceptor cell perikarya and the Müller cell microvilli between the photoreceptor segments. Thick Müller cell trunks/processes traverse the layers which contain light-scattering structures, i.e., nerve fibers and synapses. Large Müller cell somata run through the inner nuclear layer and contain flattened, elongated Müller cell nuclei which are arranged along the light path and, thus, may reduce the loss of the light intensity along the retinal light path. The oblique arrangement of many Müller cell trunks/processes in the inner plexiform layer and the large Müller cell somata in the inner nuclear layer may suggest that light guidance through Müller cells increases the visual sensitivity. Furthermore, an adaptation of the caiman retina to low light levels is strongly supported by detailed ultrastructural data of other retinal parts, e.g. by (i) the presence of a guanine-based retinal tapetum, (ii) the rod dominance of the retina, (iii) the presence of photoreceptor cell nuclei, which penetrate the outer limiting membrane, (iv) the relatively low densities of photoreceptor and neuronal cells which is compensated by (v) the presence of rods with long and thick outer segments, that may increase the probability of photon absorption. According to a cell number analysis, the central and temporal areas of the dorsal tapetal retina, which supports downward prey detection in darker water, are the sites of the highest diurnal contrast/color vision, i.e. cone vision and of the highest retinal light sensitivity, i.e. rod vision. Copyright © 2018 Elsevier Ltd. All rights reserved.

Correlation between Spectral Optical Coherence Tomography and Fundus Autofluorescence at the margins of Geographic Atrophy

PubMed Central

Brar, Manpreet; Kozak, Igor; Cheng, Lingyun; Bartsch, Dirk-Uwe G.; Yuson, Ritchie; Nigam, Nitin; Oster, Stephen F.; Mojana, Francesca; Freeman, William R.

2009-01-01

Purpose We studied the appearance of margins of Geographic atrophy in high- resolution optical coherence tomography (OCT) images and correlate those changes with fundus autofluorescence imaging. Design Retrospective observational case study. Methods Patients with geographic atrophy secondary to dry age related macular degeneration (ARMD) were assessed by means of Spectral Domain OCT (Spectralis HRA/OCT; Heidelberg Engineering, Heidelberg, Germany or OTI, Inc, Toronto, Canada) as well as Autofluoresence Imaging (HRA or Spectralis Heidelberg Engineering, Heidelberg, Germany): The outer retinal layer alterations were analyzed in the junctional zone between normal retina and atrophic retina, and correlated with corresponding fundus autofluorescence. Results 23 eyes of 16 patients aged between 62 years to 96 years were examined. There was a significant association between OCT findings and the fundus autofluorescence findings(r=0.67, p<0.0001). Severe alterations of the outer retinal layers at margins on Spectral OCT correspond significantly to increased autofluorescence; Smooth margins on OCT correspond significantly to normal fundus autofluorescence. (Kappa-0.7348, p<0.0001). Conclusion Spectral OCT provides in vivo insight into the pathogenesis of geographic atrophy and its progression. Visualization of reactive changes in the retinal pigment epithelial cells at the junctional zone and correlation with increased fundus autofluorescence; secondary to increased lipofuscin may together serve as determinants of progression of geographic atrophy. PMID:19541290

FUNDUS AUTOFLUORESCENCE LIFETIMES AND CENTRAL SEROUS CHORIORETINOPATHY.

PubMed

Dysli, Chantal; Berger, Lieselotte; Wolf, Sebastian; Zinkernagel, Martin S

2017-11-01

To quantify retinal fluorescence lifetimes in patients with central serous chorioretinopathy (CSC) and to identify disease specific lifetime characteristics over the course of disease. Forty-seven participants were included in this study. Patients with central serous chorioretinopathy were imaged with fundus photography, fundus autofluorescence, optical coherence tomography, and fluorescence lifetime imaging ophthalmoscopy (FLIO) and compared with age-matched controls. Retinal autofluorescence was excited using a 473-nm blue laser light and emitted fluorescence light was detected in 2 distinct wavelengths channels (498-560 nm and 560-720 nm). Clinical features, mean retinal autofluorescence lifetimes, autofluorescence intensity, and corresponding optical coherence tomography (OCT) images were further analyzed. Thirty-five central serous chorioretinopathy patients with a mean visual acuity of 78 ETDRS letters (range, 50-90; mean Snellen equivalent: 20/32) and 12 age-matched controls were included. In the acute stage of central serous chorioretinopathy, retinal fluorescence lifetimes were shortened by 15% and 17% in the respective wavelength channels. Multiple linear regression analysis showed that fluorescence lifetimes were significantly influenced by the disease duration (P < 0.001) and accumulation of photoreceptor outer segments (P = 0.03) but independent of the presence or absence of subretinal fluid. Prolonged central macular autofluorescence lifetimes, particularly in eyes with retinal pigment epithelial atrophy, were associated with poor visual acuity. This study establishes that autofluorescence lifetime changes occurring in central serous chorioretinopathy exhibit explicit patterns which can be used to estimate perturbations of the outer retinal layers with a high degree of statistical significance.

Outer retinal corrugations in age-related macular degeneration.

PubMed

Ooto, Sotaro; Vongkulsiri, Sritatath; Sato, Taku; Suzuki, Mihoko; Curcio, Christine A; Spaide, Richard F

2014-07-01

Optical coherence tomography (OCT) abnormalities of age-related macular degeneration (AMD) have not been fully characterized because of the complex morphology and a lack of correlative histologic studies. Expansion of our ability to interpret increasing attributes brings us closer to the goal of in vivo histologic analysis of the eye by OCT. To describe a new outer retinal finding of AMD using spectral-domain (SD) OCT and suggest histopathologic correlates. Twenty-five eyes of 16 patients with AMD with severe atrophy due to either choroidal neovascularization (CNV) or geographic atrophy (GA) and 53 donor eyes of 53 patients with late AMD were included. Imaging studies were conducted at a referral retinal practice and histopathology was done at a university research laboratory. Findings in the outer retina were evaluated in SD-OCT images in eyes with atrophy of the retinal pigment epithelium (RPE) and compared with histopathologic findings in eyes with GA or CNV that also showed loss of the RPE. Spectral-domain OCT and histologic characteristics of the outer retina. The mean (SD) age of the 16 patients was 82.7 (7.9) years. Twenty eyes had CNV and 5 eyes had GA. The mean best-corrected visual acuity was 0.800 logMAR (interquartile range, 0.350-1.000 logMAR), a Snellen equivalent of 20/126. A curvilinear hyperreflective density was identified above the Bruch membrane line within the atrophic area in the SD-OCT images. At the internal border, the material was contiguous with the outer portion of the RPE band. Below the material was a relatively hyporeflective space. The material was thrown into folds in cases with atrophy following CNV or was seen as a sheet with numerous bumps in eyes with GA. Review of histopathologic findings of eyes with advanced GA and CNV revealed a rippled layer of basal laminar deposits in an area of RPE atrophy that was located in the same level as the curvilinear line seen in the OCT images. We have described a new entity, termed outer retinal corrugations, which may correspond to histological findings of basal laminar deposits, extracellular deposits that persist in eyes with late AMD. Observation of this undulating band does not necessarily mean there is exudation or leakage; as a consequence, these patients do not need treatment based on this solitary finding.

Microglia in mouse retina contralateral to experimental glaucoma exhibit multiple signs of activation in all retinal layers

PubMed Central

2014-01-01

Background Glaucomatous optic neuropathy, a leading cause of blindness, can progress despite control of intraocular pressure - currently the main risk factor and target for treatment. Glaucoma progression shares mechanisms with neurodegenerative disease, including microglia activation. In the present model of ocular hypertension (OHT), we have recently described morphological signs of retinal microglia activation and MHC-II upregulation in both the untreated contralateral eyes and OHT eyes. By using immunostaining, we sought to analyze and quantify additional signs of microglia activation and differences depending on the retinal layer. Methods Two groups of adult Swiss mice were used: age-matched control (naïve, n = 12), and lasered (n = 12). In the lasered animals, both OHT eyes and contralateral eyes were analyzed. Retinal whole-mounts were immunostained with antibodies against Iba-1, MHC-II, CD68, CD86, and Ym1. The Iba-1+ cell number in the plexiform layers (PL) and the photoreceptor outer segment (OS), Iba-1+ arbor area in the PL, and area of the retina occupied by Iba-1+ cells in the nerve fiber layer-ganglion cell layer (NFL-GCL) were quantified. Results The main findings in contralateral eyes and OHT eyes were: i) ameboid microglia in the NFL-GCL and OS; ii) the retraction of processes in all retinal layers; iii) a higher level of branching in PL and in the OS; iv) soma displacement to the nearest cell layers in the PL and OS; v) the reorientation of processes in the OS; vi) MHC-II upregulation in all retinal layers; vii) increased CD68 immunostaining; and viii) CD86 immunolabeling in ameboid cells. In comparison with the control group, a significant increase in the microglial number in the PL, OS, and in the area occupied by Iba-1+ cells in the NFL-GCL, and significant reduction of the arbor area in the PL. In addition, rounded Iba-1+ CD86+ cells in the NFL-GCL, OS and Ym1+ cells, and rod-like microglia in the NFL-GCL were restricted to OHT eyes. Conclusions Several quantitative and qualitative signs of microglia activation are detected both in the contralateral and OHT eyes. Such activation extended beyond the GCL, involving all retinal layers. Differences between the two eyes could help to elucidate glaucoma pathophysiology. PMID:25064005

Longitudinal assessment of retinal structure and function reveals a rod-cone degeneration in a guinea pig model initially presented as night blind.

PubMed

Racine, Julie; Joly, Sandrine; Lachapelle, Pierre

2011-08-01

We have previously reported a naturally occurring retinopathy in a population of guinea pigs, where the affected animals presented a defect of the rod-mediated vision. The purpose of this study was to investigate if the mutants were affected with a stationary or degenerative retinopathy and to identify the cellular origin of this unique disorder. Electroretinogram (ERG) [postnatal day 1 (P1) to P450], light (LM) and electron microscopy (EM) [P5, P150, P450], and immunohistochemistry [P30, P150, P450] were evaluated from normal and mutant animals. Irrespective of age, the scotopic ERGs of mutants could only be evoked by bright flashes, and the resulting ERGs were of photopic waveform. Interestingly, the amplitude of the cone and the rod/cone a-waves was always of smaller amplitude in mutants, but this difference tended to decrease with age. In contrast, the b-waves were of larger amplitude than normal in photopic ERGs obtained prior to age 25 (days) and prior to age 10 for rod/cone ERGs. LM revealed, in mutants, an absence of the outer segment layer (OSL) with a reduction in the outer nuclear layer (ONL) thickness. EM disclosed the presence of cone outer segment (OS) while no rod OS could be evidenced. Immunohistochemistry revealed the presence of rhodopsin, both cone opsins as well as normal synaptophysin immunoreactivity. Finally, neither the retinal structure nor the function in the mutants achieved normal development. Results suggest that mutant animals are suffering from a degenerative retinal disorder that affects the structure and function of rods and cones.

Vascular Displacement in Idiopathic Macular Hole after Single-layered Inverted Internal Limiting Membrane Flap Surgery.

PubMed

Lee, Jae Jung; Lee, In Ho; Park, Keun Heung; Pak, Kang Yeun; Park, Sung Who; Byon, Ik Soo; Lee, Ji Eun

2017-08-01

To compare vascular displacement in the macula after surgical closure of idiopathic macular hole (MH) after single-layered inverted internal limiting membrane (ILM) flap technique and conventional ILM removal. This retrospective study included patients who underwent either vitrectomy and ILM removal only or vitrectomy with single-layered inverted ILM flap for idiopathic MH larger than 400 μm from 2012 to 2015. A customized program compared the positions of the retinal vessels in the macula between preoperative and postoperative photographs. En face images of 6 × 6 mm optical coherence tomography volume scans were registered to calculate the scale. Retinal vessel displacement was measured as a vector value by comparing its location in 16 sectors of a grid partitioned into eight sectors in two rings (inner, 2 to 4 mm; outer, 4 to 6 mm). The distance and angle of displacement were calculated as an average vector and were compared between the two groups for whole sectors, inner ring, outer ring, and for each sector. Twenty patients were included in the ILM flap group and 22 in the ILM removal group. There were no statistical differences between the groups for baseline characteristics. The average displacement in the ILM flap group and the ILM removal group was 56.6 μm at -3.4° and 64.9 μm at -2.7°, respectively, for the whole sectors (p = 0.900), 76.1 μm at -1.1° and 87.3 μm at -0.9° for the inner ring (p = 0.980), and 37.4 μm at -8.2° and 42.7 μm at -6.3° for the outer ring (p = 0.314). There was no statistical difference in the displacement of each of the sectors. Postoperative topographic changes showed no significant differences between the ILM flap and the ILM removal group for idiopathic MH. The single-layered ILM flap technique did not appear to cause additional displacement of the retinal vessels in the macula. © 2017 The Korean Ophthalmological Society

Neuroprotective therapy for argon-laser-induced retinal injury

NASA Astrophysics Data System (ADS)

Belkin, Michael; Rosner, Mordechai; Solberg, Yoram; Turetz, Yosef

1999-06-01

Laser photocoagulation treatment of the central retina is often complicated by an immediate side effect of visual impairment, caused by the unavoidable laser-induced destruction of the normal tissue lying adjacent to the lesion and not affected directly by the laser beam. Furthermore, accidental laser injuries are at present untreatable. A neuroprotective therapy for salvaging the normal tissue might enhance the benefit obtained from treatment and allow safe perifoveal photocoagulation. We have developed a rat model for studying the efficacy of putative neuroprotective compounds in ameliorating laser-induced retinal damage. Four compounds were evaluated: the corticosteroid methylprednisolone, the glutamate-receptor blocker MK-801, the anti-oxidant enzyme superoxide dismutase, and the calcim-overload antagonist flunarizine. The study was carried out in two steps: in the first, the histopathological development of retinal laser injuries was studied. Argon laser lesions were inflicted in the retinas of 18 pigmented rats. The animals were sacrificed after 3, 20 or 60 days and their retinal lesions were evaluated under the light microscope. The laser injury mainly involved the outer layers of the retina, where it destroyed significant numbers of photoreceptor cells. Over time, evidence of two major histopathological processes was observed: traction of adjacent nomral retinal cells into the central area of the lesion forming an internal retinal bulging, and a retinal pigmented epithelial proliferative reaction associated with subretinal neovascularization and invations of the retinal lesion site by phagocytes. The neuroprotective effects of each of the four compounds were verified in a second step of the study. For each drug tested, 12 rats were irradiated wtih argon laser inflictions: six of them received the tested agent while the other six were treated with the corresponding vehicle. Twenty days after laser expsoure, the rats were sacrificed and their lesions were subjected to image-analysis morphometry. The extent of retianl damage was assessed by measuring the lesion diameter and the amount of photoreceptor cell loss in the outer nuclear layer. Methylprednisolone and MI-801 were shown to ameliorate laser-induced retinal damage, whereas both superoxide dismutase and flunarizine were ineffective. Furthermore, MK-801 diminished the proliferative reaction of the retinal pigment epithelial cells. On the basis of our results we suggest that the pigmented rat model is suitable for studying and screening various compounds for their neuroprotective efficacy in treating retinal laser injury. We further suggest that glutamate might play a key role in mediating retinal injury induced by laser irradiation.

Non-image Forming Light Detection by Melanopsin, Rhodopsin, and Long-Middlewave (L/W) Cone Opsin in the Subterranean Blind Mole Rat, Spalax Ehrenbergi: Immunohistochemical Characterization, Distribution, and Connectivity

PubMed Central

Esquiva, Gema; Avivi, Aaron; Hannibal, Jens

2016-01-01

The blind mole rat, Spalax ehrenbergi, can, despite severely degenerated eyes covered by fur, entrain to the daily light/dark cycle and adapt to seasonal changes due to an intact circadian timing system. The present study demonstrates that the Spalax retina contains a photoreceptor layer, an outer nuclear layer (ONL), an outer plexiform layer (OPL), an inner nuclear layer (INL), an inner plexiform layer (IPL), and a ganglion cell layer (GCL). By immunohistochemistry, the number of melanopsin (mRGCs) and non-melanopsin bearing retinal ganglion cells was analyzed in detail. Using the ganglion cell marker RNA-binding protein with multiple splicing (RBPMS) it was shown that the Spalax eye contains 890 ± 62 RGCs. Of these, 87% (752 ± 40) contain melanopsin (cell density 788 melanopsin RGCs/mm2). The remaining RGCs were shown to co-store Brn3a and calretinin. The melanopsin cells were located mainly in the GCL with projections forming two dendritic plexuses located in the inner part of the IPL and in the OPL. Few melanopsin dendrites were also found in the ONL. The Spalax retina is rich in rhodopsin and long/middle wave (L/M) cone opsin bearing photoreceptor cells. By using Ctbp2 as a marker for ribbon synapses, both rods and L/M cone ribbons containing pedicles in the OPL were found in close apposition with melanopsin dendrites in the outer plexus suggesting direct synaptic contact. A subset of cone bipolar cells and all photoreceptor cells contain recoverin while a subset of bipolar and amacrine cells contain calretinin. The calretinin expressing amacrine cells seemed to form synaptic contacts with rhodopsin containing photoreceptor cells in the OPL and contacts with melanopsin cell bodies and dendrites in the IPL. The study demonstrates the complex retinal circuitry used by the Spalax to detect light, and provides evidence for both melanopsin and non-melanopsin projecting pathways to the brain. PMID:27375437

Non-image Forming Light Detection by Melanopsin, Rhodopsin, and Long-Middlewave (L/W) Cone Opsin in the Subterranean Blind Mole Rat, Spalax Ehrenbergi: Immunohistochemical Characterization, Distribution, and Connectivity.

PubMed

Esquiva, Gema; Avivi, Aaron; Hannibal, Jens

2016-01-01

The blind mole rat, Spalax ehrenbergi, can, despite severely degenerated eyes covered by fur, entrain to the daily light/dark cycle and adapt to seasonal changes due to an intact circadian timing system. The present study demonstrates that the Spalax retina contains a photoreceptor layer, an outer nuclear layer (ONL), an outer plexiform layer (OPL), an inner nuclear layer (INL), an inner plexiform layer (IPL), and a ganglion cell layer (GCL). By immunohistochemistry, the number of melanopsin (mRGCs) and non-melanopsin bearing retinal ganglion cells was analyzed in detail. Using the ganglion cell marker RNA-binding protein with multiple splicing (RBPMS) it was shown that the Spalax eye contains 890 ± 62 RGCs. Of these, 87% (752 ± 40) contain melanopsin (cell density 788 melanopsin RGCs/mm(2)). The remaining RGCs were shown to co-store Brn3a and calretinin. The melanopsin cells were located mainly in the GCL with projections forming two dendritic plexuses located in the inner part of the IPL and in the OPL. Few melanopsin dendrites were also found in the ONL. The Spalax retina is rich in rhodopsin and long/middle wave (L/M) cone opsin bearing photoreceptor cells. By using Ctbp2 as a marker for ribbon synapses, both rods and L/M cone ribbons containing pedicles in the OPL were found in close apposition with melanopsin dendrites in the outer plexus suggesting direct synaptic contact. A subset of cone bipolar cells and all photoreceptor cells contain recoverin while a subset of bipolar and amacrine cells contain calretinin. The calretinin expressing amacrine cells seemed to form synaptic contacts with rhodopsin containing photoreceptor cells in the OPL and contacts with melanopsin cell bodies and dendrites in the IPL. The study demonstrates the complex retinal circuitry used by the Spalax to detect light, and provides evidence for both melanopsin and non-melanopsin projecting pathways to the brain.

Müller glia: Stem cells for generation and regeneration of retinal neurons in teleost fish

PubMed Central

Lenkowski, Jenny R.; Raymond, Pamela A.

2014-01-01

Adult zebrafish generate new neurons in the brain and retina throughout life. Growth-related neurogenesis allows a vigorous regenerative response to damage, and fish can regenerate retinal neurons, including photoreceptors, and restore functional vision following photic, chemical, or mechanical destruction of the retina. Müller glial cells in fish function as radial-glial-like neural stem cells. During adult growth, Müller glial nuclei undergo sporadic, asymmetric, self-renewing mitotic divisions in the inner nuclear layer to generate a rod progenitor that migrates along the radial fiber of the Müller glia into the outer nuclear layer, proliferates, and differentiates exclusively into rod photoreceptors. When retinal neurons are destroyed, Müller glia in the immediate vicinity of the damage partially and transiently dedifferentiate, re-express retinal progenitor and stem cell markers, re-enter the cell cycle, undergo interkinetic nuclear migration (characteristic of neuroepithelial cells), and divide once in an asymmetric, self-renewing division to generate a retinal progenitor. This daughter cell proliferates rapidly to form a compact neurogenic cluster surrounding the Müller glia; these multipotent retinal progenitors then migrate along the radial fiber to the appropriate lamina to replace missing retinal neurons. Some aspects of the injury-response in fish Müller glia resemble gliosis as observed in mammals, and mammalian Müller glia exhibit some neurogenic properties, indicative of a latent ability to regenerate retinal neurons. Understanding the specific properties of fish Müller glia that facilitate their robust capacity to generate retinal neurons will inform and inspire new clinical approaches for treating blindness and visual loss with regenerative medicine. PMID:24412518

BBSome function is required for both the morphogenesis and maintenance of the photoreceptor outer segment

PubMed Central

Hsu, Ying; Kim, Gunhee; Zhang, Qihong; Datta, Poppy; Seo, Seongjin

2017-01-01

Genetic mutations disrupting the structure and function of primary cilia cause various inherited retinal diseases in humans. Bardet-Biedl syndrome (BBS) is a genetically heterogeneous, pleiotropic ciliopathy characterized by retinal degeneration, obesity, postaxial polydactyly, intellectual disability, and genital and renal abnormalities. To gain insight into the mechanisms of retinal degeneration in BBS, we developed a congenital knockout mouse of Bbs8, as well as conditional mouse models in which function of the BBSome (a protein complex that mediates ciliary trafficking) can be temporally inactivated or restored. We demonstrate that BBS mutant mice have defects in retinal outer segment morphogenesis. We further demonstrate that removal of Bbs8 in adult mice affects photoreceptor function and disrupts the structural integrity of the outer segment. Notably, using a mouse model in which a gene trap inhibiting Bbs8 gene expression can be removed by an inducible FLP recombinase, we show that when BBS8 is restored in immature retinas with malformed outer segments, outer segment extension can resume normally and malformed outer segment discs are displaced distally by normal outer segment structures. Over time, the retinas of the rescued mice become morphologically and functionally normal, indicating that there is a window of plasticity when initial retinal outer segment morphogenesis defects can be ameliorated. PMID:29049287

Enhanced Visualization of Subtle Outer Retinal Pathology by En Face Optical Coherence Tomography and Correlation with Multi-Modal Imaging

PubMed Central

Chew, Avenell L.; Lamey, Tina; McLaren, Terri; De Roach, John

2016-01-01

Purpose To present en face optical coherence tomography (OCT) images generated by graph-search theory algorithm-based custom software and examine correlation with other imaging modalities. Methods En face OCT images derived from high density OCT volumetric scans of 3 healthy subjects and 4 patients using a custom algorithm (graph-search theory) and commercial software (Heidelberg Eye Explorer software (Heidelberg Engineering)) were compared and correlated with near infrared reflectance, fundus autofluorescence, adaptive optics flood-illumination ophthalmoscopy (AO-FIO) and microperimetry. Results Commercial software was unable to generate accurate en face OCT images in eyes with retinal pigment epithelium (RPE) pathology due to segmentation error at the level of Bruch’s membrane (BM). Accurate segmentation of the basal RPE and BM was achieved using custom software. The en face OCT images from eyes with isolated interdigitation or ellipsoid zone pathology were of similar quality between custom software and Heidelberg Eye Explorer software in the absence of any other significant outer retinal pathology. En face OCT images demonstrated angioid streaks, lesions of acute macular neuroretinopathy, hydroxychloroquine toxicity and Bietti crystalline deposits that correlated with other imaging modalities. Conclusions Graph-search theory algorithm helps to overcome the limitations of outer retinal segmentation inaccuracies in commercial software. En face OCT images can provide detailed topography of the reflectivity within a specific layer of the retina which correlates with other forms of fundus imaging. Our results highlight the need for standardization of image reflectivity to facilitate quantification of en face OCT images and longitudinal analysis. PMID:27959968

Contrast visual acuity in patients with retinitis pigmentosa assessed by a contrast sensitivity tester.

PubMed

Oishi, Maho; Nakamura, Hajime; Hangai, Masanori; Oishi, Akio; Otani, Atsushi; Yoshimura, Nagahisa

2012-01-01

To assess contrast visual acuity (CVA) in patients with retinitis pigmentosa (RP) and compare the result with standard visual acuity (VA), retinal thickness, status of inner segment/outer segment junction, and central visual field. Thirty-nine eyes of 39 patients with RP and 39 eyes of 39 healthy individuals were studied. To see the difference in CVA between RP patients and normal controls, only subjects with standard VA of 1.0 (20/20) or better were included. This was a cross-sectional study. CVA in various light conditions was measured with CAT-2000 and was compared between patients and controls. CVA of patients was further analyzed for association with other parameters including foveal retinal thickness, outer nuclear layer thickness, the status of inner segment/outer segment junction measured with optical coherence tomography (OCT), and visual field mean deviation (MD) measured with Humphrey field analyzer 10-2 program. CVA impairment was evident in RP patients compared to controls (P < 0.01, in all measurement conditions). Multivariate analysis showed association of logarithm of the minimum angle of resolution (logMAR) with CVAs in several conditions. None of the OCT measurements was associated with CVA. When patients were divided into three groups based on MD, the most advanced group (MD worse than or equal to -20 dB) showed impairment of mesopic CVA (P < 0.05, under mesopic condition of 100% without glare, with glare, and 25% without glare). CVA impairment was confirmed in RP patients, especially in advanced cases. CVA measured with CAT-2000 may be a useful tool for assessing foveal function in RP patients.

Distinct Retinal Capillary Plexuses in Normal Eyes as Observed in Optical Coherence Tomography Angiography Axial Profile Analysis.

PubMed

Hirano, Takao; Chanwimol, Karntida; Weichsel, Julian; Tepelus, Tudor; Sadda, Srinivas

2018-06-20

Optical coherence tomography angiography (OCTA) allows the retinal microvasculature to be visualized at various retinal depths. Previous studies introduced OCTA axial profile analysis and showed regional variations in the number and location of axially distinct vascular retinal plexuses. OCTA acquisition and processing approaches, however, vary in terms of their resulting transverse and axial resolutions, and especially the latter could potentially influence the profile analysis results. Our study imaged normal eyes using the Spectralis OCT2 with a full-spectrum, probabilistic OCTA algorithm, that, in marked contrast to split-spectrum approaches, preserves the original high OCT axial resolution also within the resulting OCTA signal. En face OCTA images are generally created by averaging flow signals over a finite axial depth window. However, we assessed regional OCTA signal profiles at each depth position at full axial resolution. All regions had two sharp vessel density peaks near the inner and outer boundaries of the inner nuclear layer, indicating separate intermediate and deep capillary plexuses. The superficial vascular plexus (SVP) separated into two distinct peaks within the ganglion cell layer in the parafoveal zone. The nasal, superior, and inferior perifovea had a deeper SVP peak that was shifted anteriorly compared to the parafoveal zone. Axial vascular density analysis with high-resolution, full spectrum OCTA thus allows healthy retinal vasculature to be precisely reconstructed and may be useful for clinically assessing retinal pathology.

Testing the biocompatibility of a glutathione-containing intra-ocular irrigation solution by using an isolated perfused bovine retina organ culture model - an alternative to animal testing.

PubMed

Januschowski, Kai; Zhour, Ahmad; Lee, Albert; Maddani, Ramin; Mueller, Sebastien; Spitzer, Martin S; Schnichels, Sven; Schultheiss, Maximilian; Doycheva, Deshka; Bartz-Schmidt, Karl-Ulrich; Szurman, Peter

2012-03-01

The effects of a glutathione-containing intra-ocular irrigation solution, BSS Plus©, on retinal function and on the survival of ganglion cells in whole-mount retinal explants were studied. Evidence is provided that the perfused ex vivo bovine retina can serve as an alternative to in vivo animal testing. Isolated bovine retinas were prepared and perfused with an oxygen-saturated standard irrigation solution, and an electroretinogram was recorded to assess retinal function. After stable b-waves were detected, the isolated retinas were perfused with BSS Plus for 45 minutes. To investigate the effects of BSS Plus on photoreceptor function, 1mM aspartate was added to the irrigation solution in order to obtain a-waves, and the ERG trace was monitored for 75 minutes. For histological analysis, isolated whole retinal mounts were stored for 24 hours at 4°C, in the dark. The percentages of cell death in the retinal ganglion cell layer and in the outer and inner nuclear layers were estimated by using an ethidium homodimer-1 stain and the TUNEL assay. General swelling of the retina was examined with high-resolution optical coherence tomography. During perfusion with BSS Plus, no significant changes in a-wave and b-wave amplitudes were recorded. Retinas stored for 24 hours in BSS Plus showed a statistically significant smaller percentage (52.6%, standard deviation [SD] = 16.1%) of cell death in the retinal ganglion cell layer compared to the control group (69.6%, SD = 3.9, p = 0.0031). BSS Plus did not seem to affect short-term retinal function, and had a beneficial effect on the survival of retinal ganglion cells. This method for analysing the isolated perfused retina represents a valuable alternative for testing substances for their retinal biocompatibility and toxicity. 2012 FRAME.

Fundus autofluorescence and optical coherence tomography in the management of progressive outer retinal necrosis

PubMed Central

Yeh, Steven; Wong, Wai T.; Weichel, Eric D.; Lew, Julie C.; Chew, Emily Y.; Nussenblatt, Robert B.

2011-01-01

A 41 year-old female patient with acquired immune deficiency syndrome (AIDS) presented with progressive nasal visual field loss in her right eye. Ophthalmic exam revealed widespread areas of retinal opacification with hemorrhage consistent with progressive outer retinal necrosis (PORN), which was confirmed by polymerase chain reaction (PCR) for varicella zoster virus (VZV) DNA. The patient was treated with intravenous and intravitreal foscarnet and ganciclovir with a resultant improvement clinically. Optical coherence tomography (OCT) and fundus autofluorescence (FAF) imaging revealed progressive changes indicative of widespread retinal pigment epithelial (RPE) and outer retinal dysfunction. OCT was useful in documenting progressive changes in macular architecture during therapy including neurosensory elevation, cystoid macular edema, and severe outer retinal necrosis, at initial exam, 1 week, and 1 month follow-up. Fundus autofluorescence revealed areas of stippled, hyperfluorescence within extensive zones of hypofluorescence, which progressed during the follow-up period. These areas appeared to represent lipofuscin or its photoreactive components within larger regions of RPE loss. The combination of OCT and FAF was useful in the characterization of the RPE and retinal anatomy in this patient with PORN. PMID:20337261

Automated segmentation of mouse OCT volumes (ASiMOV): Validation & clinical study of a light damage model.

PubMed

Antony, Bhavna Josephine; Kim, Byung-Jin; Lang, Andrew; Carass, Aaron; Prince, Jerry L; Zack, Donald J

2017-01-01

The use of spectral-domain optical coherence tomography (SD-OCT) is becoming commonplace for the in vivo longitudinal study of murine models of ophthalmic disease. Longitudinal studies, however, generate large quantities of data, the manual analysis of which is very challenging due to the time-consuming nature of generating delineations. Thus, it is of importance that automated algorithms be developed to facilitate accurate and timely analysis of these large datasets. Furthermore, as the models target a variety of diseases, the associated structural changes can also be extremely disparate. For instance, in the light damage (LD) model, which is frequently used to study photoreceptor degeneration, the outer retina appears dramatically different from the normal retina. To address these concerns, we have developed a flexible graph-based algorithm for the automated segmentation of mouse OCT volumes (ASiMOV). This approach incorporates a machine-learning component that can be easily trained for different disease models. To validate ASiMOV, the automated results were compared to manual delineations obtained from three raters on healthy and BALB/cJ mice post LD. It was also used to study a longitudinal LD model, where five control and five LD mice were imaged at four timepoints post LD. The total retinal thickness and the outer retina (comprising the outer nuclear layer, and inner and outer segments of the photoreceptors) were unchanged the day after the LD, but subsequently thinned significantly (p < 0.01). The retinal nerve fiber-ganglion cell complex and the inner plexiform layers, however, remained unchanged for the duration of the study.

Automated segmentation of mouse OCT volumes (ASiMOV): Validation & clinical study of a light damage model

PubMed Central

Lang, Andrew; Carass, Aaron; Prince, Jerry L.; Zack, Donald J.

2017-01-01

The use of spectral-domain optical coherence tomography (SD-OCT) is becoming commonplace for the in vivo longitudinal study of murine models of ophthalmic disease. Longitudinal studies, however, generate large quantities of data, the manual analysis of which is very challenging due to the time-consuming nature of generating delineations. Thus, it is of importance that automated algorithms be developed to facilitate accurate and timely analysis of these large datasets. Furthermore, as the models target a variety of diseases, the associated structural changes can also be extremely disparate. For instance, in the light damage (LD) model, which is frequently used to study photoreceptor degeneration, the outer retina appears dramatically different from the normal retina. To address these concerns, we have developed a flexible graph-based algorithm for the automated segmentation of mouse OCT volumes (ASiMOV). This approach incorporates a machine-learning component that can be easily trained for different disease models. To validate ASiMOV, the automated results were compared to manual delineations obtained from three raters on healthy and BALB/cJ mice post LD. It was also used to study a longitudinal LD model, where five control and five LD mice were imaged at four timepoints post LD. The total retinal thickness and the outer retina (comprising the outer nuclear layer, and inner and outer segments of the photoreceptors) were unchanged the day after the LD, but subsequently thinned significantly (p < 0.01). The retinal nerve fiber-ganglion cell complex and the inner plexiform layers, however, remained unchanged for the duration of the study. PMID:28817571

Early simultaneous fundus autofluorescence and optical coherence tomography features after pars plana vitrectomy for primary rhegmatogenous retinal detachment.

PubMed

Dell'Omo, Roberto; Mura, Marco; Lesnik Oberstein, Sarit Y; Bijl, Heico; Tan, H Stevie

2012-04-01

To describe fundus autofluorescence and optical coherence tomography (OCT) features of the macula after pars plana vitrectomy for rhegmatogenous retinal detachment. Thirty-three eyes of 33 consecutive patients with repaired rhegmatogenous retinal detachment with or without the involvement of the macula were prospectively investigated with simultaneous fundus autofluorescence and OCT imaging using the Spectralis HRA+OCT (Heidelberg Engineering, Heidelberg, Germany) within a few weeks after the operation. Fundus autofluorescence imaging of the macula showed lines of increased and decreased autofluorescence in 19 cases (57.6%). On OCT, these lines corresponded to the following abnormalities: outer retinal folds, inner retinal folds, and skip reflectivity abnormalities of the photoreceptor inner segment/outer segment band. Other OCT findings, not related to abnormal lines on fundus autofluorescence, consisted of disruption of photoreceptor inner segment/outer segment band and collection of intraretinal or subretinal fluid. The presence of outer retinal folds significantly related to metamorphopsia but did not relate to poor postoperative visual acuity. Partial-thickness retinal folds occur commonly after vitrectomy for rhegmatogenous retinal detachment repair and may represent an important anatomical substrate for postoperative metamorphopsia. Fundus autofluorescence and OCT are both sensitive techniques for the detection of these abnormalities.

Design and validation of a foldable and photovoltaic wide-field epiretinal prosthesis.

PubMed

Ferlauto, Laura; Airaghi Leccardi, Marta Jole Ildelfonsa; Chenais, Naïg Aurelia Ludmilla; Gilliéron, Samuel Charles Antoine; Vagni, Paola; Bevilacqua, Michele; Wolfensberger, Thomas J; Sivula, Kevin; Ghezzi, Diego

2018-03-08

Retinal prostheses have been developed to fight blindness in people affected by outer retinal layer dystrophies. To date, few hundred patients have received a retinal implant. Inspired by intraocular lenses, we have designed a foldable and photovoltaic wide-field epiretinal prosthesis (named POLYRETINA) capable of stimulating wireless retinal ganglion cells. Here we show that within a visual angle of 46.3 degrees, POLYRETINA embeds 2215 stimulating pixels, of which 967 are in the central area of 5 mm, it is foldable to allow implantation through a small scleral incision, and it has a hemispherical shape to match the curvature of the eye. We demonstrate that it is not cytotoxic and respects optical and thermal safety standards; accelerated ageing shows a lifetime of at least 2 years. POLYRETINA represents significant progress towards the improvement of both visual acuity and visual field with the same device, a current challenging issue in the field.

In vivo optical coherence tomography of stimulus-evoked intrinsic optical signals in mouse retinas

NASA Astrophysics Data System (ADS)

Wang, Benquan; Lu, Yiming; Yao, Xincheng

2016-09-01

Intrinsic optical signal (IOS) imaging promises a noninvasive method for advanced study and diagnosis of eye diseases. Before pursuing clinical applications, it is essential to understand anatomic and physiological sources of retinal IOSs and to establish the relationship between IOS distortions and eye diseases. The purpose of this study was designed to demonstrate the feasibility of in vivo IOS imaging of mouse models. A high spatiotemporal resolution spectral domain optical coherence tomography (SD-OCT) was employed for depth-resolved retinal imaging. A custom-designed animal holder equipped with ear bar and bite bar was used to minimize eye movements. Dynamic OCT imaging revealed rapid IOS from the photoreceptor's outer segment immediately after the stimulation delivery, and slow IOS changes were observed from inner retinal layers. Comparative photoreceptor IOS and electroretinography recordings suggested that the fast photoreceptor IOS may be attributed to the early stage of phototransduction before the hyperpolarization of retinal photoreceptor.

Retinal layer segmentation in multiple sclerosis: a systematic review and meta-analysis.

PubMed

Petzold, Axel; Balcer, Laura J; Calabresi, Peter A; Costello, Fiona; Frohman, Teresa C; Frohman, Elliot M; Martinez-Lapiscina, Elena H; Green, Ari J; Kardon, Randy; Outteryck, Olivier; Paul, Friedemann; Schippling, Sven; Vermersch, Patrik; Villoslada, Pablo; Balk, Lisanne J

2017-10-01

Structural retinal imaging biomarkers are important for early recognition and monitoring of inflammation and neurodegeneration in multiple sclerosis. With the introduction of spectral domain optical coherence tomography (SD-OCT), supervised automated segmentation of individual retinal layers is possible. We aimed to investigate which retinal layers show atrophy associated with neurodegeneration in multiple sclerosis when measured with SD-OCT. In this systematic review and meta-analysis, we searched for studies in which SD-OCT was used to look at the retina in people with multiple sclerosis with or without optic neuritis in PubMed, Web of Science, and Google Scholar between Nov 22, 1991, and April 19, 2016. Data were taken from cross-sectional cohorts and from one timepoint from longitudinal studies (at least 3 months after onset in studies of optic neuritis). We classified data on eyes into healthy controls, multiple-sclerosis-associated optic neuritis (MSON), and multiple sclerosis without optic neuritis (MSNON). We assessed thickness of the retinal layers and we rated individual layer segmentation performance by random effects meta-analysis for MSON eyes versus control eyes, MSNON eyes versus control eyes, and MSNON eyes versus MSON eyes. We excluded relevant sources of bias by funnel plots. Of 25 497 records identified, 110 articles were eligible and 40 reported data (in total 5776 eyes from patients with multiple sclerosis [1667 MSON eyes and 4109 MSNON eyes] and 1697 eyes from healthy controls) that met published OCT quality control criteria and were suitable for meta-analysis. Compared with control eyes, the peripapillary retinal nerve fibre layer (RNFL) showed thinning in MSON eyes (mean difference -20·10 μm, 95% CI -22·76 to -17·44; p<0·0001) and in MSNON eyes (-7·41 μm, -8·98 to -5·83; p<0·0001). The macula showed RNFL thinning of -6·18 μm (-8·07 to -4·28; p<0·0001) in MSON eyes and -2·15 μm (-3·15 to -1·15; p<0·0001) in MSNON eyes compared with control eyes. Atrophy of the macular ganglion cell layer and inner plexiform layer (GCIPL) was -16·42 μm (-19·23 to -13·60; p<0·0001) for MSON eyes and -6·31 μm (-7·75 to -4·87; p<0·0001) for MSNON eyes compared with control eyes. A small degree of inner nuclear layer (INL) thickening occurred in MSON eyes compared with control eyes (0·77 μm, 0·25 to 1·28; p=0·003). We found no statistical difference in the thickness of the combined outer nuclear layer and outer plexiform layer when we compared MSNON or MSON eyes with control eyes, but we found a small degree of thickening of the combined layer when we compared MSON eyes with MSNON eyes (1·21 μm, 0·24 to 2·19; p=0·01). The largest and most robust differences between the eyes of people with multiple sclerosis and control eyes were found in the peripapillary RNFL and macular GCIPL. Inflammatory disease activity might be captured by the INL. Because of the consistency, robustness, and large effect size, we recommend inclusion of the peripapillary RNFL and macular GCIPL for diagnosis, monitoring, and research. None. Copyright © 2017 Elsevier Ltd. All rights reserved.

Ultrahigh resolution retinal imaging by visible light OCT with longitudinal achromatization

PubMed Central

Chong, Shau Poh; Zhang, Tingwei; Kho, Aaron; Bernucci, Marcel T.; Dubra, Alfredo; Srinivasan, Vivek J.

2018-01-01

Chromatic aberrations are an important design consideration in high resolution, high bandwidth, refractive imaging systems that use visible light. Here, we present a fiber-based spectral/Fourier domain, visible light OCT ophthalmoscope corrected for the average longitudinal chromatic aberration (LCA) of the human eye. Analysis of complex speckles from in vivo retinal images showed that achromatization resulted in a speckle autocorrelation function that was ~20% narrower in the axial direction, but unchanged in the transverse direction. In images from the improved, achromatized system, the separation between Bruch’s membrane (BM), the retinal pigment epithelium (RPE), and the outer segment tips clearly emerged across the entire 6.5 mm field-of-view, enabling segmentation and morphometry of BM and the RPE in a human subject. Finally, cross-sectional images depicted distinct inner retinal layers with high resolution. Thus, with chromatic aberration compensation, visible light OCT can achieve volume resolutions and retinal image quality that matches or exceeds ultrahigh resolution near-infrared OCT systems with no monochromatic aberration compensation. PMID:29675296

Polyphenol-enriched Vaccinium uliginosum L. fractions reduce retinal damage induced by blue light in A2E-laden ARPE19 cell cultures and mice.

PubMed

Lee, Bom-Lee; Kang, Jung-Hwan; Kim, Hye-Mi; Jeong, Se-Hee; Jang, Dae-Sik; Jang, Young-Pyo; Choung, Se-Young

2016-12-01

Polyphenols exert beneficial effects on vision. We hypothesized that polyphenol components of Vaccinium uliginosum L. (V.U.) extract protect retinal pigment epithelial (RPE) cells against blue light-induced damage. Our aim was to test extracts containing polyphenol components to ascertain effects to reduce damage against blue light in RPEs. We measured the activity in fractions eluted from water, ethanol, and HP20 resin (FH), and found that the FH fraction had the highest beneficial activity. We isolated the individual active compounds from the FH fraction using chromatographic techniques, and found that FH contained flavonoids, anthocyanins, phenyl propanoids, and iridoids. Cell cultures of A2E-laden ARPE-19 exposed to blue light after treatment with V.U. extract fractions and their individual constituents indicated improvement. V uliginosum L extract fractions and constituent compounds significantly reduced A2E photo-oxidation-induced RPE cell death and inhibited intracellular A2E accumulation. Furthermore, Balb/c male mice were exposed to blue light at 10000 lux for 1 h/d for 2 weeks to induce retinal damage. One week after the final blue light exposure, retinal damage evaluated revealed that the outer nuclear layer thickness and nuclei count were improved. Histologic examination of murine photoreceptor cells demonstrated that FH, rich in polyphenols, inhibited the loss of outer nuclear layer thickness and nuclei. Our findings suggest that V.U. extract and eluted fractions are a potential source of bioactive compounds that potentially serve a therapeutic approach for age-related macular degeneration. Copyright © 2016 Elsevier Inc. All rights reserved.

Swept Source OCT Angiography of Neovascular Macular Telangiectasia Type 2

PubMed Central

Zhang, Qinqin; Wang, Ruikang K.; Chen, Chieh-Li; Legarreta, Andrew D.; Durbin, Mary K.; An, Lin; Sharma, Utkarsh; Stetson, Paul F.; Legarreta, John E.; Roisman, Luiz; Gregori, Giovanni; Rosenfeld, Philip J.

2015-01-01

Objective To image subretinal neovascularization in proliferative macular telangiectasia type 2 (MacTel2) using swept source optical coherence tomography based microangiography (OMAG). Study Design Patients with MacTel2 were enrolled in a prospective, observational study known as the MacTel Project and evaluated using a high-speed 1050nm swept-source OCT (SS-OCT) prototype system. The OMAG algorithm generated en face flow images from three retinal layers, as well as the region bounded by the outer retina and Bruch’s membrane, the choriocapillaris, and the remaining choroidal vasculature. The en face OMAG images were compared to images from fluorescein angiography (FA) and indocyanine green angiography (ICGA). Results Three eyes with neovascular MacTel2 were imaged. The neovascularization was best identified from the en face OMAG images that included a layer between the outer retinal boundary and Bruch’s membrane. OMAG images identified these abnormal vessels better than FA and were comparable to the images obtained using ICGA. In all three cases, OMAG identified choroidal vessels communicating with the neovascularization, and these choroidal vessels were evident in the two cases with ICGA imaging. In one case, monthly injections of bevacizumab reduced the microvascular complexity of the neovascularization, as well as the telangiectatic changes within the retinal microvasculature. In another case, less frequent bevacizumab therapy was associated with growth of the subretinal neovascular complex. Conclusions OMAG imaging provided detailed, depth-resolved information about subretinal neovascularization in MacTel2 eyes demonstrating superiority to FA imaging and similarities to ICGA imaging for documenting the retinal microvascular changes, the size and extent of the neovascular complex, the communications between the neovascular complex and the choroidal circulation, and the response to monthly bevacizumab therapy. PMID:26457402

Localization of basic fibroblast growth factor binding sites in the chick embryonic neural retina.

PubMed

Cirillo, A; Arruti, C; Courtois, Y; Jeanny, J C

1990-12-01

We have investigated the localization of basic fibroblast growth factor (bFGF) binding sites during the development of the neural retina in the chick embryo. The specificity of the affinity of bFGF for its receptors was assessed by competition experiments with unlabelled growth factor or with heparin, as well as by heparitinase treatment of the samples. Two different types of binding sites were observed in the neural retina by light-microscopic autoradiography. The first type, localized mainly to basement membranes, was highly sensitive to heparitinase digestion and to competition with heparin. It was not developmentally regulated. The second type of binding site, resistant to heparin competition, appeared to be associated with retinal cells from the earliest stages studied (3-day-old embryo, stages 21-22 of Hamburger and Hamilton). Its distribution was found to vary during embryonic development, paralleling layering of the neural retina. Binding of bFGF to the latter sites was observed throughout the retinal neuroepithelium at early stages but displayed a distinct pattern at the time when the inner and outer plexiform layers were formed. During the development of the inner plexiform layer, a banded pattern of bFGF binding was observed. These bands, lying parallel to the vitreal surface, seemed to codistribute with the synaptic bands existing in the inner plexiform layer. The presence of intra-retinal bFGF binding sites whose distribution varies with embryonic development suggests a regulatory mechanism involving differential actions of bFGF on neural retinal cells.

Progressive outer retinal necrosis associated with occlusive vasculitis in acquired immunodeficiency syndrome.

PubMed

Tseng, Chien-Chi; Chen, San-Ni; Hwang, Jiunn-Feng; Lin, Chun-Ju; Chen, Huan-Sheng

2015-05-01

A 45-year-old man, a case of acquired immunodeficiency syndrome, received a highly active antiretroviral therapy at the outpatient service for 4 years without regular follow-up. He experienced progressively blurred vision for 6 months and a cutaneous zoster on his back 3 months ago. He was diagnosed with progressive outer retinal necrosis by polymerase chain reaction-restriction fragment length polymorphism using an aqueous humor sample, which revealed an existence of varicella zoster virus. He was given a combination of systemic, intravitreal antiviral and a highly active antiretroviral therapy. Occlusive vasculitis, an unusual finding for progressive outer retinal necrosis, developed in both eyes 1 week after the secondary intravitreal injection. Unfortunately, his vision deteriorated to no light perception in both eyes within 2 weeks. Progressive outer retinal necrosis is characterized clinically as showing minimal or no inflammation in the aqueous and vitreous humors, absence of retinal vasculitis, and patches of yellowish spots located deep in the retina. Physicians should pay attention to this rare case of progressive outer retinal necrosis associated occlusive vasculitis with very poor prognosis in spite of aggressive treatment. Copyright © 2015. Published by Elsevier B.V.

The anatomy of the rat eye with oxygen-induced retinopathy.

PubMed

Akula, James D; Favazza, Tara L; Mocko, Julie A; Benador, Ilan Y; Asturias, Ana L; Kleinman, Michael S; Hansen, Ronald M; Fulton, Anne B

2010-02-01

Prior studies have documented the intertwined developmental courses of retinal blood vessel tortuosity (in fundus photographs) and retinal dysfunction (in electroretinographs) in Sprague-Dawley rat models of retinopathy of prematurity (ROP). Two such models, the "50/10 model" and the "75 model," are named after the oxygen regimens used to induce retinopathy and are characterized by distinct neurovascular courses that span a range of disease severity. In this study of 50/10 and 75 model rats, retinal flatmounts were used to study the full vasculature at postnatal day (P) 15, P19 and P30. In addition, the layers of the neural retina were measured in toluidine blue-stained cross sections. Finally, gross anatomic features of the eye, including axial length, retinal surface area, and the ratio of anterior to posterior axial-lengths were evaluated. Both clock hours of neovascularization (NV) and percent avascular retina (AR) peaked at P19 and resolved by P30. Through P19, NV was found in every 50/10 model rat, but in only 60% of 75 model rats. AR was positively related to NV. All inner layers of the retina (outer plexiform layer through ganglion cell layer) were attenuated in 50/10 model rats but, in the 75 model, no layer differed significantly from that in controls. The eyes in both ROP models were smaller than those of age-matched controls. The ratio of anterior to posterior axial-lengths ranged from 0.45 in controls through 0.37 in the 75 model to 0.32 in the 50/10 model. Thus, eye growth is altered in these rat models of ROP.

FUNDUS AUTOFLUORESCENCE LIFETIMES AND CENTRAL SEROUS CHORIORETINOPATHY

PubMed Central

Dysli, Chantal; Berger, Lieselotte; Wolf, Sebastian

2017-01-01

Purpose: To quantify retinal fluorescence lifetimes in patients with central serous chorioretinopathy (CSC) and to identify disease specific lifetime characteristics over the course of disease. Methods: Forty-seven participants were included in this study. Patients with central serous chorioretinopathy were imaged with fundus photography, fundus autofluorescence, optical coherence tomography, and fluorescence lifetime imaging ophthalmoscopy (FLIO) and compared with age-matched controls. Retinal autofluorescence was excited using a 473-nm blue laser light and emitted fluorescence light was detected in 2 distinct wavelengths channels (498–560 nm and 560–720 nm). Clinical features, mean retinal autofluorescence lifetimes, autofluorescence intensity, and corresponding optical coherence tomography (OCT) images were further analyzed. Results: Thirty-five central serous chorioretinopathy patients with a mean visual acuity of 78 ETDRS letters (range, 50–90; mean Snellen equivalent: 20/32) and 12 age-matched controls were included. In the acute stage of central serous chorioretinopathy, retinal fluorescence lifetimes were shortened by 15% and 17% in the respective wavelength channels. Multiple linear regression analysis showed that fluorescence lifetimes were significantly influenced by the disease duration (P < 0.001) and accumulation of photoreceptor outer segments (P = 0.03) but independent of the presence or absence of subretinal fluid. Prolonged central macular autofluorescence lifetimes, particularly in eyes with retinal pigment epithelial atrophy, were associated with poor visual acuity. Conclusion: This study establishes that autofluorescence lifetime changes occurring in central serous chorioretinopathy exhibit explicit patterns which can be used to estimate perturbations of the outer retinal layers with a high degree of statistical significance. PMID:28099314

Evaluation of Retinal Function and Morphology of the Pink-Eyed Royal College of Surgeons (RCS) Rat: A Comparative Study of in Vivo and in Vitro Methods.

PubMed

Rösch, Sarah; Aretzweiler, Christoph; Müller, Frank; Walter, Peter

2017-02-01

To characterize the course of retinal degeneration in the pink-eyed RCS rat in vivo and in vitro. Retinal function of RCS rats at the age of 2 to 100 weeks was determined in vivo using full-field electroretinography (ERG). Retinal morphology was evaluated in vivo using spectral domain Optical Coherence Tomography (sd-OCT) and Fluorescence angiography (FA) as well as postmortem using immunohistochemistry (IH). As a control, retinal function and morphology of non-dystrophic Wistar rats were analyzed. RCS rats showed an extinction of the ERG beginning with the age of 4 weeks. In the OCT, the outer part of the retina (OPR) could be clearly distinguished from the inner part of the retina (IPR) until the age of 8 weeks. However, at this age, it was impossible to determine from OCT images whether the OPR was formed by the outer nuclear layer (ONL) or by cellular debris built in the course of retinal degeneration. In contrast, immunohistochemistry always enabled to differentiate between ONL and debris (RCS 4 weeks of age: OPR mainly formed by ONL; RCS 8 weeks of age: OPR consisted mainly of cell debris, only 1-2 cell rows of photoreceptor somata were left). In general, data obtained in vivo were confirmed by data obtained post mortem. Apart from the problem to differentiate between debris and ONL at the age of 8 weeks in the RCS rat, ERG and OCT are useful methods to evaluate retinal function and structure in vivo and to complement immunohistochemical analysis of the degeneration process.

Water maze performance of aged Sprague-Dawley rats in relation to retinal morphologic measures.

PubMed

Spencer, R L; O'Steen, W K; McEwen, B S

1995-06-01

The spatial learning ability of aged male and female Sprague-Dawley rats was assessed using the Morris water maze. To determine the influence of age-related visual deficits on performance levels, retinal morphologic measures were correlated with water maze performance for each rat. Rats were first trained on the water maze task at 21 months of age and were retrained 3 or 4 times at 6-week intervals. After the last training session the rats were killed and their eyes were removed for histopathologic and morphometric evaluation of the retinas. There was a large degree of retinal degeneration in all of the aged Sprague-Dawley rats with an average decrease in the thickness of the retinal outer nuclear layer (photoreceptor nuclei containing layer) of 85% in old males and 95% in old females. Some rats, however, had less degeneration of the retinas than others, and the degree of retinal degeneration was strongly related to performance levels on the water maze task. Among the aged rats in this study with the least retinal degeneration, there was little evidence for a subset of rats that were unable, with extensive training, to learn a platform position. Of the 41 rats with the least retinal degeneration (out of a total of 81), only one was a clear non-learner on the water maze task, whereas, of the 27 rats with the most retinal degeneration, 20 were non-learners. These results illustrate the potentially serious confounding effects of deteriorating visual ability on attempts to assess cognitive functioning of aged albino rats on tasks requiring utilization of visual cues.

Two-Photon Autofluorescence Imaging Reveals Cellular Structures Throughout the Retina of the Living Primate Eye.

PubMed

Sharma, Robin; Williams, David R; Palczewska, Grazyna; Palczewski, Krzysztof; Hunter, Jennifer J

2016-02-01

Although extrinsic fluorophores can be introduced to label specific cell types in the retina, endogenous fluorophores, such as NAD(P)H, FAD, collagen, and others, are present in all retinal layers. These molecules are a potential source of optical contrast and can enable noninvasive visualization of all cellular layers. We used a two-photon fluorescence adaptive optics scanning light ophthalmoscope (TPF-AOSLO) to explore the native autofluorescence of various cell classes spanning several layers in the unlabeled retina of a living primate eye. Three macaques were imaged on separate occasions using a custom TPF-AOSLO. Two-photon fluorescence was evoked by pulsed light at 730 and 920 nm excitation wavelengths, while fluorescence emission was collected in the visible range from several retinal layers and different locations. Backscattered light was recorded simultaneously in confocal modality and images were postprocessed to remove eye motion. All retinal layers yielded two-photon signals and the heterogeneous distribution of fluorophores provided optical contrast. Several structural features were observed, such as autofluorescence from vessel walls, Müller cell processes in the nerve fibers, mosaics of cells in the ganglion cell and other nuclear layers of the inner retina, as well as photoreceptor and RPE layers in the outer retina. This in vivo survey of two-photon autofluorescence throughout the primate retina demonstrates a wider variety of structural detail in the living eye than is available through conventional imaging methods, and broadens the use of two-photon imaging of normal and diseased eyes.

Allele-Specific Inhibition of Rhodopsin With an Antisense Oligonucleotide Slows Photoreceptor Cell Degeneration

PubMed Central

Murray, Susan F.; Jazayeri, Ali; Matthes, Michael T.; Yasumura, Douglas; Yang, Haidong; Peralta, Raechel; Watt, Andy; Freier, Sue; Hung, Gene; Adamson, Peter S.; Guo, Shuling; Monia, Brett P.; LaVail, Matthew M.; McCaleb, Michael L.

2015-01-01

Purpose To preserve photoreceptor cell structure and function in a rodent model of retinitis pigmentosa with P23H rhodopsin by selective inhibition of the mutant rhodopsin allele using a second generation antisense oligonucleotide (ASO). Methods Wild-type mice and rats were treated with ASO by intravitreal (IVT) injection and rhodopsin mRNA and protein expression were measured. Transgenic rats expressing the murine P23H rhodopsin gene (P23H transgenic rat Line 1) were administered either a mouse-specific P23H ASO or a control ASO. The contralateral eye was injected with PBS and used as a comparator control. Electroretinography (ERG) measurements and analyses of the retinal outer nuclear layer were conducted and correlated with rhodopsin mRNA levels. Results Rhodopsin mRNA and protein expression was reduced after a single ASO injection in wild-type mice with a rhodopsin-specific ASO. Transgenic rat eyes that express a murine P23H rhodopsin gene injected with a murine P23H ASO had a 181 ± 39% better maximum amplitude response (scotopic a-wave) as compared with contralateral PBS-injected eyes; the response in control ASO eyes was not significantly different from comparator contralateral eyes. Morphometric analysis of the outer nuclear layer showed a significantly thicker nuclear layer in eyes injected with murine P23H ASO (18%) versus contralateral PBS-injected eyes. Conclusions Allele-specific ASO-mediated knockdown of mutant P23H rhodopsin expression slowed the rate of photoreceptor degeneration and preserved the function of photoreceptor cells in eyes of the P23H rhodopsin transgenic rat. Our data indicate that ASO treatment is a potentially effective therapy for the treatment of retinitis pigmentosa. PMID:26436889

Autofluorescence from the outer retina and subretinal space: hypothesis and review.

PubMed

Spaide, Richard

2008-01-01

To review the pathophysiologic principles underlying increased autofluorescence from the outer retina and subretinal space using selected diseases as examples. The ocular imaging information and histopathologic features, when known, were integrated for diseases causing increased autofluorescence from the outer retina and subretinal space. Inferences were taken from this information and used to create a classification scheme. These diseases are principally those that cause separation of the outer retina from the retinal pigment epithelium, thereby preventing proper phagocytosis of photoreceptor outer segments. The separation can arise from increased exudation into the subretinal space or inadequate removal of fluid from the subretinal space. Lack of normal outer segment processing initially leads to increased accumulation of outer segments on the outer retina and subretinal space. Over time, this material is visible as an increasingly thick coating on the outer retina, is yellow, and is autofluorescent. Over time, atrophy develops with thinning of the deposited material and decreasing autofluorescence. The accumulated material is ultimately capable of inducing damage to the retinal pigment epithelium. Diseases causing accumulation of the material include central serous chorioretinopathy, vitelliform macular dystrophy, acute exudative polymorphous vitelliform maculopathy, choroidal tumors, and vitreomacular traction syndrome. The physical separation of the retinal outer segments from the retinal pigment epithelium hinders proper phagocytosis of the outer segments. Accumulation of the shed but not phagocytized outer segments plays a role in disease manifestations for a number of macular diseases.

A Framework for Modeling Competitive and Cooperative Computation in Retinal Processing

NASA Astrophysics Data System (ADS)

Moreno-Díaz, Roberto; de Blasio, Gabriel; Moreno-Díaz, Arminda

2008-07-01

The structure of the retina suggests that it should be treated (at least from the computational point of view), as a layered computer. Different retinal cells contribute to the coding of the signals down to ganglion cells. Also, because of the nature of the specialization of some ganglion cells, the structure suggests that all these specialization processes should take place at the inner plexiform layer and they should be of a local character, prior to a global integration and frequency-spike coding by the ganglion cells. The framework we propose consists of a layered computational structure, where outer layers provide essentially with band-pass space-time filtered signals which are progressively delayed, at least for their formal treatment. Specialization is supposed to take place at the inner plexiform layer by the action of spatio-temporal microkernels (acting very locally), and having a centerperiphery space-time structure. The resulting signals are then integrated by the ganglion cells through macrokernels structures. Practically all types of specialization found in different vertebrate retinas, as well as the quasilinear behavior in some higher vertebrates, can be modeled and simulated within this framework. Finally, possible feedback from central structures is considered. Though their relevance to retinal processing is not definitive, it is included here for the sake of completeness, since it is a formal requisite for recursiveness.

Neuroprotective effect of Lycium barbarum on retina of Royal College of Surgeons (RCS) rats: a preliminary study.

PubMed

Ni, Tongshang; Wei, Guangwei; Yin, Xuntao; Liu, Xianghe; Liu, Dianwei

2013-01-01

Hereditary retinal dystrophy usually leads to blindness. Using Royal College of Surgeons (RCS) rats as a hereditary retinal dystrophy model, we investigated the possible neuroprotective effects of the aqueous extract of dried Lycium barbarum (LBA). Sixty postnatal RCS rats were selected and randomly divided into a control group (CG, thirty rats) and an experimental group (EG). Ten days after birth, EG rats were treated by 1 mg/kg of LBA per day, and CG rats were normally fed. These rats were killed at postnatal day (P) 25, P35 and P50, and retinal tissue was prepared for analysis. Photoreceptor cells were assessed by hematoxylin and eosin (HE) staining, TUNEL detection and Caspase-2 protein expression. We found that in rats at P25, the outer nuclear layer (ONL) of EG was thicker and more photoreceptor cells survived. Meanwhile, the TUNEL expression in EG was obviously reduced compared with CG. The Caspase-2 positive cells were found in the ganglion cell layer and inner nuclear layer in both CG and EG at 25-50 postnatal days, but the expression in EG rats was significantly lower than in CG at P25. The results demonstrated that LBA might have a neuroprotective role on the retinal tissue of RCS rats at the early stage by protecting photoreceptors and inhibiting apoptosis involving Caspase-2 protein.

Effect of ranibizumab on high-speed indocyanine green angiography and minimum intensity projection optical coherence tomography findings in neovascular age-related macular degeneration.

PubMed

Nicholson, Benjamin P; Nigam, Divya; Toy, Brian; Stetson, Paul F; Agrón, Elvira; Jacobs-El, Naima; Cunningham, Denise; Cukras, Catherine; Wong, Wai; Wiley, Henry; Chew, Emily; Ferris, Frederick; Meyerle, Catherine B

2015-01-01

The purpose of this 1-year prospective study was to investigate how induction/pro re nata ranibizumab intravitreal treatment of eyes with neovascular age-related macular degeneration affects the anatomy of choroidal neovascularization (CNV) and the overlying outer retinal tissue. High-speed indocyanine green (HS-ICG) angiography measurements provided quantification of the CNV size in 60 patients followed for 1 year. Minimum intensity projection optical coherence tomography (MinIP OCT), a novel algorithm assessing minimum optical intensity between the internal limiting membrane and retinal pigment epithelium, measured the area of outer retinal disruption overlying the CNV. Fluorescein angiography was also assessed to evaluate late retinal leakage. After 1 year, the mean area of CNV measured with indocyanine green angiography decreased by 5.8%. The mean area of MinIP OCT of outer retinal disruption overlying the CNV decreased by 4.2%. Mean area of fluorescein angiography leakage decreased by 6.3%. Both the area of outer retinal disruption measured with MinIP OCT and the area of leakage on fluorescein angiography typically exceeded the area of CNV on indocyanine green angiography at baseline and 1 year. Choroidal neovascularization treated with induction/pro re nata intravitreal ranibizumab for 1 year essentially remained static. Minimum intensity projection optical coherence tomography suggests that the area of outer retinal disruption overlying the CNV may be greater than the CNV itself and often correlates with the leakage area on fluorescein angiography. Additionally, there was minimal change in the area of outer retinal disruption on MinIP OCT even when fluid resolved. Measurements of the extent of CNV lesions based on indocyanine green angiography and MinIP OCT may provide useful outcome variables to help assess the CNV complex longitudinally and warrant further validation.

OPTICAL COHERENCE TOMOGRAPHY FINDINGS IN CYTOMEGALOVIRUS RETINITIS: A Longitudinal Study.

PubMed

Invernizzi, Alessandro; Agarwal, Aniruddha; Ravera, Vittoria; Oldani, Marta; Staurenghi, Giovanni; Viola, Francesco

2018-01-01

To evaluate the vitreal, retinal, and choroidal features using spectral domain optical coherence tomography (SD-OCT) in eyes affected by cytomegalovirus (CMV) retinitis. Patients diagnosed with either active or inactive CMV retinitis were included in the study. Complete ophthalmic examination, serial color fundus photography, and SD-OCT (with and without enhanced depth imaging function) were performed for all the subjects at baseline and follow-up visits. The SD-OCT images were analyzed by two independent graders to evaluate the structural changes in areas of CMV retinitis. Prevalence data for vitreal, retinal, and choroidal SD-OCT features were collected. Twelve eyes from 9 patients (6 males, mean age: 52.7 ± 10.3 years) were enrolled. Nine eyes were diagnosed with active CMV retinitis at baseline. Active disease SD-OCT characteristic findings included nebulous vitritis (100%), posterior hyaloid thickening (83.3%), epiretinal membrane (100%), and retinal swelling (100%). Two distinct patterns of chorioretinal involvement were observed in active retinitis: 1) full-thickness retinitis (Full thickness retinitis) (n = 7 eyes) with choriocapillaris alterations and retinal pigment epithelial thickening and 2) cavernous retinitis (n = 3 eyes) characterized by inner retinal hyperreflectivity, large empty spaces in outer nuclear layer, and bridges of retinal tissue but retinal pigment epithelium and choriocapillaris sparing. Patients with cavernous retinitis develop retinal detachment during follow-up. Eyes with Full thickness retinitis developed choriocapillaris atrophy and choroidal thinning and retinal scars as the lesions healed. There are two distinct patterns of chorioretinal involvement in CMV retinitis. SD-OCT is a useful tool in the diagnosis, management, and prediction of the outcome of CMV retinitis.

Somatic and neuritic spines on tyrosine hydroxylase–immunopositive cells of rat retina

PubMed Central

Fasoli, Anna; Dang, James; Johnson, Jeffrey S.; Gouw, Aaron H.; Iseppe, Alex Fogli; Ishida, Andrew T.

2018-01-01

Dopamine- and tyrosine hydroxylase–immunopositive cells (TH cells) modulate visually driven signals as they flow through retinal photoreceptor, bipolar, and ganglion cells. Previous studies suggested that TH cells release dopamine from varicose axons arborizing in the inner and outer plexiform layers after glutamatergic synapses depolarize TH cell dendrites in the inner plexiform layer and these depolarizations propagate to the varicosities. Although it has been proposed that these excitatory synapses are formed onto appendages resembling dendritic spines, spines have not been found on TH cells of most species examined to date or on TH cell somata that release dopamine when exposed to glutamate receptor agonists. By use of protocols that preserve proximal retinal neuron morphology, we have examined the shape, distribution, and synapse-related immunoreactivity of adult rat TH cells. We report here that TH cell somata, tapering and varicose inner plexiform layer neurites, and varicose outer plexiform layer neurites all bear spines, that some of these spines are immunopositive for glutamate receptor and postsynaptic density proteins (viz., GluR1, GluR4, NR1, PSD-95, and PSD-93), that TH cell somata and tapering neurites are also immunopositive for a γ-aminobutyric acid (GABA) receptor subunit (GABAARα1), and that a synaptic ribbon-specific protein (RIBEYE) is found adjacent to some colocalizations of GluR1 and TH in the inner plexiform layer. These results identify previously undescribed sites at which glutamatergic and GABAergic inputs may stimulate and inhibit dopamine release, especially at somata and along varicose neurites that emerge from these somata and arborize in various levels of the retina. PMID:28035673

Macular retinal and choroidal thickness in unilateral amblyopia using swept-source optical coherence tomography.

PubMed

Araki, Syunsuke; Miki, Atsushi; Goto, Katsutoshi; Yamashita, Tsutomu; Takizawa, Go; Haruishi, Kazuko; Ieki, Yoshiaki; Kiryu, Junichi; Yaoeda, Kiyoshi

2017-09-15

To investigate macular retinal and choroidal thickness in amblyopic eyes compared to that in fellow and normal eyes using swept-source optical coherence tomography (SS-OCT). This study examined 31 patients with hyperopic anisometropic amblyopia (6.9 ± 3.8 years, mean ± standard deviation), 15 patients with strabismic amblyopia without anisometropia (7.9 ± 4.2 years), and 24 age-matched controls (7.8 ± 3.3 years). Retinal and choroidal thickness was measured by 3D scans using SS-OCT. A 6-mm area around the fovea was automatically analyzed using the Early Treatment Diabetic Retinopathy Study map. The thickness from SS-OCT was corrected for magnification error using individual axial length, spherical refraction, cylinder refraction, and corneal radius. Retinal thickness was divided into the macular retinal nerve fiber layer (mRNFL), ganglion cell layer + inner plexiform layer (GCL+IPL), ganglion cell complex (GCC), and the inner limiting membrane to the retinal pigment epithelium (ILM-RPE) thickness. Retinal and choroidal thickness was compared among amblyopic, fellow, and normal eyes. In both amblyopia groups, there was no significant difference in the mRNFL, GCL+IPL, and GCC thicknesses among the amblyopic, fellow, and control eyes. In the anisometropic amblyopia group, choroidal thickness (subfovea, center 1 mm, nasal and inferior of the inner ring, nasal of the outer ring, and center 6 mm) of amblyopic eyes were significantly greater than that of fellow and normal eyes. In contrast, none of the choroidal thicknesses were significantly different among the investigated eyes in the strabismic amblyopia group. We found no significant difference in inner retinal thickness in patients with unilateral amblyopia. Although there were significant differences in choroidal thickness with hyperopic anisometropic amblyopia, there was no significant difference for the strabismic amblyopia. The discrepancy in choroidal thickness between the two types of amblyopia may be due to both differences in ocular size and underlying mechanism.

Histopathological and immunohistochemical findings associated with a null mutation in the Norrie disease gene.

PubMed

Schroeder, B; Hesse, L; Brück, W; Gal, A

1997-06-01

To determine the clinical, histopathological, and immunohistochemical ocular changes associated with a null mutation in the Norrie disease protein (NDP) gene. Tissue from a six-month-old boy with bilateral retrolental membranes and retinal detachment was obtained during vitreoretinal surgery. Histological sections were stained immunohistochemically with specific antibodies. No eye diseases with severe visual impairment or blindness were reported in the parents and their families. The NDP gene was analyzed by standard molecular genetic methods. A severe reduction in the number of retinal ganglion cells and a largely disarranged and hypoplastic inner nuclear layer were visible in the tissue specimen. Areas of the tissue with advanced pathology displayed massive fibrovascular proliferation in the vitreous cavity. Shrinkage and traction resulted in folding and detachment of the outer retina. Immunohistochemical reactivity for MIB(1) antigen demonstrated many proliferating cells in the vitreous, but no proliferative activity in the neuroretina. Retinal neurons showed a high grade of differentiation and expressed uniformly neuron-specific enolase and synaptophysin. A 1-base pair insertion (544/545insA) in the NDP gene was found in the affected boy. This mutation predicts a 'functional null-allele' due to a shift in the reading frame and, thus, a premature termination of mRNA translation after 55 instead of 133 amino acids. Loss of function of the NDP gene causes marked hypoplasia of the inner retinal cell layers and fibrovascular proliferation in the vitreous cavity, leading to retinal folding and detachment. The NDP therefore seems to play a critical role in terminal differentiation of the inner retinal cell layers and establishment and maintaining of anti-proliferative cellular interactions in the vitreous.

Cone Photoreceptor Packing Density and the Outer Nuclear Layer Thickness in Healthy Subjects

PubMed Central

Chui, Toco Y. P.; Song, Hongxin; Clark, Christopher A.; Papay, Joel A.; Burns, Stephen A.; Elsner, Ann E.

2012-01-01

Purpose. We evaluated the relationship between cone photoreceptor packing density and outer nuclear layer (ONL) thickness within the central 15 degrees. Methods. Individual differences for healthy subjects in cone packing density and ONL thickness were examined in 8 younger and 8 older subjects, mean age 27.2 versus 56.2 years. Cone packing density was obtained using an adaptive optics scanning laser ophthalmoscope (AOSLO). The ONL thickness measurements included the ONL and the Henle fiber layer (ONL + HFL), and were obtained using spectral domain optical coherence tomography (SDOCT) and custom segmentation software. Results. There were sizeable individual differences in cone packing density and ONL + HFL thickness. Older subjects had on average lower cone packing densities, but thicker ONL + HFL measurements. Cone packing density and ONL + HFL thickness decreased with increasing retinal eccentricity. The ratio of the cone packing density-to-ONL2 was larger for the younger subjects group, and decreased with retinal eccentricity. Conclusions. The individual differences in cone packing density and ONL + HFL thickness are consistent with aging changes, indicating that normative aging data are necessary for fine comparisons in the early stages of disease or response to treatment. Our finding of ONL + HFL thickness increasing with aging is inconsistent with the hypothesis that ONL measurements with SDOCT depend only on the number of functioning cones, since in our older group cones were fewer, but thickness was greater. PMID:22570340

KCNQ and KCNE Potassium Channel Subunit Expression in Bovine Retinal Pigment Epithelium

PubMed Central

Zhang, Xiaoming; Hughes, Bret A.

2013-01-01

Human, monkey, and bovine retinal pigment epithelial (RPE) cells exhibit an M-type K+ current, which in many other cell types is mediated by channels composed of KCNQ α-subunits and KCNE auxiliary subunits. Recently, we demonstrated the expression of KCNQ1, KCNQ4, and KCNQ5 in the monkey RPE. Here, we investigated the expression of KCNQ and KCNE subunits in native bovine RPE. RT-PCR analysis revealed the expression of KCNQ1, KCNQ4, and KCNQ5 transcripts in the RPE, but, in Western blot analysis of RPE plasma membranes, only KCNQ5 was detected. Among the five members of the KCNE gene family, transcripts for KCNE1, KCNE2, KCNE3, and KCNE4 were detected in bovine RPE, but only KCNE1 and KCNE2 proteins were detected. Immunohistochemistry of frozen bovine retinal sections revealed KCNE1 expression near the apical and basal membranes of the RPE, in cone outer segments, in the outer nuclear layer, and throughout the inner retina. The localization of KCNE1 in the RPE basal membrane, where KCNQ5 was previously found to be present, suggests that this β-subunit may contribute to M-type K+ channels in this membrane. PMID:24416770

Protective Effect of Highly Polymeric A-Type Proanthocyanidins from Seed Shells of Japanese Horse Chestnut (Aesculus turbinata BLUME) against Light-Induced Oxidative Damage in Rat Retina

PubMed Central

Ishihara, Tomoe; Kaidzu, Sachiko; Kimura, Hideto; Koyama, Yasurou; Matsuoka, Yotaro

2018-01-01

Retinal tissue is exposed to oxidative stress caused by visible light. Light-damaged rat used in age-related macular degeneration (AMD) studies clarified that antioxidants decrease retinal light damage. Albino rats were exposed to 5000 Lux light for 12 h with oral administration of the polyphenolic compounds fraction (PF) from the seed shells of Japanese horse chestnut (30 mg/kg, 100 mg/kg, and 300 mg/kg body weight: BW). To evaluate the protective effects against light damage, electroretinograms (ERGs), the outer nuclear layer (ONL) thickness, the antioxidant activity of plasma, oxidized retinal lipids, and the detection of apoptosis were examined. To reveal their active compounds, PF were separated into an A-type proanthocyanidin (PAF) and a flavonol O-glycosides fraction. The protective effects of these fractions against light damage were compared by measuring the thickness of the ERGs and ONL. Compared with the negative control, the PF group (100 mg/kg and 300 mg/kg BW) significantly suppressed the decrease of the ERG amplitudes and ONL thickness. PF (300 mg/kg BW) induced the elevation of in vivo antioxidant activity, and the suppression of retinal lipid oxidation. PF administration also suppressed apoptotic cell death. The protective effects against light damage were attributable to the antioxidant activity of PAF. The light-induced damage of retinas was protected by oral administration of PF and PAF. Taken together, these compounds are potentially useful for the prevention of the disease caused by light exposure. Highlights: The protective effects of retinal damage by light exposure were evaluated using polyphenolic compounds from the seed shells of Japanese horse chestnut (Aesculus turbinata BLUME) as an antioxidant. Decreases in the electroretinographic amplitude and outer nuclear layer thickness were suppressed by the polyphenolic compounds of the seed shells. Polyphenolic compounds from the seed shells of Japanese horse chestnut inhibited the oxidation of retinal lipids. Highly polymeric A-type proanthocyanidin from the seed shells protected the rat retina from light exposure damage by inhibiting oxidative stress and apoptotic mechanisms. PMID:29748512

Protective Effect of Highly Polymeric A-Type Proanthocyanidins from Seed Shells of Japanese Horse Chestnut (Aesculus turbinata BLUME) against Light-Induced Oxidative Damage in Rat Retina.

PubMed

Ishihara, Tomoe; Kaidzu, Sachiko; Kimura, Hideto; Koyama, Yasurou; Matsuoka, Yotaro; Ohira, Akihiro

2018-05-10

Retinal tissue is exposed to oxidative stress caused by visible light. Light-damaged rat used in age-related macular degeneration (AMD) studies clarified that antioxidants decrease retinal light damage. Albino rats were exposed to 5000 Lux light for 12 h with oral administration of the polyphenolic compounds fraction (PF) from the seed shells of Japanese horse chestnut (30 mg/kg, 100 mg/kg, and 300 mg/kg body weight: BW). To evaluate the protective effects against light damage, electroretinograms (ERGs), the outer nuclear layer (ONL) thickness, the antioxidant activity of plasma, oxidized retinal lipids, and the detection of apoptosis were examined. To reveal their active compounds, PF were separated into an A-type proanthocyanidin (PAF) and a flavonol O -glycosides fraction. The protective effects of these fractions against light damage were compared by measuring the thickness of the ERGs and ONL. Compared with the negative control, the PF group (100 mg/kg and 300 mg/kg BW) significantly suppressed the decrease of the ERG amplitudes and ONL thickness. PF (300 mg/kg BW) induced the elevation of in vivo antioxidant activity, and the suppression of retinal lipid oxidation. PF administration also suppressed apoptotic cell death. The protective effects against light damage were attributable to the antioxidant activity of PAF. The light-induced damage of retinas was protected by oral administration of PF and PAF. Taken together, these compounds are potentially useful for the prevention of the disease caused by light exposure. The protective effects of retinal damage by light exposure were evaluated using polyphenolic compounds from the seed shells of Japanese horse chestnut ( Aesculus turbinata BLUME) as an antioxidant. Decreases in the electroretinographic amplitude and outer nuclear layer thickness were suppressed by the polyphenolic compounds of the seed shells. Polyphenolic compounds from the seed shells of Japanese horse chestnut inhibited the oxidation of retinal lipids. Highly polymeric A-type proanthocyanidin from the seed shells protected the rat retina from light exposure damage by inhibiting oxidative stress and apoptotic mechanisms.

In-vivo imaging of retinal nerve fiber layer vasculature: imaging - histology comparison

PubMed Central

Scoles, Drew; Gray, Daniel C; Hunter, Jennifer J; Wolfe, Robert; Gee, Bernard P; Geng, Ying; Masella, Benjamin D; Libby, Richard T; Russell, Stephen; Williams, David R; Merigan, William H

2009-01-01

Background Although it has been suggested that alterations of nerve fiber layer vasculature may be involved in the etiology of eye diseases, including glaucoma, it has not been possible to examine this vasculature in-vivo. This report describes a novel imaging method, fluorescence adaptive optics (FAO) scanning laser ophthalmoscopy (SLO), that makes possible for the first time in-vivo imaging of this vasculature in the living macaque, comparing in-vivo and ex-vivo imaging of this vascular bed. Methods We injected sodium fluorescein intravenously in two macaque monkeys while imaging the retina with an FAO-SLO. An argon laser provided the 488 nm excitation source for fluorescence imaging. Reflectance images, obtained simultaneously with near infrared light, permitted precise surface registration of individual frames of the fluorescence imaging. In-vivo imaging was then compared to ex-vivo confocal microscopy of the same tissue. Results Superficial focus (innermost retina) at all depths within the NFL revealed a vasculature with extremely long capillaries, thin walls, little variation in caliber and parallel-linked structure oriented parallel to the NFL axons, typical of the radial peripapillary capillaries (RPCs). However, at a deeper focus beneath the NFL, (toward outer retina) the polygonal pattern typical of the ganglion cell layer (inner) and outer retinal vasculature was seen. These distinguishing patterns were also seen on histological examination of the same retinas. Furthermore, the thickness of the RPC beds and the caliber of individual RPCs determined by imaging closely matched that measured in histological sections. Conclusion This robust method demonstrates in-vivo, high-resolution, confocal imaging of the vasculature through the full thickness of the NFL in the living macaque, in precise agreement with histology. FAO provides a new tool to examine possible primary or secondary role of the nerve fiber layer vasculature in retinal vascular disorders and other eye diseases, such as glaucoma. PMID:19698151

Cone Photoreceptor Abnormalities Correlate with Vision Loss in Patients with Stargardt Disease

PubMed Central

Chen, Yingming; Ratnam, Kavitha; Sundquist, Sanna M.; Lujan, Brandon; Ayyagari, Radha; Gudiseva, V. Harini; Roorda, Austin

2011-01-01

Purpose. To study the relationship between macular cone structure, fundus autofluorescence (AF), and visual function in patients with Stargardt disease (STGD). Methods. High-resolution images of the macula were obtained with adaptive optics scanning laser ophthalmoscopy (AOSLO) and spectral domain optical coherence tomography in 12 patients with STGD and 27 age-matched healthy subjects. Measures of retinal structure and AF were correlated with visual function, including best-corrected visual acuity, color vision, kinetic and static perimetry, fundus-guided microperimetry, and full-field electroretinography. Mutation analysis of the ABCA4 gene was completed in all patients. Results. Patients were 15 to 55 years old, and visual acuity ranged from 20/25–20/320. Central scotomas were present in all patients, although the fovea was spared in three patients. The earliest cone spacing abnormalities were observed in regions of homogeneous AF, normal visual function, and normal outer retinal structure. Outer retinal structure and AF were most normal near the optic disc. Longitudinal studies showed progressive increases in AF followed by reduced AF associated with losses of visual sensitivity, outer retinal layers, and cones. At least one disease-causing mutation in the ABCA4 gene was identified in 11 of 12 patients studied; 1 of 12 patients showed no disease-causing ABCA4 mutations. Conclusions. AOSLO imaging demonstrated abnormal cone spacing in regions of abnormal fundus AF and reduced visual function. These findings provide support for a model of disease progression in which lipofuscin accumulation results in homogeneously increased AF with cone spacing abnormalities, followed by heterogeneously increased AF with cone loss, then reduced AF with cone and RPE cell death. (ClinicalTrials.gov number, NCT00254605.) PMID:21296825

High levels of retinal membrane docosahexaenoic acid increase susceptibility to stress-induced degenerations⃞

PubMed Central

Tanito, Masaki; Brush, Richard S.; Elliott, Michael H.; Wicker, Lea D.; Henry, Kimberly R.; Anderson, Robert E.

2009-01-01

The fat-1 gene cloned from C. elegans encodes an n-3 fatty acid desaturase that converts n-6 to n-3 PUFA. Mice carrying the fat-1 transgene and wild-type controls were fed an n-3-deficient/n-6-enriched diet [fat-1- safflower oil (SFO) and wt-SFO, respectively]. Fatty acid profiles of rod outer segments (ROS), cerebellum, plasma, and liver demonstrated significantly lower n-6/n-3 ratios and higher docosahexaenoic acid (DHA) levels in fat-1-SFO compared with wt-SFO. When mice were exposed to light stress: 1) the outer nuclear layer (ONL) thickness was reduced; 2) amplitudes of the electroretinogram (ERG) were lower; 3) the number of apoptotic photoreceptor cells was greater; and 4) modification of retinal proteins by 4-hydroxyhexenal (4-HHE), an end-product of n-3 PUFA oxidation was increased in both fat-1-SFO and wt mice fed a regular lab chow diet compared with wt-SFO. The results indicate a positive correlation between the level of DHA, the degree of n-3 PUFA lipid peroxidation, and the vulnerability of the retina to photooxidative stress. In mice not exposed to intense light, the reduction in DHA resulted in reduced efficacy in phototransduction gain steps, while no differences in the retinal morphology or retinal biochemistry. These results highlight the dual roles of DHA in cellular physiology and pathology. PMID:19023138

Retinal degeneration is delayed by tissue factor pathway inhibitor-2 in RCS rats and a sodium-iodate-induced model in rabbits.

PubMed

Obata, R; Yanagi, Y; Tamaki, Y; Hozumi, K; Mutoh, M; Tanaka, Y

2005-04-01

To investigate the in vivo effects of tissue factor pathway inhibitor 2 (TFPI-2), which stimulates proliferation of retinal pigment epithelial cells, but not the proliferation of fibroblast and vascular endothelial cells in vitro, on retinal degeneration using a sodium-iodate (SI)-induced model in rabbits and Royal Collage of Surgeons (RCS) rats. 79 microg of recombinant TFPI-2 (rTFPI-2) or vehicle alone was injected intravitreously to 18 eyes of 12 pigmented rabbits a day after 20 mg/kg of SI was intravenously administered. Retinal function was assessed 4, 7, 14, and 21 days after the injection by analysing amplitudes of the c-wave of a bright flash electroretinogram. Additionally, 10 microg of rTFPI-2 or vehicle alone was injected intravitreously to 11 eyes of RCS rats at both 3 and 4 weeks old, then the retina was examined histologically at 5 weeks old. The rTFPI-2-treated eyes in rabbits showed a significantly less decrease in the relative amplitude of the c-wave than control eyes on days 4 and 7. The thickness of the outer nuclear layer was significantly thicker and the vacuole in the photoreceptor layer was less frequently observed in the rTFPI-2-treated RCS rats than the controls. Intravitreal injection of TFPI-2 rescues SI-induced retinal degeneration in rabbits and naturally occurring retinal degeneration in RCS rats at least partly. These results may suggest that this compound can be utilized in the treatment of retinal degeneration.

Foveal shape and structure in a normal population.

PubMed

Tick, Sarah; Rossant, Florence; Ghorbel, Itebeddine; Gaudric, Alain; Sahel, José-Alain; Chaumet-Riffaud, Philippe; Paques, Michel

2011-07-29

The shape of the human fovea presents important but still poorly characterized variations. In this study, the variability of the shape and structure of normal foveae were examined. In a group of 110 eyes of 57 healthy adults, the shape and structure of the fovea were analyzed by automated segmentation of retinal layer on high-resolution optical coherence tomography scans. In an additional group of 10 normal eyes of 10 patients undergoing fluorescein angiography, the size of the foveal avascular zone (FAZ) was correlated to foveal shape. From the thickest to the thinnest fovea, there was a structural continuum ranging from a shallow pit with continuity of the inner nuclear layer (INL) over the center (seven eyes; 6.7%), to a complete separation of inner layers overlying a flat and thinner central outer nuclear layer (ONL; eight eyes; 7.3%). Central foveal thickness correlated inversely to the degree of inner layer separation and to the surface of the FAZ. Foveal structure strongly correlates with its neurovascular organization. The findings support a developmental model in which the size of the FAZ determines the extent of centrifugal migration of inner retinal layers, which counteracts in some way the centripetal packing of cone photoreceptors.

Transient spectral domain optical coherence tomography findings in classic MEWDS: a case report.

PubMed

Lavigne, Luciana Castro; Isaac, David Leonardo Cruvinel; Duarte Júnior, José Osório; Avila, Marcos Pereira de

2014-01-01

The purpose of this study was to describe a patient with multiple evanescent white dot syndrome (MEWDS) who presented with classic retinal findings and transient changes in outer retinal anatomy. A 20-year-old man presented with mild blurred vision in the left eye, reporting flu-like symptoms 1 week before the visual symptoms started. Fundus examination of the left eye revealed foveal granularity and multiple scattered spots deep to the retina in the posterior pole. Fluorescein angiography and indocyanine green angiography showed typical MEWDS findings. Spectral Domain Optical Coherence Tomography has shown transient changes in outer retinal anatomy with disappearance of inner segment-outer segment junction and mild attenuation of external limiting membrane. Six months later, Spectral Domain Optical Coherence Tomography has shown complete resolution with recovery of normal outer retinal aspect.

Astrocytes and Müller Cell Alterations During Retinal Degeneration in a Transgenic Rat Model of Retinitis Pigmentosa

PubMed Central

Fernández-Sánchez, Laura; Lax, Pedro; Campello, Laura; Pinilla, Isabel; Cuenca, Nicolás

2015-01-01

Purpose: Retinitis pigmentosa includes a group of progressive retinal degenerative diseases that affect the structure and function of photoreceptors. Secondarily to the loss of photoreceptors, there is a reduction in retinal vascularization, which seems to influence the cellular degenerative process. Retinal macroglial cells, astrocytes, and Müller cells provide support for retinal neurons and are fundamental for maintaining normal retinal function. The aim of this study was to investigate the evolution of macroglial changes during retinal degeneration in P23H rats. Methods: Homozygous P23H line-3 rats aged from P18 to 18 months were used to study the evolution of the disease, and SD rats were used as controls. Immunolabeling with antibodies against GFAP, vimentin, and transducin were used to visualize macroglial cells and cone photoreceptors. Results: In P23H rats, increased GFAP labeling in Müller cells was observed as an early indicator of retinal gliosis. At 4 and 12 months of age, the apical processes of Müller cells in P23H rats clustered in firework-like structures, which were associated with ring-like shaped areas of cone degeneration in the outer nuclear layer. These structures were not observed at 16 months of age. The number of astrocytes was higher in P23H rats than in the SD matched controls at 4 and 12 months of age, supporting the idea of astrocyte proliferation. As the disease progressed, astrocytes exhibited a deteriorated morphology and marked hypertrophy. The increase in the complexity of the astrocytic processes correlated with greater connexin 43 expression and higher density of connexin 43 immunoreactive puncta within the ganglion cell layer (GCL) of P23H vs. SD rat retinas. Conclusions: In the P23H rat model of retinitis pigmentosa, the loss of photoreceptors triggers major changes in the number and morphology of glial cells affecting the inner retina. PMID:26733810

Progressive outer retinal necrosis and immunosuppressive therapy in myasthenia gravis.

PubMed

Coisy, Solène; Ebran, Jean-Marc; Milea, Dan

2014-01-01

Progressive outer retinal necrosis (PORN) is a rare but devastating infectious retinitis associated with varicella zoster virus (VZV) and responsible for severe visual loss. A 59-year-old man treated for generalized myasthenia with oral azathioprine and prednisone presented with severe unilateral necrotizing retinitis. Polymerase chain reaction of the aqueous and vitreous humors was diagnostic for VZV PORN. VZV PORN is a severe potential ocular complication of immunosuppression, prompting urgent diagnosis and appropriate treatment.

LONGITUDINAL STRUCTURAL CHANGES IN LATE-ONSET RETINAL DEGENERATION.

PubMed

Cukras, Catherine; Flamendorf, Jason; Wong, Wai T; Ayyagari, Radha; Cunningham, Denise; Sieving, Paul A

2016-12-01

To characterize longitudinal structural changes in early stages of late-onset retinal degeneration to investigate pathogenic mechanisms. Two affected siblings, both with a S163R missense mutation in the causative gene C1QTNF5, were followed for 8+ years. Color fundus photos, fundus autofluorescence images, near-infrared reflectance fundus images, and spectral domain optical coherence tomography scans were acquired during follow-up. Both patients, aged 45 and 50 years, had good visual acuities (>20/20) in the context of prolonged dark adaptation. Baseline color fundus photography demonstrated yellow-white, punctate lesions in the temporal macula that correlated with a reticular pattern on fundus autofluorescence and near-infrared reflectance imaging. Baseline spectral domain optical coherence tomography imaging revealed subretinal deposits that resemble reticular pseudodrusen described in age-related macular degeneration. During follow-up, these affected areas developed confluent thickening of the retinal pigment epithelial layer and disruption of the ellipsoid zone of photoreceptors before progressing to overt retinal pigment epithelium and outer retinal atrophy. Structural changes in early stages of late-onset retinal degeneration, revealed by multimodal imaging, resemble those of reticular pseudodrusen observed in age-related macular degeneration and other retinal diseases. Longitudinal follow-up of these lesions helps elucidate their progression to frank atrophy and may lend insight into the pathogenic mechanisms underlying diverse retinal degenerations.

BDNF improves the efficacy ERG amplitude maintenance by transplantation of retinal stem cells in RCS rats.

PubMed

Tian, Chunyu; Weng, Chuan Chuang; Yin, Zheng Qin

2010-01-01

The aim of this study was to evaluate the efficacy of subretinal transplantation of rat retinal stem cell when combined with Brain-derived neurotrophic factor (BDNF) in a rat model of retinal degeneration - Royal College of Surgeons (RCS) rats. Retinal stem cells were derived from embryonic day 17 Long-Evans rats and pre-labeled with fluorescence pigment-DiI prior to transplant procedures. RCS rats received injections of retinal stem cells, stem cells+BDNF, phosphate buffered saline or BNDF alone (n = 3 eyes for each procedure). At 1, 2 and 3 months after transplantation, the electroretinogram (ERG) was assessed and the outer nuclear layer thickness measured. The eyes receiving retinal stem cell and stem cell+BDNF transplants showed better photoreceptor maintenance than the other groups (P < 0.01) at all time points. One month after retina transplantation, the amplitudes of rod-ERG and Max-ERG b waves were significantly higher the eyes with stem cells+BDNF (P < 0.01), however, this difference was not seen at two and three months post transplantation. BDNF treatment alone group (without transplanted cells) had no effect when compared to buffer injections. The present results indicate that BDNF can enhance the short-term efficacy of the retinal stem cell transplantation in treating retinal degenerative disease.

Two-Photon Autofluorescence Imaging Reveals Cellular Structures Throughout the Retina of the Living Primate Eye

PubMed Central

Sharma, Robin; Williams, David R.; Palczewska, Grazyna; Palczewski, Krzysztof; Hunter, Jennifer J.

2016-01-01

Purpose Although extrinsic fluorophores can be introduced to label specific cell types in the retina, endogenous fluorophores, such as NAD(P)H, FAD, collagen, and others, are present in all retinal layers. These molecules are a potential source of optical contrast and can enable noninvasive visualization of all cellular layers. We used a two-photon fluorescence adaptive optics scanning light ophthalmoscope (TPF-AOSLO) to explore the native autofluorescence of various cell classes spanning several layers in the unlabeled retina of a living primate eye. Methods Three macaques were imaged on separate occasions using a custom TPF-AOSLO. Two-photon fluorescence was evoked by pulsed light at 730 and 920 nm excitation wavelengths, while fluorescence emission was collected in the visible range from several retinal layers and different locations. Backscattered light was recorded simultaneously in confocal modality and images were postprocessed to remove eye motion. Results All retinal layers yielded two-photon signals and the heterogeneous distribution of fluorophores provided optical contrast. Several structural features were observed, such as autofluorescence from vessel walls, Müller cell processes in the nerve fibers, mosaics of cells in the ganglion cell and other nuclear layers of the inner retina, as well as photoreceptor and RPE layers in the outer retina. Conclusions This in vivo survey of two-photon autofluorescence throughout the primate retina demonstrates a wider variety of structural detail in the living eye than is available through conventional imaging methods, and broadens the use of two-photon imaging of normal and diseased eyes. PMID:26903224

Intravitreal injection of exendin-4 analogue protects retinal cells in early diabetic rats.

PubMed

Zhang, Yu; Zhang, Jingfa; Wang, Qingping; Lei, Xia; Chu, Qing; Xu, Guo-Tong; Ye, Wen

2011-01-05

To evaluate the protective effect of intravitreal injection of exendin-4 analogue (E4a) in early diabetic retinopathy (DR) and to explore its possible mechanism. Forty Sprague-Dawley rats were divided into three groups: normal (N), diabetic (D), and E4a-treated diabetic rats (E4a). Diabetes was induced by streptozotocin. Rats in the E4a group were treated with E4a (0.1 μg/2μL/eye), whereas the N and D groups were treated with the equivalent volume of normal saline. Electroretinography was performed at 1 month and 3 months after diabetes onset. Thicknesses and cell counts in each layer of the retina were evaluated. The concentration of glutamate was measured by high-performance liquid chromatography (HPLC). Expressions of glucagon-like peptide-1 receptor (GLP-1R) and GLAST (excitatory amino acid transporter) were detected at mRNA and protein levels and verified by immunohistochemistry in vitro and in vivo. The rMc-1 cells were cultured under high-glucose medium (25 mM), which mimicked diabetic conditions. Effects of E4a (10 μg/mL) were also tested in the rMc-1 culture system. E4a prevented the reduction in b-wave amplitude and oscillatory potential amplitude caused by diabetes. It also prevented the cell loss of outer nuclear layer and inner nuclear layer; the thickness and cell count in the outer nuclear layer were decreased in 1-month diabetic rats. The concentration of glutamate in the retina was higher in diabetic rats and was significantly reduced in the E4a-treated group. Consistent with such changes, retinal GLP-1R and GLAST expression were reduced in the diabetic retina but upregulated in E4a-treated rats. No improvement was found in the retina in both functional and morphologic parameters 3 months after treatment. Intravitreal administration of E4a can prevent the retina, functionally and morphologically, from the insults of diabetes in rats. GLP-1R and GLAST were proved to exist in the rat retina, and their lowered expressions in the diabetic retina might be related to retinal damage by increasing the retinal glutamate. E4a might protect the retina by reducing the glutamate level through upregulating GLP-1R and GLAST, as observed in retinal Müller cells in this study, but this protective effect was transient. Thus, this could be a potential approach for the treatment of DR.

Neural Retinal Disorganization as a Robust Marker of Visual Acuity in Current and Resolved Diabetic Macular Edema

PubMed Central

Radwan, Salma H.; Soliman, Ahmed Z.; Lammer, Jan; Lin, Michael M.; Prager, Sonja G.; Silva, Paolo S.; Aiello, Lloyd Bryce; Aiello, Lloyd Paul

2015-01-01

Despite treatment advances, diabetic eye disease remains a leading cause of visual acuity (VA) loss worldwide. No methods to prospectively determine which patients will gain or lose vision exist, limiting individualized risk assessment and management. We investigated whether noninvasive, readily obtainable spectral domain optical coherence tomography parameters were correlated with VA in eyes with current or resolved center-involved diabetic macular edema (DME). Images were evaluated for disorganization of the retinal inner layers (DRIL), cysts, epiretinal membranes, microaneurysms, subretinal fluid, and outer layer disruption/reflectivity. DRIL affecting ≥50% of the 1-mm central retinal zone was associated with worse VA in all eyes, eyes with current edema, and eyes with resolved edema. Furthermore, early 4-month change in DRIL extent predicted VA change from baseline to 1 year. These data suggest that DRIL is a robust predictor of VA in eyes with present or previous DME and more highly correlated with VA than other widely used measures, such as retinal thickness. If further studies confirm DRIL as a predictive biomarker of future VA, physicians would gain a new tool of substantial clinical and investigative importance that could significantly change the approach to ophthalmic counseling and therapeutic management in patients with diabetes. PMID:25633419

[Effects of Nomega-nitro-L-arginine on photoreceptor apoptosis in inherited retinal degeneration of RCS rats].

PubMed

Li, Ai-jun; Fang, Jun; Zhu, Xiu-an

2004-08-18

To investigate inducible nitric oxide synthase(iNOS) activity of retina and the effects of N(omega)-nitro-L-arginine(N-Arg) on photoreceptor apoptosis in inherited retinal degeneration of Royal College of Surgeons (RCS) rats. iNOS activity was assayed in the whole retinal homogenates of RCS rats and Wistar rats by monitoring the conversion rate of (3)H-arginine to (3)H-citrulline. Intravitreal injection of the NOS inhibitor, N(omega)-nitro-L-arginine(N-Arg), in one lateral eye on postnatal days 17 (P17), P22, P27 and P32 was performed, while the other lateral eye was treated with PBS by intravitreal injection as controls. Then the retinas of the RCS rats were studied by TdT-mediated biotin-dUTP nick-end labeling (TUNEL) for apoptosis on P38. The enzymatic activity of iNOS was elevated in RCS rat retinas on P25. In RCS rats on P38, the percent area of apoptotic photoreceptor nuclei and the thickness of rod and cone layer in the treated group were significantly reduced compared with the controls, while the thickness of outer nuclear layer (ONL) was increased. The inhibitor of NOS might supply a potential medicine for inherited retinal degeneration.

Age-Dependent Changes of Monocarboxylate Transporter 8 Availability in the Postnatal Murine Retina

PubMed Central

Henning, Yoshiyuki; Szafranski, Karol

2016-01-01

The thyroid hormones (TH) triiodothyronine (T3) and its prohormone thyroxine (T4) are crucial for retinal development and function, and increasing evidence points at TH dysregulation as a cause for retinal degenerative diseases. Thus, precise regulation of retinal TH supply is required for proper retinal function, but knowledge on these mechanisms is still fragmentary. Several transmembrane transporters have been described as key regulators of TH availability in target tissues of which the monocarboxylate transporter 8 (MCT8), a high affinity transporter for T4 and T3, plays an essential role in the central nervous system. Moreover, in the embryonic chicken retina, MCT8 is highly expressed, but the postnatal availability of MCT8 in the mammalian retina was not reported to date. In the present study, spatiotemporal retinal MCT8 availability was examined in mice of different age. For this purpose, we quantified expression levels of Mct8 via Real-Time Reverse-Transcriptase PCR in mouse eyecups (C57BL/6) of juvenile and adult age groups. Additionally, age-dependent MCT8 protein levels were quantified via Western blotting and localized via immunofluorescence confocal microscopy. While no difference in Mct8 expression levels could be detected between age groups, MCT8 protein levels in juvenile animals were about two times higher than in adult animals based on Western blot analyses. Immunohistochemical analyses showed that MCT8 immunoreactivity in the eyecup was restricted to the retina and the retinal pigment epithelium. In juvenile mice, MCT8 was broadly observed along the apical membrane of the retinal pigment epithelium, tightly surrounding photoreceptor outer segments. Distinct immunopositive staining was also detected in the inner nuclear layer and the ganglion cell layer. However, in adult specimens, immunoreactivity visibly declined in all layers, which was in line with Western blot analyses. Since MCT8 was abundantly present in juvenile and about twofold lower in adult retinae, our findings suggest a pivotal role of MCT8 especially during postnatal maturation. The present study provides novel insights into age-dependent retinal TH supply, which might help to understand different aspects regarding retinal development, function, and disorders. PMID:27616981

Rapid light-induced activation of retinal microglia in mice lacking Arrestin-1.

PubMed

Levine, Emily S; Zam, Azhar; Zhang, Pengfei; Pechko, Alina; Wang, Xinlei; FitzGerald, Paul; Pugh, Edward N; Zawadzki, Robert J; Burns, Marie E

2014-09-01

Microglia dynamically prune synaptic contacts during development, and digest waste that accumulates in degeneration and aging. In many neurodegenerative diseases, microglial activation and phagocytosis gradually increase over months or years, with poorly defined initial triggering events. Here, we describe rapid retinal microglial activation in response to physiological light levels in a mouse model of photoreceptor degeneration that arises from defective rhodopsin deactivation and prolonged signaling. Activation, migration and proliferation of microglia proceeded along a well-defined time course apparent within 12 h of light onset. Retinal imaging in vivo with optical coherence tomography revealed dramatic increases in light-scattering from photoreceptors prior to the outer nuclear layer thinning classically used as a measure of retinal neurodegeneration. This model is valuable for mechanistic studies of microglial activation in a well-defined and optically accessible neural circuit, and for the development of novel methods for detecting early signs of pending neurodegeneration in vivo. Copyright © 2014 Elsevier Ltd. All rights reserved.

Localization of damage in progressive hydroxychloroquine retinopathy on and off the drug: inner versus outer retina, parafovea versus peripheral fovea.

PubMed

de Sisternes, Luis; Hu, Julia; Rubin, Daniel L; Marmor, Michael F

2015-05-01

To evaluate the relative involvement of inner and outer retina in hydroxychloroquine (HCQ) retinopathy while on the drug, and after drug cessation, using data from spectral-domain optical coherence tomography (SD-OCT). A total of 102 SD-OCT scans were obtained from 11 patients (classified as having early, moderate, or severe stages of toxicity) over a period of 4 years after cessation of HCQ. The inner and outer retina boundaries were identified automatically to measure thickness and characterize progression topographically. The segmentation of retinal layers was verified in SD-OCT cross-sections for all eyes and scans included in this study (a total of 102 scans). Topographic analysis showed that inner retina was not involved in HCQ toxicity to any meaningful degree, either between stages of retinopathy or after the drug is stopped. The characteristic bull's eye pattern of outer macula thinning appears when comparing moderate retinopathy (before any RPE damage) to the early stage. Later damage, as toxicity evolved to a severe stage, was diffuse across most of the macula. If the drug was stopped at an early or moderate stage, progression was limited to the first year and occurred diffusely without parafoveal localization. Hydroxychloroquine retinopathy primarily involves outer retina (photoreceptors). Outer retinal thinning while using HCQ initially involves the parafovea, but becomes diffuse across the macula as damage progresses or after drug cessation. When HCQ is stopped at an early or moderate stage (before RPE damage), progression seems to be limited to the first year.

Accumulation of neurocan, a brain chondroitin sulfate proteoglycan, in association with the retinal vasculature in RCS rats.

PubMed

Zhang, Yiqin; Rauch, Uwe; Perez, Maria-Thereza R

2003-03-01

To examine whether and how the retinal distribution of the chondroitin sulfate proteoglycan neurocan is affected after photoreceptor cell loss and whether it correlates with the multiple secondary cellular changes that accompany the photoreceptor degeneration. Retinas from normal rats (Sprague-Dawley; postnatal days [P]0-P70), RCS rats with dystrophic retinas (P0-P300), RCS-rdy(+) congenic rats with nondystrophic retinas (P0-202), and rhodopsin mutant rats, P23H (P0-P257) and S334ter (P0-P220), were processed for immunohistochemistry using a polyclonal antibody to rat neurocan. The overall distribution of neurocan was similar in all retinas examined. Neurocan immunostaining was detected over the nerve fiber layer, the plexiform layers, the photoreceptor outer segments region, and the ciliary epithelium. With age, labeling throughout the plexiform layers decreased continuously. In RCS rats however, conspicuous labeling was also seen in association with retinal vessels, from P15 onward. Accumulation of neurocan in association with the retinal vasculature does not correlate with photoreceptor cell loss, because it was not observed in the rhodopsin mutant rats. During the earliest stages of the disease, accumulation of debris in the subretinal space in RCS rats may be sufficient per se to initiate a cascade of metabolic changes that result in accumulation of neurocan. With time, the neurocan accumulated perivascularly may, by interaction with other matrix molecules, modulate at least some of the vascular alterations observed in this animal model.

Progressive Outer Retinal Necrosis and Immunosuppressive Therapy in Myasthenia Gravis

PubMed Central

Coisy, Solène; Ebran, Jean-Marc; Milea, Dan

2014-01-01

Introduction Progressive outer retinal necrosis (PORN) is a rare but devastating infectious retinitis associated with varicella zoster virus (VZV) and responsible for severe visual loss. Case Report A 59-year-old man treated for generalized myasthenia with oral azathioprine and prednisone presented with severe unilateral necrotizing retinitis. Polymerase chain reaction of the aqueous and vitreous humors was diagnostic for VZV PORN. Conclusion VZV PORN is a severe potential ocular complication of immunosuppression, prompting urgent diagnosis and appropriate treatment. PMID:24926266

Inner Segment Remodeling and Mitochondrial Translocation in Cone Photoreceptors in Age-Related Macular Degeneration With Outer Retinal Tubulation.

PubMed

Litts, Katie M; Messinger, Jeffrey D; Freund, K Bailey; Zhang, Yuhua; Curcio, Christine A

2015-04-01

To quantify impressions of mitochondrial translocation in degenerating cones and to determine the nature of accumulated material in the subretinal space with apparent inner segment (IS)-like features by examining cone IS ultrastructure. Human donor eyes with advanced age-related macular degeneration (AMD) were screened for outer retinal tubulation (ORT) in macula-wide, high-resolution digital sections. Degenerating cones inside ORT (ORT cones) and outside ORT (non-ORT cones) from AMD eyes and unaffected cones in age-matched control eyes were imaged using transmission electron microscopy. The distances of mitochondria to the external limiting membrane (ELM), cone IS length, and cone IS width at the ELM were measured. Outer retinal tubulation and non-ORT cones lose outer segments (OS), followed by shortening of IS and mitochondria. In non-ORT cones, IS broaden. Outer retinal tubulation and non-ORT cone IS myoids become undetectable due to mitochondria redistribution toward the nucleus. Some ORT cones were found lacking IS and containing mitochondria in the outer fiber (between soma and ELM). Unlike long, thin IS mitochondria in control cones, ORT and non-ORT IS mitochondria are ovoid or reniform. Shed IS, some containing mitochondria, were found in the subretinal space. In AMD, macula cones exhibit loss of detectable myoid due to IS shortening in addition to OS loss, as described. Mitochondria shrink and translocate toward the nucleus. As reflectivity sources, translocating mitochondria may be detectable using in vivo imaging to monitor photoreceptor degeneration in retinal disorders. These results improve the knowledge basis for interpreting high-resolution clinical retinal imaging.

Recapitulating X-Linked Juvenile Retinoschisis in Mouse Model by Knock-In Patient-Specific Novel Mutation.

PubMed

Chen, Ding; Xu, Tao; Tu, Mengjun; Xu, Jinlin; Zhou, Chenchen; Cheng, Lulu; Yang, Ruqing; Yang, Tanchu; Zheng, Weiwei; He, Xiubin; Deng, Ruzhi; Ge, Xianglian; Li, Jin; Song, Zongming; Zhao, Junzhao; Gu, Feng

2017-01-01

X-linked juvenile retinoschisis (XLRS) is a retinal disease caused by mutations in the gene encoding retinoschisin (RS1), which leads to a significant proportion of visual impairment and blindness. To develop personalized genome editing based gene therapy, knock-in animal disease models that have the exact mutation identified in the patients is extremely crucial, and that the way which genome editing in knock-in animals could be easily transferred to the patients. Here we recruited a family diagnosed with XLRS and identified the causative mutation ( RS1 , p.Y65X), then a knock-in mouse model harboring this disease-causative mutation was generated via TALEN (transcription activator-like effector nucleases). We found that the b-wave amplitude of the ERG of the RS1 -KI mice was significantly decreased. Moreover, we observed that the structure of retina in RS1 -KI mice has become disordered, including the disarray of inner nuclear layer and outer nuclear layer, chaos of outer plexiform layer, decreased inner segments of photoreceptor and the loss of outer segments. The novel knock-in mice ( RS1 -KI) harboring patient-specific mutation will be valuable for development of treatment via genome editing mediated gene correction.

[Bilateral acute retinal necrosis in a patient with acquired immunodeficiency syndrome].

PubMed

Menerath, J M; Gerard, M; Laurichesse, H; Goldschmidt, P; Peigue-Lafeuille, H; Rozenberg, F; Beytout, J

1995-01-01

A case of bilateral progressive outer retinal necrosis occurred after herpes zoster ophthalmicus in a patient with acquired immunodeficiency syndrome. This case does not correspond to the classical picture of progressive outer retinal necrosis. The disease led to blindness despite intravenous therapy with acyclovir and foscarnet. PCR could not identify any virus in the aqueous humour, but VZV is evidenced in cerebrospinal fluid. Acute retinal necrosis is now clearly defined by the American Uveitis Society, which should allow to determine its incidence and risk factors. Herpes zoster usually precedes the acute outer retinal necrosis. The infectious theory (VZV, HSV, CMV) widely prevails over the immune theory. We prefer the virus genome identification in the aqueous humor or in the vitreous by PCR to confirm diagnosis rather than the specific antibody titration. Therapy consists in acyclovir, foscarnet and ganciclovir. But whatever the treatment, the visual prognosis is poor.

The architecture of the avian retina following exposure to chronic 2 G

NASA Technical Reports Server (NTRS)

Orlando, R. G.; Negulesco, J. A.

1980-01-01

Rhode Island Red female chicks at 2 weeks posthatch were subjected, for 7 d, to either earth gravity of 1 G or a 2-G hypergravity environment by chronic whole-body centrifugation. Animals were sacrificed at 3 weeks posthatch and the eyes were enucleated, fixed in 10% BNF, doubly embedded, sectioned at 7-8 microns and routinely processed with H & E for histological examination. Compared to normogravity controls, animal exposure for 1 week to the chronic effects of 2-G resulted in a significantly decreased mean width of the photoreceptor, inner nuclear, and inner plexiform retinal layers. The outer nuclear, outer plexiform, and ganglion cell layers of the retina appeared minimally affected by the hypergravity state since the mean width of these layers showed no noticeable differences from earth gravity control animals. The present anatomic findings suggest a reduction in the detection of motion or rapid changes in illumination by the avian retina when the animal is exposed at a 2-G environment.

Histologic development of the human fovea from midgestation to maturity.

PubMed

Hendrickson, Anita; Possin, Daniel; Vajzovic, Lejla; Toth, Cynthia A

2012-11-01

To describe the histologic development of the human central retina from fetal week (Fwk) 22 to 13 years. Retrospective observational case series. Retinal layers and neuronal substructures were delineated on foveal sections of fixed tissue stained in azure II-methylene blue and on frozen sections immunolabeled for cone, rod, or glial proteins. Postmortem tissue was from 11 eyes at Fwk 20-27; 8 eyes at Fwk 28-37; 6 eyes at postnatal 1 day to 6 weeks; 3 eyes at 9 to 15 months; and 5 eyes at 28 months to 13 years. At Fwk 20-22 the fovea could be identified by the presence of a single layer of cones in the outer nuclear layer. Immunolabeling detected synaptic proteins, cone and rod opsins, and Müller glial processes separating the photoreceptors. The foveal pit appeared at Fwk 25, involving progressive peripheral displacement of ganglion cell, inner plexiform, and inner nuclear layers. The pit became wider and shallower after birth, and appeared mature by 15 months. Between Fwk 25 and Fwk 38, all photoreceptors developed more distinct inner and outer segments, but these were longer on peripheral than foveal cones. After birth the foveal outer nuclear layer became much thicker as cone packing occurred. Cone packing and neuronal migration during pit formation combined to form long central photoreceptor axons, which changed the outer plexiform layer from a thin sheet of synaptic pedicles into the thickest layer in the central retina by 15 months. Foveal inner and outer segment length matched peripheral cones by 15 months and was 4 times longer by 13 years. These data are necessary to understand the marked changes in human retina from late gestation to early adulthood. They provide qualitative and quantitative morphologic information required to interpret the changes in hyper- and hyporeflexive bands in pediatric spectral-domain optical coherence tomography images at the same ages. Copyright © 2012 Elsevier Inc. All rights reserved.

Acute progressive paravascular placoid neuroretinopathy with negative-type electroretinography in paraneoplastic retinopathy.

PubMed

Chen, Fred K; Chew, Avenell L; Zhang, Dan; Chen, Shang-Chih; Chelva, Enid; Chandrasekera, Erandi; Koay, Eleanor M H; Forrester, John; McLenachan, Samuel

2017-06-01

Paraneoplastic retinopathy can be the first manifestation of systemic malignancy. A subset of paraneoplastic retinopathy is characterized by negative-type electroretinography (ERG) without fundus abnormality. Here we describe the multimodal imaging and clinico-pathological correlation of a unique case of acute progressive paravascular placoid neuroretinopathy with suspected retinal depolarizing bipolar cell dysfunction preceding the diagnosis of metastatic small cell carcinoma of the prostate. ERG was performed according to the International Society for Clinical Electrophysiology of Vision standards. Imaging modalities included near-infrared reflectance, blue-light autofluorescence, fluorescein and indocyanine green angiographies, spectral domain optical coherence tomography, ultra-widefield colour and green-light autofluorescence imaging, microperimetry and adaptive optics imaging. Patient serum was screened for anti-retinal antibodies using western blotting. Immunostaining and histological analyses were performed on sections from human retinal tissues and a patient prostate biopsy. Serial multimodal retinal imaging, microperimetry and adaptive optics photography demonstrated a paravascular distribution of placoid lesions characterized by hyper-reflectivity within the outer nuclear layer resembling type 2 acute macular neuroretinopathy. There was no visible lesion within the inner nuclear layer despite electronegative-type ERG. Six months later, the patient presented with metastatic small cell carcinoma of the prostate. Tumour cells were immunopositive for glyceraldehyde-3-phosphate dehydrogenase, enolase and recoverin as well as neuroendocrine markers. The patient's serum reacted to cytoplasmic and nuclear antigens in the prostate biopsy and in human retina. Anti-retinal antibodies against several antigens were detected by both commercial and in-house western blots. A spectrum of autoreactive anti-retinal antibodies is associated with a unique phenotype of acute progressive paravascular placoid neuroretinopathy resulting in degeneration of photoreceptor cells, inner retinal dysfunction and classic electronegative ERG in paraneoplastic retinopathy. Detailed clinical, functional and immunological phenotyping of paraneoplastic retinopathy illustrated the complex mechanism of paraneoplastic syndrome.

Altered Expression of Retinal Molecular Markers in the Canine RPE65 Model of Leber Congenital Amaurosis

PubMed Central

Hernández, Maria; Pearce-Kelling, Susan E.; Rodriguez, F. David; Aguirre, Gustavo D.; Vecino, Elena

2010-01-01

Purpose. Leber congenital amaurosis (LCA) is a group of childhood-onset retinal diseases characterized by severe visual impairment or blindness. One form is caused by mutations in the RPE65 gene, which encodes the retinal pigment epithelium (RPE) isomerase. In this study, the retinal structure and expression of molecular markers for different retinal cell types were characterized, and differences between control and RPE65 mutant dogs during the temporal evolution of the disease were analyzed. Methods. Retinas from normal and mutant dogs of different ages were examined by immunofluorescence with a panel of 16 different antibodies. Results. Cones and rods were preserved in the mutant retinas, and the number of cones was normal. However, there was altered expression of cone arrestin and delocalization of rod opsin. The ON bipolar cells showed sprouting of the dendritic arbors toward the outer nuclear layer (ONL) and retraction of their axons in the inner nuclear layer (INL). A decreased expression of GABA, and an increased expression of intermediate filament glial markers was also found in the mutant retinas. These changes were more evident in the adult than the young mutant retinas. Conclusions. The structure of the retina is well preserved in the mutant retina, but several molecular changes take place in photoreceptors and in bipolar and amacrine cells. Some of these changes are structural, whereas others reflect a change in localization of the examined proteins. This study provides new information that can be applied to the interpretation of outcomes of retinal gene therapy in animal models and humans. PMID:20671290

Development and recovery of laser-induced retinal injury in rats

NASA Astrophysics Data System (ADS)

Belokopytov, Mark; Dubinsky, Galina; Belkin, Michael; Epstein, Yoram; Rosner, Mordechai

2005-04-01

Retinal photocoagulation lesions undergo primary and secondary degeneration followed by partial healing. This study follows the sequential changes in laser-induced retinal lesion over a time span of 60 days. Argon laser lesions were created in 36 pigmented rats. Sections of the retinal lesions were evaluated by light microscopy 1, 24, 48, 72 hours, and 20, and 60 days after the injury (six animals at each time point). The diameter of the lesion was equal to that of the laser spot 1h after irradiation and increased by 24h. It decreased later, slightly during the following 48h and significantly by 20 days. The destruction of photoreceptors was most severe after 24-48h. The nuclei in the outer-nuclear layer were pyknotic at the lesion site at 1h and disappeared later. Healing processes began 72h after the irradiation and was completed by 60 days. Filling-in by sliding of near nuclei was observed by the 60th day. Reversible changes were seen also in the retinal pigment epithelium (with formation of a plaque at 72h and its degradation later on) and in the choroid (disorganization of capillaries by 48h with later reorganization). Conclusions: The development of a laser-induced injury is gradual. The photoreceptors are damaged first and than the damage spreads to other layers of retina and to areas adjacent the primary injury site. The extension of the damage is later stopped and the adjacent tissues tend to fill the lesion and remodel the retina.

Radioprotective effect of a metalloporphyrin compound in rat eye model.

PubMed

Mao, X W; Crapo, J D; Mekonnen, T; Lindsey, N; Martinez, P; Gridley, D S; Slater, J M

2009-01-01

The purpose of this study was to evaluate the efficacy of the antioxidant Mn (III) tetrakis (N-ethylpyridinium-2-yl) porphyrin (MnTE-2-PyP) in protecting ocular tissue and retinal microvasculature from radiation damage. 75 rats were treated with Mn TE-2-PyP at 2.5 micro g/injection into one eye an hour before proton irradiation. The radiation was delivered in a single fraction to total doses of 8 Gray (Gy) or 28 Gy; Rats were sacrificed 3 days and 3, 6, 9, and 12 months thereafter for histology and quantification of photoreceptor cell populations and retinal capillary changes. By 6 months following radiation, there was significant loss of retinal outer and inner nuclear layers in eyes receiving radiation only (8 and 28 Gy) (p < 0.05) compared to their controls and to the eyes of rats treated with radiation plus metalloporphyrin. Retinal microvessel length density decreased significantly 6 months following 28 Gy (p < 0.05) compared to their controls and to MnTE-2-PyP treated rats. By 12 months following irradiation, irradiated eyes showed extensive damage to the photoreceptor layer, whereas the eyes of animals receiving radiation plus MnTE-2-PyP showed almost no morphological damage. MnTE-2-PyP treatment also suppressed radiation-induced apoptosis in our study. These results demonstrated that MnTE-2-PyP protected both photoreceptors and retinal capillaries from radiation damage, suggesting that this metalloporphyrin antioxidant is effective in regulating the damage induced by proton radiation.

Solid lipid nanoparticle-based vectors intended for the treatment of X-linked juvenile retinoschisis by gene therapy: In vivo approaches in Rs1h-deficient mouse model.

PubMed

Apaolaza, P S; Del Pozo-Rodríguez, A; Torrecilla, J; Rodríguez-Gascón, A; Rodríguez, J M; Friedrich, U; Weber, B H F; Solinís, M A

2015-11-10

X-linked juvenile retinoschisis (XLRS), which results from mutations in the gene RS1 that encodes the protein retinoschisin, is a retinal degenerative disease affecting between 1/5000 and 1/25,000 people worldwide. Currently, there is no cure for this disease and the treatment is based on the application of low-vision aids. The aim of the present work was the in vitro and in vivo evaluation of two different non-viral vectors based on solid lipid nanoparticles (SLNs), protamine and two anionic polysaccharides, hyaluronic acid (HA) or dextran (DX), for the treatment of XLRS. First, the vectors containing a plasmid which encodes both the reporter green fluorescent protein (GFP) and the therapeutic protein retinoschisin, under the control of CMV promoters, were characterized in vitro. Then, the vectors were subretinally or intravitreally administrated to C57BL/6 wild type mice. One week later, GFP was detected in all treated mice and in all retinal layers except in the Outer Nuclear Layer (ONL) and the Inner Nuclear Layer (INL), regardless of the administration route and the vector employed. Finally, two weeks after subretinal or intravitreal injection to Rs1h-deficient mice, GFP and retinoschisin expression was detected in all retinal layers, except in the ONL, which was maintained for at least two months after subretinal administration. The structural analysis of the treated Rs1h-deficient eyes showed a partial recovery of the retina related to the production of retinoschisin. This work shows for the first time a successful RS1 gene transfer to Rs1h-deficient animals using non-viral nanocarriers, with promising results that point to non-viral gene therapy as a feasible future therapeutic tool for retinal disorders.

Quantifying the effect of light activated outer and inner retinal inhibitory pathways on glutamate release from mixed bipolar cells.

PubMed

Lipin, Mikhail Y; Vigh, Jozsef

2018-05-01

Inhibition mediated by horizontal and amacrine cells in the outer and inner retina, respectively, are fundamental components of visual processing. Here, our purpose was to determine how these different inhibitory processes affect glutamate release from ON bipolar cells when the retina is stimulated with full-field light of various intensities. Light-evoked membrane potential changes (ΔV m ) were recorded directly from axon terminals of intact bipolar cells receiving mixed rod and cone inputs (Mbs) in slices of dark-adapted goldfish retina. Inner and outer retinal inhibition to Mbs was blocked with bath applied picrotoxin (PTX) and NBQX, respectively. Then, control and pharmacologically modified light responses were injected into axotomized Mb terminals as command potentials to induce voltage-gated Ca 2+ influx (Q Ca ) and consequent glutamate release. Stimulus-evoked glutamate release was quantified by the increase in membrane capacitance (ΔC m ). Increasing depolarization of Mb terminals upon removal of inner and outer retinal inhibition enhanced the ΔV m /Q Ca ratio equally at a given light intensity and inhibition did not alter the overall relation between Q Ca and ΔC m . However, relative to control, light responses recorded in the presence of PTX and PTX + NBQX increased ΔC m unevenly across different stimulus intensities: at dim stimulus intensities predominantly the inner retinal GABAergic inhibition controlled release from Mbs, whereas the inner and outer retinal inhibition affected release equally in response to bright stimuli. Furthermore, our results suggest that non-linear relationship between Q Ca and glutamate release can influence the efficacy of inner and outer retinal inhibitory pathways to mediate Mb output at different light intensities. © 2018 Wiley Periodicals, Inc.

ZEISS Angioplex™ Spectral Domain Optical Coherence Tomography Angiography: Technical Aspects.

PubMed

Rosenfeld, Philip J; Durbin, Mary K; Roisman, Luiz; Zheng, Fang; Miller, Andrew; Robbins, Gillian; Schaal, Karen B; Gregori, Giovanni

2016-01-01

ZEISS Angioplex™ optical coherence tomography (OCT) angiography generates high-resolution three-dimensional maps of the retinal and choroidal microvasculature while retaining all of the capabilities of the existing CIRRUS™ HD-OCT Model 5000 instrument. Angioplex™ OCT angiographic imaging on the CIRRUS™ HD-OCT platform was made possible by increasing the scanning rate to 68,000 A-scans per second and introducing improved tracking software known as FastTrac™ retinal-tracking technology. The generation of en face microvascular flow images with Angioplex™ OCT uses an algorithm known as OCT microangiography-complex, which incorporates differences in both the phase and intensity information contained within sequential B-scans performed at the same position. Current scanning patterns for en face angiographic visualization include a 3 × 3 and a 6 × 6 mm scan pattern on the retina. A volumetric dataset showing erythrocyte flow information can then be displayed as a color-coded retinal depth map in which the microvasculature of the superficial, deep, and avascular layers of the retina are displayed together with the colors red, representing the superficial microvasculature; green, representing the deep retinal vasculature; and blue, representing any vessels present in the normally avascular outer retina. Each retinal layer can be viewed separately, and the microvascular layers representing the choriocapillaris and the remaining choroid can be viewed separately as well. In addition, readjusting the contours of the slabs to target different layers of interest can generate custom en face flow images. Moreover, each en face flow image is accompanied by an en face intensity image to help with the interpretation of the flow results. Current clinical experience with this technology would suggest that OCT angiography should replace fluorescein angiography for retinovascular diseases involving any area of the retina that can be currently scanned with the CIRRUS™ HD-OCT instrument and may replace fluorescein angiography and indocyanine green angiography for some choroidal vascular diseases. © 2016 S. Karger AG, Basel.

Suppression of HSP27 Restores Retinal Function and Protects Photoreceptors From Apoptosis in a Light-Induced Retinal Degeneration Animal Model.

PubMed

Chien, Chih-Cheng; Huang, Chi-Jung; Tien, Lu-Tai; Cheng, Yu-Che; Ke, Chia-Ying; Lee, Yih-Jing

2017-06-01

We used a light-induced retinal degeneration animal model to investigate possible roles of heat shock protein 27 (HSP27) in retinal/photoreceptor protection. Sprague-Dawley rats were used for the light-induced retinal degeneration animal model. The histology of eye sections was observed for morphologic changes in the retina. Cell apoptosis was examined in each group using the terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, and electroretinography was used to evaluate retinal function. Protein and mRNA expression levels of different retinal cell markers were also detected through immunofluorescence staining, Western blotting, and real-time PCR. The thickness of the outer nuclear layer significantly decreased after 7-day light exposure. Moreover, we injected a viral vector for silencing HSP27 expression into the eyes and observed that photoreceptors were better preserved in the HSP27-suppressed (sHSP27) retina 2 weeks after injection. HSP27 suppression also reduced retinal cell apoptosis caused by light exposure. In addition, the loss of retinal function caused by light exposure was reversed on suppressing HSP27 expression. We subsequently found that the expression of the Rho gene and immunofluorescence staining of rhodopsin and arrestin (cell markers for photoreceptors) increased in sHSP27-treated retinas. HSP27 suppression did not affect the survival of ganglion and amacrine cells. Retinal cell apoptosis and functional loss were observed after 7-day light exposure. However, in the following 2 weeks after light exposure, HSP27 suppression may initiate a protective effect for retinal cells, particularly photoreceptors, from light-induced retinal degeneration.

Long-term safety of human retinal progenitor cell transplantation in retinitis pigmentosa patients.

PubMed

Liu, Yong; Chen, Shao Jun; Li, Shi Ying; Qu, Ling Hui; Meng, Xiao Hong; Wang, Yi; Xu, Hai Wei; Liang, Zhi Qing; Yin, Zheng Qin

2017-09-29

Retinitis pigmentosa is a common genetic disease that causes retinal degeneration and blindness for which there is currently no curable treatment available. Vision preservation was observed in retinitis pigmentosa animal models after retinal stem cell transplantation. However, long-term safety studies and visual assessment have not been thoroughly tested in retinitis pigmentosa patients. In our pre-clinical study, purified human fetal-derived retinal progenitor cells (RPCs) were transplanted into the diseased retina of Royal College of Surgeons (RCS) rats, a model of retinal degeneration. Based on these results, we conducted a phase I clinical trial to establish the safety and tolerability of transplantation of RPCs in eight patients with advanced retinitis pigmentosa. Patients were studied for 24 months. After RPC transplantation in RCS rats, we observed moderate recovery of vision and maintenance of the outer nuclear layer thickness. Most importantly, we did not find tumor formation or immune rejection. In the retinis pigmentosa patients given RPC injections, we also did not observe immunological rejection or tumorigenesis when immunosuppressive agents were not administered. We observed a significant improvement in visual acuity (P < 0.05) in five patients and an increase in retinal sensitivity of pupillary responses in three of the eight patients between 2 and 6 months after the transplant, but this improvement did not appear by 12 months. Our study for the first time confirmed the long-term safety and feasibility of vision repair by stem cell therapy in patients blinded by retinitis pigmentosa. WHO Trial Registration, ChiCTR-TNRC-08000193 . Retrospectively registered on 5 December 2008.

Progression of hydroxychloroquine toxic effects after drug therapy cessation: new evidence from multimodal imaging.

PubMed

Mititelu, Mihai; Wong, Brandon J; Brenner, Marie; Bryar, Paul J; Jampol, Lee M; Fawzi, Amani A

2013-09-01

Given the infrequent occurrence of hydroxychloroquine toxic effects, few data are available about the presenting features and long-term follow-up of patients with hydroxychloroquine retinopathy, making it difficult to surmise the clinical course of patients after cessation of drug treatment. To report functional and structural findings of hydroxychloroquine retinal toxic effects after drug therapy discontinuation. A retrospective medical record review was performed to identify patients taking hydroxychloroquine who were screened for toxic effects from January 1, 2009, through August 31, 2012, in the eye centers of Northwestern University and the University of Southern California. Northwestern University Sorrel Rosin Eye Center, Chicago, Illinois, and the Doheny Eye Institute at the University of Southern California, Los Angeles. Seven consecutive patients diagnosed as having hydroxychloroquine retinal toxic effects. Retinal toxic effects. Seven patients (1 man and 6 women) with a mean age of 55.9 years (age range, 25-74 years) developed retinal toxic effects after using hydroxychloroquine for a mean of 10.4 years (range, 3-19 years). Fundus examination revealed macular pigmentary changes in all 7 patients, corresponding to abnormal fundus autofluorescence (FAF). On spectral domain optical coherence tomography, there was outer retinal foveal resistance (preservation of the external limiting membrane and the photoreceptor layer) in 6 patients. After drug therapy discontinuation, 5 patients experienced outer retinal regeneration (3 subfoveally and 2 parafoveally), with associated functional visual improvement on static perimetry in 2 patients. Over time, FAF remained stable in 3 patients, whereas the remaining patients had a pattern of hypoautofluorescence that replaced areas of initial hyperautofluorescence (2 patients) and enlargement of the total area of abnormal FAF (2 patients). Preservation of the external limiting membrane carries a positive prognostic value in hydroxychloroquine toxic effects because it may be associated with regeneration of the photoreceptor layer and with potential functional visual improvement on static perimetry. The patterns of abnormal FAF persist despite cessation of the medication, with enlargement of the total area of abnormal FAF being the hallmark of severe toxic effects. Relative foveal resistance in hydroxychloroquine toxic effects was supported by this case series. These findings emphasize the importance of early detection and the need for correlating clinical observations with multimodal imaging, particularly FAF and spectral domain optical coherence tomography.

Simple explant culture of the embryonic chicken retina with long-term preservation of photoreceptors.

PubMed

Thangaraj, Gopenath; Greif, Alexander; Layer, Paul G

2011-10-01

Structurally stable in vitro-model systems are indispensible to analyse neural development during embryogenesis, follow cellular differentiation and evaluate neurotoxicological or growth factor effects. Here we describe a three-dimensional, long-term in vitro-culture system of the embryonic chick retina which supports photoreceptor development. Retinal tissue was isolated from E6 chick eye, and cultured as explants by continuous orbital rotation to allow free floatation without any supporting materials. Young stage (E6) immature retinas were cultured for various time periods in order to follow the differentiation of cell types and plexiform layers by immunocytochemical methods. These explants could be cultured for at least 2-3 weeks with remarkable retention of retinal architecture. Interestingly, photoreceptors developed in the absence of pigment epithelium. Electron microscopic studies revealed formation of structures resembling photoreceptor outer segments, a feature not reported previously. Thus, the verification of photoreceptors, Müller cells, inner retinal cells and the inner plexiform layer described in our study establishes this explant culture as a valuable in vivo-like model system. Crown Copyright © 2011. Published by Elsevier Ltd. All rights reserved.

The Time Course of Deafness and Retinal Degeneration in a Kunming Mouse Model for Usher Syndrome.

PubMed

Yao, Lu; Zhang, Lei; Qi, Lin-Song; Liu, Wei; An, Jing; Wang, Bin; Xue, Jun-Hui; Zhang, Zuo-Ming

2016-01-01

Usher syndrome is a group of autosomal recessive diseases characterized by congenital deafness and retinitis pigmentosa. In a mouse model for Usher syndrome, KMush/ush, discovered in our laboratory, we measured the phenotypes, characterized the architecture and morphology of the retina, and quantified the level of expression of pde6b and ush2a between postnatal (P) days 7, and 56. Electroretinograms and auditory brainstem response were used to measure visual and auditory phenotypes. Fundus photography and light microscopy were used to measure the architecture and morphology of the retina. Quantitative real-time PCR was used to measure the expression levels of mRNA. KMush/ush mice had low amplitudes and no obvious waveforms of Electroretinograms after P14 compared with controls. Thresholds of auditory brainstem response in our model were higher than those of controls after P14. By P21, the retinal vessels of KMush/ush mice were attenuated and their optic discs had a waxy pallor. The retinas of KMush/ush mice atrophied and the choroidal vessels were clearly visible. Notably, the architecture of each retinal layer was not different as compared with control mice at P7, while the outer nuclear layer (ONL) and other retinal layers of KMush/ush mice were attenuated significantly between P14 and P21. ONL cells were barely seen in KMush/ush mice at P56. As compared with control mice, the expression of pde6b and ush2a in KMush/ush mice declined significantly after P7. This study is a first step toward characterizing the progression of disease in our mouse model. Future studies using this model may provide insights about the etiology of the disease and the relationships between genotypes and phenotypes providing a valuable resource that could contribute to the foundation of knowledge necessary to develop therapies to prevent the retinal degeneration in patients with Usher Syndrome.

Progression of Pro23His Retinopathy in a Miniature Swine Model of Retinitis Pigmentosa

PubMed Central

Scott, Patrick A.; de Castro, Juan P. Fernandez; DeMarco, Paul J.; Ross, Jason W.; Njoka, Josephat; Walters, Eric; Prather, Randall S.; McCall, Maureen A.; Kaplan, Henry J.

2017-01-01

Purpose We characterize the progression of retinopathy in Filial 1 (F1) progeny of a transgenic (Tg) founder miniswine exhibiting severe Pro23His (P23H) retinopathy. Methods The F1 TgP23H miniswine progeny were created by crossing TgP23H founder miniswine 53-1 with wild type (WT) inbred miniature swine. Scotopic (rod-driven) and photopic (cone-driven) retinal functions were evaluated in F1 TgP23H and WT littermates using full field electroretinograms (ffERGs) at 1, 2, 3, 6, 9, 12, and 18 months of age, as well as the Tg founder miniswine at 6 years of age. Miniswine were euthanized and their retinas processed for morphologic evaluation at the light and electron microscopic level. Retinal morphology of a 36-month-old Tg miniswine also was examined. Results Wild type littermates reached mature scotopic and photopic retinal function by 3 months, while TgP23H miniswine showed abnormal scotopic ffERGs at the earliest time point, 1 month, and depressed photopic ffERGs after 2 months. Rod and cone photoreceptors (PR) exhibited morphologic abnormalities and dropout from the outer nuclear layer at 1 month, with only a monolayer of cone PR somata remaining after 2 months. The retinas showed progressive neural remodeling of the outer retina that included dendritic retraction of rod bipolar cells and glial seal formation by Müller cells. The TgP23H founder miniswine showed cone PR with relatively intact morphology exclusive to the area centralis. Conclusions The F1 Tg miniswine and the TgP23H founder miniswine exhibit similar retinopathy. Translational Relevance TgP23H miniswine are a useful large-eye model to study pathogenesis and preservation cone PRs in humans with retinitis pigmentosa. PMID:28316877

Fgf Signaling is Required for Photoreceptor Maintenance in the Adult Zebrafish Retina

PubMed Central

Hochmann, Sarah; Kaslin, Jan; Hans, Stefan; Weber, Anke; Machate, Anja; Geffarth, Michaela; Funk, Richard H. W.; Brand, Michael

2012-01-01

Fibroblast growth factors (Fgf) are secreted signaling molecules that have mitogenic, patterning, neurotrophic and angiogenic properties. Their importance during embryonic development in patterning and morphogenesis of the vertebrate eye is well known, but less is known about the role of Fgfs in the adult vertebrate retina. To address Fgf function in adult retina, we determined the spatial distribution of components of the Fgf signaling pathway in the adult zebrafish retina. We detected differential expression of Fgf receptors, ligands and downstream Fgf targets within specific retinal layers. Furthermore, we blocked Fgf signaling in the retina, by expressing a dominant negative variant of Fgf receptor 1 conditionally in transgenic animals. After blocking Fgf signaling we observe a fast and progressive photoreceptor degeneration and disorganization of retinal tissue, coupled with cell death in the outer nuclear layer. Following the degeneration of photoreceptors, a profound regeneration response is triggered that starts with proliferation in the inner nuclear layer. Ultimately, rod and cone photoreceptors are regenerated completely. Our study reveals the requirement of Fgf signaling to maintain photoreceptors and for proliferation during regeneration in the adult zebrafish retina. PMID:22291943

'Toy' laser macular burns in children: 12-month update.

PubMed

Raoof, N; O'Hagan, J; Pawlowska, N; Quhill, F

2016-03-01

There is increasing evidence that high-powered hand-held laser devices cause retinal injury. We present 12-month follow-up data for three patients that we previously reported with such retinal injuries. A retrospective case series of three children with maculopathy secondary to exposure to high-power hand-held laser devices. All children underwent clinical examination and spectral domain optical coherence tomography (SD-OCT) at presentation and follow-up. Fundus-controlled microperimetry was also undertaken 12-19 months after exposure. Three children sustained macular injury after exposure to a high-powered hand-held laser. Acutely, they presented with a 'vitelliform-like' maculopathy with reduced vision. Over the course of follow-up, the best corrected Snellen acuity in all three patients improved to 'normal' levels (range 6/6-6/9). Long-term deficits in foveal retinal sensitivity were identified in two patients using fundus-controlled microperimetry. SD-OCT imaging showed persistent disruption of the foveal outer photoreceptor layers in all three children. Although visual acuity improved over time, deficits in microperimetry and SD-OCT persisted. All three children had retinal pigment epithelium changes, requiring follow-up for longer-term sequelae of laser injuries such as expansion of retinal atrophy and development of choroidal neovascular membranes.

Optic neuritis and rapidly progressive necrotizing retinitis as the initial signs of subacute sclerosing panencephalitis: a case report with clinical and histopathologic findings.

PubMed

Oray, Merih; Tuncer, Samuray; Kir, Nur; Karacorlu, Murat; Tugal-Tutkun, Ilknur

2014-08-01

We report a case of subacute sclerosing panencephalitis (SSPE) presenting first with optic neuritis and rapidly progressive necrotizing retinitis at the posterior pole. We reviewed the clinical, laboratory, photographic, angiographic, and histopathologic records of a patient with SSPE. A 15-year-old girl was referred after rapid loss of vision due to optic neuritis and macular necrosis in the right eye. She had a history of cardiac valve surgery, but had no systemic symptoms and extensive work-up was unrewarding. Contralateral involvement with rapidly progressive optic neuritis and macular necrotizing retinitis prompted retinochoroidal biopsy of the right eye, which revealed necrosis of inner retinal layers and perivascular lymphoplasmocytic infiltration with intact choroid and outer retina without any findings of inclusion bodies, microorganisms, or atypical cells. The diagnosis was based on histopathologic findings consistent with SSPE, and detection of elevated measles antibody titers in cerebrospinal fluid and serum. It was further confirmed by development of typical electroencephalography pattern at 6 months and neurological symptoms at 4-year follow-up. Clinicians need to be aware that optic neuritis and necrotizing retinitis at the posterior pole may be the presenting features of SSPE.

Multiple Independent Oscillatory Networks in the Degenerating Retina

PubMed Central

Euler, Thomas; Schubert, Timm

2015-01-01

During neuronal degenerative diseases, microcircuits undergo severe structural alterations, leading to remodeling of synaptic connectivity. This can be particularly well observed in the retina, where photoreceptor degeneration triggers rewiring of connections in the retina’s first synaptic layer (e.g., Strettoi et al., 2003; Haq et al., 2014), while the synaptic organization of inner retinal circuits appears to be little affected (O’Brien et al., 2014; Figures 1A,B). Remodeling of (outer) retinal circuits and diminishing light-driven activity due to the loss of functional photoreceptors lead to spontaneous activity that can be observed at different retinal levels (Figure 1C), including the retinal ganglion cells, which display rhythmic spiking activity in the degenerative retina (Margolis et al., 2008; Stasheff, 2008; Menzler and Zeck, 2011; Stasheff et al., 2011). Two networks have been suggested to drive the oscillatory activity in the degenerating retina: a network of remnant cone photoreceptors, rod bipolar cells (RBCs) and horizontal cells in the outer retina (Haq et al., 2014), and the AII amacrine cell-cone bipolar cell network in the inner retina (Borowska et al., 2011). Notably, spontaneous rhythmic activity in the inner retinal network can be triggered in the absence of synaptic remodeling in the outer retina, for example, in the healthy retina after photo-bleaching (Menzler et al., 2014). In addition, the two networks show remarkable differences in their dominant oscillation frequency range as well as in the types and numbers of involved cells (Menzler and Zeck, 2011; Haq et al., 2014). Taken together this suggests that the two networks are self-sustained and can be active independently from each other. However, it is not known if and how they modulate each other. In this mini review, we will discuss: (i) commonalities and differences between these two oscillatory networks as well as possible interaction pathways; (ii) how multiple self-sustained networks may hamper visual restoration strategies employing, for example, microelectronic implants, optogenetics or stem cells, and briefly; and (iii) how the finding of diverse (independent) networks in the degenerative retina may relate to other parts of the neurodegenerative central nervous system. PMID:26617491

Photoreceptor Outer Segment-like Structures in Long-Term 3D Retinas from Human Pluripotent Stem Cells.

PubMed

Wahlin, Karl J; Maruotti, Julien A; Sripathi, Srinivasa R; Ball, John; Angueyra, Juan M; Kim, Catherine; Grebe, Rhonda; Li, Wei; Jones, Bryan W; Zack, Donald J

2017-04-10

The retinal degenerative diseases, which together constitute a leading cause of hereditary blindness worldwide, are largely untreatable. Development of reliable methods to culture complex retinal tissues from human pluripotent stem cells (hPSCs) could offer a means to study human retinal development, provide a platform to investigate the mechanisms of retinal degeneration and screen for neuroprotective compounds, and provide the basis for cell-based therapeutic strategies. In this study, we describe an in vitro method by which hPSCs can be differentiated into 3D retinas with at least some important features reminiscent of a mature retina, including exuberant outgrowth of outer segment-like structures and synaptic ribbons, photoreceptor neurotransmitter expression, and membrane conductances and synaptic vesicle release properties consistent with possible photoreceptor synaptic function. The advanced outer segment-like structures reported here support the notion that 3D retina cups could serve as a model for studying mature photoreceptor development and allow for more robust modeling of retinal degenerative disease in vitro.

Longitudinal Structural changes in Late-onset Retinal Degeneration

PubMed Central

Cukras, Catherine; Flamendorf, Jason; Wong, Wai T; Ayyagari, Radha; Cunningham, Denise; Sieving, Paul A.

2016-01-01

Purpose To characterize longitudinal structural changes in early stages of late-onset retinal degeneration (L-ORD) to investigate pathogenic mechanisms. Methods Two affected siblings, both with a S163R missense mutation in the causative gene C1QTNF5, were followed for 8+ years. Color fundus photos, fundus autofluorescence (FAF) images, near infrared reflectance (NIR-R) fundus images, and spectral domain optical coherence tomography (SD-OCT) scans were acquired during follow-up. Results Both patients, aged 45 and 50 years, had good visual acuities (> 20/20 OU) in the context of prolonged dark adaptation. Baseline color fundus photography demonstrated yellow-white, punctate lesions in the temporal macula that correlated with a reticular pattern on FAF and NIR-R imaging. Baseline SD-OCT imaging revealed subretinal deposits that resemble reticular pseudodrusen (RPD) described in age-related macular degeneration (AMD). During follow-up, these affected areas developed confluent thickening of the retinal pigment epithelial (RPE) layer and disruption of the ellipsoid zone of photoreceptors before progressing to overt RPE and outer retinal atrophy. Conclusions Structural changes in early stage L-ORD revealed by multimodal imaging resemble those of RPD observed in AMD and other retinal diseases. Longitudinal follow-up of these lesions helps elucidate their progression to frank atrophy and may lend insight into the pathogenic mechanisms underlying diverse retinal degenerations. PMID:27388725

UTILIZATION OF FUNDUS AUTOFLUORESCENCE, SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY, AND ENHANCED DEPTH IMAGING IN THE CHARACTERIZATION OF BIETTI CRYSTALLINE DYSTROPHY IN DIFFERENT STAGES.

PubMed

Li, Qian; Li, Yang; Zhang, Xiaohui; Xu, Zhangxing; Zhu, Xiaoqing; Ma, Kai; She, Haicheng; Peng, Xiaoyan

2015-10-01

To characterize Bietti crystalline dystrophy (BCD) in different stages using multiple imaging modalities. Sixteen participants clinically diagnosed as BCD were included in the retrospective study and were categorized into 3 stages according to fundus photography. Eleven patients were genetically confirmed. Fundus autofluorescence, spectral domain optical coherence tomography, and enhanced depth imaging features of BCD were analyzed. On fundus autofluorescence, the abnormal autofluorescence was shown to enlarge in area and decrease in intensity with stages. Using spectral domain optical coherence tomography, the abnormalities in Stage 1 were observed to localize in outer retinal layers, whereas in Stage 2 and Stage 3, more extensive retinal atrophy was seen. In enhanced depth imaging, the subfoveal choroidal layers were delineated clearly in Stage 1; in Stage 2, destructions were primarily found in the choriocapillaris with associated alterations in the outer vessels; Stage 3 BCD displayed severe choroidal thinning. Choroidal neovascularization and macular edema were exhibited with high incidence. IVS6-8del17bp/inGC of the CYP4V2 gene was the most common mutant allele. Noninvasive fundus autofluorescence, spectral domain optical coherence tomography, and enhanced depth imaging may help to characterize the chorioretinal pathology of BCD at different degrees, and therefore, we propose staging of BCD depending on those methods. Physicians should be cautious of the vision-threatening complications of the disease.

Progression of varicella-zoster virus necrotizing retinopathy in an HIV-negative patient with transient immune deviation.

PubMed

Lim, Wee-Kiak; Chee, Soon-Phaik; Nussenblatt, Robert Burton

2005-06-01

To report a case of unilateral varicella-zoster virus (VZV) necrotizing retinopathy that progressed from outer retinitis with features of progressive outer retinal necrosis (PORN) to typical acute retinal necrosis (ARN) in an HIV-negative patient with a transient decrease in CD4 lymphocyte counts and CD4/CD8 ratio. Case report. A 41-year-old Chinese man presenting with blurred vision in the right eye was diagnosed with herpetic necrotizing retinitis without vitritis. Fundus examination revealed retinal arteritis and extensive deep whitish retinal lesions in the mid-periphery with minimal vitritis. Aqueous humor and vitreous PCR were positive for VZV. His CD4 count on presentation was depressed (239 cells/ul) and the CD4/CD8 ratio was low (0.8). The referring ophthalmologist had treated him with prednisolone 60 mg/day. At our institution, when intravenous acyclovir was started and the steroid therapy discontinued, he developed severe vitritis and the deep retinal lesions progressed to full-thickness retinitis typical of ARN. Repeat CD4 count was 512 cells/ul at day 14. In total, he was treated with 14 days of i.v. acyclovir (12 mg/kg 8-hourly) followed by oral valaciclovir 500 mg three times a day for 3 months. Prednisolone 30 mg once daily was restarted and tapered over 3 months. Despite prophylactic argon retinal photocoagulation to the edge of the retinitis, the patient developed a total retinal detachment at 3 months. VZV retinal infection in an HIV-negative patient with transient immune deviation can manifest initially as outer retinitis with features similar to PORN and progress to typical ARN when CD4 counts return to normal.

Ectopic Six3 expression in the dragon eye goldfish.

PubMed

Ma, Dong-Mei; Zhu, Hua-Ping; Gui, Jian-Fang

2008-02-01

For goldfish (Carassius auratus), there are many varieties with different eye phenotypes due to artificial selection and adaptive evolution. Dragon eye is a variant eye characterized by a large-size eyeball protruding out of the socket similar to the eye of dragon in Chinese legends. In this study, anatomical structure of the goldfish dragon eye was compared with that of the common eye, and a stretching of the retina was observed in the enlarged dragon eye. Moreover, the homeobox-containing transcription factor Six3 cDNAs were cloned from the two types of goldfish, and the expression patterns were analyzed in both normal eye and dragon eye goldfish. No amino acid sequence differences were observed between the two deduced peptides, and the expression pattern of Six3 protein in dragon eye is quite similar to common eye during embryogenesis, but from 2 days after hatching, ectopic Six3 expression began to occur in the dragon eye, especially in the outer nuclear layer cells. With eye development, more predominant Six3 distribution was detected in the outer nuclear layer cells of dragon eye than that of normal eye, and fewer cell-layers in outer nuclear layer were observed in dragon eye retina than in normal eye retina. The highlight of this study is that higher Six3 expression occurs in dragon eye goldfish than in normal eye goldfish during retinal development of larvae.

The Effect of Cone Opsin Mutations on Retinal Structure and the Integrity of the Photoreceptor Mosaic

PubMed Central

Carroll, Joseph; Dubra, Alfredo; Gardner, Jessica C.; Mizrahi-Meissonnier, Liliana; Cooper, Robert F.; Dubis, Adam M.; Nordgren, Rick; Genead, Mohamed; Connor, Thomas B.; Stepien, Kimberly E.; Sharon, Dror; Hunt, David M.; Banin, Eyal; Hardcastle, Alison J.; Moore, Anthony T.; Williams, David R.; Fishman, Gerald; Neitz, Jay; Neitz, Maureen; Michaelides, Michel

2012-01-01

Purpose. To evaluate retinal structure and photoreceptor mosaic integrity in subjects with OPN1LW and OPN1MW mutations. Methods. Eleven subjects were recruited, eight of whom have been previously described. Cone and rod density was measured using images of the photoreceptor mosaic obtained from an adaptive optics scanning light ophthalmoscope (AOSLO). Total retinal thickness, inner retinal thickness, and outer nuclear layer plus Henle fiber layer (ONL+HFL) thickness were measured using cross-sectional spectral-domain optical coherence tomography (SD-OCT) images. Molecular genetic analyses were performed to characterize the OPN1LW/OPN1MW gene array. Results. While disruptions in retinal lamination and cone mosaic structure were observed in all subjects, genotype-specific differences were also observed. For example, subjects with “L/M interchange” mutations resulting from intermixing of ancestral OPN1LW and OPN1MW genes had significant residual cone structure in the parafovea (∼25% of normal), despite widespread retinal disruption that included a large foveal lesion and thinning of the parafoveal inner retina. These subjects also reported a later-onset, progressive loss of visual function. In contrast, subjects with the C203R missense mutation presented with congenital blue cone monochromacy, with retinal lamination defects being restricted to the ONL+HFL and the degree of residual cone structure (8% of normal) being consistent with that expected for the S-cone submosaic. Conclusions. The photoreceptor phenotype associated with OPN1LW and OPN1MW mutations is highly variable. These findings have implications for the potential restoration of visual function in subjects with opsin mutations. Our study highlights the importance of high-resolution phenotyping to characterize cellular structure in inherited retinal disease; such information will be critical for selecting patients most likely to respond to therapeutic intervention and for establishing a baseline for evaluating treatment efficacy. PMID:23139274

A level-set method for pathology segmentation in fluorescein angiograms and en face retinal images of patients with age-related macular degeneration

NASA Astrophysics Data System (ADS)

Mohammad, Fatimah; Ansari, Rashid; Shahidi, Mahnaz

2013-03-01

The visibility and continuity of the inner segment outer segment (ISOS) junction layer of the photoreceptors on spectral domain optical coherence tomography images is known to be related to visual acuity in patients with age-related macular degeneration (AMD). Automatic detection and segmentation of lesions and pathologies in retinal images is crucial for the screening, diagnosis, and follow-up of patients with retinal diseases. One of the challenges of using the classical level-set algorithms for segmentation involves the placement of the initial contour. Manually defining the contour or randomly placing it in the image may lead to segmentation of erroneous structures. It is important to be able to automatically define the contour by using information provided by image features. We explored a level-set method which is based on the classical Chan-Vese model and which utilizes image feature information for automatic contour placement for the segmentation of pathologies in fluorescein angiograms and en face retinal images of the ISOS layer. This was accomplished by exploiting a priori knowledge of the shape and intensity distribution allowing the use of projection profiles to detect the presence of pathologies that are characterized by intensity differences with surrounding areas in retinal images. We first tested our method by applying it to fluorescein angiograms. We then applied our method to en face retinal images of patients with AMD. The experimental results included demonstrate that the proposed method provided a quick and improved outcome as compared to the classical Chan-Vese method in which the initial contour is randomly placed, thus indicating the potential to provide a more accurate and detailed view of changes in pathologies due to disease progression and treatment.

Protective Effect of Proanthocyanidins from Sea Buckthorn (Hippophae Rhamnoides L.) Seed against Visible Light-Induced Retinal Degeneration in Vivo.

PubMed

Wang, Yong; Zhao, Liang; Huo, Yazhen; Zhou, Feng; Wu, Wei; Lu, Feng; Yang, Xue; Guo, Xiaoxuan; Chen, Peng; Deng, Qianchun; Ji, Baoping

2016-05-02

Dietary proanthocyanidins (PACs) as health-protective agents have become an important area of human nutrition research because of their potent bioactivities. We investigated the retinoprotective effects of PACs from sea buckthorn (Hippophae rhamnoides L.) seed against visible light-induced retinal degeneration in vivo. Pigmented rabbits were orally administered sea buckthorn seed PACs (50 and 100 mg/kg/day) for 14 consecutive days of pre-illumination and seven consecutive days of post-illumination. Retinal function was quantified via electroretinography 7 days after light exposure. Retinal damage was evaluated by measuring the thickness of the full-thickness retina and outer nuclear layer 7 days after light exposure. Sea buckthorn seed PACs significantly attenuated the destruction of electroretinograms and maintained the retinal structure. Increased retinal photooxidative damage was expressed by the depletion of glutathione peroxidase and catalase activities, the decrease of total antioxidant capacity level and the increase of malondialdehyde level. Light exposure induced a significant increase of inflammatory cytokines (IL-1β, TNF-α and IL-6) and angiogenesis (VEGF) levels in retina. Light exposure upregulated the expression of pro-apoptotic proteins Bax and caspase-3 and downregulated the expression of anti-apoptotic protein Bcl-2. However, sea buckthorn seed PACs ameliorated these changes induced by light exposure. Sea buckthorn seed PACs mediated the protective effect against light-induced retinal degeneration via antioxidant, anti-inflammatory and antiapoptotic mechanisms.

Protective Effect of Proanthocyanidins from Sea Buckthorn (Hippophae Rhamnoides L.) Seed against Visible Light-Induced Retinal Degeneration in Vivo

PubMed Central

Wang, Yong; Zhao, Liang; Huo, Yazhen; Zhou, Feng; Wu, Wei; Lu, Feng; Yang, Xue; Guo, Xiaoxuan; Chen, Peng; Deng, Qianchun; Ji, Baoping

2016-01-01

Dietary proanthocyanidins (PACs) as health-protective agents have become an important area of human nutrition research because of their potent bioactivities. We investigated the retinoprotective effects of PACs from sea buckthorn (Hippophae rhamnoides L.) seed against visible light-induced retinal degeneration in vivo. Pigmented rabbits were orally administered sea buckthorn seed PACs (50 and 100 mg/kg/day) for 14 consecutive days of pre-illumination and seven consecutive days of post-illumination. Retinal function was quantified via electroretinography 7 days after light exposure. Retinal damage was evaluated by measuring the thickness of the full-thickness retina and outer nuclear layer 7 days after light exposure. Sea buckthorn seed PACs significantly attenuated the destruction of electroretinograms and maintained the retinal structure. Increased retinal photooxidative damage was expressed by the depletion of glutathione peroxidase and catalase activities, the decrease of total antioxidant capacity level and the increase of malondialdehyde level. Light exposure induced a significant increase of inflammatory cytokines (IL-1β, TNF-α and IL-6) and angiogenesis (VEGF) levels in retina. Light exposure upregulated the expression of pro-apoptotic proteins Bax and caspase-3 and downregulated the expression of anti-apoptotic protein Bcl-2. However, sea buckthorn seed PACs ameliorated these changes induced by light exposure. Sea buckthorn seed PACs mediated the protective effect against light-induced retinal degeneration via antioxidant, anti-inflammatory and antiapoptotic mechanisms. PMID:27144578

Arap1 Deficiency Causes Photoreceptor Degeneration in Mice.

PubMed

Moshiri, Ala; Humpal, Devin; Leonard, Brian C; Imai, Denise M; Tham, Addy; Bower, Lynette; Clary, Dave; Glaser, Thomas M; Lloyd, K C Kent; Murphy, Christopher J

2017-03-01

Small guanosine triphosphatase (GTPase) ADP-ribosylation factors (Arfs) regulate membrane traffic and actin reorganization under the control of GTPase-activating proteins (GAPs). Arap1 is an Arf-directed GAP that inhibits the trafficking of epidermal growth factor receptor (EGFR) to the early endosome, but the diversity of its functions is incompletely understood. The aim of this study was to determine the role of Arap1 in the mammalian retina. Genetically engineered Arap1 knockout mice were screened for ocular abnormalities in the National Institutes of Health Knockout Mouse Production and Phenotyping (KOMP2) Project. Arap1 knockout and wild-type eyes were imaged using optical coherence tomography and fundus photography, and analyzed by immunohistochemistry. Arap1-/- mice develop a normal appearing retina, but undergo photoreceptor degeneration starting at 4 weeks postnatal age. The fundus appearance of mutants is notable for pigmentary changes, optic nerve pallor, vascular attenuation, and outer retinal thinning, reminiscent of retinitis pigmentosa in humans. Immunohistochemical studies suggest the cell death is predominantly in the outer nuclear layer. Functional evaluation of the retina by electroretinography reveals amplitudes are reduced. Arap1 is detected most notably in Müller glia, and not in photoreceptors, implicating a role for Müller glia in photoreceptor survival. Arap1 is necessary for normal photoreceptor survival in mice, and may be a novel gene relevant to human retinal degenerative processes, although its mechanism is unknown. Further studies in this mouse model of retinal degeneration will give insights into the cellular functions and signaling pathways in which Arap1 participates.

Outer Retinal Tubulation in Advanced Age-Related Macular Degeneration: Optical Coherence Tomographic Findings Correspond to Histology

PubMed Central

Schaal, Karen B.; Freund, K. Bailey; Litts, Katie M.; Zhang, Yuhua; Messinger, Jeffrey D.; Curcio, Christine A.

2014-01-01

Purpose To compare optical coherence tomography (OCT) and histology of outer retinal tubulation (ORT) secondary to advanced age-related macular degeneration (AMD) in patients and in post-mortem specimens, with particular attention to the basis of the hyper-reflective border of ORT. Method A private referral practice (imaging) and an academic research laboratory (histology) collaborated on two retrospective case series. High-resolution OCT raster scans of 43 eyes (34 patients) manifesting ORT secondary to advanced AMD were compared to high-resolution histological sections through the fovea and superior perifovea of donor eyes (13 atrophic AMD and 40 neovascular AMD) preserved ≤4 hours after death. Results ORT seen on OCT corresponded to histologic findings of tubular structures comprised largely of cones lacking outer segments (OS) and lacking inner segments (IS). Four phases of cone degeneration were histologically distinguishable in ORT lumenal walls, nascent, mature, degenerate, and end-stage (IS and OS; IS only; no IS; no photoreceptors and only Müller cells forming external limiting membrane, ELM, respectively). Mitochondria, which are normally long and bundled within IS ellipsoids, were small and scattered within shrunken IS and cell bodies of surviving cones. A lumenal border was delimited by an ELM. ORT observed in closed and open configurations were distinguishable from cysts and photoreceptor islands on both OCT and histology. Hyper-reflective lumenal material seen on OCT represents trapped retinal pigment epithelium (RPE) and non-RPE cells. Conclusions The defining OCT features of ORT are location in the outer nuclear layer (ONL), a hyper-reflective band differentiating it from cysts, and RPE that is either dysmorphic or absent. ORT histologic and OCT findings corresponded in regard to composition, location, shape, and stages of formation. The reflectivity of ORT lumenal walls on OCT apparently does not require an OS or an IS/OS junction, indicating an independent reflectivity source, possibly mitochondria, in the IS. PMID:25635579

In Vivo Protection against Retinal Neurodegeneration by Sigma Receptor 1 Ligand (+)-Pentazocine

PubMed Central

Smith, Sylvia B.; Duplantier, Jennifer; Dun, Ying; Mysona, Barbara; Roon, Penny; Martin, Pamela M.; Ganapathy, Vadivel

2008-01-01

Purpose To evaluate the neuroprotective properties of the sigma receptor 1 (σR1) ligand, (+)-pentazocine in an in vivo model of retinal neurodegeneration. Methods Spontaneously diabetic Ins2Akita/+ and wild-type mice received intraperitoneal injections of (+)-pentazocine for 22 weeks beginning at diabetes onset. Retinal mRNA and protein were analyzed by RT-PCR and Western blot analysis. Retinal histologic sections were measured to determine total retinal thickness, thicknesses of inner-outer nuclear and plexiform layers (INL, ONL, IPL, INL), and the number of cell bodies in the ganglion cell layer (GCL). Immunolabeling experiments were performed using antibodies specific for 4-hydroxynonenal and nitrotyrosine, markers of lipid peroxidation, and reactive nitrogen species, respectively, and an antibody specific for vimentin to view radial Müller fibers. Results σR1 mRNA and protein levels in the Ins2Akita/+ retina were comparable to those in the wild-type, indicating that σR1 is an available target during the disease process. Histologic evaluation of eyes of Ins2Akita/+ mice showed disruption of retinal architecture. By 17 to 25 weeks after birth, Ins2Akita/+ mice demonstrated ∼30% and 25% decreases in IPL and INL thicknesses, respectively, and a 30% reduction in ganglion cells. In the (+)-pentazocine-treated group, retinas of Ins2Akita/+ mice showed remarkable preservation of retinal architecture; IPL and INL thicknesses of (+)-pentazocinetreated Ins2Akita/+ mouse retinas were within normal limits. The number of ganglion cells was 15.6 ± 1.5 versus 10.4 ± 1.2 cells/100 μm retinal length in (+)-pentazocine-treated versus nontreated mutant mice. Levels of nitrotyrosine and 4-hydroxynonenal increased in Ins2Akita/+ retinas, but were reduced in (+)-pentazocine-treated mice. Retinas of Ins2Akita/+ mice showed loss of the uniform organization of radial Müller fibers. Retinas of (+)-pentazocine-treated mice maintained the radial organization of glial processes. Conclusion Sustained (+)-pentazocine treatment in an in vivo model of retinal degeneration conferred significant neuroprotection, reduced evidence of oxidative stress, and preserved retinal architecture, suggesting that σR1 ligands are promising therapeutic agents for intervention in neurodegenerative diseases of the retina. PMID:18469181

Deep Retinal Capillary Nonperfusion Is Associated With Photoreceptor Disruption in Diabetic Macular Ischemia.

PubMed

Scarinci, Fabio; Nesper, Peter L; Fawzi, Amani A

2016-08-01

To report outer retinal structural changes associated with macular capillary nonperfusion at the level of deep capillary plexus (DCP) in diabetic patients. Prospective observational cross-sectional study. The study included 14 eyes of 10 patients who were diagnosed as having diabetic retinopathy. To study the outer retina and localize areas of capillary nonperfusion at the superficial (SCP) or DCP, we used the spectral-domain optical coherence tomography (SDOCT) device (RTVue-XR Avanti; Optovue Inc, Fremont, California, USA) with split-spectrum amplitude-decorrelation angiography (SSADA) software for optical coherence tomography angiography (OCTA). Two independent masked graders (F.S. and A.A.F.) qualitatively evaluated SDOCT scans as either normal or having outer retina disruption. The angiographic images were examined to define the presence and location of capillary nonperfusion. Eight eyes showed outer retinal disruption on SDOCT that co-localized to areas of enlarged foveal avascular zone, areas of no flow between capillaries, and capillary nonperfusion of the DCP. Six eyes without outer retinal changes on SDOCT showed robust perfusion of the DCP. Using OCTA, this study shows that macular photoreceptor disruption on SDOCT in patients with diabetic retinopathy corresponds to areas of capillary nonperfusion at the level of the DCP. This is important in highlighting the contribution of the DCP to the oxygen requirements of the photoreceptors as well as the outer retina in diabetic macular ischemia. Copyright © 2016 Elsevier Inc. All rights reserved.

Progressive outer retinal necrosis (PORN) in AIDS patients: a different appearance of varicella-zoster retinitis.

PubMed

Pavesio, C E; Mitchell, S M; Barton, K; Schwartz, S D; Towler, H M; Lightman, S

1995-01-01

Retinal infections caused by the varicella-zoster virus (VZV) have been reported in immunocompetent and immunocompromised individuals. Two cases of a VZV-related retinitis are described with the characteristic features of the recently described progressive outer retinal necrosis (PORN) syndrome. Both patients suffered from the acquired immunodeficiency syndrome (AIDS) with greatly reduced peripheral blood CD4+ T lymphocyte counts, and presented with macular retinitis without vitritis. The disease was bilateral in one case and unilateral in the other. The clinical course was rapidly progressive with widespread retinal involvement and the development of rhegmatogenous retinal detachment with complete loss of vision in the affected eyes despite intensive intravenous antiviral therapy. VZV DNA was identified in vitreous biopsies, by molecular techniques based on the polymerase chain reaction (PCR), in both patients. At present, the use of very high-dose intravenous acyclovir may be the best therapeutic option in these patients for whom the visual prognosis is poor. Intravitreal antiviral drugs could also contribute to the management of these cases.

Membrane Peeling-Induced Retinal Alterations on Intraoperative OCT in Vitreomacular Interface Disorders From the PIONEER Study.

PubMed

Ehlers, Justis P; Han, Jaehong; Petkovsek, Daniel; Kaiser, Peter K; Singh, Rishi P; Srivastava, Sunil K

2015-11-01

To assess retinal architectural alterations that occur following membrane peeling procedures and the impact of peel technique on these alterations utilizing intraoperative optical coherence tomography (iOCT). This is a subanalysis of the prospective PIONEER iOCT study of eyes undergoing a membrane peeling for a vitreomacular interface (VMI) disorder. Intraoperative scanning was performed with a microscope-mounted OCT system. Macroarchitectural alterations (e.g., full-thickness retinal elevations) and microarchitectural alterations (e.g., relative layer thickness alterations) were analyzed. Video/iOCT correlation was performed to identify instrument-tissue manipulations resulting in macroarchitectural alterations. One hundred sixty-three eyes were included in the macroarchitectural analysis. Instrumentation utilized for membrane peeling included forceps alone for 73 eyes (45%), combined diamond-dusted membrane scraper (DDMS) and forceps for 87 eyes (53%), and other techniques in three eyes (2%). Focal retinal elevations were identified in 45 of 163 eyes (28%). Video/iOCT correlation identified 69% of alterations involved forceps compared to 26% due to DDMS. Sixteen percent of retinal alterations persisted 1 month following surgery. The microarchitectural analysis included 134 eyes. Immediately following membrane peeling, there was a significant increase in the ellipsoid zone to retinal pigment epithelium height (+20%, P < 0.00001) and the cone outer segment tips to retinal pigment epithelium height (+18%, P < 0.00001). Significant subclinical retinal architectural changes occur during membrane peeling for VMI conditions. Differences in surgical instruments may impact these architectural alterations.

Detailed functional and structural phenotype of Bietti crystalline dystrophy associated with mutations in CYP4V2 complicated by choroidal neovascularization.

PubMed

Fuerst, Nicole M; Serrano, Leona; Han, Grace; Morgan, Jessica I W; Maguire, Albert M; Leroy, Bart P; Kim, Benjamin J; Aleman, Tomas S

2016-12-01

To describe in detail the phenotype of a patient with Bietti crystalline dystrophy (BCD) complicated by choroidal neovascularization (CNV) and the response to intravitreal Bevacizumab (Avastin ® ; Genentech/Roche). A 34-year-old woman with BCD and mutations in CYP4V2 (c.802-8_806del13/p.H331P:c992A>C) underwent a complete ophthalmic examination, full-field flash electroretinography (ERG), kinetic and two-color dark-adapted perimetry, and dark-adaptometry. Imaging was performed with spectral domain optical coherence tomography (SD-OCT), near infrared (NIR) and short wavelength (SW) fundus autofluorescence (FAF), and fluorescein angiography (FA). Best-corrected visual acuity (BCVA) was 20/20 and 20/60 for the right and left eye, respectively. There were corneal paralimbal crystal-like deposits. Kinetic fields were normal in the peripheral extent. Retinal crystals were most obvious on NIR-reflectance and corresponded with hyperreflectivities within the RPE on SD-OCT. There was parafoveal/perifoveal hypofluorescence on SW-FAF and NIR-FAF. Rod > cone sensitivity loss surrounded fixation and extended to ~10° of eccentricity corresponding to regions of photoreceptor outer segment-retinal pigmented epithelium (RPE) interdigitation abnormalities. The outer nuclear layer was normal in thickness. Recovery of sensitivity following a ~76% rhodopsin bleach was normal. ERGs were normal. A subretinal hemorrhage in the left eye co-localized with elevation of the RPE on SD-OCT and leakage on FA, suggestive of CNV. Three monthly intravitreal injections of Bevacizumab led to restoration of BCVA to baseline (20/25). crystals in BCD were predominantly located within the RPE. Photoreceptor outer segment and apical RPE abnormalities underlie the relatively extensive retinal dysfunction observed in relatively early-stage BCD. Intravitreal Bevacizumab was effective in treating CNV in this setting.

Photoreceptor Layer Thickness Changes During Dark Adaptation Observed With Ultrahigh-Resolution Optical Coherence Tomography.

PubMed

Lu, Chen D; Lee, ByungKun; Schottenhamml, Julia; Maier, Andreas; Pugh, Edward N; Fujimoto, James G

2017-09-01

To examine outer retinal band changes after flash stimulus and subsequent dark adaptation with ultrahigh-resolution optical coherence tomography (UHR-OCT). Five dark-adapted left eyes of five normal subjects were imaged with 3-μm axial-resolution UHR-OCT during 30 minutes of dark adaptation following 96%, 54%, 23%, and 0% full-field and 54% half-field rhodopsin bleach. We identified the ellipsoid zone inner segment/outer segment (EZ[IS/OS]), cone interdigitation zone (CIZ), rod interdigitation zone (RIZ), retinal pigment epithelium (RPE), and Bruch's membrane (BM) axial positions and generated two-dimensional thickness maps of the EZ(IS/OS) to the four bands. The average thickness over an area of the thickness map was compared against that of the dark-adapted baselines. The time-dependent thickness changes (photoresponses) were statistically compared against 0% bleach. Dark adaptometry was performed with the same bleaching protocol. The EZ(IS/OS)-CIZ photoresponse was significantly different at 96% (P < 0.0001) and 54% (P = 0.006) bleach. At all three bleaching levels, the EZ(IS/OS)-RIZ, -RPE, and -BM responses were significantly different (P < 0.0001). The EZ(IS/OS)-CIZ and EZ(IS/OS)-RIZ time courses were similar to the recovery of rod- and cone-mediated sensitivity, respectively, measured with dark adaptometry. The maximal EZ(IS/OS)-CIZ and EZ(IS/OS)-RIZ response magnitudes doubled from 54% to 96% bleach. Both EZ(IS/OS)-RPE and EZ(IS/OS)-BM responses resembled dampened oscillations that were graded in amplitude and duration with bleaching intensity. Half-field photoresponses were localized to the stimulated retina. With noninvasive, near-infrared UHR-OCT, we characterized three distinct, spatially localized photoresponses in the outer retinal bands. These photoresponses have potential value as physical correlates of photoreceptor function.

High-Speed Ultra-High-Resolution Optical Coherence Tomography Findings in Hydroxychloroquine Retinopathy

PubMed Central

Rodriguez-Padilla, Julio A.; Hedges, Thomas R.; Monson, Bryan; Srinivasan, Vivek; Wojtkowski, Maciej; Reichel, Elias; Duker, Jay S.; Schuman, Joel S.; Fujimoto, James G.

2007-01-01

Objectives To compare structural changes in the retina seen on high-speed ultra–high-resolution optical coherence tomography (hsUHR-OCT) with multifocal electroretinography (mfERG) and automated visual fields in patients receiving hydroxychloroquine. Methods Fifteen patients receiving hydroxychloroquine were evaluated clinically with hsUHR-OCT, mfERG, and automated visual fields. Six age-matched subjects were imaged with hsUHR-OCT and served as controls. Results Distinctive discontinuity of the perifoveal photoreceptor inner segment/outer segment junction and thinning of the outer nuclear layer were seen with hsUHR-OCT in patients with mild retinal toxic effects. Progression to complete loss of the inner segment/outer segment junction and hyperscattering at the outer segment level were seen in more advanced cases. The mfERG abnormalities correlated with the hsUHR-OCT findings. Asymptomatic patients had normal hsUHR-OCT and mfERG results. Conclusion Distinctive abnormalities in the perifoveal photoreceptor inner segment/outer segment junction were seen on hsUHR-OCT in patients receiving hydroxychloroquine who also were symptomatic and had abnormalities on automated visual fields and mfERG. PMID:17562988

Biomedical Applications of Mid-Infrared Spectroscopic Imaging and Multivariate Data Analysis: Contribution to the Understanding of Diabetes Pathogenesis

NASA Astrophysics Data System (ADS)

Aboualizadeh, Ebrahim

Diabetic retinopathy (DR) is a microvascular complication of diabetes and a leading cause of adult vision loss. Although a great deal of progress has been made in ophthalmological examinations and clinical approaches to detect the signs of retinopathy in patients with diabetes, there still remain outstanding questions regarding the molecular and biochemical changes involved. To discover the biochemical mechanisms underlying the development and progression of changes in the retina as a result of diabetes, a more comprehensive understanding of the bio-molecular processes, in individual retinal cells subjected to hyperglycemia, is required. Animal models provide a suitable resource for temporal detection of the underlying pathophysiological and biochemical changes associated with DR, which is not fully attainable in human studies. In the present study, I aimed to determine the nature of diabetes-induced, highly localized biochemical changes in the retinal tissue from Ins2Akita/+ (Akita/+; a model of Type I diabetes) male mice with different duration of diabetes. Employing label-free, spatially resolved Fourier transform infrared (FT-IR) imaging engaged with chemometric tools enabled me to identify temporal-dependent reproducible biomarkers of the diabetic retinal tissue from mice with 6 or 12 weeks, and 6 or 10 months of diabetes. I report, for the first time, the origin of molecular changes in the biochemistry of individual retinal layers with different duration of diabetes. A robust classification between distinctive retinal layers - namely photoreceptor layer (PRL), outer plexiform layer (OPL), inner nuclear layer (INL), and inner plexiform layer (IPL) - and associated temporal-dependent spectral biomarkers, were delineated. Spatially-resolved super resolution chemical images revealed oxidative stress-induced structural and morphological alterations within the nucleus of the photoreceptors. Comparison among the PRL, OPL, INL, and IPL suggested that the photoreceptor layer is the most susceptible layer to the oxidative stress with short-duration of diabetes. Moreover, for the first time, we present the temporal-dependent molecular alterations for the PRL, OPL, INL, and IPL from Akita/+ mice, with progression of diabetes. These findings are potentially important and may be of particular benefit in understanding the molecular and biological activity of retinal cells during oxidative stress in diabetes. Our integrating paradigm provides a new conceptual framework and a significant rationale for a better understanding of the molecular and cellular mechanisms underlying the development and progression of DR. This approach may yield alternative and potentially complimentary methods for the assessment of diabetes changes. It is expected that the conclusions drawn from this work will bridge the gap in our knowledge regarding the biochemical mechanisms of the DR and address some critical needs in the biomedical community.

Measuring In Vivo Free Radical Production by the Outer Retina

PubMed Central

Berkowitz, Bruce A.; Bredell, Bryce X.; Davis, Christopher; Samardzija, Marijana; Grimm, Christian; Roberts, Robin

2015-01-01

Purpose Excessive and continuously produced free radicals in the outer retina are implicated in retinal aging and the pathogenesis of sight-threatening retinopathies, yet measuring outer retinal oxidative stress in vivo remains a challenge. Here, we test the hypothesis that continuously produced paramagnetic free radicals from the outer retina can be measured in vivo using high-resolution (22-μm axial resolution) 1/T1magnetic resonance imaging (MRI) without and with a confirmatory quench (quench-assisted MRI). Methods Low-dose sodium iodate–treated and diabetic C57Bl6/J mice (and their controls), and rod-dominated (129S6) or cone-only R91W;Nrl−/− mice were studied. In dark-adapted groups, 1/T1 was mapped transretinally in vivo without or with (1) the antioxidant combination of methylene blue (MB) and α-lipoic acid (LPA), or (2) light exposure; in subgroups, retinal superoxide production was measured ex vivo (lucigenin). Results In the sodium iodate model, retinal superoxide production and outer retina-specific 1/T1 values were both significantly greater than normal and corrected to baseline with MB+LPA therapy. Nondiabetic mice at two ages and 1.2-month diabetic mice (before the appearance of oxidative stress) had similar transretinal 1/T1 profiles. By 2.3 months of diabetes, only outer retinal 1/T1 values were significantly greater than normal and were corrected to baseline with MB+LPA therapy. In mice with healthy photoreceptors, a light quench caused 1/T1 of rods, but not cones, to significantly decrease from their values in the dark. Conclusions Quench-assisted MRI is a feasible method for noninvasively measuring normal and pathologic production of free radicals in photoreceptors/RPE in vivo. PMID:26670830

Acute Zonal Cone Photoreceptor Outer Segment Loss.

PubMed

Aleman, Tomas S; Sandhu, Harpal S; Serrano, Leona W; Traband, Anastasia; Lau, Marisa K; Adamus, Grazyna; Avery, Robert A

2017-05-01

The diagnostic path presented narrows down the cause of acute vision loss to the cone photoreceptor outer segment and will refocus the search for the cause of similar currently idiopathic conditions. To describe the structural and functional associations found in a patient with acute zonal occult photoreceptor loss. A case report of an adolescent boy with acute visual field loss despite a normal fundus examination performed at a university teaching hospital. Results of a complete ophthalmic examination, full-field flash electroretinography (ERG) and multifocal ERG, light-adapted achromatic and 2-color dark-adapted perimetry, and microperimetry. Imaging was performed with spectral-domain optical coherence tomography (SD-OCT), near-infrared (NIR) and short-wavelength (SW) fundus autofluorescence (FAF), and NIR reflectance (REF). The patient was evaluated within a week of the onset of a scotoma in the nasal field of his left eye. Visual acuity was 20/20 OU, and color vision was normal in both eyes. Results of the fundus examination and of SW-FAF and NIR-FAF imaging were normal in both eyes, whereas NIR-REF imaging showed a region of hyporeflectance temporal to the fovea that corresponded with a dense relative scotoma noted on light-adapted static perimetry in the left eye. Loss in the photoreceptor outer segment detected by SD-OCT co-localized with an area of dense cone dysfunction detected on light-adapted perimetry and multifocal ERG but with near-normal rod-mediated vision according to results of 2-color dark-adapted perimetry. Full-field flash ERG findings were normal in both eyes. The outer nuclear layer and inner retinal thicknesses were normal. Localized, isolated cone dysfunction may represent the earliest photoreceptor abnormality or a distinct entity within the acute zonal occult outer retinopathy complex. Acute zonal occult outer retinopathy should be considered in patients with acute vision loss and abnormalities on NIR-REF imaging, especially if multimodal imaging supports an intact retinal pigment epithelium and inner retina but an abnormal photoreceptor outer segment.

Optical Coherence Tomography Findings of Exophytic Retinal Capillary Hemangiomas of the Posterior Pole

PubMed Central

Chin, Eric K.; Trikha, Rupan; Morse, Lawrence S.; Zawadzki, Robert J.; Werner, John S.; Park, Susanna S.

2013-01-01

Exophytic retinal capillary hemangiomas (RCH) can be a diagnostic challenge in subjects without von Hippel-Lin-dau disease (VHL). This report of two cases describes the optical coherence tomographic (OCT) characteristics of RCH in two eyes of a subject with VHL and in one eye of an otherwise normal subject. Three different OCT instruments were used (Stratus, Cirrus and/or custom high resolution Fourier-domain OCT with 4.5 μm axial resolution) depending on availability. All instruments localized the tumor to the outer retina. A sharp border between the tumor and overlying inner retina was noted. The tumor bulged into the subretinal space and showed marked shadowing. Associated cystoid macular edema and sub-retinal fluid were noted. High-resolution Fourier-domain OCT showed a focal photoreceptor layer rip in the adjacent tumor-free macula in one eye with poor vision after treatment. OCT may be a useful tool in diagnosing RCH and studying associated morphologic changes. PMID:20337341

Correlation of Optical Coherence Tomography and Autofluorescence in the Outer Retina and Choroid of Patients With Choroideremia.

PubMed

Xue, Kanmin; Oldani, Marta; Jolly, Jasleen K; Edwards, Thomas L; Groppe, Markus; Downes, Susan M; MacLaren, Robert E

2016-07-01

To evaluate the relationships between RPE, photoreceptor, and choroidal degeneration in choroideremia. Enhanced-depth imaging optical coherence tomography (EDI-OCT), scanning laser ophthalmoscopy (SLO), and autofluorescence (AF) were performed on 39 patients (78 eyes) with choroideremia. The edges of surviving outer retina on OCT and residual AF were aligned. The distribution of outer retinal tubulations was mapped over a range of ages (16-71 years), and comparison made between pre- and postsubretinal gene therapy. Subfoveal choroidal thickness (SFCT) was compared between 23 choroideremia patients (42 eyes) and 20 age- and refraction-matched male controls (40 eyes). The edges of RPE AF aligned with a reduction in outer nuclear layer thickness (Spearman's rho = 0.9992). Correlation was also found between the quality of AF and integrity of ellipsoid zone within islands of surviving retina. Tubulations existed in 71 of 78 (91%) eyes with choroideremia and remained stable following gene therapy. Subfoveal choroidal thickness was reduced at baseline in choroideremia (179.7 ± 17.2 μm) compared with controls (302.0 ± 4.8 μm; P < 0.0001), but did not undergo significant thinning until end-stage retinal degeneration (43.1 ± 6.5 μm). The data suggest that RPE loss is the primary cause of photoreceptor degeneration in choroideremia. The choroid is thinner than controls from early stages, in keeping with a mild developmental defect. Photoreceptors appear to lose outer segments following loss of underlying RPE and form tubulations at the edges of degeneration. The preservation of tubulations over time and after subretinal injection would be consistent with these structures maintaining attachment to the inner retina and hence being potentially light responsive (ClinicalTrials.gov, NCT01461213).

Correlation of Optical Coherence Tomography and Autofluorescence in the Outer Retina and Choroid of Patients With Choroideremia

PubMed Central

Xue, Kanmin; Oldani, Marta; Jolly, Jasleen K.; Edwards, Thomas L.; Groppe, Markus; Downes, Susan M.; MacLaren, Robert E.

2016-01-01

Purpose To evaluate the relationships between RPE, photoreceptor, and choroidal degeneration in choroideremia. Methods Enhanced-depth imaging optical coherence tomography (EDI-OCT), scanning laser ophthalmoscopy (SLO), and autofluorescence (AF) were performed on 39 patients (78 eyes) with choroideremia. The edges of surviving outer retina on OCT and residual AF were aligned. The distribution of outer retinal tubulations was mapped over a range of ages (16–71 years), and comparison made between pre- and postsubretinal gene therapy. Subfoveal choroidal thickness (SFCT) was compared between 23 choroideremia patients (42 eyes) and 20 age- and refraction-matched male controls (40 eyes). Results The edges of RPE AF aligned with a reduction in outer nuclear layer thickness (Spearman's rho = 0.9992). Correlation was also found between the quality of AF and integrity of ellipsoid zone within islands of surviving retina. Tubulations existed in 71 of 78 (91%) eyes with choroideremia and remained stable following gene therapy. Subfoveal choroidal thickness was reduced at baseline in choroideremia (179.7 ± 17.2 μm) compared with controls (302.0 ± 4.8 μm; P < 0.0001), but did not undergo significant thinning until end-stage retinal degeneration (43.1 ± 6.5 μm). Conclusions The data suggest that RPE loss is the primary cause of photoreceptor degeneration in choroideremia. The choroid is thinner than controls from early stages, in keeping with a mild developmental defect. Photoreceptors appear to lose outer segments following loss of underlying RPE and form tubulations at the edges of degeneration. The preservation of tubulations over time and after subretinal injection would be consistent with these structures maintaining attachment to the inner retina and hence being potentially light responsive (ClinicalTrials.gov, NCT01461213). PMID:27403996

Development of an MRI biomarker sensitive to tetrameric visual arrestin 1 and its reduction via light-evoked translocation in vivo.

PubMed

Berkowitz, Bruce A; Gorgis, Jawan; Patel, Ankit; Baameur, Faiza; Gurevich, Vsevolod V; Craft, Cheryl M; Kefalov, Vladimir J; Roberts, Robin

2015-02-01

Rod tetrameric arrestin 1 (tet-ARR1), stored in the outer nuclear layer/inner segments in the dark, modulates photoreceptor synaptic activity; light exposure stimulates a reduction via translocation to the outer segments for terminating G-protein coupled phototransduction signaling. Here, we test the hypothesis that intraretinal spin-lattice relaxation rate in the rotating frame (1/T1ρ), an endogenous MRI contrast mechanism, has high potential for evaluating rod tet-ARR1 and its reduction via translocation. Dark- and light-exposed mice (null for the ARR1 gene, overexpressing ARR1, diabetic, or wild type with or without treatment with Mn2+, a calcium channel probe) were studied using 1/T1ρ MRI. Immunohistochemistry and single-cell recordings of the retinas were also performed. In wild-type mice with or without treatment with Mn2+, 1/T1ρ of avascular outer retina (64% to 72% depth) was significantly (P < 0.05) greater in the dark than in the light; a significant (P < 0.05) but opposite pattern was noted in the inner retina (<50% depth). Light-evoked outer retina Δ1/T1ρ was absent in ARR1-null mice and supernormal in overexpressing mice. In diabetic mice, the outer retinal Δ1/T1ρ pattern suggested normal dark-to-light tet-ARR1 translocation and chromophore content, conclusions confirmed ex vivo. Light-stimulated Δ1/T1ρ in inner retina was linked to changes in blood volume. Our data support 1/T1ρ MRI for noninvasively assessing rod tet-ARR1 and its reduction via protein translocation, which can be combined with other metrics of retinal function in vivo. © FASEB.

Novel grading system for quantification of cystic macular lesions in Usher syndrome.

PubMed

Sliesoraityte, Ieva; Peto, Tunde; Mohand-Said, Saddek; Sahel, Jose Alain

2015-12-10

To evaluate novel grading system used to quantify optical coherence tomography (OCT) scans for cystic macular lesions (CML) in Usher syndrome (USH) patients, focusing on CML associated alterations in MOY7A and USH2A mutations. Two readers evaluated 76 patients' (mean age 42 ± 14 years) data prospectively uploaded on Eurush database. OCT was used to obtain high quality cross-sectional images through the fovea. The CML was graded as none, mild, moderate or severe, depending on the following features set: subretinal fluid without clearly detectable CML boundaries; central macular thickness; largest diameter of CML; calculated mean of all detectable CML; total number of detectable CML; retinal layers affected by CML. Intra-and inter-grader reproducibility was evaluated. CML were observed in 37 % of USH eyes, while 45 % were observed in MYO7A and 29 % in USH2A cases. Of those with CML: 52 % had mild, 22 % had moderate and 26 % had severe changes, respectively. CML were found in following retinal layers: 50 % inner nuclear layer, 44 % outer nuclear layer, 6 % retinal ganglion cell layer. For the inter-grader repeatability analysis, agreements rates for CML were 97 % and kappa statistics was 0.91 (95 % CI 0.83-0.99). For the intra-grader analysis, agreement rates for CML were 98 %, while kappa statistics was 0.96 (95 % CI 0.92-0.99). The novel grading system is a reproducible tool for grading OCT images in USH complicated by CML, and potentially could be used for objective tracking of macular pathology in clinical therapy trials.

Using Stem Cells to Model Diseases of the Outer Retina.

PubMed

Yvon, Camille; Ramsden, Conor M; Lane, Amelia; Powner, Michael B; da Cruz, Lyndon; Coffey, Peter J; Carr, Amanda-Jayne F

2015-01-01

Retinal degeneration arises from the loss of photoreceptors or retinal pigment epithelium (RPE). It is one of the leading causes of irreversible blindness worldwide with limited effective treatment options. Generation of induced pluripotent stem cell (IPSC)-derived retinal cells and tissues from individuals with retinal degeneration is a rapidly evolving technology that holds a great potential for its use in disease modelling. IPSCs provide an ideal platform to investigate normal and pathological retinogenesis, but also deliver a valuable source of retinal cell types for drug screening and cell therapy. In this review, we will provide some examples of the ways in which IPSCs have been used to model diseases of the outer retina including retinitis pigmentosa (RP), Usher syndrome (USH), Leber congenital amaurosis (LCA), gyrate atrophy (GA), juvenile neuronal ceroid lipofuscinosis (NCL), Best vitelliform macular dystrophy (BVMD) and age related macular degeneration (AMD).

Fine structure of the retinal pigment epithelium of the great horned owl (Bubo virginianus).

PubMed

Braekevelt, C R; Thorlakson, I J

1993-01-01

The fine structure of the retinal epithelium (RPE), choriocapillaries and Bruch's membrane (complexus basalis) has been studied by light and electron microscopy in the great horned owl (Bubo virginianus). The RPE consists of a single layer of cuboidal cells joined laterally in the mid to basal region by a series of tight junctions forming part of the blood-ocular barrier. Basally (sclerally) the epithelial cells show numerous deep infoldings while apically (vitreally) a wealth of microvillar processes interdigitate with the photoreceptor cells. Internally the RPE cells display a large vesicular nucleus, plentiful smooth endoplasmic reticulum (SER) and polysomes with only small scattered profiles of rough endoplasmic reticulum (RER). Numerous pleomorphic mitochondria are basally located. In the light-adapted state the melanosomes are located almost exclusively within the apical processes indicating retinomotor movements. Myeloid bodies are numerous and often show ribosomes on their outer surface. Bruch's membrane is typical of avian species in that it is pentalaminate and the lamina densa is displaced towards the choriocapillaris. The choriocapillaris itself is but minimally fenestrated facing Bruch's membrane. Most fenestrations present show a single layered diaphragm while others display a double-layered diaphragm.

Foveal cone spacing and cone photopigment density difference: objective measurements in the same subjects.

PubMed

Marcos, S; Tornow, R P; Elsner, A E; Navarro, R

1997-07-01

Foveal cone spacing was measured in vivo using an objective technique: ocular speckle interferometry. Cone packing density was computed from cone spacing data. Foveal cone photopigment density difference was measured in the same subjects using retinal densitometry with a scanning laser ophthalmoscope. Both the cone packing density and cone photopigment density difference decreased sharply with increasing retinal eccentricity. From the comparison of both sets of measurements, the computed amounts of photopigment per cone increased slightly with increasing retinal eccentricity. Consistent with previous results, decreases in cone outer segment length are over-compensated by an increase in the outer segment area, at least in retinal eccentricities up to 1 deg.

Use of optical coherence tomography to evaluate visual acuity and visual field changes in dengue fever.

PubMed

Rhee, Taek Kwan; Han, Jung Il

2014-02-01

Dengue fever is a viral disease that is transmitted by mosquitoes and affects humans. In rare cases, dengue fever can cause visual impairment, which usually occurs within 1 month after contracting dengue fever and ranges from mild blurring of vision to severe blindness. Visual impairment due to dengue fever can be detected through angiography, retinography, optical coherence tomography (OCT) imaging, electroretinography, event electroencephalography (visually evoked potentials), and visual field analysis. The purpose of this study is to report changes in the eye captured using fluorescein angiography, indocyanine green, and OCT in 3 cases of dengue fever visual impairment associated with consistent visual symptoms and similar retinochoroidopathic changes. The OCT results of the three patients with dengue fever showed thinning of the outer retinal layer and disruption of the inner segment/outer segment (IS/OS) junction. While thinning of the retina outer layer is an irreversible process, disruption of IS/OS junction is reported to be reversible. Follow-up examination of individuals with dengue fever and associated visual impairment should involve the use of OCT to evaluate visual acuity and visual field changes in patients with acute choroidal ischemia.

Effects of photocoagulation on intraretinal PO2 in cat.

PubMed

Budzynski, Ewa; Smith, Jennifer H; Bryar, Paul; Birol, Gulnur; Linsenmeier, Robert A

2008-01-01

To test the hypothesis that intraretinal Po(2) increases after photocoagulation. Anesthetized cats underwent retinal argon laser photocoagulation. At least 4 weeks after treatment, Po(2)-sensitive microelectrodes were used to record intraretinal Po(2) profiles from healed photocoagulation lesions in anesthetized cats breathing air. Histopathologic examination of the retinas was used to confirm that the photoreceptors were destroyed and that the inner retinal layers were preserved, though somewhat disorganized, as in human panretinal photocoagulation (PRP). The retina and tapetum were thinner in the lesioned retina than in the nonphotocoagulated retina. Average Po(2) across the inner 50% of the retina was higher (22 +/- 10 mm Hg) in photocoagulated retina than in untreated retina (14 +/- 7 mm Hg; P < 0.01; n = 13 cats). The minimum Po(2) was also significantly higher, whereas choroidal Po(2) was significantly lower in the photocoagulated retina than in untreated retina. No significant difference was found in the preretinal vitreous. After lesions, inner retinal Po(2) could also be maintained above zero, even in the absence of retinal circulation. Previous measurements showed increased Po(2) in the preretinal vitreous of rabbits and pigs (but not cats) after photocoagulation of the outer retina. These intraretinal measurements in cats provide further evidence for a chronic increase in inner retinal Po(2) in lesioned areas during air breathing.

[The eye and nutrition].

PubMed

Amemiya, T

1999-12-01

To examine the effect of vitamins and trace elements on ocular tissue. Rats or mice were fed diets deficient in the trace elements Zn, Cu, Mn, Se, Mg, and Cr or in vitamins A, B12, C, and E. In some rats Al and vitamin A were injected in excessive amounts. We studied the conjunctiva, cornea, retina, and optic nerve with a light microscope, transmission and scanning electron microscopes, an energy dispersive X-ray analyser, and an ion microscope. Histochemical, cytochemical, and immunohistochemical techniques were applied to the pathological specimens. Deficiencies of Zn, Cu, Mn, and vitamins A, C and E caused a loss of goblet cells in the conjunctiva and a prominent decrease of microvilli and microplicae in the conjunctiva and cornea. The elements in the goblet cells were changed in these conditions. In addition, epithelial cells showed poor fibrous development and abnormal distribution of chromatin in the nucleus. Zn, Cu, Mn, and vitamins A and E deficiencies caused photoreceptor cells to degenerate and disappear. Se deficiency reduced the horizontal and amacrine cells. Vitamin B12 deficiency reduced nerve fibers in the nerve fiber layer of the retina. Mg deficiency induced multifocal necrosis in the retinal pigment epithelium and apoptotic nuclear changes in the photoreceptor cells. Cr deficiency showed abnormal phagocytosis of the photoreceptor outer segment discs in the retinal pigment epithelium. Vitamin B12 was found to be related to the circadian rhythm in the retina. Deficiencies of Zn, Cu, Mn, and vitamins A, B12, and E induced degeneration and disappearance of myelin lamellae in the myelinated optic nerve fibers. In hypervitaminosis A, lipid droplets appeared in the retinal pigment epithelium and alcohol dehydrogenase disappeared in the retinal pigment epithelium and photoreceptor outer segments. Excessive Al was toxic to the retina, which showed disappearance of photoreceptor cells. Al deposits were seen in dendrites and neurons in the outer plexiform layer. Zn seemed to be necessary for corneal epithelial cell wound healing. Trace elements usually are contained in enzymes, which have many metabolic functions. They are related to synthesis and breakdown of many substances. Some trace elements such as Zn, Cu, Mn, and Se and vitamins including vitamins A, C, and E prevent peroxidation of lipids. Some vitamins have an affinity for specific tissues such as epithelial cells, nerve fibers, and neuronal cells and are needed for cell differentiation, development, and maintenance. Cu, Zn, Mn, Se, Mg, and Cr and vitamins A, B12, C, and E are necessary for maintenance of cellular structure and metabolism.

The eye and nutrition

PubMed

Amemiya

2000-05-01

Purpose: To examine the effect of vitamins and trace elements on ocular tissue.Materials and Methods: Rats or mice were fed diets deficient in the trace elements Zn, Cu, Mn, Se, Mg, and Cr or in vitamins A, B(12), C, and E. In some rats Al and vitamin A were injected in excessive amounts. We studied the conjunctiva, cornea, retina, and optic nerve with a light microscope, transmission and scanning electron microscopes, an energy dispersive X-ray analyzer, and an ion microscope. Histochemical, cytochemical, and immunohistochemical techniques were applied to the pathological specimens.Results: Deficiencies of Zn, Cu, Mn, and vitamins A, C and E caused a loss of goblet cells in the conjunctiva and a prominent decrease of microvilli and microplicae in the conjunctiva and cornea. The elements in the goblet cells were changed in these conditions. In addition, epithelial cells showed poor fibrous development and abnormal distribution of chromatin in the nucleus.Zn, Cu, Mn, and vitamins A and E deficiencies caused photoreceptor cells to degenerate and disappear. Se deficiency reduced the horizontal and amacrine cells. Vitamin B(12) deficiency reduced nerve fibers in the nerve fiber layer of the retina. Mg deficiency induced multifocal necrosis in the retinal pigment epithelium and apoptotic nuclear changes in the photoreceptor cells. Cr deficiency showed abnormal phagocytosis of the photoreceptor outer segment discs in the retinal pigment epithelium. Vitamin B(12) was found to be related to the circadian rhythm in the retina.Deficiencies of Zn, Cu, Mn, and vitamins A, B(12), and E induced degeneration and disappearance of myelin lamellae in the myelinated optic nerve fibers.In hypervitaminosis A, lipid droplets appeared in the retinal pigment epithelium and alcohol dehydrogenase disappeared in the retinal pigment epithelium and photoreceptor outer segments. Excessive Al was toxic to the retina, which showed disappearance of photoreceptor cells. Al deposits were seen in dendrites and neurons in the outer plexiform layer.Zn seemed to be necessary for corneal epithelial cell wound healing.Discussion: Trace elements usually are contained in enzymes, which have many metabolic functions. They are related to synthesis and breakdown of many substances. Some trace elements such as Zn, Cu, Mn, and Se and vitamins including vitamins A, C, and E prevent peroxidation of lipids. Some vitamins have an affinity for specific tissues such as epithelial cells, nerve fibers, and neuronal cells and are needed for cell differentiation, development, and maintenance.Conclusion: Cu, Zn, Mn, Se, Mg, and Cr and vitamins A, B(12), C, and E are necessary for maintenance of cellular structure and metabolism.

Blue light-induced retinal lesions, intraretinal vascular leakage and edema formation in the all-cone mouse retina

PubMed Central

Geiger, P; Barben, M; Grimm, C; Samardzija, M

2015-01-01

Little is known about the mechanisms underlying macular degenerations, mainly for the scarcity of adequate experimental models to investigate cone cell death. Recently, we generated R91W;Nrl−/− double-mutant mice, which display a well-ordered all-cone retina with normal retinal vasculature and a strong photopic function that generates useful vision. Here we exposed R91W;Nrl−/− and wild-type (wt) mice to toxic levels of blue light and analyzed their retinas at different time points post illumination (up to 10 days). While exposure of wt mice resulted in massive pyknosis in a focal region of the outer nuclear layer (ONL), the exposure of R91W;Nrl−/− mice led to additional cell death detected within the inner nuclear layer. Microglia/macrophage infiltration at the site of injury was more pronounced in the all-cone retina of R91W;Nrl−/− than in wt mice. Similarly, vascular leakage was abundant in the inner and outer retina in R91W;Nrl−/− mice, whereas it was mild and restricted to the subretinal space in wt mice. This was accompanied by retinal swelling and the appearance of cystoid spaces in both inner and ONLs of R91W;Nrl−/− mice indicating edema in affected areas. In addition, basal expression levels of tight junction protein-1 encoding ZO1 were lower in R91W;Nrl−/− than in wt retinas. Collectively, our data suggest that exposure of R91W;Nrl−/− mice to blue light not only induces cone cell death but also disrupts the inner blood–retinal barrier. Macular edema in humans is a result of diffuse capillary leakage and microaneurysms in the macular region. Blue light exposure of the R91W;Nrl−/− mouse could therefore be used to study molecular events preceding edema formation in a cone-rich environment, and thus potentially help to develop treatment strategies for edema-based complications in macular degenerations. PMID:26583326

Progressive outer retinal necrosis: a missed diagnosis and a blind, young woman.

PubMed

Parekh, Parth; Oldfield, Edward C; Marik, Paul E

2013-04-22

We present a 33-year-old woman with a history significant for HIV/AIDS (CD4 count of 17) and diabetes mellitus who was diagnosed as having progressive outer retinal necrosis (PORN) after presenting with peripheral vision loss. This case provided a diagnostic challenge and demonstrates the devastating effects of a misdiagnosis as it pertains to PORN.

Progressive outer retinal necrosis: a missed diagnosis and a blind, young woman

PubMed Central

Parekh, Parth; Oldfield, Edward C; Marik, Paul E

2013-01-01

We present a 33-year-old woman with a history significant for HIV/AIDS (CD4 count of 17) and diabetes mellitus who was diagnosed as having progressive outer retinal necrosis (PORN) after presenting with peripheral vision loss. This case provided a diagnostic challenge and demonstrates the devastating effects of a misdiagnosis as it pertains to PORN. PMID:23608868

Retrospective cohort study exploring whether an association exists between spatial distribution of cystoid spaces in cystoid macular oedema secondary to retinitis pigmentosa and response to treatment with carbonic anhydrase inhibitors.

PubMed

Strong, Stacey A; Hirji, Nashila; Quartilho, Ana; Kalitzeos, Angelos; Michaelides, Michel

2018-04-29

Carbonic anhydrase inhibitors (CAIs) are frequently used as an initial step to treat retinitis pigmentosa-associated cystoid macular oedema (RP-CMO). Interestingly, it has been postulated that CAIs might reduce outer nuclear layer (ONL) fluid more effectively than inner nuclear layer (INL) fluid due to better access to retinal pigment epithelium basolateral membrane than neurosensory retina. This retrospective cohort study explores if an association between spatial distribution of cystoid spaces in RP-CMO and CAI response exists. Two independent graders reviewed pretreatment and post-treatment optical coherence tomography (OCT) images of 25 patients (43 eyes) initiated on topical and/or oral CAIs between January 2013 and December 2014. Documentation included the presence/absence of fluid (and layer(s) involved), external limiting membrane, epiretinal membrane (ERM), vitreomacular adhesion/traction, lamellar/full-thickness macular hole and central macular thickness (CMT)/volume. INL fluid was found in all study eyes. All 13 'responders' (at least 11% reduction of CMT after treatment) demonstrated pretreatment ONL fluid. In seven patients (four responders and three non-responders), complete clearance of ONL fluid was achieved despite persistence of INL fluid. ERM presence was similar in responders and non-responders. In this study, INL fluid was found to be the most common spatial distribution of RP-CMO. However, patients who were classed as a 'responder' to CAI treatment all demonstrated coexisting ONL fluid on their pretreatment OCT scans. This may be explained by CAIs having better access to retinal pigment epithelium basolateral membrane than neurosensory retina. Our study also suggests a minimal impact on response to CAIs by ERM. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Müller glial cells of the primate foveola: An electron microscopical study.

PubMed

Syrbe, Steffen; Kuhrt, Heidrun; Gärtner, Ulrich; Habermann, Gunnar; Wiedemann, Peter; Bringmann, Andreas; Reichenbach, Andreas

2018-02-01

Previous studies on the ultrastructure of the primate foveola suggested the presence of an inverted cone-like structure which is formed by 25-35 specialized Müller cells overlying the area of high photoreceptor density. We investigated the ultrastructure of the Müller cells in the foveola of a human and macaque retina. Sections through the posterior poles of an eye of a 40 years-old human donor and an eye of an adult cynomolgus monkey (Macaca fascicularis) were investigated with transmission electron microscopy. The foveola consisted of an inner layer (thickness, 5.5-12 μm) which mainly contained somata (including nuclei) and inner processes of Müller cells; this layer overlaid the central Henle fibers and outer nuclear layer. The inner layer contained numerous watery cysts and thin lamelliform and tubular Müller cell processes which spread along the inner limiting membrane (ILM). The cytoplasm of the outer Müller cell processes became increasingly dispersed and electron-lucent in the course towards the outer limiting membrane. The ILM of the foveola was formed by a very thin basal lamina (thickness, <40 nm) while the basal lamina of the parafovea was thick (0.9-1 μm). The data show that there are various conspicuous features of foveolar Müller cells. The numerous thin Müller cell processes below the ILM may smooth the inner surface of the foveola (to minimize image distortion resulting from varying light refraction angles at an uneven retinal surface), create additional barriers to the vitreous cavity (compensating the thinness of the ILM), and provide mechanical stability to the tissue. The decreasing density of the outer process cytoplasm may support the optical function of the foveola. Copyright © 2017. Published by Elsevier Ltd.

Characteristics of intraretinal deposits in acute central serous chorioretinopathy.

PubMed

Plateroti, Andrea M; Witmer, Matthew T; Kiss, Szilárd; D'Amico, Donald J

2014-01-01

To describe the temporal and spatial characteristics of intraretinal deposits in patients with acute central serous chorioretinopathy (CSC) using spectral domain optical coherence tomography (OCT). We retrospectively reviewed the medical records of all patients that presented with acute CSC to Weill Cornell Medical College from January 2012 to May 2013. Acute CSC was defined as a diagnosis of CSC within 4 months of the onset of symptoms. Only one eye per patient was included in the study. Each patient was imaged with spectral domain OCT at the initial office visit. The decision to reimage these patients was made by the treating physician. A total of 25 patients (25 eyes; 17 men and eight nonpregnant women) were included in this review. Seven of 25 patients (28%) demonstrated intraretinal deposits within the outer plexiform layer during the initial OCT, with deposits appearing as early as the same day as the onset of symptoms. A total of 25 of 25 patients (100%) demonstrated intraretinal deposits in the outer nuclear layer upon initial (76%) or follow-up OCT, as early as 2 days after the onset of symptoms. A total of 24 of 25 patients (96%) demonstrated deposits in the external limiting membrane upon a follow-up OCT, as early as 7 days from symptoms appearing. A total of 24 of 25 patients (96%) developed intraretinal deposits in the inner segment/outer segment layer upon follow-up OCT, appearing as early as 14 days after symptom onset. At the time of resolution of subretinal fluid, 20 of 25 patients (80%) demonstrated intraretinal deposits. Intraretinal deposits are present in the outer retinal layers in patients with acute CSC, with the deposits appearing progressively deeper within the retina as the condition evolves. Upon resolution of subretinal fluid, the deposits slowly resolve.

Radiation-induced ocular injury in the dog: a histological study.

PubMed

Ching, S V; Gillette, S M; Powers, B E; Roberts, S M; Gillette, E L; Withrow, S J

1990-08-01

Radiation-induced ocular injury secondary to treatment of nasal cancer occurs in humans and animals. Dogs with nasal carcinomas were randomized to receive 36 to 67.5 Gy in fractionated doses given in 4 weeks using a 6 MV linear accelerator. Ophthalmic examinations were performed according to a predetermined protocol and eyes were removed for histologic examination when dogs were euthanatized. The eye in the radiation field exhibited greater injury than the contralateral eye with nasal areas of the globe having more severe lesions than temporal areas. Lesions occurred in all dogs and at all doses. At 1 month or less postirradiation treatment, all dogs had blepharitis, keratoconjunctivitis and corneal epithelial atrophy. Surface lesions persisted in all eyes, becoming less severe and more chronic with time. At 3-6 months postirradiation treatment, degenerative angiopathy of retinal vessels appeared with multifocal retinal hemorrhage and mild diffuse retinal degeneration which affected outer layers first and progressed inwardly with time. At 6 months postirradiation treatment, there were cataracts, fibrosis of retinal vessel walls with loss of vascular smooth muscle, retinal hemorrhage, and mild to moderate retinal degeneration. At 1 year postirradiation treatment, retinal vessels remained sclerotic, retinal hemorrhage was less frequent, and there was moderate retinal degeneration with swelling and loss of ganglion cells. By 2 years or more postirradiation treatment, optic nerve axonal degeneration secondary to retinal changes had appeared. Tapetal and choroidal atrophy were inconsistently seen. Thus, ocular lesions at the doses received developed along a relatively predictable time course and recovery was not seen. Structures of the canine eye appear sufficiently sensitive that even relatively low total doses given in small doses per fraction cause significant long-term injury.

Upregulation of the endothelin A (ETA) receptor and its association with neurodegeneration in a rodent model of glaucoma.

PubMed

McGrady, Nolan R; Minton, Alena Z; Stankowska, Dorota L; He, Shaoqing; Jefferies, Hayden B; Krishnamoorthy, Raghu R

2017-03-01

Primary open angle glaucoma is a heterogeneous group of optic neuropathies that results in optic nerve degeneration and a loss of retinal ganglion cells (RGCs) ultimately causing blindness if allowed to progress. Elevation of intraocular pressure (IOP) is the most attributable risk factor for developing glaucoma and lowering of IOP is currently the only available therapy. However, despite lowering IOP, neurodegenerative effects persist in some patients. Hence, it would be beneficial to develop approaches to promote neuroprotection of RGCs in addition to IOP lowering therapies. The endothelin system is a key target for intervention against glaucomatous neurodegeneration. The endothelin family of peptides and receptors, particularly endothelin-1 (ET-1) and endothelin B (ET B ) receptor, has been shown to have neurodegenerative roles in glaucoma. The purpose of this study was to examine changes in endothelin A (ET A ) receptor protein expression in the retinas of adult male Brown Norway rats following IOP elevation by the Morrison's model of ocular hypertension and the impact of ET A receptor overexpression on RGC viability in vitro. IOP elevation was carried out in one eye of Brown Norway rats by injection of hypertonic saline through episcleral veins. After 2 weeks of IOP elevation, immunohistochemical analysis of retinal sections from rat eyes showed an increasing trend in immunostaining for ET A receptors in multiple retinal layers including the inner plexiform layer, ganglion cell layer and outer plexiform layer. Following 4 weeks of IOP elevation, a significant increase in immunostaining for ET A receptor expression was found in the retina, primarily in the inner plexiform layer and ganglion cells. A modest increase in staining for ET A receptors was also found in the outer plexiform layer in the retina of rats with IOP elevation. Cell culture studies showed that overexpression of ET A receptors in 661W cells as well as primary RGCs decreases cell viability, compared to empty vector transfected cells. Adeno-associated virus mediated overexpression of the ET A receptor produced an increase in the ET B receptor in primary RGCs. Elevated IOP results in an appreciable change in ET A receptor expression in the retina. Overexpression of the ET A receptor results in an overall decrease in cell viability, accompanied by an increase in ET B receptor levels, suggesting the involvement of both ET A and ET B receptors in mediating cell death. These findings raise possibilities for the development of ET A /ET B dual receptor antagonists as neuroprotective treatments for glaucomatous neuropathy.

Ganglion cell loss in relation to visual disability in multiple sclerosis.

PubMed

Walter, Scott D; Ishikawa, Hiroshi; Galetta, Kristin M; Sakai, Reiko E; Feller, Daniel J; Henderson, Sam B; Wilson, James A; Maguire, Maureen G; Galetta, Steven L; Frohman, Elliot; Calabresi, Peter A; Schuman, Joel S; Balcer, Laura J

2012-06-01

We used high-resolution spectral-domain optical coherence tomography (SD-OCT) with retinal segmentation to determine how ganglion cell loss relates to history of acute optic neuritis (ON), retinal nerve fiber layer (RNFL) thinning, visual function, and vision-related quality of life (QOL) in multiple sclerosis (MS). Cross-sectional study. A convenience sample of patients with MS (n = 122; 239 eyes) and disease-free controls (n = 31; 61 eyes). Among MS eyes, 87 had a history of ON before enrollment. The SD-OCT images were captured using Macular Cube (200×200 or 512×128) and ONH Cube 200×200 protocols. Retinal layer segmentation was performed using algorithms established for glaucoma studies. Thicknesses of the ganglion cell layer/inner plexiform layer (GCL+IPL), RNFL, outer plexiform/inner nuclear layers (OPL+INL), and outer nuclear/photoreceptor layers (ONL+PRL) were measured and compared in MS versus control eyes and MS ON versus non-ON eyes. The relation between changes in macular thickness and visual disability was also examined. The OCT measurements of GCL+IPL and RNFL thickness; high contrast visual acuity (VA); low-contrast letter acuity (LCLA) at 2.5% and 1.25% contrast; on the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) and 10-Item Neuro-Ophthalmic Supplement composite score. Macular RNFL and GCL+IPL were significantly decreased in MS versus control eyes (P<0.001 and P = 0.001) and in MS ON versus non-ON eyes (P<0.001 for both measures). Peripapillary RNFL, macular RNFL, GCL+IPL, and the combination of macular RNFL+GCL+IPL were significantly correlated with VA (P≤0.001), 2.5% LCLA (P<0.001), and 1.25% LCLA (P≤0.001). Among OCT measurements, reductions in GCL+IPL (P<0.001), macular RNFL (P = 0.006), and the combination (macular RNFL+GCL+IPL; P<0.001) were most strongly associated with lower (worse) NEI-VFQ-25 and 10-Item Supplement QOL scores; GCL+IPL thinning was significant even accounting for macular RNFL thickness (P = 0.03 for GCL+IPL, P = 0.39 for macular RNFL). We demonstrated that GCL+IPL thinning is most significantly correlated with both visual function and vision-specific QOL in MS, and may serve as a useful structural marker of disease. Our findings parallel those of magnetic resonance imaging studies that show gray matter disease is a marker of neurologic disability in MS. Proprietary or commercial disclosure may be found after the references. Copyright © 2012 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Classical and alternative complement activation on photoreceptor outer segments drives monocyte-dependent retinal atrophy.

PubMed

Katschke, Kenneth J; Xi, Hongkang; Cox, Christian; Truong, Tom; Malato, Yann; Lee, Wyne P; McKenzie, Brent; Arceo, Rommel; Tao, Jianhua; Rangell, Linda; Reichelt, Mike; Diehl, Lauri; Elstrott, Justin; Weimer, Robby M; Campagne, Menno van Lookeren

2018-05-09

Geographic atrophy (GA), the advanced form of dry age-related macular degeneration (AMD), is characterized by progressive loss of retinal pigment epithelium cells and photoreceptors in the setting of characteristic extracellular deposits and remains a serious unmet medical need. While genetic predisposition to AMD is dominated by polymorphisms in complement genes, it remains unclear how complement activation contributes to retinal atrophy. Here we demonstrate that complement is activated on photoreceptor outer segments (POS) in the retina peripheral to atrophic lesions associated with GA. When exposed to human serum following outer blood-retinal barrier breakdown, POS act as potent activators of the classical and alternative complement pathway. In mouse models of retinal degeneration, classical and alternative pathway complement activation on photoreceptors contributed to the loss of photoreceptor function. This was dependent on C5a-mediated recruitment of peripheral blood monocytes but independent of resident microglia. Genetic or pharmacologic inhibition of both classical and alternative complement C3 and C5 convertases was required to reduce progressive degeneration of photoreceptor rods and cones. Our study implicates systemic classical and alternative complement proteins and peripheral blood monocytes as critical effectors of localized retinal degeneration with potential relevance for the contribution of complement activation to GA.

Localization of Usher 1 proteins to the photoreceptor calyceal processes, which are absent from mice.

PubMed

Sahly, Iman; Dufour, Eric; Schietroma, Cataldo; Michel, Vincent; Bahloul, Amel; Perfettini, Isabelle; Pepermans, Elise; Estivalet, Amrit; Carette, Diane; Aghaie, Asadollah; Ebermann, Inga; Lelli, Andrea; Iribarne, Maria; Hardelin, Jean-Pierre; Weil, Dominique; Sahel, José-Alain; El-Amraoui, Aziz; Petit, Christine

2012-10-15

The mechanisms underlying retinal dystrophy in Usher syndrome type I (USH1) remain unknown because mutant mice lacking any of the USH1 proteins-myosin VIIa, harmonin, cadherin-23, protocadherin-15, sans-do not display retinal degeneration. We found here that, in macaque photoreceptor cells, all USH1 proteins colocalized at membrane interfaces (i) between the inner and outer segments in rods and (ii) between the microvillus-like calyceal processes and the outer segment basolateral region in rods and cones. This pattern, conserved in humans and frogs, was mediated by the formation of an USH1 protein network, which was associated with the calyceal processes from the early embryonic stages of outer segment growth onwards. By contrast, mouse photoreceptors lacked calyceal processes and had no USH1 proteins at the inner-outer segment interface. We suggest that USH1 proteins form an adhesion belt around the basolateral region of the photoreceptor outer segment in humans, and that defects in this structure cause the retinal degeneration in USH1 patients.

Localization of Usher 1 proteins to the photoreceptor calyceal processes, which are absent from mice

PubMed Central

Sahly, Iman; Dufour, Eric; Schietroma, Cataldo; Michel, Vincent; Bahloul, Amel; Perfettini, Isabelle; Pepermans, Elise; Estivalet, Amrit; Carette, Diane; Aghaie, Asadollah; Ebermann, Inga; Lelli, Andrea; Iribarne, Maria; Hardelin, Jean-Pierre; Weil, Dominique; Sahel, José-Alain

2012-01-01

The mechanisms underlying retinal dystrophy in Usher syndrome type I (USH1) remain unknown because mutant mice lacking any of the USH1 proteins—myosin VIIa, harmonin, cadherin-23, protocadherin-15, sans—do not display retinal degeneration. We found here that, in macaque photoreceptor cells, all USH1 proteins colocalized at membrane interfaces (i) between the inner and outer segments in rods and (ii) between the microvillus-like calyceal processes and the outer segment basolateral region in rods and cones. This pattern, conserved in humans and frogs, was mediated by the formation of an USH1 protein network, which was associated with the calyceal processes from the early embryonic stages of outer segment growth onwards. By contrast, mouse photoreceptors lacked calyceal processes and had no USH1 proteins at the inner–outer segment interface. We suggest that USH1 proteins form an adhesion belt around the basolateral region of the photoreceptor outer segment in humans, and that defects in this structure cause the retinal degeneration in USH1 patients. PMID:23045546

Different foveal schisis patterns in each retinal layer in eyes with hereditary juvenile retinoschisis evaluated by en-face optical coherence tomography.

PubMed

Yoshida-Uemura, Tomoyo; Katagiri, Satoshi; Yokoi, Tadashi; Nishina, Sachiko; Azuma, Noriyuki

2017-04-01

To analyze the structures of schisis in eyes with hereditary juvenile retinoschisis using en-face optical coherence tomography (OCT) imaging. In this retrospective observational study, we reviewed the medical records of patients with hereditary juvenile retinoschisis who underwent comprehensive ophthalmic examinations including swept-source OCT. OCT images were obtained from 16 eyes of nine boys (mean age ± standard deviation, 10.6 ± 4.0 years). The horizontal OCT images at the fovea showed inner nuclear layer (INL) schisis in one eye (6.3 %), ganglion cell layer (GCL) and INL schisis in 12 eyes (75.0 %), INL and outer plexiform layer (OPL) schisis in two eyes (12.5 %), and GCL, INL, and OPL schisis in one eye (6.3 %). En-face OCT images showed characteristic schisis patterns in each retinal layer, which were represented by multiple hyporeflective holes in the parafoveal region in the GCL, a spoke-like pattern in the foveal region, a reticular pattern in the parafoveal region in the INL, and multiple hyporeflective polygonal cavities with partitions in the OPL. Our results using en-face OCT imaging clarified different patterns of schisis formation among the GCL, INL, and OPL, which lead to further recognition of structure in hereditary juvenile retinoschisis.

Vasoinhibins regulate the inner and outer blood-retinal barrier and limit retinal oxidative stress.

PubMed

Arredondo Zamarripa, David; Díaz-Lezama, Nundehui; Meléndez García, Rodrigo; Chávez Balderas, Jesús; Adán, Norma; Ledesma-Colunga, Maria G; Arnold, Edith; Clapp, Carmen; Thebault, Stéphanie

2014-01-01

Vasoinhibins are prolactin fragments present in the retina, where they have been shown to prevent the hypervasopermeability associated with diabetes. Enhanced bradykinin (BK) production contributes to the increased transport through the blood-retina barrier (BRB) in diabetes. Here, we studied if vasoinhibins regulate BRB permeability by targeting the vascular endothelium and retinal pigment epithelium (RPE) components of this barrier. Intravitreal injection of BK in male rats increased BRB permeability. Vasoinhibins prevented this effect, as did the B2 receptor antagonist Hoe-140. BK induced a transient decrease in mouse retinal and brain capillary endothelial monolayer resistance that was blocked by vasoinhibins. Both vasoinhibins and the nitric oxide (NO) synthase inhibitor L-NAME, but not the antioxidant N-acetyl cysteine (NAC), blocked the transient decrease in bovine umbilical vein endothelial cell (BUVEC) monolayer resistance induced by BK; this block was reversed by the NO donor DETANONOate. Vasoinhibins also prevented the BK-induced actin cytoskeleton redistribution, as did L-NAME. BK transiently decreased human RPE (ARPE-19) cell monolayer resistance, and this effect was blocked by vasoinhibins, L-NAME, and NAC. DETANONOate reverted the blocking effect of vasoinhibins. Similar to BK, the radical initiator Luperox induced a reduction in ARPE-19 cell monolayer resistance, which was prevented by vasoinhibins. These effects on RPE resistance coincided with actin cytoskeleton redistribution. Intravitreal injection of vasoinhibins reduced the levels of reactive oxygen species (ROS) in retinas of streptozotocin-induced diabetic rats, particularly in the RPE and capillary-containing layers. Thus, vasoinhibins reduce BRB permeability by targeting both its main inner and outer components through NO- and ROS-dependent pathways, offering potential treatment strategies against diabetic retinopathies.

IQCB1 and PDE6B Mutations Cause Similar Early Onset Retinal Degenerations in Two Closely Related Terrier Dog Breeds

PubMed Central

Goldstein, Orly; Mezey, Jason G.; Schweitzer, Peter A.; Boyko, Adam R.; Gao, Chuan; Bustamante, Carlos D.; Jordan, Julie Ann; Aguirre, Gustavo D.; Acland, Gregory M.

2013-01-01

Purpose. To identify the causative mutations in two early-onset canine retinal degenerations, crd1 and crd2, segregating in the American Staffordshire terrier and the Pit Bull Terrier breeds, respectively. Methods. Retinal morphology of crd1- and crd2-affected dogs was evaluated by light microscopy. DNA was extracted from affected and related unaffected controls. Association analysis was undertaken using the Illumina Canine SNP array and PLINK (crd1 study), or the Affymetrix Version 2 Canine array, the “MAGIC” genotype algorithm, and Fisher's Exact test for association (crd2 study). Positional candidate genes were evaluated for each disease. Results. Structural photoreceptor abnormalities were observed in crd1-affected dogs as young as 11-weeks old. Rod and cone inner segment (IS) and outer segments (OS) were abnormal in size, shape, and number. In crd2-affected dogs, rod and cone IS and OS were abnormal as early as 3 weeks of age, progressing with age to severe loss of the OS, and thinning of the outer nuclear layer (ONL) by 12 weeks of age. Genome-wide association study (GWAS) identified association at the telomeric end of CFA3 in crd1-affected dogs and on CFA33 in crd2-affected dogs. Candidate gene evaluation identified a three bases deletion in exon 21 of PDE6B in crd1-affected dogs, and a cytosine insertion in exon 10 of IQCB1 in crd2-affected dogs. Conclusions. Identification of the mutations responsible for these two early-onset retinal degenerations provides new large animal models for comparative disease studies and evaluation of potential therapeutic approaches for the homologous human diseases. PMID:24045995

Vasoinhibins regulate the inner and outer blood-retinal barrier and limit retinal oxidative stress

PubMed Central

Arredondo Zamarripa, David; Díaz-Lezama, Nundehui; Meléndez García, Rodrigo; Chávez Balderas, Jesús; Adán, Norma; Ledesma-Colunga, Maria G.; Arnold, Edith; Clapp, Carmen; Thebault, Stéphanie

2014-01-01

Vasoinhibins are prolactin fragments present in the retina, where they have been shown to prevent the hypervasopermeability associated with diabetes. Enhanced bradykinin (BK) production contributes to the increased transport through the blood-retina barrier (BRB) in diabetes. Here, we studied if vasoinhibins regulate BRB permeability by targeting the vascular endothelium and retinal pigment epithelium (RPE) components of this barrier. Intravitreal injection of BK in male rats increased BRB permeability. Vasoinhibins prevented this effect, as did the B2 receptor antagonist Hoe-140. BK induced a transient decrease in mouse retinal and brain capillary endothelial monolayer resistance that was blocked by vasoinhibins. Both vasoinhibins and the nitric oxide (NO) synthase inhibitor L-NAME, but not the antioxidant N-acetyl cysteine (NAC), blocked the transient decrease in bovine umbilical vein endothelial cell (BUVEC) monolayer resistance induced by BK; this block was reversed by the NO donor DETANONOate. Vasoinhibins also prevented the BK-induced actin cytoskeleton redistribution, as did L-NAME. BK transiently decreased human RPE (ARPE-19) cell monolayer resistance, and this effect was blocked by vasoinhibins, L-NAME, and NAC. DETANONOate reverted the blocking effect of vasoinhibins. Similar to BK, the radical initiator Luperox induced a reduction in ARPE-19 cell monolayer resistance, which was prevented by vasoinhibins. These effects on RPE resistance coincided with actin cytoskeleton redistribution. Intravitreal injection of vasoinhibins reduced the levels of reactive oxygen species (ROS) in retinas of streptozotocin-induced diabetic rats, particularly in the RPE and capillary-containing layers. Thus, vasoinhibins reduce BRB permeability by targeting both its main inner and outer components through NO- and ROS-dependent pathways, offering potential treatment strategies against diabetic retinopathies. PMID:25368550

Frequency Responses of Rat Retinal Ganglion Cells

PubMed Central

Cloherty, Shaun L.; Hung, Yu-Shan; Kameneva, Tatiana; Ibbotson, Michael R.

2016-01-01

There are 15–20 different types of retinal ganglion cells (RGC) in the mammalian retina, each encoding different aspects of the visual scene. The mechanism by which post-synaptic signals from the retinal network generate spikes is determined by each cell’s intrinsic electrical properties. Here we investigate the frequency responses of morphologically identified rat RGCs using intracellular injection of sinusoidal current waveforms, to assess their intrinsic capabilities with minimal contributions from the retinal network. Recorded cells were classified according to their morphological characteristics (A, B, C or D-type) and their stratification (inner (i), outer (o) or bistratified) in the inner plexiform layer (IPL). Most cell types had low- or band-pass frequency responses. A2, C1 and C4o cells were band-pass with peaks of 15–30 Hz and low-pass cutoffs above 56 Hz (A2 cells) and ~42 Hz (C1 and C4o cells). A1 and C2i/o cells were low-pass with peaks of 10–15 Hz (cutoffs 19–25 Hz). Bistratified D1 and D2 cells were also low-pass with peaks of 5–10 Hz (cutoffs ~16 Hz). The least responsive cells were the B2 and C3 types (peaks: 2–5 Hz, cutoffs: 8–11 Hz). We found no difference between cells stratifying in the inner and outer IPL (i.e., ON and OFF cells) or between cells with large and small somas or dendritic fields. Intrinsic physiological properties (input resistance, spike width and sag) had little impact on frequency response at low frequencies, but account for 30–40% of response variability at frequencies >30 Hz. PMID:27341669

Intravitreal Injection of Proinsulin-Loaded Microspheres Delays Photoreceptor Cell Death and Vision Loss in the rd10 Mouse Model of Retinitis Pigmentosa.

PubMed

Isiegas, Carolina; Marinich-Madzarevich, Jorge A; Marchena, Miguel; Ruiz, José M; Cano, María J; de la Villa, Pedro; Hernández-Sánchez, Catalina; de la Rosa, Enrique J; de Pablo, Flora

2016-07-01

The induction of proinsulin expression by transgenesis or intramuscular gene therapy has been shown previously to retard retinal degeneration in mouse and rat models of retinitis pigmentosa (RP), a group of inherited conditions that result in visual impairment. We investigated whether intraocular treatment with biodegradable poly (lactic-co-glycolic) acid microspheres (PLGA-MS) loaded with proinsulin has cellular and functional neuroprotective effects in the retina. Experiments were performed using the Pde6brd10 mouse model of RP. Methionylated human recombinant proinsulin (hPI) was formulated in PLGA-MS, which were administered by intravitreal injection on postnatal days (P) 14 to 15. Retinal neuroprotection was assessed at P25 by electroretinography, and by evaluating outer nuclear layer (ONL) cellular preservation. The attenuation of photoreceptor cell death by hPI was determined by TUNEL assay in cultured P22 retinas, as well as Akt phosphorylation by immunoblotting. We successfully formulated hPI PLGA-MS to deliver the active molecule for several weeks in vitro. The amplitude of b-cone and mixed b-waves in electroretinographic recording was significantly higher in eyes injected with hPI-PLGA-MS compared to control eyes. Treatment with hPI-PLGA-MS attenuated photoreceptor cell loss, as revealed by comparing ONL thickness and the number of cell rows in this layer in treated versus untreated retinas. Finally, hPI prevented photoreceptor cell death and increased AktThr308 phosphorylation in organotypic cultured retinas. Retinal degeneration in the rd10 mouse was slowed by a single intravitreal injection of hPI-PLGA-MS. Human recombinant proinsulin elicited a rapid and effective neuroprotective effect when administered in biodegradable microspheres, which may constitute a future potentially feasible delivery method for proinsulin-based treatment of RP.

Whole-Retina Reduced Electrophysiological Activity in Mice Bearing Retina-Specific Deletion of Vesicular Acetylcholine Transporter.

PubMed

Bedore, Jake; Martyn, Amanda C; Li, Anson K C; Dolinar, Eric A; McDonald, Ian S; Coupland, Stuart G; Prado, Vania F; Prado, Marco A; Hill, Kathleen A

2015-01-01

Despite rigorous characterization of the role of acetylcholine in retinal development, long-term effects of its absence as a neurotransmitter are unknown. One of the unanswered questions is how acetylcholine contributes to the functional capacity of mature retinal circuits. The current study investigates the effects of disrupting cholinergic signalling in mice, through deletion of vesicular acetylcholine transporter (VAChT) in the developing retina, pigmented epithelium, optic nerve and optic stalk, on electrophysiology and structure of the mature retina. A combination of electroretinography, optical coherence tomography imaging and histological evaluation assessed retinal integrity in mice bearing retina- targeted (embryonic day 12.5) deletion of VAChT (VAChTSix3-Cre-flox/flox) and littermate controls at 5 and 12 months of age. VAChTSix3-Cre-flox/flox mice did not show any gross changes in nuclear layer cellularity or synaptic layer thickness. However, VAChTSix3-Cre-flox/flox mice showed reduced electrophysiological response of the retina to light stimulus under scotopic conditions at 5 and 12 months of age, including reduced a-wave, b-wave, and oscillatory potential (OP) amplitudes and decreased OP peak power and total energy. Reduced a-wave amplitude was proportional to the reduction in b-wave amplitude and not associated with altered a-wave 10%-90% rise time or inner and outer segment thicknesses. This study used a novel genetic model in the first examination of function and structure of the mature mouse retina with disruption of cholinergic signalling. Reduced amplitude across the electroretinogram wave form does not suggest dysfunction in specific retinal cell types and could reflect underlying changes in the retinal and/or extraretinal microenvironment. Our findings suggest that release of acetylcholine by VAChT is essential for the normal electrophysiological response of the mature mouse retina.

Omega-3 Fatty Acids Supplementation: Therapeutic Potential in a Mouse Model of Stargardt Disease.

PubMed

Prokopiou, Ekatherine; Kolovos, Panagiotis; Kalogerou, Maria; Neokleous, Anastasia; Nicolaou, Orthodoxia; Sokratous, Kleitos; Kyriacou, Kyriacos; Georgiou, Tassos

2018-06-01

To evaluate the therapeutic effects of omega-3 (ω3) fatty acids on retinal degeneration in the ABCA4-/- model of Stargardt disease when the blood level of arachidonic acid (AA)/eicosapentaenoic acid (EPA) ratio is between 1 and 1.5. Eight-month-old mice were allocated to three groups: wild type (129S1), ABCA4-/- untreated, and ABCA4-/- ω3 treated. ω3 treatment lasted 3 months and comprised daily gavage administration of EPA and docosahexaenoic acid (DHA). Blood and retinal fatty acid analysis was performed using gas chromatography to adjust the blood AA/EPA ∼1 to 1.5. Eyecups were histologically examined using transmission electron microscopy and confocal microscopy to evaluate lipofuscin granules and the photoreceptor layer. Retinal N-retinylidene-N-retinylethanolamine (A2E), a major component of retinal pigment epithelium lipofuscin, was quantified using liquid chromatography and tandem mass spectrometry, in addition to retinal proteomic analysis to determine changes in inflammatory proteins. EPA levels increased and AA levels decreased in the blood and retinas of the treatment group. Significantly less A2E and lipofuscin granules were observed in the treatment group. The thickness of the outer nuclear layer was significantly greater in the treatment group (75.66 ± 4.80 μm) than in the wild-type (61.40 ± 1.84 μm) or untreated ABCA4-/- (56.50 ± 3.24 μm) groups. Proteomic analysis indicated lower levels of complement component 3 (C3) in the treatment group, indicative of lower complement-induced inflammatory response. Three months of ω3 supplementation (AA/EPA ∼1-1.5) reduces A2E levels, lipofuscin granules, and C3 levels in the ABCA4-/- mouse model of Stargardt disease, consistent with slowing of the disease.

Retinal toxicity related to hydroxychloroquine in patients with systemic lupus erythematosus and rheumatoid arthritis.

PubMed

Telek, Hande Husniye; Yesilirmak, Nilufer; Sungur, Gulten; Ozdemir, Yaprak; Yesil, Nesibe Karahan; Ornek, Firdevs

2017-12-01

To compare the retinal toxicity due to hydroxychloroquine (HCQ) use in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) using multifocal electroretinography (mfERG), fundus autofluorescence (FAF) and optical coherence tomography (OCT). Patients who were using HCQ due to SLE and RA, and healthy subjects evaluated in this study. Central foveal thickness (CFT), inner-outer segment (IS-OS) junction irregularity, retinal nerve fiber layer thickness, mfERG and FAF measurements were performed to evaluate retinal toxicity. Study included 35 eyes of 35 SLE patients, 40 eyes of 40 RA patients and 20 eyes of 20 healthy subjects. In SLE group, retinal abnormality was found in three eyes with mfERG, in one eye with FAF and in four eyes with OCT. In RA group, retinal abnormality was found in 10 eyes with mfERG, in five eyes with FAF and in nine eyes with OCT. A statistically significant difference was found with respect to mfERG between "eyes with abnormal responses and without abnormal responses" and "eyes with abnormal responses and controls" (p < 0.05). A statistically significant difference was found with respect to CFT between "eyes with IS-OS junction irregularities and without IS-OS junction irregularities" and "eyes with/without IS-OS junction irregularities and controls" (p < 0.05). The use of HCQ seems to cause retinal toxicity more often in RA patients compared to SLE patients. For the early detection of retinal changes, OCT and mfERG can be used as screening tools due to their higher sensitivity rates compared to other tests.

Characterization of punctate inner choroidopathy using enhanced depth imaging optical coherence tomography.

PubMed

Zarranz-Ventura, Javier; Sim, Dawn A; Keane, Pearse A; Patel, Praveen J; Westcott, Mark C; Lee, Richard W; Tufail, Adnan; Pavesio, Carlos E

2014-09-01

To perform qualitative and quantitative analyses of retinal and choroidal morphology in patients with punctate inner choroidopathy (PIC) using enhanced depth imaging optical coherence tomography (EDI-OCT). Cross-sectional, consecutive series. A total of 2242 patients attending 2 tertiary referral uveitis clinics at Moorfields Eye Hospital were screened; 46 patients with PIC diagnosis were identified, and 35 eyes (35 patients) had clinically inactive PIC had EDI-OCT images that met the inclusion criteria. Punctate inner choroidopathy lesions were qualitatively assessed for retinal features, such as (1) focal elevation of the retinal pigment epithelium (RPE), (2) focal atrophy of the outer retina/RPE, and (3) presence of sub-RPE hyperreflective deposits and choroidal features: (a) presence of focal hyperreflective dots in the inner choroid and (b) focal thinning of the choroid adjacent to PIC lesions. Quantitative analyses of the retina, choroid, and choroidal sublayers were performed, and associations with clinical and demographic data were examined. Prevalence of each lesion pattern and thickness of retinal and choroidal layers. A total of 90 discrete PIC lesions were captured; 46.6% of PIC lesions consisted of focal atrophy of the outer retina and RPE; 34.4% consisted of sub-RPE hyperreflective deposits; and 18.8% consisted of localized RPE elevation with underlying hyporeflective space. Focal hyperreflective dots were seen in the inner choroid of 68.5% of patients, with 17.1% of eyes presenting focal choroidal thinning underlying PIC lesions. By excluding high myopes, patients with "atypical" PIC had reduced retinal thickness compared with patients with "typical" PIC (246.65±30.2 vs. 270.05±24.6 μm; P = 0.04), and greater disease duration was associated with decreases in retinal thickness (r = -0.53; P = 0.01). A significant correlation was observed between best-corrected visual acuity and foveal retinal thickness (r = -0.40; P = 0.03). In a large series of patients with clinically inactive PIC, one fifth of the lesions analyzed revealed RPE elevation with underlying hyporeflective space, described before as a sign of activity and suggesting subclinical inflammation. Retinal thickness seems to be associated with disease type and duration of disease in non-highly myopic eyes. Improved visualization of the inner choroid using EDI-OCT may allow noninvasive assessment of inflammatory status. Copyright © 2014 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

THE SECOND BLIND SPOT: SMALL RETINAL VESSEL VASCULOPATHY AFTER VACCINATION AGAINST NEISSERIA MENINGITIDIS AND YELLOW FEVER.

PubMed

Moysidis, Stavros N; Koulisis, Nicole; Patel, Vivek R; Kashani, Amir H; Rao, Narsing A; Humayun, Mark S; Rodger, Damien C

2017-01-01

To describe a case of small retinal vessel vasculopathy postvaccination. We report the case of a 41-year-old white man who presented with a "second blind spot," describing a nasal scotoma in the right eye that started 4 days after vaccinations against Neisseria meningitidis and the yellow fever virus, and after a 2-month period of high stress and decreased sleep. Clinical examination, Humphrey visual field testing, and multimodal imaging with fundus photographs, autofluorescence, fluorescein angiography, and spectral domain optical coherence tomography and angiography were performed. Clinical examination revealed a well-circumscribed, triangular area of retinal graying of about 1-disk diameter in size, located at the border of the temporal macula. This corresponded to a deep scotoma similar in size to the physiologic blind spot on Humphrey visual field 24-2 testing. There was mild hypoautofluoresence of this lesion on autofluorescence, hypofluorescence on fluorescein angiography, and focal attenuation of a small artery just distal to the bifurcation of an artery supplying the involved area. Spectral domain optical coherence tomography through the lesion conveyed hyperreflectivity most prominent in the inner and outer plexiform layers, with extension of the hyperreflectivity into the ganglion cell and inner nuclear layers. Spectral domain optical coherence tomography angiography demonstrated arteriolar and capillary dropout, more pronounced in the superficial retinal layer compared to the deeper retinal layer. At 1-month follow-up, his scotoma improved with monitoring, with reduction from -32 dB to -7 dB on Humphrey visual field testing. There was clinical resolution of the area of graying and decreased hyperreflectivity on spectral domain optical coherence tomography, with atrophy of the inner retina. Spectral domain optical coherence tomography angiography showed progression of arteriolar and capillary dropout, more so in the superficial than in the deep capillary plexus. We describe a case of small artery occlusion in a previously healthy patient, 4 days after vaccination against N. meningitidis and yellow fever. Fluorescein angiography yielded greater diagnostic value than OCTA for evaluating the occlusion, whereas spectral domain optical coherence tomography angiography enabled better visualization of capillary dropout and layer-specific assessment. Further research is required to determine whether vaccination in general, or directed specifically at N. meningitidis or yellow fever, is associated with small vessel vasculopathy and the underlying pathogenesis.

Progressive outer retinal necrosis after rituximab and cyclophosphamide therapy.

PubMed

Dogra, Mohit; Bajgai, Priya; Kumar, Ashok; Sharma, Aman

2018-04-01

We report a case of progressive outer retinal necrosis (PORN) in a patient of microscopic polyangitis (MPA), being treated with immunosuppressive drugs such as cyclophosphamide and rituximab. Her aqueous tap was positive for Varicella Zoster virus and she was treated with oral and intravitreal antivirals, along with discontinuation of one of the immunosuppressive agents, i.e. rituximab, which might have led to reactivation of the virus causing necrotizing retinitis lesions. Rituximab and cyclophosphamide are extremely potent drugs, which are necessary to manage immunological disorders such as MPA. However, they may predispose the patient to serious complications like viral infections, including PORN.

Restoration of outer segments of foveal photoreceptors after resolution of central serous chorioretinopathy.

PubMed

Ojima, Yumiko; Tsujikawa, Akitaka; Yamashiro, Kenji; Ooto, Sotaro; Tamura, Hiroshi; Yoshimura, Nagahisa

2010-01-01

To study morphologically and functionally the prognosis of damaged outer segments of the foveal photoreceptor layer in eyes with resolved central serous chorioretinopathy (CSC). We studied retrospectively the medical records of 70 patients (74 eyes) with resolved CSC. Optical coherence tomography was used to detect the junctions between inner and outer segments of the photoreceptors (IS/OS) as a hallmark of the integrity of the outer photoreceptor layer. In 53 eyes (71.6%), the IS/OS line was clearly detected beneath the fovea immediately after resolution of the retinal detachment, with good visual acuity (VA). In the remaining 21 eyes (28.4%), however, the foveal IS/OS line could not be detected shortly after resolution of CSC, and VA was variable, ranging from 0.1 to 1.5 (median, 0.9). Of these 21 eyes, 15 had a follow-up examination with OCT, and in four the foveal IS/OS line was not detected at the follow-up and vision in these eyes remained poor. However, nine eyes showed recovery of the foveal IS/OS line during follow-up, and these eyes had substantial visual recovery. Immediately after resolution of active CSC, although the IS/OS line cannot be detected beneath the fovea, it often shows restoration over time, with visual recovery, though in some eyes no restoration takes place and the prognosis remains poor.

Concentric retinitis pigmentosa: clinicopathologic correlations.

PubMed

Milam, A H; De Castro, E B; Smith, J E; Tang, W X; John, S K; Gorin, M B; Stone, E M; Aguirre, G D; Jacobson, S G

2001-10-01

Progressive concentric (centripetal) loss of vision is one pattern of visual field loss in retinitis pigmentosa. This study provides the first clinicopathologic correlations for this form of retinitis pigmentosa. A family with autosomal dominant concentric retinitis pigmentosa was examined clinically and with visual function tests. A post-mortem eye of an affected 94 year old family member was processed for histopathology and immunocytochemistry with retinal cell specific antibodies. Unrelated simplex/multiplex patients with concentric retinitis pigmentosa were also examined. Affected family members of the eye donor and patients from the other families had prominent peripheral pigmentary retinopathy with more normal appearing central retina, good visual acuity, concentric field loss, normal or near normal rod and cone sensitivity within the preserved visual field, and reduced rod and cone electroretinograms. The eye donor, at age 90, had good acuity and function in a central island. Grossly, the central region of the donor retina appeared thinned but otherwise normal, while the far periphery contained heavy bone spicule pigment. Microscopically the central retina showed photoreceptor outer segment shortening and some photoreceptor cell loss. The mid periphery had a sharp line of demarcation where more central photoreceptors were near normal except for very short outer segments and peripheral photoreceptors were absent. Rods and cones showed abrupt loss of outer segments and cell death at this interface. It is concluded that concentric retinitis pigmentosa is a rare but recognizable phenotype with slowly progressive photoreceptor death from the far periphery toward the central retina. The disease is retina-wide but shows regional variation in severity of degeneration; photoreceptor death is severe in the peripheral retina with an abrupt edge between viable and degenerate photoreceptors. Peripheral to central gradients of unknown retinal molecule(s) may be defective or modify photoreceptor degeneration in concentric retinitis pigmentosa.

Cell Fate of Müller Cells During Photoreceptor Regeneration in an N-Methyl-N-nitrosourea-Induced Retinal Degeneration Model of Zebrafish.

PubMed

Ogai, Kazuhiro; Hisano, Suguru; Sugitani, Kayo; Koriyama, Yoshiki; Kato, Satoru

2016-01-01

Zebrafish can regenerate several organs such as the tail fin, heart, central nervous system, and photoreceptors. Very recently, a study has demonstrated the photoreceptor regeneration in the alkylating agent N-methyl-N-nitrosourea (MNU)-induced retinal degeneration (RD) zebrafish model, in which whole photoreceptors are lost within a week after MNU treatment and then regenerated within a month. The research has also shown massive proliferation of Müller cells within a week. To address the question of whether proliferating Müller cells are the source of regenerating photoreceptors, which remains unknown in the MNU-induced zebrafish RD model, we employed a BrdU pulse-chase technique to label the proliferating cells within a week after MNU treatment. As a result of the BrdU pulse-chase technique, a number of BrdU(+) cells were observed in the outer nuclear layer as well as the inner nuclear layer. This implies that regenerating photoreceptors are derived from proliferating Müller cells in the zebrafish MNU-induced RD model.

Tauroursodeoxycholic Acid (TUDCA) Protects Photoreceptors from Cell Death after Experimental Retinal Detachment

PubMed Central

Mantopoulos, Dimosthenis; Murakami, Yusuke; Comander, Jason; Thanos, Aristomenis; Roh, Miin; Miller, Joan W.; Vavvas, Demetrios G.

2011-01-01

Background Detachment of photoreceptors from the underlying retinal pigment epithelium is seen in various retinal disorders such as retinal detachment and age-related macular degeneration and leads to loss of photoreceptors and vision. Pharmacologic inhibition of photoreceptor cell death may prevent this outcome. This study tests whether systemic administration of tauroursodeoxycholic acid (TUDCA) can protect photoreceptors from cell death after experimental retinal detachment in rodents. Methodology/Principal Findings Retinal detachment was created in rats by subretinal injection of hyaluronic acid. The animals were treated daily with vehicle or TUDCA (500 mg/kg). TUNEL staining was used to evaluate cell death. Photoreceptor loss was evaluated by measuring the relative thickness of the outer nuclear layer (ONL). Macrophage recruitment, oxidative stress, cytokine levels, and caspase levels were also quantified. Three days after detachment, TUDCA decreased the number of TUNEL-positive cells compared to vehicle (651±68/mm2 vs. 1314±68/mm2, P = 0.001) and prevented the reduction of ONL thickness ratio (0.84±0.03 vs. 0.65±0.03, P = 0.002). Similar results were obtained after 5 days of retinal detachment. Macrophage recruitment and expression levels of TNF-a and MCP-1 after retinal detachment were not affected by TUDCA treatment, whereas increases in activity of caspases 3 and 9 as well as carbonyl-protein adducts were almost completely inhibited by TUDCA treatment. Conclusions/Significance Systemic administration of TUDCA preserved photoreceptors after retinal detachment, and was associated with decreased oxidative stress and caspase activity. TUDCA may be used as a novel therapeutic agent for preventing vision loss in diseases that are characterized by photoreceptor detachment. PMID:21961034

Optical coherence tomography study of retinal changes in normal aging and after ischemia.

PubMed

Shariati, Mohammad Ali; Park, Joyce Ho; Liao, Yaping Joyce

2015-05-01

Age-related thinning of the retinal ganglion cell axons in the nerve fiber layer has been measured in humans using optical coherence tomography (OCT). In this study, we used OCT to measure inner retinal changes in 3-month-, 1-year-, and 2-year-old mice and after experimental anterior ischemic optic neuropathy (AION). We used OCT to quantify retinal thickness in over 200 eyes at different ages before and after a photochemical thrombosis model of AION. The scans were manually or automatically segmented. In normal aging, there was 1.3-μm thinning of the ganglion cell complex (GCC) between 3 months and 1 year (P < 0.0001) and no further thinning at 2 years. In studying age-related inner retinal changes, measurement of the GCC (circular scan) was superior to that of the total retinal thickness (posterior pole scan) despite the need for manual segmentation because it was not contaminated by outer retinal changes. Three weeks after AION, there was 8.9-μm thinning of the GCC (circular scan; P < 0.0001), 50-μm thinning of the optic disc (posterior pole scan; P < 0.0001), and 17-μm thinning of the retina (posterior pole scan; P < 0.0001) in the 3-month-old group. Changes in the older eyes after AION were similar to those of the 3-month-old group. Optical coherence tomography imaging of a large number of eyes showed that, like humans, mice exhibited small, age-related inner retinal thinning. Measurement of the GCC was superior to total retinal thickness in quantifying age-related changes, and both circular and posterior pole scans were useful to track short-term changes after AION.

Dendrimer-based targeted intravitreal therapy for sustained attenuation of neuroinflammation in retinal degeneration.

PubMed

Iezzi, Raymond; Guru, Bharath R; Glybina, Inna V; Mishra, Manoj K; Kennedy, Alexander; Kannan, Rangaramanujam M

2012-01-01

Retinal neuroinflammation, mediated by activated microglia, plays a key role in the pathogenesis of photoreceptor and retinal pigment epithelial cell loss in age-related macular degeneration and retinitis pigmentosa. Targeted drug therapy for attenuation of neuroinflammation in the retina was explored using hydroxyl-terminated polyamidoamine (PAMAM) dendrimer-drug conjugate nanodevices. We show that, upon intravitreal administration, PAMAM dendrimers selectively localize within activated outer retinal microglia in two rat models of retinal degeneration, but not in the retina of healthy controls. This pathology-dependent biodistribution was exploited for drug delivery, by covalently conjugating fluocinolone acetonide to the dendrimer. The conjugate released the drug in a sustained manner over 90 days. In vivo efficacy was assessed using the Royal College of Surgeons (RCS) rat retinal degeneration model over a four-week period when peak retinal degeneration occurs. One intravitreal injection of 1 μg of FA conjugated to 7 μg of the dendrimer was able to arrest retinal degeneration, preserve photoreceptor outer nuclear cell counts, and attenuate activated microglia, for an entire month. These studies suggest that PAMAM dendrimers (with no targeting ligands) have an intrinsic ability to selectively localize in activated microglia, and can deliver drugs inside these cells for a sustained period for the treatment of retinal neuroinflammation. Copyright © 2011 Elsevier Ltd. All rights reserved.

A case of atypical progressive outer retinal necrosis after highly active antiretroviral therapy.

PubMed

Woo, Se Joon; Yu, Hyeong Gon; Chung, Hum

2004-06-01

This is a report of an atypical case of progressive outer retinal necrosis (PORN) and the effect of highly active antiretroviral therapy (HAART) on the clinical course of viral retinitis in an acquired immunodeficiency syndrome (AIDS) patient. A 22-year-old male patient infected with human immunodeficiency virus (HIV) presented with unilaterally reduced visual acuity and a dense cataract. After cataract extraction, retinal lesions involving the peripheral and macular areas were found with perivascular sparing and the mud-cracked, characteristic appearance of PORN. He was diagnosed as having PORN based on clinical features and was given combined antiviral treatment. With concurrent HAART, the retinal lesions regressed, with the regression being accelerated by further treatment with intravenous acyclovir and ganciclovir. This case suggests that HAART may change the clinical course of PORN in AIDS patients by improving host immunity. PORN should be included in the differential diagnosis of acute unilateral cataract in AIDS patients.

Experimental oral iron administration: Histological investigations and expressions of iron handling proteins in rat retina with aging.

PubMed

Kumar, Pankaj; Nag, Tapas Chandra; Jha, Kumar Abhiram; Dey, Sanjay Kumar; Kathpalia, Poorti; Maurya, Meenakshi; Gupta, Chandan Lal; Bhatia, Jagriti; Roy, Tara Sankar; Wadhwa, Shashi

2017-12-01

Iron is implicated in age-related macular degeneration (AMD). The aim of this study was to see if long-term, experimental iron administration with aging modifies retinal and choroidal structures and expressions of iron handling proteins, to understand some aspects of iron homeostasis. Male Wistar rats were fed with ferrous sulphate heptahydrate (500mg/kg body weight/week, oral; elemental iron availability: 20%) from 2 months of age onward until they were 19.5 month-old. At 8, 14 and 20 months of age, they were sacrificed and serum and retinal iron levels were detected by HPLC. Oxidative stress was analyzed by TBARS method. The retinas were examined for cell death (TUNEL), histology (electron microscopy) and the expressions of transferrin, transferrin receptor-1 [TFR-1], H- and L-ferritin. In control animals, at any age, there was no difference in the serum and retinal iron levels, but the latter increased significantly in 14- and 20 month-old iron-fed rats, indicating that retinal iron accumulation proceeds with progression of aging (>14 months). The serum and retinal TBARS levels increased significantly with progression of aging in experimental but not in control rats. There was significant damage to choriocapillaris, accumulation of phagosomes in retinal pigment epithelium and increased incidence of TUNEL+ cells in outer nuclear layer and vacuolation in inner nuclear layer (INL) of 20 month-aged experimental rats, compared to those in age-matched controls. Vacuolations in INL could indicate a long-term effect of iron accumulation in the inner retina. These events paralleled the increased expression of ferritins and transferrin and a decrease in the expression of TFR-1 in iron-fed rats with aging, thereby maintaining iron homeostasis in the retina. As some of these changes mimic with those happening in eyes with AMD, this model can be utilized to understand iron-induced pathophysiological changes in AMD. Copyright © 2017 Elsevier B.V. All rights reserved.

ROCK-1 mediates diabetes-induced retinal pigment epithelial and endothelial cell blebbing: Contribution to diabetic retinopathy.

PubMed

Rothschild, Pierre-Raphaël; Salah, Sawsen; Berdugo, Marianne; Gélizé, Emmanuelle; Delaunay, Kimberley; Naud, Marie-Christine; Klein, Christophe; Moulin, Alexandre; Savoldelli, Michèle; Bergin, Ciara; Jeanny, Jean-Claude; Jonet, Laurent; Arsenijevic, Yvan; Behar-Cohen, Francine; Crisanti, Patricia

2017-08-18

In diabetic retinopathy, the exact mechanisms leading to retinal capillary closure and to retinal barriers breakdown remain imperfectly understood. Rho-associated kinase (ROCK), an effector of the small GTPase Rho, involved in cytoskeleton dynamic regulation and cell polarity is activated by hyperglycemia. In one year-old Goto Kakizaki (GK) type 2 diabetic rats retina, ROCK-1 activation was assessed by its cellular distribution and by phosphorylation of its substrates, MYPT1 and MLC. In both GK rat and in human type 2 diabetic retinas, ROCK-1 is activated and associated with non-apoptotic membrane blebbing in retinal vessels and in retinal pigment epithelium (RPE) that respectively form the inner and the outer barriers. Activation of ROCK-1 induces focal vascular constrictions, endoluminal blebbing and subsequent retinal hypoxia. In RPE cells, actin cytoskeleton remodeling and membrane blebs in RPE cells contributes to outer barrier breakdown. Intraocular injection of fasudil, significantly reduces both retinal hypoxia and RPE barrier breakdown. Diabetes-induced cell blebbing may contribute to ischemic maculopathy and represent an intervention target.

Bcl-2 expression during the development and degeneration of RCS rat retinae.

PubMed

Sharma, R K

2001-12-14

In various hereditary retinal degenerations, including that in Royal College of Surgeons (RCS) rats, the photoreceptors ultimately die by apoptosis. Bcl-2 is one of the genes, which regulates apoptosis and is thought to promote survival of cells. This study has investigated the developmental expression of Bcl-2 in RCS rat, which is a well-studied animal model for hereditary retinal degeneration. An antibody against Bcl-2 was used for its immunohistochemical localization in dystrophic RCS rat retinae from postnatal (PN) days 4, 7, 13, 35, 45, 70, 202 and 14 months. Results were compared with Bcl-2 localization in congenic non-dystrophic rats from PN 4, 7, 13, 44, 202 and 14 months. Bcl-2 immunoreactivity in non-dystrophic retinae was already present in PN 4 retinae in the nerve fiber layer (presumably in the endfeet of immature Müller cells) and in the proximal parts of certain radially aligned neuroepithelial cells/immature Müller cell radial processes. With increasing age the immunoreactivity in relatively more mature Müller cell radial processes spread distally towards the outer retina and between PN 13 and 44 it reached the adult distribution. No cell bodies in the ganglion cell layer were found to be immunoreactive. Expression of Bcl-2 immunoreactivity in dystrophic RCS rat retinae closely resembled that of non-dystrophic retinae. No immunoreactivity was seen in photoreceptors or retinal pigment epithelium in dystrophic or non-dystrophic retinae. In conclusion, Bcl-2 expression is not altered, either in terms of its chronology or the cell type expressing it, during retinal degeneration in RCS rats.

Efficacy of a Fatty Acids Dietary Supplement in a Polyethylene Glycol-Induced Mouse Model of Retinal Degeneration

PubMed Central

Locri, Filippo; Lardner, Emma; Kvanta, Anders; Rusciano, Dario; Bagnoli, Paola

2017-01-01

Current knowledge of the benefits of nutrition supplements for eye pathologies is based largely on the use of appropriate animal models, together with defined dietary supplementation. Here, C57BL6 mice were subretinally injected with polyethylene glycol (PEG)-400, an established model of retinal degeneration with a dry age-related macular degeneration (AMD)-like phenotype, an eye pathology that lacks treatment. In response to PEG-400, markers of the complement system, angiogenesis, inflammation, gliosis, and macrophage infiltration were upregulated in both retinas and retinal pigment epithelium (RPE)/choroids, whereas dietary supplementation with a mixture based on fatty acids counteracted their upregulation. Major effects include a reduction of inflammation, in both retinas and RPE/choroids, and an inhibition of macrophage infiltration in the choroid, yet not in the retina, suggesting a targeted action through the choroidal vasculature. Histological analysis revealed a thinning of the outer nuclear layer (ONL), together with dysregulation of the epithelium layer in response to PEG-400. In addition, immunohistofluorescence demonstrated Müller cell gliosis and macrophage infiltration into subretinal tissues supporting the molecular findings. Reduced ONL thickness, gliosis, and macrophage infiltration were counteracted by the diet supplement. The present data suggest that fatty acids may represent a useful form of diet supplementation to prevent or limit the progression of dry AMD. PMID:28961167

Biophysical mechanism of transient retinal phototropism in rod photoreceptors.

PubMed

Zhao, Xiaohui; Thapa, Damber; Wang, Benquan; Gai, Shaoyan; Yao, Xincheng

2016-02-13

Oblique light stimulation evoked transient retinal phototropism (TRP) has been recently detected in frog and mouse retinas. High resolution microscopy of freshly isolated retinas indicated that the TRP is predominated by rod photoreceptors. Comparative confocal microscopy and optical coherence tomography (OCT) revealed that the TRP predominantly occurred from the photoreceptor outer segment (OS). However, biophysical mechanism of rod OS change is still unknown. In this study, frog retinal slices, which open a cross section of retinal photoreceptor and other functional layers, were used to test the effect of light stimulation on rod OS. Near infrared light microscopy was employed to monitor photoreceptor changes in retinal slices stimulated by a rectangular-shaped visible light flash. Rapid rod OS length change was observed after the stimulation delivery. The magnitude and direction of the rod OS change varied with the position of the rods within the stimulated area. In the center of stimulated region the length of the rod OS shrunk, while in the peripheral region the rod OS tip swung towards center region in the plane perpendicular to the incident stimulus light. Our experimental result and theoretical analysis suggest that the observed TRP may reflect unbalanced disc-shape change due to localized pigment bleaching. Further investigation is required to understand biochemical mechanism of the observed rod OS kinetics. Better study of the TRP may provide a noninvasive biomarker to enable early detection of age-related macular degeneration (AMD) and other diseases that are known to produce retinal photoreceptor dysfunctions.

AAV-Mediated Clarin-1 Expression in the Mouse Retina: Implications for USH3A Gene Therapy.

PubMed

Dinculescu, Astra; Stupay, Rachel M; Deng, Wen-Tao; Dyka, Frank M; Min, Seok-Hong; Boye, Sanford L; Chiodo, Vince A; Abrahan, Carolina E; Zhu, Ping; Li, Qiuhong; Strettoi, Enrica; Novelli, Elena; Nagel-Wolfrum, Kerstin; Wolfrum, Uwe; Smith, W Clay; Hauswirth, William W

2016-01-01

Usher syndrome type III (USH3A) is an autosomal recessive disorder caused by mutations in clarin-1 (CLRN1) gene, leading to progressive retinal degeneration and sensorineural deafness. Efforts to develop therapies for preventing photoreceptor cell loss are hampered by the lack of a retinal phenotype in the existing USH3 mouse models and by conflicting reports regarding the endogenous retinal localization of clarin-1, a transmembrane protein of unknown function. In this study, we used an AAV-based approach to express CLRN1 in the mouse retina in order to determine the pattern of its subcellular localization in different cell types. We found that all major classes of retinal cells express AAV-delivered CLRN1 driven by the ubiquitous, constitutive small chicken β-actin promoter, which has important implications for the design of future USH3 gene therapy studies. Within photoreceptor cells, AAV-expressed CLRN1 is mainly localized at the inner segment region and outer plexiform layer, similar to the endogenous expression of other usher proteins. Subretinal delivery using a full strength viral titer led to significant loss of retinal function as evidenced by ERG analysis, suggesting that there is a critical limit for CLRN1 expression in photoreceptor cells. Taken together, these results suggest that CLRN1 expression is potentially supported by a variety of retinal cells, and the right combination of AAV vector dose, promoter, and delivery method needs to be selected to develop safe therapies for USH3 disorder.

Biophysical mechanism of transient retinal phototropism in rod photoreceptors

NASA Astrophysics Data System (ADS)

Zhao, Xiaohui; Thapa, Damber; Wang, Benquan; Gai, Shaoyan; Yao, Xincheng

2016-03-01

Oblique light stimulation evoked transient retinal phototropism (TRP) has been recently detected in frog and mouse retinas. High resolution microscopy of freshly isolated retinas indicated that the TRP is predominated by rod photoreceptors. Comparative confocal microscopy and optical coherence tomography (OCT) revealed that the TRP predominantly occurred from the photoreceptor outer segment (OS). However, biophysical mechanism of rod OS change is still unknown. In this study, frog retinal slices, which open a cross section of retinal photoreceptor and other functional layers, were used to test the effect of light stimulation on rod OS. Near infrared light microscopy was employed to monitor photoreceptor changes in retinal slices stimulated by a rectangular-shaped visible light flash. Rapid rod OS length change was observed after the stimulation delivery. The magnitude and direction of the rod OS change varied with the position of the rods within the stimulated area. In the center of stimulated region the length of the rod OS shrunk, while in the peripheral region the rod OS tip swung towards center region in the plane perpendicular to the incident stimulus light. Our experimental result and theoretical analysis suggest that the observed TRP may reflect unbalanced disc-shape change due to localized pigment bleaching. Further investigation is required to understand biochemical mechanism of the observed rod OS kinetics. Better study of the TRP may provide a noninvasive biomarker to enable early detection of age-related macular degeneration (AMD) and other diseases that are known to produce retinal photoreceptor dysfunctions.

Effect of duration and severity of migraine on retinal nerve fiber layer, ganglion cell layer, and choroidal thickness.

PubMed

Abdellatif, Mona K; Fouad, Mohamed M

2018-03-01

To investigate the factors in migraine that have the highest significance on retinal and choroidal layers' thickness. Ninety patients with migraine and 40 age-matched healthy participants were enrolled in this observational, cross-sectional study. After full ophthalmological examination, spectral domain-optical coherence tomography was done for all patients measuring the thickness of ganglion cell layer and retinal nerve fiber layer. Enhanced depth imaging technique was used to measure the choroidal thickness. There was significant thinning in the superior and inferior ganglion cell layers, all retinal nerve fiber layer quadrants, and all choroidal quadrants (except for the central subfield) in migraineurs compared to controls. The duration of migraine was significantly correlated with ganglion cell layer, retinal nerve fiber layer, and all choroidal quadrants, while the severity of migraine was significantly correlated with ganglion cell layer and retinal nerve fiber layer only. Multiregression analysis showed that the duration of migraine is the most important determinant factor of the superior retinal nerve fiber layer quadrant (β = -0.375, p = 0.001) and in all the choroidal quadrants (β = -0.531, -0.692, -0.503, -0.461, -0.564, respectively, p  < 0.001), while severity is the most important determinant factor of inferior, nasal, and temporal retinal nerve fiber layer quadrants (β = -0.256, -0.335, -0.308; p  = 0.036, 0.005, 0.009, respectively) and the inferior ganglion cell layer hemisphere (β = -0.377 and p = 0.001). Ganglion cell layer, retinal nerve fiber layer, and choroidal thickness are significantly thinner in patients with migraine. The severity of migraine has more significant influence in the thinning of ganglion cell layer and retinal nerve fiber layer, while the duration of the disease affected the choroidal thickness more.

A splicing mutation in Aryl Hydrocarbon Receptor associated with retinitis pigmentosa.

PubMed

Zhou, Yu; Li, Shijin; Huang, Lulin; Yang, Yeming; Zhang, Lin; Yang, Mu; Liu, Wenjing; Ramasamy, Kim; Jiang, Zhilin; Sundaresan, Periasamy; Zhu, Xianjun; Yang, Zhenglin

2018-05-02

Retinitis pigmentosa (RP) refers to a group of retinal degenerative diseases, which often lead to vision loss. Although 70 genes have been identified in RP patients, the genetic cause of approximately 30% of RP cases remains unknown. We aimed to identify the cause of the disease in a cohort of RP families by whole exome sequencing. A rare homozygous splicing variant, c.1160 + 1G>A, which introduced skipping of exon 9 of the aryl hydrocarbon receptor (AHR), was identified in family RD-134. This variant is very rare in several exome databases and leads to skipping of exon 9 in the transcript. AHR is expressed in the human retina and is a ligand-activated transcription factor with multiple functions. Mutant AHR failed to promote 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced Xenobiotic Responsive Element (XRE) luciferase activity. In parallel, mutation in AHR abolished activation of its downstream target gene, such as CYP1A1 and CYP1A2. To investigate the in vivo roles of Ahr in the retina, we generated a retina-specific conditional knockout mouse model of Ahr. Comparing with wildtype mouse, Ahr knockout mice exhibited reduced electroretinogram responses at 9 months of age. Retinal histology revealed Retinal histology showed the degeneration of photoreceptors with a thinner outer nuclear layer. Thus, our data demonstrate that AHR is associated with RP.

Progressive outer retinal necrosis after rituximab and cyclophosphamide therapy

PubMed Central

Dogra, Mohit; Bajgai, Priya; Kumar, Ashok; Sharma, Aman

2018-01-01

We report a case of progressive outer retinal necrosis (PORN) in a patient of microscopic polyangitis (MPA), being treated with immunosuppressive drugs such as cyclophosphamide and rituximab. Her aqueous tap was positive for Varicella Zoster virus and she was treated with oral and intravitreal antivirals, along with discontinuation of one of the immunosuppressive agents, i.e. rituximab, which might have led to reactivation of the virus causing necrotizing retinitis lesions. Rituximab and cyclophosphamide are extremely potent drugs, which are necessary to manage immunological disorders such as MPA. However, they may predispose the patient to serious complications like viral infections, including PORN. PMID:29582832

THE ORGANOPHOSPHOROUS INSECTICIDE FENTHION DOES NOT AFFECT PHAGOCYTOSIS OF ROD OUTER SEGMENTS BY RETINAL PIGMENT EPITHELIUM CELLS IN CULTURE.

EPA Science Inventory

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Exposure to the organophosphorous insecticide fenthion has been associated with retinal degeneration in occupational studies. It has also been associated with pigmentary changes of the retina. Because retinal degeneration and pigmentary changes may be due to dysfunction of t...

Real-time emulation of neural images in the outer retinal circuit.

PubMed

Hasegawa, Jun; Yagi, Tetsuya

2008-12-01

We describe a novel real-time system that emulates the architecture and functionality of the vertebrate retina. This system reconstructs the neural images formed by the retinal neurons in real time by using a combination of analog and digital systems consisting of a neuromorphic silicon retina chip, a field-programmable gate array, and a digital computer. While the silicon retina carries out the spatial filtering of input images instantaneously, using the embedded resistive networks that emulate the receptive field structure of the outer retinal neurons, the digital computer carries out the temporal filtering of the spatially filtered images to emulate the dynamical properties of the outer retinal circuits. The emulations of the neural image, including 128 x 128 bipolar cells, are carried out at a frame rate of 62.5 Hz. The emulation of the response to the Hermann grid and a spot of light and an annulus of lights has demonstrated that the system responds as expected by previous physiological and psychophysical observations. Furthermore, the emulated dynamics of neural images in response to natural scenes revealed the complex nature of retinal neuron activity. We have concluded that the system reflects the spatiotemporal responses of bipolar cells in the vertebrate retina. The proposed emulation system is expected to aid in understanding the visual computation in the retina and the brain.

Acute Zonal Cone Photoreceptor Outer Segment Loss

PubMed Central

Sandhu, Harpal S.; Serrano, Leona W.; Traband, Anastasia; Lau, Marisa K.; Adamus, Grazyna; Avery, Robert A.

2017-01-01

Importance The diagnostic path presented narrows down the cause of acute vision loss to the cone photoreceptor outer segment and will refocus the search for the cause of similar currently idiopathic conditions. Objective To describe the structural and functional associations found in a patient with acute zonal occult photoreceptor loss. Design, Setting, and Participants A case report of an adolescent boy with acute visual field loss despite a normal fundus examination performed at a university teaching hospital. Main Outcomes and Measures Results of a complete ophthalmic examination, full-field flash electroretinography (ERG) and multifocal ERG, light-adapted achromatic and 2-color dark-adapted perimetry, and microperimetry. Imaging was performed with spectral-domain optical coherence tomography (SD-OCT), near-infrared (NIR) and short-wavelength (SW) fundus autofluorescence (FAF), and NIR reflectance (REF). Results The patient was evaluated within a week of the onset of a scotoma in the nasal field of his left eye. Visual acuity was 20/20 OU, and color vision was normal in both eyes. Results of the fundus examination and of SW-FAF and NIR-FAF imaging were normal in both eyes, whereas NIR-REF imaging showed a region of hyporeflectance temporal to the fovea that corresponded with a dense relative scotoma noted on light-adapted static perimetry in the left eye. Loss in the photoreceptor outer segment detected by SD-OCT co-localized with an area of dense cone dysfunction detected on light-adapted perimetry and multifocal ERG but with near-normal rod-mediated vision according to results of 2-color dark-adapted perimetry. Full-field flash ERG findings were normal in both eyes. The outer nuclear layer and inner retinal thicknesses were normal. Conclusions and Relevance Localized, isolated cone dysfunction may represent the earliest photoreceptor abnormality or a distinct entity within the acute zonal occult outer retinopathy complex. Acute zonal occult outer retinopathy should be considered in patients with acute vision loss and abnormalities on NIR-REF imaging, especially if multimodal imaging supports an intact retinal pigment epithelium and inner retina but an abnormal photoreceptor outer segment. PMID:28384671

Layer-by-Layer Bioprinting of Stem Cells for Retinal Tissue Regeneration

DTIC Science & Technology

2015-10-01

AWARD NUMBER: W81XWH-14-1-0522 TITLE: Layer-by-Layer Bioprinting of Stem Cells for Retinal Tissue Regeneration PRINCIPAL INVESTIGATOR...TITLE AND SUBTITLE Layer-by-Layer Bioprinting of Stem Cells for Retinal Tissue Regeneration 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-14-1-0522 5c...bioprinting process using stem cells for retinal tissue regeneration. The LBL nature of the bioprinting process matches nicely with the native

Photoreceptor layer map using spectral-domain optical coherence tomography.

PubMed

Lee, Ji Eun; Lim, Dae Won; Bae, Han Yong; Park, Hyun Jin

2009-12-01

To develop a novel method for analysis of the photoreceptor layer map (PLM) generated using spectral-domain optical coherence tomography (OCT). OCT scans were obtained from 20 eyes, 10 with macular holes (MH) and 10 with central serous chorioretinopathy (CSC) using the Macular Cube (512 x 128) protocol of the Cirrus HD-OCT (Carl Zeiss). The scanned data were processed using embedded tools of the advanced visualization. A partial thickness OCT fundus image of the photoreceptor layer was generated by setting the region of interest to a 50-microm thick layer that was parallel and adjacent to the retinal pigment epithelium. The resulting image depicted the photoreceptor layer as a map of the reflectivity in OCT. The PLM was compared with fundus photography, auto-fluorescence, tomography, and retinal thickness map. The signal from the photoreceptor layer of every OCT scan in each case was demonstrated as a single image of PLM in a fundus photograph fashion. In PLM images, detachment of the sensory retina is depicted as a hypo-reflective area, which represents the base of MH and serous detachment in CSC. Relative hypo-reflectivity, which was also noted at closed MH and at recently reattached retina in CSC, was associated with reduced signal from the junction between the inner and outer segments of photoreceptors in OCT images. Using PLM, changes in the area of detachment and reflectivity of the photoreceptor layer could be efficiently monitored. The photoreceptor layer can be analyzed as a map using spectral-domain OCT. In the treatment of both MH and CSC, PLM may provide new pathological information about the photoreceptor layer to expand our understanding of these diseases.

In vivo thickness and birefringence determination of the human retinal nerve fiber layer using polarization-sensitive optical coherence tomography.

PubMed

Cense, B; Chen, T C; de Boer, J F

2006-01-01

Thinning of the retinal nerve fiber layer and changes in retinal nerve fiber layer birefringence may both precede clinically detectable glaucomatous vision loss. We present in vivo thickness and depth-resolved birefringence measurements of the human retinal nerve fiber layer (RNFL) by use of polarization-sensitive optical coherence tomography (PS-OCT). Using a fiber-based PS-OCT setup real-time images of the human retina in vivo were recorded, co-registered with retinal video images of the location of PS-OCT scans. PS-OCT scans around the optic nerve head (ONH) of two healthy young volunteers were made using 10 concentric circles of increasing radius. Both the mean retinal nerve fiber layer thickness and mean retinal nerve fiber birefringence for each of 48 sectors on a circle were determined. The retinal nerve fiber layer thickness and birefringence varied as a function of sector around the ONH. Measured double pass phase retardation per unit depth values around the ONH range between 0.10 and 0.35 degrees/microm. The retinal nerve fiber layer becomes thinner with increasing distance from the ONH. In contrast, the birefringence does not vary significantly with increasing distance from the ONH.

Improving image segmentation performance and quantitative analysis via a computer-aided grading methodology for optical coherence tomography retinal image analysis.

PubMed

Debuc, Delia Cabrera; Salinas, Harry M; Ranganathan, Sudarshan; Tátrai, Erika; Gao, Wei; Shen, Meixiao; Wang, Jianhua; Somfai, Gábor M; Puliafito, Carmen A

2010-01-01

We demonstrate quantitative analysis and error correction of optical coherence tomography (OCT) retinal images by using a custom-built, computer-aided grading methodology. A total of 60 Stratus OCT (Carl Zeiss Meditec, Dublin, California) B-scans collected from ten normal healthy eyes are analyzed by two independent graders. The average retinal thickness per macular region is compared with the automated Stratus OCT results. Intergrader and intragrader reproducibility is calculated by Bland-Altman plots of the mean difference between both gradings and by Pearson correlation coefficients. In addition, the correlation between Stratus OCT and our methodology-derived thickness is also presented. The mean thickness difference between Stratus OCT and our methodology is 6.53 microm and 26.71 microm when using the inner segment/outer segment (IS/OS) junction and outer segment/retinal pigment epithelium (OS/RPE) junction as the outer retinal border, respectively. Overall, the median of the thickness differences as a percentage of the mean thickness is less than 1% and 2% for the intragrader and intergrader reproducibility test, respectively. The measurement accuracy range of the OCT retinal image analysis (OCTRIMA) algorithm is between 0.27 and 1.47 microm and 0.6 and 1.76 microm for the intragrader and intergrader reproducibility tests, respectively. Pearson correlation coefficients demonstrate R(2)>0.98 for all Early Treatment Diabetic Retinopathy Study (ETDRS) regions. Our methodology facilitates a more robust and localized quantification of the retinal structure in normal healthy controls and patients with clinically significant intraretinal features.

Improving image segmentation performance and quantitative analysis via a computer-aided grading methodology for optical coherence tomography retinal image analysis

NASA Astrophysics Data System (ADS)

Cabrera Debuc, Delia; Salinas, Harry M.; Ranganathan, Sudarshan; Tátrai, Erika; Gao, Wei; Shen, Meixiao; Wang, Jianhua; Somfai, Gábor M.; Puliafito, Carmen A.

2010-07-01

We demonstrate quantitative analysis and error correction of optical coherence tomography (OCT) retinal images by using a custom-built, computer-aided grading methodology. A total of 60 Stratus OCT (Carl Zeiss Meditec, Dublin, California) B-scans collected from ten normal healthy eyes are analyzed by two independent graders. The average retinal thickness per macular region is compared with the automated Stratus OCT results. Intergrader and intragrader reproducibility is calculated by Bland-Altman plots of the mean difference between both gradings and by Pearson correlation coefficients. In addition, the correlation between Stratus OCT and our methodology-derived thickness is also presented. The mean thickness difference between Stratus OCT and our methodology is 6.53 μm and 26.71 μm when using the inner segment/outer segment (IS/OS) junction and outer segment/retinal pigment epithelium (OS/RPE) junction as the outer retinal border, respectively. Overall, the median of the thickness differences as a percentage of the mean thickness is less than 1% and 2% for the intragrader and intergrader reproducibility test, respectively. The measurement accuracy range of the OCT retinal image analysis (OCTRIMA) algorithm is between 0.27 and 1.47 μm and 0.6 and 1.76 μm for the intragrader and intergrader reproducibility tests, respectively. Pearson correlation coefficients demonstrate R2>0.98 for all Early Treatment Diabetic Retinopathy Study (ETDRS) regions. Our methodology facilitates a more robust and localized quantification of the retinal structure in normal healthy controls and patients with clinically significant intraretinal features.

Involvement of Autophagic Pathway in the Progression of Retinal Degeneration in a Mouse Model of Diabetes.

PubMed

Piano, Ilaria; Novelli, Elena; Della Santina, Luca; Strettoi, Enrica; Cervetto, Luigi; Gargini, Claudia

2016-01-01

The notion that diabetic retinopathy (DR) is essentially a micro-vascular disease has been recently challenged by studies reporting that vascular changes are preceded by signs of damage and loss of retinal neurons. As to the mode by which neuronal death occurs, the evidence that apoptosis is the main cause of neuronal loss is far from compelling. The objective of this study was to investigate these controversies in a mouse model of streptozotocin (STZ) induced diabetes. Starting from 8 weeks after diabetes induction there was loss of rod but not of cone photoreceptors, together with reduced thickness of the outer and inner synaptic layers. Correspondingly, rhodopsin expression was downregulated and the scotopic electroretinogram (ERG) is suppressed. In contrast, cone opsin expression and photopic ERG response were not affected. Suppression of the scotopic ERG preceded morphological changes as well as any detectable sign of vascular alteration. Only sparse apoptotic figures were detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and glia was not activated. The physiological autophagy flow was altered instead, as seen by increased LC3 immunostaining at the level of outer plexiform layer (OPL) and upregulation of the autophagic proteins Beclin-1 and Atg5. Collectively, our results show that the streptozotocin induced DR in mouse initiates with a functional loss of the rod visual pathway. The pathogenic pathways leading to cell death develop with the initial dysregulation of autophagy well before the appearance of signs of vascular damage and without strong involvement of apoptosis.

Involvement of Autophagic Pathway in the Progression of Retinal Degeneration in a Mouse Model of Diabetes

PubMed Central

Piano, Ilaria; Novelli, Elena; Della Santina, Luca; Strettoi, Enrica; Cervetto, Luigi; Gargini, Claudia

2016-01-01

The notion that diabetic retinopathy (DR) is essentially a micro-vascular disease has been recently challenged by studies reporting that vascular changes are preceded by signs of damage and loss of retinal neurons. As to the mode by which neuronal death occurs, the evidence that apoptosis is the main cause of neuronal loss is far from compelling. The objective of this study was to investigate these controversies in a mouse model of streptozotocin (STZ) induced diabetes. Starting from 8 weeks after diabetes induction there was loss of rod but not of cone photoreceptors, together with reduced thickness of the outer and inner synaptic layers. Correspondingly, rhodopsin expression was downregulated and the scotopic electroretinogram (ERG) is suppressed. In contrast, cone opsin expression and photopic ERG response were not affected. Suppression of the scotopic ERG preceded morphological changes as well as any detectable sign of vascular alteration. Only sparse apoptotic figures were detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and glia was not activated. The physiological autophagy flow was altered instead, as seen by increased LC3 immunostaining at the level of outer plexiform layer (OPL) and upregulation of the autophagic proteins Beclin-1 and Atg5. Collectively, our results show that the streptozotocin induced DR in mouse initiates with a functional loss of the rod visual pathway. The pathogenic pathways leading to cell death develop with the initial dysregulation of autophagy well before the appearance of signs of vascular damage and without strong involvement of apoptosis. PMID:26924963

Role of Caspase-3 in acute light damage to retina of rats.

PubMed

Wang, Xiao; Hu, Shi-Xing; Li, Wei; Lin, Shao-Chun

2007-03-01

To investigate the role of Caspase-3 in retinal damage caused by light exposure in rats. Light injury to retina was induced by persistent exposure to illumination (intensity: 30 000 +/- 50 lux) of operating microscope for 30 minutes in the right eyes of Sprague-Dawley rats. The pathological changes of retina were observed under optical and electron microscopies at different time points, which were 6 hours, 1, 3, 7, and 15 days after the light exposure. Apoptosis of retinal cells was analyzed by flow cytometry. The activity of Caspase-3 was evaluated by using the Caspase-3 assay kit. At the same time, the expression of Caspase-3 protease was determined with Western blot analysis. The examination results of optical and transmission electron microscopes showed that edema of inner and outer segments of the retina, especially the chondriosome inside the inner segment, became obvious 6 hours after the light exposure. The change was deteriorated along with the increasing time. The structures of the discoidal valve dissociated in the outer segment simultaneously. Disorderly arranged nuclei, karyopycnosis, and thinning in the outer nuclear layer were observed. The retinal pigment epithelium almost disappeared during the later stage. The staining results of Annexin-V combined with PI demonstrated that the proportion of apoptotic cells increased with time. The proportion between 7th day (82.7%) and 15th day (80.4%), however, showed no significant difference. Caspase-3 became remarkably active with the lapse of time, which increased from 0.02 at 6th hour to the peak of 9.8 at 7th day before it started to descend. The Western blot detected a expression of the active form of Caspase-3 at 7th day and 15th day. Apoptosis of photoreceptor cells is markedly involved in the light damage and Caspase-3 protease may play an important role in the apoptotic process of the retina after light exposure in rats.

Detailed Functional and Structural Phenotype of Bietti Crystalline Dystrophy Associated with Mutations in CYP4V2 Complicated by Choroidal Neovascularization

PubMed Central

Fuerst, Nicole M.; Serrano, Leona; Han, Grace; Morgan, Jessica I. W.; Maguire, Albert M.; Leroy, Bart P.; Kim, Benjamin J.; Aleman, Tomas S.

2016-01-01

Purpose To describe in detail the phenotype of a patient with Bietti crystalline dystrophy (BCD) complicated by choroidal neovascularization (CNV) and the response to intravitreal Bevacizumab (Avastin ®; Genentech/Roche). Methods A 34-year-old woman with BCD and mutations in CYP4V2 (c.802-8_806del13/p.H331P:c992A>C) underwent a complete ophthalmic examination, full-field flash electroretinography (ERG), kinetic and two-color dark-adapted perimetry, and dark-adaptometry. Imaging was performed with spectral domain optical coherence tomography (SD-OCT), near infrared (NIR) and short wavelength (SW) fundus autofluorescence (FAF), and fluorescein angiography (FA). Results Best-corrected visual acuity (BCVA) was 20/20 and 20/60 for the right and left eye, respectively. There were corneal paralimbal crystal-like deposits. Kinetic fields were normal in peripheral extent. Retinal crystals were most obvious on NIR-reflectance and corresponded with hyperreflectivities within the RPE on SD-OCT. There was parafoveal/perifoveal hypofluorescence on SW-FAF and NIR-FAF. Rod > cone sensitivity loss surrounded fixation and extended to ~10° of eccentricity corresponding to regions of photoreceptor outer segment-retinal pigmented epithelium (RPE) interdigitation abnormalities. The outer nuclear layer was normal in thickness. Recovery of sensitivity following a ~76% rhodopsin bleach was normal. ERGs were normal. A subretinal hemorrhage in the left eye co-localized with elevation of the RPE on SD-OCT and leakage on FA, suggestive of CNV. Three monthly intravitreal injections of Bevacizumab led to restoration of BCVA to baseline (20/25). Conclusion Crystals in BCD were predominantly located within the RPE. Photoreceptor outer segment and apical RPE abnormalities underlie the relatively extensive retinal dysfunction observed in relatively early-stage BCD. Intravitreal Bevacizumab was effective in treating CNV in this setting. PMID:27028354

Photoreceptor Layer Thickness Changes During Dark Adaptation Observed With Ultrahigh-Resolution Optical Coherence Tomography

PubMed Central

Lu, Chen D.; Lee, ByungKun; Schottenhamml, Julia; Maier, Andreas; Pugh, Edward N.; Fujimoto, James G.

2017-01-01

Purpose To examine outer retinal band changes after flash stimulus and subsequent dark adaptation with ultrahigh-resolution optical coherence tomography (UHR-OCT). Methods Five dark-adapted left eyes of five normal subjects were imaged with 3-μm axial-resolution UHR-OCT during 30 minutes of dark adaptation following 96%, 54%, 23%, and 0% full-field and 54% half-field rhodopsin bleach. We identified the ellipsoid zone inner segment/outer segment (EZ[IS/OS]), cone interdigitation zone (CIZ), rod interdigitation zone (RIZ), retinal pigment epithelium (RPE), and Bruch's membrane (BM) axial positions and generated two-dimensional thickness maps of the EZ(IS/OS) to the four bands. The average thickness over an area of the thickness map was compared against that of the dark-adapted baselines. The time-dependent thickness changes (photoresponses) were statistically compared against 0% bleach. Dark adaptometry was performed with the same bleaching protocol. Results The EZ(IS/OS)-CIZ photoresponse was significantly different at 96% (P < 0.0001) and 54% (P = 0.006) bleach. At all three bleaching levels, the EZ(IS/OS)-RIZ, -RPE, and -BM responses were significantly different (P < 0.0001). The EZ(IS/OS)-CIZ and EZ(IS/OS)-RIZ time courses were similar to the recovery of rod- and cone-mediated sensitivity, respectively, measured with dark adaptometry. The maximal EZ(IS/OS)-CIZ and EZ(IS/OS)-RIZ response magnitudes doubled from 54% to 96% bleach. Both EZ(IS/OS)-RPE and EZ(IS/OS)-BM responses resembled dampened oscillations that were graded in amplitude and duration with bleaching intensity. Half-field photoresponses were localized to the stimulated retina. Conclusions With noninvasive, near-infrared UHR-OCT, we characterized three distinct, spatially localized photoresponses in the outer retinal bands. These photoresponses have potential value as physical correlates of photoreceptor function. PMID:28898357

Retinal pigment epithelial changes in chronic Vogt-Koyanagi-Harada disease: fundus autofluorescence and spectral domain-optical coherence tomography findings.

PubMed

Vasconcelos-Santos, Daniel V; Sohn, Elliott H; Sadda, Srinivas; Rao, Narsing A

2010-01-01

The purpose of this study was to determine whether fundus autofluorescence (FAF) and spectral domain-optical coherence tomography (SD-OCT) imaging allow better assessment of retinal pigment epithelium and the outer retina in subjects with chronic Vogt-Koyanagi-Harada disease compared with examination and angiography alone. A cross-sectional analysis of a series of seven consecutive patients with chronic Vogt-Koyanagi-Harada disease undergoing FAF and SD-OCT was conducted. Chronic disease was defined as duration of intraocular inflammation >3 months. Color fundus photographs were correlated to FAF and SD-OCT images. The images were later correlated to fluorescein angiography and indocyanine green angiography. All patients had sunset glow fundus, which resulted in no apparent corresponding abnormality on FAF or SD-OCT. Lesions with decreased autofluorescence signal were observed in 11 eyes (85%), being associated with loss of the retinal pigment epithelium and involvement of the outer retina on SD-OCT. In 5 eyes (38%), some of these lesions were very subtle on clinical examination but easily detected by FAF. Lesions with increased autofluorescence signal were seen in 8 eyes (61.5%), showing variable involvement of the outer retina on SD-OCT and corresponding clinically to areas of retinal pigment epithelium proliferation and cystoid macular edema. Combined use of FAF and SD-OCT imaging allowed noninvasive delineation of retinal pigment epithelium/outer retina changes in patients with chronic Vogt-Koyanagi-Harada disease, which were consistent with previous histopathologic reports. Some of these changes were not apparent on clinical examination.

Sarcocystis neurona retinochoroiditis in a sea otter (Enhydra lutris kenyoni)

USGS Publications Warehouse

Dubey, J.P.; Thomas, N.J.

2011-01-01

Sarcocystis neurona is an important cause of fatal disease in sea otters in the USA. Encephalitis is the predominant lesion and parasites are confined to the central nervous system and muscles. Here we report retinochoroiditis in a sea otter (Enhydra lutris kenyoni) found dead on Copalis Beach, WA, USA. Salient lesions were confined to the brain and eye. Multifocal nonsuppurative meningoencephalitis was present in the cerebrum and cerebellum associated with S. neurona schizonts. The retina of one eye had a focus of inflammation that contained numerous S. neurona schizonts and merozoites. The focus extended from the retinal pigment epithelium inward through all layers of the retina, but inflammation was most concentrated at the inner surface of the tapetum and the outer retina. The inner and outer nuclear layers of the retina were disorganized and irregular at the site of inflammation. There was severe congestion and mild hemorrhage in the choroid, and mild hemorrhage into the vitreous body. Immunohistochemistry with S. neurona-specific polyclonal rabbit antibodies stained schizonts and merozoites. To our knowledge this is the first report of S. neurona-associated retinochoroiditis in any naturally infected animal.

Development of an MRI biomarker sensitive to tetrameric visual arrestin 1 and its reduction via light-evoked translocation in vivo

PubMed Central

Berkowitz, Bruce A.; Gorgis, Jawan; Patel, Ankit; Baameur, Faiza; Gurevich, Vsevolod V.; Craft, Cheryl M.; Kefalov, Vladimir J.; Roberts, Robin

2015-01-01

Rod tetrameric arrestin 1 (tet-ARR1), stored in the outer nuclear layer/inner segments in the dark, modulates photoreceptor synaptic activity; light exposure stimulates a reduction via translocation to the outer segments for terminating G-protein coupled phototransduction signaling. Here, we test the hypothesis that intraretinal spin-lattice relaxation rate in the rotating frame (1/T1ρ), an endogenous MRI contrast mechanism, has high potential for evaluating rod tet-ARR1 and its reduction via translocation. Dark- and light-exposed mice (null for the ARR1 gene, overexpressing ARR1, diabetic, or wild type with or without treatment with Mn2+, a calcium channel probe) were studied using 1/T1ρ MRI. Immunohistochemistry and single-cell recordings of the retinas were also performed. In wild-type mice with or without treatment with Mn2+, 1/T1ρ of avascular outer retina (64% to 72% depth) was significantly (P < 0.05) greater in the dark than in the light; a significant (P < 0.05) but opposite pattern was noted in the inner retina (<50% depth). Light-evoked outer retina Δ1/T1ρ was absent in ARR1-null mice and supernormal in overexpressing mice. In diabetic mice, the outer retinal Δ1/T1ρ pattern suggested normal dark-to-light tet-ARR1 translocation and chromophore content, conclusions confirmed ex vivo. Light-stimulated Δ1/T1ρ in inner retina was linked to changes in blood volume. Our data support 1/T1ρ MRI for noninvasively assessing rod tet-ARR1 and its reduction via protein translocation, which can be combined with other metrics of retinal function in vivo.—Berkowitz, B. A., Gorgis, J., Patel, A., Baameur, F., Gurevich, V. V., Craft, C. M., Kefalov, V. J., Roberts, R. Development of an MRI biomarker sensitive to tetrameric visual arrestin 1 and its reduction via light-evoked translocation in vivo. PMID:25351983

Comparative investigation of stimulus-evoked rod outer segment movement and retinal electrophysiological activity

NASA Astrophysics Data System (ADS)

Lu, Yiming; Wang, Benquan; Yao, Xincheng

2017-02-01

Transient retinal phototropism (TRP) has been observed in rod photoreceptors activated by oblique visible light flashes. Time-lapse confocal microscopy and optical coherence tomography (OCT) revealed rod outer segment (ROS) movements as the physical source of TRP. However, the physiological source of TRP is still not well understood. In this study, concurrent TRP and electroretinogram (ERG) measurements disclosed a remarkably earlier onset time of the ROS movements (<=10 ms) than that ( 38 ms) of the ERG a-wave. Furthermore, low sodium treatment reversibly blocked the photoreceptor ERG a-wave, which is known to reflect hyperpolarization of retinal photoreceptors, but preserved the TRP associated rod OS movements well. Our experimental results and theoretical analysis suggested that the physiological source of TRP might be attributed to early stages of phototransduction, before the hyperpolarization of retinal photoreceptors.

In-vivo mapping of drusen by fundus autofluorescence and spectral-domain optical coherence tomography imaging.

PubMed

Göbel, Arno P; Fleckenstein, Monika; Heeren, Tjebo F C; Holz, Frank G; Schmitz-Valckenberg, Steffen

2016-01-01

To determine fundus autofluorescence (FAF) signal variations and corresponding microstructural alterations on spectral-domain optical coherence tomography (SD-OCT) in areas of funduscopically visible drusen associated with age-related macular degeneration (AMD). Thirty eyes from 22 patients with geographic atrophy (GA) secondary to AMD (median age 74, range 64-87 years), who had undergone retinal imaging including color fundus photography (CFP), FAF and SD-OCT (Spectralis HRA+OCT; Heidelberg Engineering GmbH, Heidelberg, Germany) were retrospectively analyzed. In each eye, at least one druse (≥ 63 μm) in the perilesional zone of GA recorded on CFP was analyzed. Relative FAF intensities and alterations in SD-OCT bands at the site of each druse were evaluated. A total of 73 drusen were analyzed, which were associated with heterogeneous corresponding alterations on FAF and SD-OCT. The FAF signal was normal, increased, decreased or not evaluable in 32 (44 %), 27 (37 %), 12 (16 %), and 2 (3 %) drusen, respectively. Focal hyperreflectivity overlying drusen was most frequently spatially confined to increased FAF (present in 9 (33 %) of 27 drusen with increased FAF). Outer nuclear layer thinning and choroidal hyperreflectivity were associated with decreased FAF (present in 7 [58 %] of 12 and 6 [50 %] of 12 drusen with decreased FAF, respectively). The appearance of soft drusen on CFP does not allow for differentiation between preserved and markedly compromised outer retinal integrity, including incipient atrophy and focal neurosensory alterations of reflectivity overlying extracellular sub-retinal pigment epithelium (RPE) deposits. Multimodal imaging reveals a broad spectrum of microstructural changes, which may reflect different stages in the evolution of drusen.

Biallelic Mutations in PLA2G5, Encoding Group V Phospholipase A2, Cause Benign Fleck Retina

PubMed Central

Sergouniotis, Panagiotis I.; Davidson, Alice E.; Mackay, Donna S.; Lenassi, Eva; Li, Zheng; Robson, Anthony G.; Yang, Xu; Kam, Jaimie Hoh; Isaacs, Timothy W.; Holder, Graham E.; Jeffery, Glen; Beck, Jonathan A.; Moore, Anthony T.; Plagnol, Vincent; Webster, Andrew R.

2011-01-01

Flecked-retina syndromes, including fundus flavimaculatus, fundus albipunctatus, and benign fleck retina, comprise a group of disorders with widespread or limited distribution of yellow-white retinal lesions of various sizes and configurations. Three siblings who have benign fleck retina and were born to consanguineous parents are the basis of this report. A combination of homozygosity mapping and exome sequencing helped to identify a homozygous missense mutation, c.133G>T (p.Gly45Cys), in PLA2G5, a gene encoding a secreted phospholipase (group V phospholipase A2). A screen of a further four unrelated individuals with benign fleck retina detected biallelic variants in the same gene in three patients. In contrast, no loss of function or common (minor-allele frequency>0.05%) nonsynonymous PLA2G5 variants have been previously reported (EVS, dbSNP, 1000 Genomes Project) or were detected in an internal database of 224 exomes (from subjects with adult onset neurodegenerative disease and without a diagnosis of ophthalmic disease). All seven affected individuals had fundoscopic features compatible with those previously described in benign fleck retina and no visual or electrophysiological deficits. No medical history of major illness was reported. Levels of low-density lipoprotein were mildly elevated in two patients. Optical coherence tomography and fundus autofluorescence findings suggest that group V phospholipase A2 plays a role in the phagocytosis of photoreceptor outer-segment discs by the retinal pigment epithelium. Surprisingly, immunohistochemical staining of human retinal tissue revealed localization of the protein predominantly in the inner and outer plexiform layers. PMID:22137173

Ocular Lesions in Red-Tailed Hawks ( Buteo jamaicensis) With Naturally Acquired West Nile Disease.

PubMed

Wünschmann, A; Armién, A G; Khatri, M; Martinez, L C; Willette, M; Glaser, A; Alvarez, J; Redig, P

2017-03-01

Ocular lesions are common in red-tailed hawks with West Nile (WN) disease. These lesions consist of pectenitis, choroidal or retinal inflammation, or retinal necrosis, but detailed investigation of the ocular lesions is lacking. Postmortem examination of the eyes of 16 red-tailed hawks with naturally acquired WN disease and 3 red-tailed hawks without WN disease was performed using histopathology, immunohistochemistry for West Nile virus (WNV) antigen, glial fibrillary acid protein, cleaved caspase-3, and the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling method. Retinal lesions were classified as type I or type II lesions. Type I lesions were characterized by lymphoplasmacytic infiltrates in the subjacent choroid with degeneration limited to the outer retina (type Ia lesion) or with degeneration and necrosis of the outer retina or outer and inner retina (type Ib lesion) while retinal collapse, atrophy, and scarring were hallmarks of type II lesions. Type II retinal lesions were associated with a more pronounced choroiditis. Although not statistically significant, WNV antigen tended to be present in larger quantity in type Ib lesions. Type I lesions are considered acute while type II lesions are chronic. The development of retinal lesions was associated with the presence of an inflammatory infiltrate in the choroid. A breakdown of the blood-retina barrier is suspected to be the main route of infection of the retina. Within the retina, virus appeared to spread via both neuronal and Müller cell processes.

Profound re-organization of cell surface proteome in equine retinal pigment epithelial cells in response to in vitro culturing.

PubMed

Szober, Christoph M; Hauck, Stefanie M; Euler, Kerstin N; Fröhlich, Kristina J H; Alge-Priglinger, Claudia; Ueffing, Marius; Deeg, Cornelia A

2012-10-31

The purpose of this study was to characterize the cell surface proteome of native compared to cultured equine retinal pigment epithelium (RPE) cells. The RPE plays an essential role in visual function and represents the outer blood-retinal barrier. We are investigating immunopathomechanisms of equine recurrent uveitis, an autoimmune inflammatory disease in horses leading to breakdown of the outer blood-retinal barrier and influx of autoreactive T-cells into affected horses' vitrei. Cell surface proteins of native and cultured RPE cells from eye-healthy horses were captured by biotinylation, analyzed by high resolution mass spectrometry coupled to liquid chromatography (LC MS/MS), and the most interesting candidates were validated by PCR, immunoblotting and immunocytochemistry. A total of 112 proteins were identified, of which 84% were cell surface membrane proteins. Twenty-three of these proteins were concurrently expressed by both cell states, 28 proteins exclusively by native RPE cells. Among the latter were two RPE markers with highly specialized RPE functions: cellular retinaldehyde-binding protein (CRALBP) and retinal pigment epithelium-specific protein 65kDa (RPE65). Furthermore, 61 proteins were only expressed by cultured RPE cells and absent in native cells. As we believe that initiating events, leading to the breakdown of the outer blood-retinal barrier, take place at the cell surface of RPE cells as a particularly exposed barrier structure, this differential characterization of cell surface proteomes of native and cultured equine RPE cells is a prerequisite for future studies.

Inner retinal vasculopathy in Zika virus disease.

PubMed

Singh, Mandeep S; Marquezan, Maria Carolina; Omiadze, Revaz; Reddy, Ashvini K; Belfort, Rubens; May, William N

2018-06-01

Zika virus infection is associated with vision-threatening ocular complications including uveitis and outer retinopathy. The aim of this report is to describe a case of an adult patient with serologically confirmed Zika infection who presented with retinal vascular abnormalities that coincided with systemic post-viral neurological manifestations of the disease. A 34-year-old white female presented with symptoms of peripheral neuropathy following serologically confirmed Zika virus infection that was acquired in Puerto Rico four months prior to presentation. Ocular evaluation revealed perifoveal microaneurysms which were not associated with visual symptoms. These data potentially expand the phenotypic spectrum of Zika virus retinopathy. In addition to outer retinal abnormalities which are well-described in infants and adults, inner retinal vascular abnormalities may also occur and may be temporally associated with post-viral neurological sequelae of Zika virus infection. Clinicians should be aware of potential retinal involvement in affected patients who present with neurological symptoms after recovery from acute Zika virus infection.

Mutation K42E in dehydrodolichol diphosphate synthase (DHDDS) causes recessive retinitis pigmentosa.

PubMed

Lam, Byron L; Züchner, Stephan L; Dallman, Julia; Wen, Rong; Alfonso, Eduardo C; Vance, Jeffery M; Peričak-Vance, Margaret A

2014-01-01

A single-nucleotide mutation in the gene that encodes DHDDS has been identified by whole exome sequencing as the cause of the non-syndromic recessive retinitis pigmentosa (RP) in a family of Ashkenazi Jewish origin in which three of the four siblings have early onset retinal degeneration. The peripheral retinal degeneration in the affected siblings was evident in the initial examination in 1992 and only one had detectable electroretinogram (ERG) that suggested cone-rod dysfunction. The pigmentary retinal degeneration subsequently progressed rapidly. The identified mutation changes the highly conserved residue Lys42 to Glu, resulting in lower catalytic efficiency. Patterns of plasma transferrin isoelectric focusing gel were normal in all family members, indicating no significant abnormality in protein glycosylation. Dolichols have been shown to influence the fluidity and of the membrane and promote vesicle fusion. Considering that photoreceptor outer segments contain stacks of membrane discs, we believe that the mutation may lead to low dolichol levels in photoreceptor outer segments, resulting in unstable membrane structure that leads to photoreceptor degeneration.

Evaluation of retinal nerve fiber layer thickness in the area of apparently normal hemifield in glaucomatous eyes with optical coherence tomography.

PubMed

Kee, Changwon; Cho, Changhwan

2003-06-01

The authors investigated the correlation between visual field defects detected by automated perimetry and the thickness of the retinal nerve fiber layer measured with optical coherence tomography, and examined whether there is a decrease in retinal nerve fiber layer thickness in the apparently normal hemifield of glaucomatous eyes. Forty-one patients with glaucoma and 41 normal control subjects were included in this study. Statistical correlations between the sum of the total deviation of 37 stimuli of each hemifield and the ratio of decrease in retinal nerve fiber layer thickness were evaluated. The statistical difference between the retinal nerve fiber layer thickness of the apparently normal hemifield in glaucomatous eyes and that of the corresponding hemifield in normal subjects was also evaluated. There was a statistically significant correlation in the sum of the total deviation and retinal nerve fiber layer thickness decrease ratio (superior hemifield, P = 0.001; inferior hemifield, P = 0.003). There was no significant decrease in retinal nerve fiber layer thickness in the area that corresponded to the normal visual field in the hemifield defect with respect to the horizontal meridian in glaucomatous eyes (superior side, P = 0.148; inferior side, P = 0.341). Optical coherence tomography was capable of demonstrating and measuring retinal nerve fiber layer abnormalities. No changes in the retinal nerve fiber layer thickness of the apparently normal hemifield were observed in glaucomatous eyes.

Topographic specializations of catecholaminergic cells and ganglion cells and distribution of calcium binding proteins in the crepuscular rock cavy (Kerodon rupestris) retina.

PubMed

Oliveira, Francisco Gilberto; Nascimento-Júnior, Expedito Silva do; Cavalcante, Judney Cley; Guzen, Fausto Pierdoná; Cavalcante, Jeferson de Souza; Soares, Joacil Germano; Cavalcanti, José Rodolfo Lopes de Paiva; Freitas, Leandro Moura de; Costa, Miriam Stela Maris de Oliveira; Andrade-da-Costa, Belmira Lara da Silveira

2018-07-01

The rock cavy (Kerodon rupestris) is a crepuscular Hystricomorpha rodent that has been used in comparative analysis of retinal targets, but its retinal organization remains to be investigated. In order to better characterize its visual system, the present study analyzed neurochemical features related to the topographic organization of catecholaminergic cells and ganglion cells, as well the distribution of calcium-binding proteins in the outer and inner retina. Retinal sections and/or wholemounts were processed using tyrosine hydroxylase (TH), GABA, calbindin, parvalbumin and calretinin immunohistochemistry or Nissl staining. Two types of TH-immunoreactive (TH-IR) cells were found which differ in soma size, dendritic arborization, intensity of TH immunoreactivity and stratification pattern in the inner plexiform layer. The topographic distribution of all TH-IR cells defines a visual streak along the horizontal meridian in the superior retina. The ganglion cells are also distributed in a visual streak and the visual acuity estimated considering their peak density is 4.13 cycles/degree. A subset of TH-IR cells express GABA or calbindin. Calretinin is abundant in most of retinal layers and coexists with calbindin in horizontal cells. Parvalbumin is less abundant and expressed by presumed amacrine cells in the INL and some ganglion cells in the GCL. The topographic distribution of TH-IR cells and ganglion cells in the rock cavy retina indicate a suitable adaptation for using a broad extension of its inferior visual field in aspects that involve resolution, adjustment to ambient light intensity and movement detection without specialized eye movements. Copyright © 2017 Elsevier B.V. All rights reserved.

The Effects of Diabetic Retinopathy and Pan-Retinal Photocoagulation on Photoreceptor Cell Function as Assessed by Dark Adaptometry

PubMed Central

Bavinger, J. Clay; Dunbar, Grace E.; Stem, Maxwell S.; Blachley, Taylor S.; Kwark, Leon; Farsiu, Sina; Jackson, Gregory R.; Gardner, Thomas W.

2016-01-01

Purpose The pathophysiology of vision loss in persons with diabetic retinopathy (DR) is complex and incompletely defined. We hypothesized that retinal pigment epithelium (RPE) and rod and cone photoreceptor dysfunction, as measured by dark adaptometry, would increase with severity of DR, and that pan-retinal photocoagulation (PRP) would exacerbate this dysfunction. Methods Dark adaptation (DA) was measured in subjects with diabetes mellitus and healthy controls. Dark adaptation was measured at 5° superior to the fovea following a flash bleach, and the data were analyzed to yield cone and rod sensitivity curves. Retinal layer thicknesses were quantified using spectral-domain optical coherence tomography (OCT). Results The sample consisted of 23 controls and 73 diabetic subjects. Subjects with moderate nonproliferative diabetic retinopathy (NPDR) exhibited significant impairment of rod recovery rate compared with control subjects (P = 0.04). Cone sensitivity was impaired in subjects with proliferative diabetic retinopathy (PDR) (type 1 diabetes mellitus [T1DM]: P = 0.0047; type 2 diabetes mellitus [T2DM]: P < 0.001). Subjects with untreated PDR compared with subjects treated with PRP exhibited similar rod recovery rates and cone sensitivities. Thinner RPE as assessed by OCT was associated with slower rod recovery and lower cone sensitivity, and thinner photoreceptor inner segment/outer segment layer was associated with lower cone sensitivity. Conclusions The results suggest that RPE and photoreceptor cell dysfunction, as assessed by cone sensitivity level and rod- and RPE-mediated dark adaptation, progresses with worsening DR, and rod recovery dysfunction occurs earlier than cone dysfunction. Function was preserved following PRP. The findings suggest multiple defects in retinoid function and provide potential points to improve visual function in persons with PDR. PMID:26803796

Surface characterization of retinal tissues for the enhancement of vitreoretinal surgical methods

NASA Astrophysics Data System (ADS)

Valentin-Rodriguez, Celimar

Diabetic retinopathy is the most common ophthalmic complication of diabetes and the leading cause of blindness among adults, ages 30 to 70. Surgery to remove scar tissue in the eye is the only corrective treatment once the retina is affected. Visual recovery is often hampered by retinal trauma during surgery and by low patient compliance. Our work in this project aimed to improve vitreoretinal surgical methods from information gathered by sensitive surface analysis of pre-retinal tissues found at the vitreoretinal interface. Atomic force microscopy characterization of human retinal tissues revealed that surgically excised inner limiting membrane (ILM) has a heterogeneous surface and is mainly composed of globular and fibrous structures. ILM tissues also show low adhesion for clean unmodified surfaces as opposed to those with functional groups attractive to those on the ILM surface, due to their charge. Based on these observations, layer-by-layer films with embedded gold nanoparticles with a positive outer charge were designed. These modifications increased the adhesion between surgical instruments and ILM by increasing the roughness and tuning the film surface charge. These films proved to be stable under physiological conditions. Finally, the effect of vital dyes on the topographical characteristics of ILMs was characterized and new imaging modes to further reveal ILM topography were utilized. Roughness and adhesion force data suggest that second generation dyes have no effect on the surface nanostructure of ILMs, but increase adhesion at the tip sample interface. This project clearly illustrates that physicochemical information from tissues can be used to rationally re-design surgical procedures, in this case for tissue removal purposes. This rational design method can be applied to other soft tissue excision procedures as is the case of cataract surgery or laparoscopic removal of endometrial tissue.

Vitreal IgM autoantibodies target neurofilament medium in a spontaneous model of autoimmune uveitis.

PubMed

Swadzba, Margarete E; Hirmer, Sieglinde; Amann, Barbara; Hauck, Stefanie M; Deeg, Cornelia A

2012-01-25

Although the presence of IgG autoantibodies in the vitreous of spontaneous cases of equine recurrent uveitis (ERU) has been demonstrated, the potential role of IgM reactivities during ERU pathogenesis remains unexplored. The purpose of this study was to examine the presence of IgM autoantibodies in vitreous specimens of ERU-affected horses and to test their binding specificity to intraocularly expressed proteins. To test IgM autoantibody responses to retinal tissue, vitreous samples of eye-healthy controls and ERU patients were analyzed via two-dimensional Western blot analysis with equine retinal tissue as an antigen source. A candidate protein, the peptide neurofilament medium (NF-M), was identified via mass spectrometry and validated via enzyme-linked immunosorbent assay. Immunohistochemistry for NF-M expression was performed on healthy and ERU-affected retinal sections. Whereas autoreactivity was never detected in the healthy vitreous samples, NF-M was specifically targeted by vitreal IgM autoantibodies in 44% of the ERU cases. Vitreal anti-NF-M IgG was detected in only 8% of the ERU samples, pointing to a persistent IgM response. In healthy horse retina, NF-M was located in the retinal ganglion cells and their processes, with additional staining in the outer plexiform layer. NF-M expression in ERU-affected retinas decreased considerably, and the remaining expression was limited to the nerve fiber layer. Intraocular anti NF-M IgM autoantibodies occur with high prevalence in vitreous of spontaneous autoimmune uveitis cases. The IgM dominated response may indicate a thymus-independent response to NF-M and merits further investigation in ERU, as well as in its human counterpart, autoimmune uveitis.

Cytomegalovirus implicated in a case of progressive outer retinal necrosis (PORN).

PubMed

Sfeir, Maroun

2015-08-01

Progressive outer retinal necrosis, also known as PORN, has been described as a variant of necrotizing herpetic retinopathy, occurring particularly in patients with acquired immune deficiency syndrome (AIDS). Although the etiologic organism has been reported to be Varicella-zoster virus, cytomegalovirus (CMV) can be an etiologic agent. Our case illustrates the occurrence of two opportunistic infections: PORN associated with CMV and Mycobacterium avium intracellulare duodenitis in a patient with uncontrolled HIV infection. Copyright © 2015 Elsevier B.V. All rights reserved.

Changes in Macular Retinal Layers and Peripapillary Nerve Fiber Layer Thickness after 577-nm Pattern Scanning Laser in Patients with Diabetic Retinopathy

PubMed Central

Shin, Ji Soo

2017-01-01

Purpose The aim of this study was to evaluate the changes in thickness of each macular retinal layer, the peripapillary retinal nerve fiber layer (RNFL), and central macular thickness (CMT) after 577-nm pattern scanning laser (PASCAL) photocoagulation in patients with diabetic retinopathy. Methods This retrospective study included 33 eyes with diabetic retinopathy that underwent 577-nm PASCAL photocoagulation. Each retinal layer thickness, peripapillary RNFL thickness, and CMT were measured by spectral-domain optical coherence tomography before 577-nm PASCAL photocoagulation, as well as at 1, 6, and 12 months after 577-nm PASCAL photocoagulation. Computerized intraretinal segmentation of optical coherence tomography was performed to identify the thickness of each retinal layer. Results The average thickness of the RNFL, ganglion cell layer, inner plexiform layer, inner nuclear layer, inner retinal layer, and CMT at each follow-up increased significantly from baseline (p < 0.001), whereas that of the retinal pigment epithelium at each follow-up decreased significantly from baseline (p < 0.001). The average thickness of the peripapillary RNFL increased significantly at one month (p < 0.001). This thickness subsequently recovered to 7.48 µm, and there were no significant changes at six or 12 months compared to baseline (p > 0.05). Conclusions Each macular retinal layer and CMT had a tendency to increase for one year after 577-nm PASCAL photocoagulation, whereas the average thickness of retinal pigment epithelium decreased at one-year follow-up compared to the baseline. Although an increase in peripapillary RNFL thickness was observed one month after 577-nm PASCAL photocoagulation, there were no significant changes at the one-year follow-up compared to the baseline. PMID:29022292

Changes in Macular Retinal Layers and Peripapillary Nerve Fiber Layer Thickness after 577-nm Pattern Scanning Laser in Patients with Diabetic Retinopathy.

PubMed

Shin, Ji Soo; Lee, Young Hoon

2017-12-01

The aim of this study was to evaluate the changes in thickness of each macular retinal layer, the peripapillary retinal nerve fiber layer (RNFL), and central macular thickness (CMT) after 577-nm pattern scanning laser (PASCAL) photocoagulation in patients with diabetic retinopathy. This retrospective study included 33 eyes with diabetic retinopathy that underwent 577-nm PASCAL photocoagulation. Each retinal layer thickness, peripapillary RNFL thickness, and CMT were measured by spectral-domain optical coherence tomography before 577-nm PASCAL photocoagulation, as well as at 1, 6, and 12 months after 577-nm PASCAL photocoagulation. Computerized intraretinal segmentation of optical coherence tomography was performed to identify the thickness of each retinal layer. The average thickness of the RNFL, ganglion cell layer, inner plexiform layer, inner nuclear layer, inner retinal layer, and CMT at each follow-up increased significantly from baseline (p < 0.001), whereas that of the retinal pigment epithelium at each follow-up decreased significantly from baseline (p < 0.001). The average thickness of the peripapillary RNFL increased significantly at one month (p < 0.001). This thickness subsequently recovered to 7.48 μm, and there were no significant changes at six or 12 months compared to baseline (p > 0.05). Each macular retinal layer and CMT had a tendency to increase for one year after 577-nm PASCAL photocoagulation, whereas the average thickness of retinal pigment epithelium decreased at one-year follow-up compared to the baseline. Although an increase in peripapillary RNFL thickness was observed one month after 577-nm PASCAL photocoagulation, there were no significant changes at the one-year follow-up compared to the baseline. © 2017 The Korean Ophthalmological Society

Assessment of Adeno-Associated Virus Serotype Tropism in Human Retinal Explants.

PubMed

Wiley, Luke A; Burnight, Erin R; Kaalberg, Emily E; Jiao, Chunhua; Riker, Megan J; Halder, Jennifer A; Luse, Meagan A; Han, Ian C; Russell, Stephen R; Sohn, Elliott H; Stone, Edwin M; Tucker, Budd A; Mullins, Robert F

2018-04-01

Advances in the discovery of the causes of monogenic retinal disorders, combined with technologies for the delivery of DNA to the retina, offer enormous opportunities for the treatment of previously untreatable blinding diseases. However, for gene augmentation to be most effective, vectors that have the correct cell-type specificity are needed. While animal models are very useful, they often exhibit differences in retinal cell surface receptors compared to the human retina. This study evaluated the use of an ex vivo organotypic explant system to test the transduction efficiency and tropism of seven different adeno-associated virus type 2 (AAV2) serotypes in the human retina and retinal pigment epithelium-choroid-AAV2/1, AAV2/2, AAV2/4, AAV2/5, AAV2/6, AAV2/8, and AAV2/9-all driving expression of GFP under control of the cytomegalovirus promoter. After 7 days in culture, it was found that AAV2/4 and AAV2/5 were particularly efficient at transducing photoreceptor cells and that AAV2/5 was highly specific to the outer nuclear layer, whereas AAV2/8 displayed consistently low transduction of photoreceptors. To validate the authenticity of the organotypic culture system, the transduction of the same set of AAVs was also compared in a pig model, in which sub-retinal injections in vivo were compared to cultured and transduced organotypic cultures ex vivo. This study shows how different AAV serotypes behave in the human retina and provides insight for further investigation of each of these serotypes for gene augmentation-based treatment of inherited retinal degeneration.

Progressive outer retinal necrosis: manifestation of human immunodeficiency virus infection.

PubMed

Lo, Phey Feng; Lim, Rongxuan; Antonakis, Serafeim N; Almeida, Goncalo C

2015-05-06

We present the case of a 54-year-old man who developed progressive outer retinal necrosis (PORN) as an initial manifestation of HIV infection without any significant risk factors for infection with HIV. PORN is usually found as a manifestation of known AIDS late in the disease. Our patient presented with transient visual loss followed by decrease in visual acuity and facial rash. Subsequent investigation revealed anterior chamber tap positive for varicella zoster virus (VZV), as well as HIV positivity, with an initial CD4 count of 48 cells/µL. Systemic and intravitreal antivirals against VZV, and highly active antiretroviral therapy against HIV were started, which halted further progression of retinal necrosis. This case highlights the importance of suspecting PORN where there is a rapidly progressive retinitis, and also testing the patient for HIV, so appropriate treatment can be started. 2015 BMJ Publishing Group Ltd.

Progressive outer retinal necrosis: manifestation of human immunodeficiency virus infection

PubMed Central

Lo, Phey Feng; Lim, Rongxuan; Antonakis, Serafeim N; Almeida, Goncalo C

2015-01-01

We present the case of a 54-year-old man who developed progressive outer retinal necrosis (PORN) as an initial manifestation of HIV infection without any significant risk factors for infection with HIV. PORN is usually found as a manifestation of known AIDS late in the disease. Our patient presented with transient visual loss followed by decrease in visual acuity and facial rash. Subsequent investigation revealed anterior chamber tap positive for varicella zoster virus (VZV), as well as HIV positivity, with an initial CD4 count of 48 cells/µL. Systemic and intravitreal antivirals against VZV, and highly active antiretroviral therapy against HIV were started, which halted further progression of retinal necrosis. This case highlights the importance of suspecting PORN where there is a rapidly progressive retinitis, and also testing the patient for HIV, so appropriate treatment can be started. PMID:25948844

Pathological findings in retina and visual pathways associated to natural Scrapie in sheep.

PubMed

Hortells, Paloma; Monzón, Marta; Monleón, Eva; Acín, Cristina; Vargas, Antonia; Bolea, Rosa; Luján, Lluís; Badiola, Juan José

2006-09-07

This work represents a comprehensive pathological description of the retina and visual pathways in naturally affected Scrapie sheep. Twenty naturally affected Scrapie sheep and 6 matched controls were used. Eyes, optic nerves and brain from each animal were fixed and histologically processed using hematoxylin-eosin, followed by immunohistochemical staining for prion protein (PrPsc) and glial fibrillar acidic protein (GFAP). Retinal histopathological changes were observed in only 7 clinically affected animals and mainly consisted of loss of outer limitant layer definition, outer plexiform layer atrophy, disorganization and loss of nuclei in both nuclear layers, and Müller glia hypertrophy. PrPsc was detected in the retina of 19 of the 20 sheep and characterized by a disseminated granular deposit across layers and intraneuronally in ganglion cells. The inner plexiform and the ganglion cell layers were the structures most severely affected by PrPsc deposits. PrPsc exhibited a tendency to spread from these two layers to the others. A marked increase in the number and intensity of GFAP-expressing Müller cells was observed in the clinical stage, especially at the terminal stage of the disease. Spongiosis and PrPsc were detected within the visual pathways at the preclinical stage, their values increasing during the course of the disease but varying between the areas examined. PrPsc was detected in only 3 optic nerves. The results suggest that the presence of PrPsc in the retina correlates with disease progression during the preclinical and clinical stages, perhaps using the inner plexiform layer as a first entry site and diffusing from the brain using a centrifugal model.

Quantitative Analysis of Mouse Retinal Layers Using Automated Segmentation of Spectral Domain Optical Coherence Tomography Images

PubMed Central

Dysli, Chantal; Enzmann, Volker; Sznitman, Raphael; Zinkernagel, Martin S.

2015-01-01

Purpose Quantification of retinal layers using automated segmentation of optical coherence tomography (OCT) images allows for longitudinal studies of retinal and neurological disorders in mice. The purpose of this study was to compare the performance of automated retinal layer segmentation algorithms with data from manual segmentation in mice using the Spectralis OCT. Methods Spectral domain OCT images from 55 mice from three different mouse strains were analyzed in total. The OCT scans from 22 C57Bl/6, 22 BALBc, and 11 C3A.Cg-Pde6b+Prph2Rd2/J mice were automatically segmented using three commercially available automated retinal segmentation algorithms and compared to manual segmentation. Results Fully automated segmentation performed well in mice and showed coefficients of variation (CV) of below 5% for the total retinal volume. However, all three automated segmentation algorithms yielded much thicker total retinal thickness values compared to manual segmentation data (P < 0.0001) due to segmentation errors in the basement membrane. Conclusions Whereas the automated retinal segmentation algorithms performed well for the inner layers, the retinal pigmentation epithelium (RPE) was delineated within the sclera, leading to consistently thicker measurements of the photoreceptor layer and the total retina. Translational Relevance The introduction of spectral domain OCT allows for accurate imaging of the mouse retina. Exact quantification of retinal layer thicknesses in mice is important to study layers of interest under various pathological conditions. PMID:26336634

Constituents of Bile, Bilirubin and TUDCA, Protect Against Oxidative Stress-Induced Retinal Degeneration

PubMed Central

Oveson, Brian C.; Iwase, Takeshi; Hackett, Sean F.; Lee, Sun Young; Usui, Shinichi; Sedlak, Thomas W.; Snyder, Solomon H.; Campochiaro, Peter A.; Sung, Jennifer U.

2014-01-01

Two constituents of bile, bilirubin and tauroursodeoxycholic acid (TUDCA), have antioxidant activity. However, bilirubin can also cause damage to some neurons and glial cells, particularly immature neurons. In this study, we tested the effects of bilirubin and TUDCA in two models in which oxidative stress contributes to photoreceptor cell death, prolonged light exposure and rd10+/+ mice. In albino BALB/c mice, intraperitoneal (IP) injection of 5 mg/kg of bilirubin or 500 mg/kg of TUDCA prior to exposure to 5,000 lux of white light for 8 hours significantly reduced loss of rod and cone function assessed by electroretinograms (ERGs). Both treatments also reduced light-induced accumulation of superoxide radicals in the outer retina, rod cell death assessed by outer nuclear layer (ONL) thickness, and disruption of cone inner and outer segments. In rd10+/+ mice, IP injections of 5 or 50 mg/kg of bilirubin or 500 mg/kg of TUDCA every 3 days starting at postnatal day (P) 6, caused significant preservation of cone cell number and cone function at P50. Rods were not protected at P50, but both bilirubin and TUDCA provided modest preservation of ONL thickness and rod function at P30. These data suggest that correlation of serum bilirubin levels with rate of vision loss in patients with retinitis pigmentosa (RP) could provide a useful strategy to test the hypothesis that cones die from oxidative damage in patients with RP. If proof-of-concept is established, manipulation of bilirubin levels and administration of TUDCA could be tested in interventional trials. PMID:21054389

Differentiation of Swine iPSC into Rod Photoreceptors and Their Integration into the Retina

PubMed Central

Zhou, Liang; Wang, Wei; Liu, Yongqing; de Castro, Juan Fernandez; Ezashi, Toshihiko; Telugu, Bhanu Prakash V.L.; Roberts, R. Michael; Kaplan, Henry J.; Dean, Douglas C.

2014-01-01

Absence of a regenerative pathway for damaged retina following injury or disease has led to experiments utilizing stem cell transplantation for retinal repair, and encouraging results have been obtained in rodents. The swine eye is a closer anatomical and physiological match to the human eye, but embryonic stem cells have not been isolated from pig, and photoreceptor differentiation has not been demonstrated with swine induced pluripotent stem cells (iPSC). Here, we subjected swine iPSC to a rod photoreceptor differentiation protocol consisting of floating culture as embryoid bodies followed by differentiation in adherent culture. Real time PCR and immunostaining of differentiated cells demonstrated loss of expression of the pluripotent genes POU5F1, NANOG and SOX2 and induction of rod photoreceptor genes RCVRN, NRL, RHO and ROM1. While these differentiated cells displayed neuronal morphology, culturing on a Matrigel substratum triggered a further morphological change resulting in concentration of RHO and ROM1 in outer segment-like projections resembling those on primary cultures of rod photoreceptors. The differentiated cells were transplanted into the subretinal space of pigs treated with iodoacetic acid to eliminate rod photoreceptors. Three weeks after transplantation, engrafted RHO+ cells were evident in the outer nuclear layer where photoreceptors normally reside. A portion of these transplanted cells had generated projections resembling outer segments. These results demonstrate that swine iPSC can differentiate into photoreceptors in culture and these cells can integrate into the damaged swine neural retina thus laying a foundation for future studies using the pig as a model for retinal stem cell transplantation. PMID:21491544

Comparative study of the retinal nerve fibre layer thickness performed with optical coherence tomography and GDx scanning laser polarimetry in patients with primary open-angle glaucoma.

PubMed

Wasyluk, Jaromir T; Jankowska-Lech, Irmina; Terelak-Borys, Barbara; Grabska-Liberek, Iwona

2012-03-01

We compared the parameters of retinal nerve fibre layer in patients with advanced glaucoma with the use of different OCT (Optical Coherence Tomograph) devices in relation to analogical measurements performed with GDx VCC (Nerve Fiber Analyzer with Variable Corneal Compensation) scanning laser polarimetry. Study subjects had advanced primary open-angle glaucoma, previously treated conservatively, diagnosed and confirmed by additional examinations (visual field, ophthalmoscopy of optic nerve, gonioscopy), A total of 10 patients were enrolled (9 women and 1 man), aged 18-70 years of age. Nineteen eyes with advanced glaucomatous neuropathy were examined. 1) Performing a threshold perimetry Octopus, G2 strategy and ophthalmoscopy of optic nerve to confirm the presence of advanced primary open-angle glaucoma; 2) performing a GDx VCC scanning laser polarimetry of retinal nerve fibre layer; 3) measuring the retinal nerve fibre layer thickness with 3 different optical coherence tomographs. The parameters of the retinal nerve fibre layer thickness are highly correlated between the GDx and OCT Stratus and 3D OCT-1000 devices in mean retinal nerve fibre layer thickness, retinal nerve fibre layer thickness in the upper sector, and correlation of NFI (GDx) with mean retinal nerve fibre layer thickness in OCT examinations. Absolute values of the retinal nerve fibre layer thickness (measured in µm) differ significantly between GDx and all OCT devices. Examination with OCT devices is a sensitive diagnostic method of glaucoma, with good correlation with the results of GDx scanning laser polarimetry of the patients.

Review of the mechanisms and therapeutic avenues for retinal and choroidal vascular dysfunctions in retinopathy of prematurity.

PubMed

Rivera, José Carlos; Madaan, Ankush; Zhou, Tianwei Ellen; Chemtob, Sylvain

2016-12-01

Retinopathy of prematurity (ROP) is a multifactorial disease and the main cause of visual impairment and blindness in premature neonates. The inner retina has been considered the primary region affected in ROP, but choroidal vascular degeneration and progressive outer retinal dysfunctions have also been observed. This review focuses on observations regarding neurovascular dysfunctions in both the inner and outer immature retina, the mechanisms and the neuronal-derived factors implicated in the development of ROP, as well potential therapeutic avenues for this disorder. Alterations in the neurovascular integrity of the inner and outer retina contribute to the development of ROP. ©2016 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.

Characterization of an Early-Onset, Autosomal Recessive, Progressive Retinal Degeneration in Bengal Cats.

PubMed

Ofri, Ron; Reilly, Christopher M; Maggs, David J; Fitzgerald, Paul G; Shilo-Benjamini, Yael; Good, Kathryn L; Grahn, Robert A; Splawski, Danielle D; Lyons, Leslie A

2015-08-01

A form of retinal degeneration suspected to be hereditary was discovered in a family of Bengal cats. A breeding colony was established to characterize disease progression clinically, electrophysiologically, and morphologically, and to investigate the mode of inheritance. Affected and related cats were donated by owners for breeding trials and pedigree analysis. Kittens from test and complementation breedings underwent ophthalmic and neuro-ophthalmic examinations and ERG, and globes were evaluated using light microscopy. Pedigree analysis, along with test and complementation breedings, indicated autosomal recessive inheritance and suggested that this disease is nonallelic to a retinal degeneration found in Persian cats. Mutation analysis confirmed the disease is not caused by CEP290 or CRX variants found predominantly in Abyssinian and Siamese cats. Ophthalmoscopic signs of retinal degeneration were noted at 9 weeks of age and became more noticeable over the next 4 months. Visual deficits were behaviorally evident by 1 year of age. Electroretinogram demonstrated reduced rod and cone function at 7 and 9 weeks of age, respectively. Rod responses were mostly extinguished at 14 weeks of age; cone responses were minimal by 26 weeks. Histologic degeneration was first observed at 8 weeks, evidenced by reduced photoreceptor numbers, then rapid deterioration of the photoreceptor layer and, subsequently, severe outer retinal degeneration. A recessively inherited primary photoreceptor degeneration was characterized in the Bengal cat. The disease is characterized by early onset, with histologic, ophthalmoscopic, and electrophysiological signs evident by 2 months of age, and rapid progression to blindness.

ON-retinal bipolar cell survival in RCS rats.

PubMed

Zhang, Chen Xing; Yin, Zheng Qin; Chen, Li-Feng; Weng, Chuang-Huang; Zeng, Yu-Xiao

2010-11-01

In retinitis pigmentosa (RP), the slow and progressive death of inner retinal neurons is thought to be inevitable after the death of photoreceptors. However, even in the advanced stage of RP, all inner retinal neurons are not completely lost. The morphological and electrophysiological modifications in ON-retinal bipolar cells (ON-RBCs) of Royal College of Surgeons (RCS) rats (RCS-ON-RBCs) were investigated to elucidate the mechanisms of survival of RCS-ON-RBCs in RP. Control (CTR) and RCS rats were divided into age groups according to postnatal stage: postnatal day 21 (Pn21d), postnatal day 30 (Pn30d), postnatal day 60 (Pn60d), and postnatal day 90 (Pn90d). Lucifer yellow staining of single ON-RBCs and double-immunofluorescence of the retinal frozen sections were used to detect the morphological modifications and loss of RCS-ON-RBCs in different retinal regions. The whole-cell patch clamping technique was used to record the electrophysiological properties of ON-RBCs. There was a significant loss of RCS-ON-RBCs compared with CTR (p < 0.01) at Pn60d. Loss of the RCS-ON-RBCs differed by region. From Pn60d onwards, the loss was more severe in the peripheral retinal regions (p < 0.01). From Pn21d, the ectopic neurites from the RCS-ON-RBCs reached the outer and inner nuclear layers. At Pn60d, terminal branches of RCS-ON-RBCs axons vanished and ectopic neurites from the RCS-ON-RBCs became entwined. The resting membrane potential, input resistance and outward membrane current amplitude of RCS-ON-RBCs were significantly higher than those of the ON-RBCs of CTR rats at Pn60d (p < 0.05). Our results indicate that more RCS-ON-RBCs survived in the central retinal area near cone clusters, potentially as a result of ectopic neuritis. Meanwhile the surviving RCS-ON-RBCs remained immature and had no normal electrophysiological characteristics.

Nuclear Receptor Rev-erb Alpha (Nr1d1) Functions in Concert with Nr2e3 to Regulate Transcriptional Networks in the Retina

PubMed Central

Mollema, Nissa J.; Yuan, Yang; Jelcick, Austin S.; Sachs, Andrew J.; von Alpen, Désirée; Schorderet, Daniel; Escher, Pascal; Haider, Neena B.

2011-01-01

The majority of diseases in the retina are caused by genetic mutations affecting the development and function of photoreceptor cells. The transcriptional networks directing these processes are regulated by genes such as nuclear hormone receptors. The nuclear hormone receptor gene Rev-erb alpha/Nr1d1 has been widely studied for its role in the circadian cycle and cell metabolism, however its role in the retina is unknown. In order to understand the role of Rev-erb alpha/Nr1d1 in the retina, we evaluated the effects of loss of Nr1d1 to the developing retina and its co-regulation with the photoreceptor-specific nuclear receptor gene Nr2e3 in the developing and mature retina. Knock-down of Nr1d1 expression in the developing retina results in pan-retinal spotting and reduced retinal function by electroretinogram. Our studies show that NR1D1 protein is co-expressed with NR2E3 in the outer neuroblastic layer of the developing mouse retina. In the adult retina, NR1D1 is expressed in the ganglion cell layer and is co-expressed with NR2E3 in the outer nuclear layer, within rods and cones. Several genes co-targeted by NR2E3 and NR1D1 were identified that include: Nr2c1, Recoverin, Rgr, Rarres2, Pde8a, and Nupr1. We examined the cyclic expression of Nr1d1 and Nr2e3 over a twenty-four hour period and observed that both nuclear receptors cycle in a similar manner. Taken together, these studies reveal a novel role for Nr1d1, in conjunction with its cofactor Nr2e3, in regulating transcriptional networks critical for photoreceptor development and function. PMID:21408158

Induction of blindness by formoguanamine hydrochloride in adult male roseringed parakeets (Psittacula krameri).

PubMed

Sengupta, Anamika; Obara, Yoshihiko; Banerji, Tapan K; Maitra, Saumen K

2002-12-01

Formoguanamine (2,4-diamino-s-triazine) was known to be an effective chemical agent in inducing blindness in poultry chicks, but not in adult birds. The present study was undertaken to demonstrate the influences, if any, of this chemical on the visual performance and retinal histology in an adult sub-tropical wild bird the roseringed parakeet (Psittacula krameri). Formoguanamine (FG) hydrochloride was subcutaneously injected into adult parakeets at the dosage of 25 mg (dissolved in 0.75 ml physiological saline)/100 g body weight/day, for two consecutive days while the control birds were injected only with the placebo. The effects were studied after 10, 20, and 30 days of the last treatment of FG. Within 24 h of the treatment of FG, about 90% of the total birds exhibited lack of visual responses to any light stimulus and even absence of pupillary light reactions. The remaining birds became totally blind on the day following the last injection of FG and remained so till the end of investigation. At the microscopic level, conspicuous degenerative changes were noted in the outer pigmented epithelium and the photoreceptive layer of rods and cones in the retinas of FG treated birds. A significant reduction in the thickness of the outer nuclear layer was also found in the retinas of FG treated parakeets, compared to that in the control birds. However, the inner cell layers of the retina in the control and FG administered parakeets were almost identical. It deserves special mention that the effects of FG, noted after 30 days of last treatment, were not very different from those noted just after 10 days of treatment. Collectively, the results of the present investigation demonstrate that FG can be used as a potent pharmacological agent for inducing irreversible blindness through selective damage in retinal tissue even in the adult wild bird, thereby making FG treatment an alternative euthanasic device to a cumbersome, stressful, surgical method of enucleation of the ocular system for laboratory studies.

[Sulfhydryl group distribution along the axis of the rod outer segment in the frog].

PubMed

Derevianchenko, T G; Fedorovich, I B; Ostrovskiĭ, M A

1985-10-01

The existence of SH-group concentration axial gradient in frog's retinal rod outer segments has been shown. A diminution of SH-groups in the outer segment apical part points to a damage of the vision pigment during the life span of the rod disks.

Microstructural abnormalities in MEWDS demonstrated by ultrahigh resolution optical coherence tomography.

PubMed

Nguyen, My Hanh T; Witkin, Andre J; Reichel, Elias; Ko, Tony H; Fujimoto, James G; Schuman, Joel S; Duker, Jay S

2007-01-01

Histopathological studies of acute multiple evanescent white dot syndrome (MEWDS) have not been reported because of the transient and benign nature of the disease. Ultrahigh resolution optical coherence tomography (UHR-OCT), capable of high resolution in vivo imaging, offers a unique opportunity to visualize retinal microstructure in the disease. UHR-OCT images of the maculae of five patients with MEWDS were obtained and analyzed. Diagnosis was based on clinical presentation, examination, visual field testing, and angiography. UHR-OCT revealed disturbances in the photoreceptor inner/outer segment junction (IS/OS) in each of the five patients (six eyes) with MEWDS. In addition, thinning of the outer nuclear layer was seen in the case of recurrent MEWDS, suggesting that repeated episodes of MEWDS may result in photoreceptor atrophy. Subtle disruptions of the photoreceptor IS/OS are demonstrated in all eyes affected by MEWDS. UHR-OCT may be a useful adjunct to diagnosis and monitoring of MEWDS.

Retinal nerve fiber layer thickness and neuropsychiatric manifestations in systemic lupus erythematosus.

PubMed

Shulman, S; Shorer, R; Wollman, J; Dotan, G; Paran, D

2017-11-01

Background Cognitive impairment is frequent in systemic lupus erythematosus. Atrophy of the corpus callosum and hippocampus have been reported in patients with systemic lupus erythematosus, and diffusion tensor imaging studies have shown impaired white matter integrity, suggesting that white matter damage in systemic lupus erythematosus may underlie the cognitive impairment as well as other neuropsychiatric systemic lupus erythematosus manifestations. Retinal nerve fiber layer thickness, as assessed by optical coherence tomography, has been suggested as a biomarker for white matter damage in neurologic disorders such as multiple sclerosis, Alzheimer's disease and Parkinson's disease. Retinal nerve fiber layer thinning may occur early, even in patients with mild clinical symptoms. Aim The objective of this study was to assess the association of retinal nerve fiber layer thickness, as a biomarker of white matter damage in systemic lupus erythematosus patients, with neuropsychiatric systemic lupus erythematosus manifestations, including cognitive impairment. Methods Twenty-one consecutive patients with systemic lupus erythematosus underwent neuropsychological testing using a validated computerized battery of tests as well as the Rey-Auditory verbal learning test. All 21 patients, as well as 11 healthy, age matched controls, underwent optical coherence tomography testing to assess retinal nerve fiber layer thickness. Correlations between retinal nerve fiber layer thickness and results in eight cognitive domains assessed by the computerized battery of tests as well as the Rey-Auditory verbal learning test were assessed in patients with systemic lupus erythematosus, with and without neuropsychiatric systemic lupus erythematosus, and compared to retinal nerve fiber layer thickness in healthy controls. Results No statistically significant correlation was found between retinal nerve fiber layer thickness in patients with systemic lupus erythematosus as compared to healthy controls. When evaluating by subgroups, no correlation was found between patients with or without neuropsychiatric systemic lupus erythematosus or cognitive impairment and retinal nerve fiber layer thickness. Conclusion Retinal nerve fiber layer thickness of systemic lupus erythematosus patients was not found to be statistically different compared to controls. Within systemic lupus erythematosus patients there was no correlation between retinal nerve fiber layer thickness and cognitive impairment or other neuropsychiatric systemic lupus erythematosus manifestations.

RefMoB, a Reflectivity Feature Model-Based Automated Method for Measuring Four Outer Retinal Hyperreflective Bands in Optical Coherence Tomography

PubMed Central

Ross, Douglas H.; Clark, Mark E.; Godara, Pooja; Huisingh, Carrie; McGwin, Gerald; Owsley, Cynthia; Litts, Katie M.; Spaide, Richard F.; Sloan, Kenneth R.; Curcio, Christine A.

2015-01-01

Purpose. To validate a model-driven method (RefMoB) of automatically describing the four outer retinal hyperreflective bands revealed by spectral-domain optical coherence tomography (SDOCT), for comparison with histology of normal macula; to report thickness and position of bands, particularly band 2 (ellipsoid zone [EZ], commonly called IS/OS). Methods. Foveal and superior perifoveal scans of seven SDOCT volumes of five individuals aged 28 to 69 years with healthy maculas were used (seven eyes for validation, five eyes for measurement). RefMoB determines band thickness and position by a multistage procedure that models reflectivities as a summation of Gaussians. Band thickness and positions were compared with those obtained by manual evaluators for the same scans, and compared with an independent published histological dataset. Results. Agreement among manual evaluators was moderate. Relative to manual evaluation, RefMoB reported reduced thickness and vertical shifts in band positions in a band-specific manner for both simulated and empirical data. In foveal and perifoveal scans, band 1 was thick relative to the anatomical external limiting membrane, band 2 aligned with the outer one-third of the anatomical IS ellipsoid, and band 3 (IZ, interdigitation of retinal pigment epithelium and photoreceptors) was cleanly delineated. Conclusions. RefMoB is suitable for automatic description of the location and thickness of the four outer retinal hyperreflective bands. Initial results suggest that band 2 aligns with the outer ellipsoid, thus supporting its recent designation as EZ. Automated and objective delineation of band 3 will help investigations of structural biomarkers of dark-adaptation changes in aging. PMID:26132776

Laser-induced retinal damage thresholds for annular retinal beam profiles

NASA Astrophysics Data System (ADS)

Kennedy, Paul K.; Zuclich, Joseph A.; Lund, David J.; Edsall, Peter R.; Till, Stephen; Stuck, Bruce E.; Hollins, Richard C.

2004-07-01

The dependence of retinal damage thresholds on laser spot size, for annular retinal beam profiles, was measured in vivo for 3 μs, 590 nm pulses from a flashlamp-pumped dye laser. Minimum Visible Lesion (MVL)ED50 thresholds in rhesus were measured for annular retinal beam profiles covering 5, 10, and 20 mrad of visual field; which correspond to outer beam diameters of roughly 70, 160, and 300 μm, respectively, on the primate retina. Annular beam profiles at the retinal plane were achieved using a telescopic imaging system, with the focal properties of the eye represented as an equivalent thin lens, and all annular beam profiles had a 37% central obscuration. As a check on experimental data, theoretical MVL-ED50 thresholds for annular beam exposures were calculated using the Thompson-Gerstman granular model of laser-induced thermal damage to the retina. Threshold calculations were performed for the three experimental beam diameters and for an intermediate case with an outer beam diameter of 230 μm. Results indicate that the threshold vs. spot size trends, for annular beams, are similar to the trends for top hat beams determined in a previous study; i.e., the threshold dose varies with the retinal image area for larger image sizes. The model correctly predicts the threshold vs. spot size trends seen in the biological data, for both annular and top hat retinal beam profiles.

Axonal loss from acute optic neuropathy documented by scanning laser polarimetry

PubMed Central

Meier, F M; Bernasconi, P; Stürmer, J; Caubergh, M-J; Landau, K

2002-01-01

Background/aims: Retinal nerve fibre layer analysis by scanning laser polarimetry has been shown to facilitate diagnosis of glaucoma while its role in glaucoma follow up is still unclear. A major difficulty is the slow reduction of retinal nerve fibre layer thickness in glaucomatous optic neuropathy. Eyes of patients were studied after acute retrobulbar optic nerve lesion in order to evaluate the usefulness of scanning laser polarimetry in documenting retinal nerve fibre layer loss over time. Methods: Five patients who suffered severe retrobulbar optic neuropathy have had repeated measurements of the retinal nerve fibre layer using scanning laser polarimetry at various intervals, the first examination being within 1 week of injury. Results: All eyes showed a marked decrease in peripapillary retinal nerve fibre layer thickness, which followed an exponential curve and occurred predominantly within 8 weeks of injury. Compared to a previous study using red-free photographs, scanning laser polarimetry showed retinal nerve fibre layer loss earlier in the course of descending atrophy. Conclusion: Scanning laser polarimetry is useful for early detection and documentation of retinal nerve fibre layer loss following acute injury to the retrobulbar optic nerve. It seems to be a promising tool for follow up of individual glaucoma patients. PMID:11864884

Impairment of photoreceptor ribbon synapses in a novel Pomt1 conditional knockout mouse model of dystroglycanopathy.

PubMed

Rubio-Fernández, Marcos; Uribe, Mary Luz; Vicente-Tejedor, Javier; Germain, Francisco; Susín-Lara, Cristina; Quereda, Cristina; Montoliu, Lluis; de la Villa, Pedro; Martín-Nieto, José; Cruces, Jesús

2018-06-04

Hypoglycosylation of α-dystroglycan (α-DG) resulting from deficiency of protein O-mannosyltransferase 1 (POMT1) may cause severe neuromuscular dystrophies with brain and eye anomalies, named dystroglycanopathies. The retinal involvement of these disorders motivated us to generate a conditional knockout (cKO) mouse experiencing a Pomt1 intragenic deletion (exons 3-4) during the development of photoreceptors, mediated by the Cre recombinase expressed from the cone-rod homeobox (Crx) gene promoter. In this mouse, retinal α-DG was unglycosylated and incapable of binding laminin. Retinal POMT1 deficiency caused significant impairments in both electroretinographic recordings and optokinetic reflex in Pomt1 cKO mice, and immunohistochemical analyses revealed the absence of β-DG and of the α-DG-interacting protein, pikachurin, in the outer plexiform layer (OPL). At the ultrastructural level, noticeable alterations were observed in the ribbon synapses established between photoreceptors and bipolar cells. Therefore, O-mannosylation of α-DG in the retina carried out by POMT1 is crucial for the establishment of proper synapses at the OPL and transmission of visual information from cones and rods to their postsynaptic neurons.

Effect of green light spectra on the reduction of retinal damage and stress in goldfish, Carassius auratus.

PubMed

Song, Jin Ah; Kim, Na Na; Choi, Young Jae; Choi, Cheol Young

2016-07-22

We investigated the effect of light spectra on retinal damage and stress in goldfish using green (530 nm) and red (620 nm) light emitting diodes (LEDs) at three intensities each (0.5, 1.0, and 1.5 W/m(2)). We measured the change in the levels of plasma cortisol and H2O2 and expression and levels of caspase-3. The apoptotic response of green and red LED spectra was assessed using the terminal transferase dUTP nick end labeling (TUNEL) assay. Stress indicator (cortisol and H2O2) and apoptosis-related genes (caspase-3) decreased in green light, but increased in red light with higher light intensities over time. The TUNEL assay revealed that more apoptotic cells were detected in outer nuclear layers after exposure to red LED over time with the increase in light intensity, than the other spectra. These results indicate that green light efficiently reduces retinal damage and stress, whereas red light induces it. Therefore, red light-induced retina damage may induce apoptosis in goldfish retina. Copyright © 2016 Elsevier Inc. All rights reserved.

The photoreceptor cell-specific nuclear receptor gene (PNR) accounts for retinitis pigmentosa in the Crypto-Jews from Portugal (Marranos), survivors from the Spanish Inquisition.

PubMed

Gerber, S; Rozet, J M; Takezawa, S I; dos Santos, L C; Lopes, L; Gribouval, O; Penet, C; Perrault, I; Ducroq, D; Souied, E; Jeanpierre, M; Romana, S; Frézal, J; Ferraz, F; Yu-Umesono, R; Munnich, A; Kaplan, J

2000-09-01

The last Crypto-Jews (Marranos) are the survivors of Spanish Jews who were persecuted in the late fifteenth century, escaped to Portugal and were forced to convert to save their lives. Isolated groups still exist in mountainous areas such as Belmonte in the Beira-Baixa province of Portugal. We report here the genetic study of a highly consanguineous endogamic population of Crypto-Jews of Belmonte affected with autosomal recessive retinitis pigmentosa (RP). A genome-wide search for homozygosity allowed us to localize the disease gene to chromosome 15q22-q24 (Zmax=2.95 at theta=0 at the D15S131 locus). Interestingly, the photoreceptor cell-specific nuclear receptor (PNR) gene, the expression of which is restricted to the outer nuclear layer of retinal photoreceptor cells, was found to map to the YAC contig encompassing the disease locus. A search for mutations allowed us to ascribe the RP of Crypto-Jews of Belmonte to a homozygous missense mutation in the PNR gene. Preliminary haplotype studies support the view that this mutation is relatively ancient but probably occurred after the population settled in Belmonte.

Comparative study of the retinal nerve fibre layer thickness performed with optical coherence tomography and GDx scanning laser polarimetry in patients with primary open-angle glaucoma

PubMed Central

Wasyluk, Jaromir T.; Jankowska-Lech, Irmina; Terelak-Borys, Barbara; Grabska-Liberek, Iwona

2012-01-01

Summary Background We compared the parameters of retinal nerve fibre layer in patients with advanced glaucoma with the use of different OCT (Optical Coherence Tomograph) devices in relation to analogical measurements performed with GDx VCC (Nerve Fiber Analyzer with Variable Corneal Compensation) scanning laser polarimetry. Material/Methods Study subjects had advanced primary open-angle glaucoma, previously treated conservatively, diagnosed and confirmed by additional examinations (visual field, ophthalmoscopy of optic nerve, gonioscopy), A total of 10 patients were enrolled (9 women and 1 man), aged 18–70 years of age. Nineteen eyes with advanced glaucomatous neuropathy were examined. 1) Performing a threshold perimetry Octopus, G2 strategy and ophthalmoscopy of optic nerve to confirm the presence of advanced primary open-angle glaucoma; 2) performing a GDx VCC scanning laser polarimetry of retinal nerve fibre layer; 3) measuring the retinal nerve fibre layer thickness with 3 different optical coherence tomographs. Results The parameters of the retinal nerve fibre layer thickness are highly correlated between the GDx and OCT Stratus and 3D OCT-1000 devices in mean retinal nerve fibre layer thickness, retinal nerve fibre layer thickness in the upper sector, and correlation of NFI (GDx) with mean retinal nerve fibre layer thickness in OCT examinations. Absolute values of the retinal nerve fibre layer thickness (measured in μm) differ significantly between GDx and all OCT devices. Conclusions Examination with OCT devices is a sensitive diagnostic method of glaucoma, with good correlation with the results of GDx scanning laser polarimetry of the patients. PMID:22367131

Immunocytochemical localization of the NMDA-R2A receptor subunit in the cat retina.

PubMed

Goebel, D J; Aurelia, J L; Tai, Q; Jojich, L; Poosch, M S

1998-10-19

Immunocytochemical studies were performed to determine the distribution and cellular localization of the NMDA-R2A receptor subunit (R2A) in the cat retina. R2A-immunoreactivity (R2A-IR) was noted in all layers of the retina, with specific localizations in the outer segments of red/green and blue cone photoreceptors, B-type horizontal cells, several types of amacrine cells, Müller cells and the majority of cells in the ganglion cell layer. In the inner nuclear layer, 48% of all cells residing in the amacrine cell layer were R2A-IR including a cell resembling the GABAergic A17 amacrine cell. Interestingly, the AII rod amacrine cell was devoid of R2A-IR. Although the localization of the R2A subunit was anticipated in ganglion cells, amacrines and Müller cells, the presence of this receptor subunit to the cells in the outer retina was not expected. Here, both the R2A and the R2B subunits were found to be present in the outer segments of cone photoreceptors and to the tips of rod outer segments. Although the function of these receptor subunits in rod and cone photoreceptors remains to be determined, the fact that both R2A and R2B receptor subunits are localized to cone outer segments suggests a possible alternative pathway for calcium entry into a region where this cation plays such a crucial role in the process of phototransduction. To further classify the cells that display NR2A-IR, we performed dual labeling experiments showing the relationship between R2A-labeled cells with GABA. Results showed that all GABAergic-amacrines and displaced amacrines express the R2A-subunit protein. In addition, approximately 11% of the NR2A-labeled amacrines, did not stain for GABA. These findings support pharmacological data showing that NMDA directly facilitates GABA release in retina and retinal cultures [I.L. Ferreira, C.B. Duarte, P.F. Santos, C.M. Carvalho, A.P. Carvalho, Release of [3H]GABA evoked by glutamate receptor agonist in cultured chick retinal cells: effect of Ca2+, Brain Res. 664 (1994) 252-256; G.D. Zeevalk, W.J. Nicklas, Action of the anti-ischemic agent ifenprodil on N-methyl-d-aspartate and kainate-mediated excitotoxicity, Brain Res. 522 (1990) 135-139; R. Huba, H.D. Hofmann, Transmitter-gated currents of GABAergic amacrine-like cells in chick retinal cultures, Vis. Neurosci. 6 (1991) 303-314; M. Yamashita, R. Huba, H.D. Hofmann, Early in vitro development of voltage- and transmitter-gated currents in GABAergic amacrine cells, Dev. Brain Res. 82 (1994) 95-102; R. Ientile, S. Pedale, V. Picciurro, V. Macaione, C. Fabiano, S. Macaione, Nitric oxide mediates NMDA-evoked [3H]GABA release from chick retina cells, FEBS Lett. 417 (1997) 345-348; R.C. Kubrusly, M.C. deMello, F.G. deMello, Aspartate as a selective NMDA agonist in cultured cells from the avian retina, Neurochem. Intl. 32 (1998) 47-52] or reduction of GABA in vivo [N.N. Osborn, A.J. Herrera, The effect of experimental ischaemia and excitatory amino acid agonist on the GABA and serotonin immunoreactivities in the rabbit retina, Neurosci. 59 (1994) 1071-1081]. Since the majority of GABAergic synapses in the inner retina are onto both rod and cone bipolar axon terminals [R.G. Pourcho, M.T. Owzcarzak, Distribution of GABA immunoreactivity in the cat retina: A light and electron-microscopic study, Vis. Neurosci. 2 (1989) 425-435], we hypothesize that the NMDA-receptor plays a crucial role in providing feedback inhibition onto rod and cone bipolar cells. Copyright 1998 Elsevier Science B.V.

Developing rods transplanted into the degenerating retina of Crx-knockout mice exhibit neural activity similar to native photoreceptors

PubMed Central

Homma, Kohei; Okamoto, Satoshi; Mandai, Michiko; Gotoh, Norimoto; Rajasimha, Harsha K.; Chang, Yi-Sheng; Chen, Shan; Li, Wei; Cogliati, Tiziana; Swaroop, Anand; Takahashi, Masayo

2013-01-01

Replacement of dysfunctional or dying photoreceptors offers a promising approach for retinal neurodegenerative diseases, including age-related macular degeneration and retinitis pigmentosa. Several studies have demonstrated the integration and differentiation of developing rod photoreceptors when transplanted in wild type or degenerating retina; however, the physiology and function of the donor cells are not adequately defined. Here, we describe the physiological properties of developing rod photoreceptors that are tagged with GFP driven by the promoter of rod differentiation factor, Nrl. GFP-tagged developing rods show Ca2+ responses and rectifier outward currents that are smaller than those observed in fully developed photoreceptors, suggesting their immature developmental state. These immature rods also exhibit hyperpolarization-activated current (Ih) induced by the activation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. When transplanted into the subretinal space of wild type or retinal degeneration mice, GFP-tagged developing rods can integrate into the photoreceptor outer nuclear layer in wild-type mouse retina, and exhibit Ca2+ responses and membrane current comparable to native rod photoreceptors. A proportion of grafted rods develop rhodopsin-positive outer segment-like structures within two weeks after transplantation into the retina of Crx-knockout mice, and produce rectifier outward current and Ih upon membrane depolarization and hyperpolarization. GFP-positive rods derived from induced pluripotent stem (iPS) cells also display similar membrane current Ih as native developing rod photoreceptors, express rod-specific phototransduction genes, and HCN-1 channels. We conclude that Nrl-promoter driven GFP-tagged donor photoreceptors exhibit physiological characteristics of rods and that iPS cell-derived rods in vitro may provide a renewable source for cell replacement therapy. PMID:23495178

Cone structure in patients with usher syndrome type III and mutations in the Clarin 1 gene.

PubMed

Ratnam, Kavitha; Västinsalo, Hanna; Roorda, Austin; Sankila, Eeva-Marja K; Duncan, Jacque L

2013-01-01

To study macular structure and function in patients with Usher syndrome type III (USH3) caused by mutations in the Clarin 1 gene (CLRN1). High-resolution macular images were obtained by adaptive optics scanning laser ophthalmoscopy and spectral domain optical coherence tomography in 3 patients with USH3 and were compared with those of age-similar control subjects. Vision function measures included best-corrected visual acuity, kinetic and static perimetry, and full-field electroretinography. Coding regions of the CLRN1 gene were sequenced. CLRN1 mutations were present in all the patients; a 20-year-old man showed compound heterozygous mutations (p.N48K and p.S188X), and 2 unrelated women aged 25 and 32 years had homozygous mutations (p.N48K). Best-corrected visual acuity ranged from 20/16 to 20/40, with scotomas beginning at 3° eccentricity. The inner segment-outer segment junction or the inner segment ellipsoid band was disrupted within 1° to 4° of the fovea, and the foveal inner and outer segment layers were significantly thinner than normal. Cones near the fovea in patients 1 and 2 showed normal spacing, and the preserved region ended abruptly. Retinal pigment epithelial cells were visible in patient 3 where cones were lost. Cones were observed centrally but not in regions with scotomas, and retinal pigment epithelial cells were visible in regions without cones in patients with CLRN1 mutations. High-resolution measures of retinal structure demonstrate patterns of cone loss associated with CLRN1 mutations. These findings provide insight into the effect of CLRN1 mutations on macular cone structure, which has implications for the development of treatments for USH3. clinicaltrials.gov Identifier: NCT00254605.

Ultra-Wide-Field Fundus Autofluorescence and Spectral-Domain Optical Coherence Tomography Findings in Syphilitic Outer Retinitis.

PubMed

Saleh, Mohamed G A; Campbell, John Peter; Yang, Paul; Lin, Phoebe

2017-03-01

To determine the ultra-wide-field fundus autofluorescence (UWFFAF) and optical coherence tomography (OCT) features of syphilitic outer retinopathy (SOR). Retrospective chart review. Three patients with SOR were investigated. Treatment with parenteral penicillin led to improvement of outer retinopathy, visual acuity, and symptoms. UWFFAF showed speckled hyperautofluorescence, hypoautofluorescence, and normal autofluorescence, similar to what has been described as a trizonal pattern in acute zonal occult outer retinopathy (AZOOR) in the chronic case of SOR, but with hyperautofluorescent areas in the two acute cases. OCT showed disruption of the photoreceptor outer segment ellipsoid zone and external limiting membrane, which improved after penicillin treatment, and corresponded to normalization of the hyperautofluorescent areas on UWFFAF. There was irregularity and nodular thickening of retinal pigment epithelium on OCT in areas of mottled hyperautofluorescence. SOR can present similarly to AZOOR on UWFFAF and should be highly suspected in cases presenting like AZOOR. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:208-215. ]. Copyright 2017, SLACK Incorporated.

Thioredoxin plays a key role in retinal neuropathy prior to endothelial damage in diabetic mice

PubMed Central

Ren, Xiang; Li, Chen; Liu, Junli; Zhang, Chenghong; Fu, Yuzhen; Wang, Nina; Ma, Haiying; Lu, Heyuan; Kong, Hui; Kong, Li

2017-01-01

Diabetes is a chronic metabolic syndrome that results in changes in carbohydrate, lipid and protein metabolism. With diabetes for a long time, it increases the risk of diabetic retinopathy (DR) and long-term morbidity and mortality. Moreover, emerging evidence suggests that neuron damage occurs earlier than microvascular complications in DR patients, but the underlying mechanism is unclear. We investigated diabetes-induced retinal neuropathy and elucidated key molecular events to identify new therapeutic targets for the clinical treatment and prevention of DR. For in vivo studies, a high-fat diet and streptozotocin (STZ) injection were used to generate the diabetes model. Hematoxylin-eosin staining was used for morphological observations and measurements of the outer nuclear layer thickness. Electroretinography (ERG) was used to assess retinal function. For in vitro studies, Neuro2a cells were incubated in normal (5.5 mM) and high-glucose (30 mM) conditions. Flow cytometry assays were performed to analyze apoptosis. Additionally, real-time PCR and Western blotting analyses were carried out to determine gene and protein expression in vitro and in vivo. Taken together, the results indicated that retinal neuropathy occurred prior to endothelial damage induced by diabetes, and thioredoxin (Trx) plays a key role in this process. This underlying mechanism may be related to activation of the Trx/ASK1/p-p38/Trx-interacting protein pathway. PMID:28977868

Effect of green light spectra on the reduction of retinal damage and stress in goldfish, Carassius auratus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Song, Jin Ah; Kim, Na Na; Choi, Young Jae

We investigated the effect of light spectra on retinal damage and stress in goldfish using green (530 nm) and red (620 nm) light emitting diodes (LEDs) at three intensities each (0.5, 1.0, and 1.5 W/m{sup 2}). We measured the change in the levels of plasma cortisol and H{sub 2}O{sub 2} and expression and levels of caspase-3. The apoptotic response of green and red LED spectra was assessed using the terminal transferase dUTP nick end labeling (TUNEL) assay. Stress indicator (cortisol and H{sub 2}O{sub 2}) and apoptosis-related genes (caspase-3) decreased in green light, but increased in red light with higher light intensities over time.more » The TUNEL assay revealed that more apoptotic cells were detected in outer nuclear layers after exposure to red LED over time with the increase in light intensity, than the other spectra. These results indicate that green light efficiently reduces retinal damage and stress, whereas red light induces it. Therefore, red light-induced retina damage may induce apoptosis in goldfish retina. -- Highlights: •Green light efficiently reduces retinal damage and stress. •Green spectra reduce caspase production and apoptosis. •Red light-induced retina damage may induce apoptosis in goldfish retina. •The retina of goldfish recognizes green spectra as a stable environment.« less

Evaluation of Retinal Changes in Progressive Supranuclear Palsy and Parkinson Disease.

PubMed

Gulmez Sevim, Duygu; Unlu, Metin; Gultekin, Murat; Karaca, Cagatay; Mirza, Meral; Mirza, Galip Ertugrul

2018-06-01

Differentiating Parkinson disease (PD) from progressive supranuclear palsy (PSP) can be challenging early in the clinical course. The aim of our study was to see if specific retinal changes could serve as a distinguishing feature. We used spectral domain optical coherence tomography (SD-OCT) with automatic segmentation to measure peripapillary nerve fiber layer thickness and the thickness and volume of retinal layers at the macula. Thicknesses of superior peripapillary retinal nerve fiber layer (pRNFL), macular ganglion cell layer, inner plexiform layer, inner nuclear layer, and macular volume were more affected in PSP compared with PD (P < 0.05). Thicker inferotemporal pRNFL and lower macular volume were detected in levodopa users compared with nonusers in patients with PD. PD and PSP are associated with distinct changes in retinal morphology, which can be assessed with SD-OCT.

User-guided segmentation for volumetric retinal optical coherence tomography images

PubMed Central

Yin, Xin; Chao, Jennifer R.; Wang, Ruikang K.

2014-01-01

Abstract. Despite the existence of automatic segmentation techniques, trained graders still rely on manual segmentation to provide retinal layers and features from clinical optical coherence tomography (OCT) images for accurate measurements. To bridge the gap between this time-consuming need of manual segmentation and currently available automatic segmentation techniques, this paper proposes a user-guided segmentation method to perform the segmentation of retinal layers and features in OCT images. With this method, by interactively navigating three-dimensional (3-D) OCT images, the user first manually defines user-defined (or sketched) lines at regions where the retinal layers appear very irregular for which the automatic segmentation method often fails to provide satisfactory results. The algorithm is then guided by these sketched lines to trace the entire 3-D retinal layer and anatomical features by the use of novel layer and edge detectors that are based on robust likelihood estimation. The layer and edge boundaries are finally obtained to achieve segmentation. Segmentation of retinal layers in mouse and human OCT images demonstrates the reliability and efficiency of the proposed user-guided segmentation method. PMID:25147962

User-guided segmentation for volumetric retinal optical coherence tomography images.

PubMed

Yin, Xin; Chao, Jennifer R; Wang, Ruikang K

2014-08-01

Despite the existence of automatic segmentation techniques, trained graders still rely on manual segmentation to provide retinal layers and features from clinical optical coherence tomography (OCT) images for accurate measurements. To bridge the gap between this time-consuming need of manual segmentation and currently available automatic segmentation techniques, this paper proposes a user-guided segmentation method to perform the segmentation of retinal layers and features in OCT images. With this method, by interactively navigating three-dimensional (3-D) OCT images, the user first manually defines user-defined (or sketched) lines at regions where the retinal layers appear very irregular for which the automatic segmentation method often fails to provide satisfactory results. The algorithm is then guided by these sketched lines to trace the entire 3-D retinal layer and anatomical features by the use of novel layer and edge detectors that are based on robust likelihood estimation. The layer and edge boundaries are finally obtained to achieve segmentation. Segmentation of retinal layers in mouse and human OCT images demonstrates the reliability and efficiency of the proposed user-guided segmentation method.

Development of an Advanced Aidman Vision Screener (AVS) for selective assessment of outer and inner laser induced retinal injury

NASA Astrophysics Data System (ADS)

Boye, Michael W.; Zwick, Harry; Stuck, Bruce E.; Edsall, Peter R.; Akers, Andre

2007-02-01

The need for tools that can assist in evaluating visual function is an essential and a growing requirement as lasers on the modern battlefield mature and proliferate. The requirement for rapid and sensitive vision assessment under field conditions produced the USAMRD Aidman Vision Screener (AVS), designed to be used as a field diagnostic tool for assessing laser induced retinal damage. In this paper, we describe additions to the AVS designed to provide a more sensitive assessment of laser induced retinal dysfunction. The AVS incorporates spectral LogMar Acuity targets without and with neural opponent chromatic backgrounds. Thus, it provides the capability of detecting selective photoreceptor damage and its functional consequences at the level of both the outer and inner retina. Modifications to the original achromatic AVS have been implemented to detect selective cone system dysfunction by providing LogMar acuity Landolt rings associated with the peak spectral absorption regions of the S (short), M (middle), and L (long) wavelength cone photoreceptor systems. Evaluation of inner retinal dysfunction associated with selective outer cone damage employs LogMar spectral acuity charts with backgrounds that are neurally opponent. Thus, the AVS provides the capability to assess the effect of selective cone dysfunction on the normal neural balance at the level of the inner retinal interactions. Test and opponent background spectra have been optimized by using color space metrics. A minimal number of three AVS evaluations will be utilized to provide an estimate of false alarm level.

Peripapillary nerve fiber layer thickness measurement reproducibility using optical coherence tomography.

PubMed

Villain, Max A; Greenfield, David S

2003-01-01

To assess reproducibility of quadrantic and clock hour sectors of retinal nerve fiber layer thickness in normal eyes using optical coherence tomography. Normal eyes of healthy volunteers meeting eligibility criteria were imaged by two inexperienced operators. Six 360 degrees circular scans with a diameter of 3.4 mm centered on the optic disc were obtained during each scanning session, and a baseline image was formed using 3 high-quality images defined by the software. Images were obtained on three different days within a 4-week period. Variance and coefficient of variation (CV) were calculated for quadrantic and retinal nerve fiber layer clock hour sectors obtained from the baseline image. Five normal eyes were scanned. Intraoperator reproducibility was high. The mean (+/- SD) CV for total retinal nerve fiber layer thickness was 5.3 +/- 3.82% and 4.33 +/- 3.7% for operators 1 and 2, respectively. Interoperator reproducibility was good with statistically similar variance for all quadrantic and clock hour retinal nerve fiber layer parameters (P = .42 to .99). The nasal retinal nerve fiber layer was the most variable sector for both operators (mean CV: 10.42% and 7.83% for operators 1 and 2, respectively). Differences in mean total, nasal, temporal, and superior retinal nerve fiber layer thickness were not statistically significant between operators for all eyes; however, for inferior retinal nerve fiber layer thickness, there was a significant (P = .0007) difference between operators in one eye. Peripapillary retinal nerve fiber layer thickness assessments using optical coherence tomography have good intraoperator and interoperator reproducibility. Inexperienced operators can generate useful measurement data with acceptable levels of variance.

Metabolic physiology in age related macular degeneration.

PubMed

Stefánsson, Einar; Geirsdóttir, Asbjörg; Sigurdsson, Haraldur

2011-01-01

Ischemia and hypoxia have been implicated in the pathophysiology of age related macular degeneration (AMD). This has mostly been based on studies on choroidal perfusion, which is not the only contributor to retinal hypoxia found in AMD eyes. Other features of AMD may also interfere with retinal oxygen metabolism including confluent drusen, serous or hemorrhagic retinal detachment, retinal edema and vitreoretinal adhesion. Each of these features contributes to retinal hypoxia: the drusen and retinal elevation by increasing the distance between the choriocapillaris and retina; vitreoretinal adhesion by reducing diffusion and convection of oxygen towards and vascular endothelial growth factor (VEGF) away from hypoxic retinal areas. Hypoxia-inducible-factor is known to exist in subretinal neovascularization and hypoxia is the main stimulus for the production of VEGF. Each feature may not by itself create enough hypoxia and VEGF accumulation to stimulate wet AMD, but they may combine to do so. Choroidal ischemia in AMD has been demonstrated by many researchers, using different technologies. Choroidal ischemia obviously decreases oxygen delivery to the outer retina. Confluent drusen, thickening of Bruch's membrane and any detachment of retina or retinal pigment epithelium, increases the distance between the choriocapillaris and the retina and thereby reduces the oxygen flux from the choroid to the outer retina according to Fick's law of diffusion. Retinal elevation and choroidal ischemia may combine forces to reduce choroidal oxygen delivery to the outer retina, produce retinal hypoxia. Hypoxia leads to production of VEGF leading to neovascularization and tissue edema. A vicious cycle may develop, where VEGF production increases effusion, retinal detachment and edema, further increasing hypoxia and VEGF production. Adhesion of the viscous posterior vitreous cortex to the retina maintains a barrier to diffusion and convection currents in the vitreous cavity according to the laws of Fick's, Stokes-Einstein and Hagen-Poiseuille. If the vitreous is detached from the surface of the retina, the low viscosity fluid transports oxygen and nutrients towards an ischemic area of the retina, and cytokines away from the retina, at a faster rate than through attached vitreous gel. Vitreoretinal adhesion can exacerbate retinal hypoxia and accumulation of cytokines, such as VEGF. Vitreoretinal traction can also cause hypoxia by retinal elevation. Conceivably, the basic features of AMD, drusen, choroidal ischemia, and vitreoretinal adhesion are independently determined by genetics and environment and may combine in variable proportions. If the resulting hypoxia and consequent VEGF accumulation crosses a threshold, this will trigger effusion and neovascularization. 2010 Elsevier Ltd. All rights reserved.

Effect of subretinal injection on retinal structure and function in a rat oxygen-induced retinopathy model.

PubMed

Becker, Silke; Wang, Haibo; Stoddard, Gregory J; Hartnett, M Elizabeth

2017-01-01

Subretinal injections are used to deliver agents in experimental studies of retinal diseases, often through viral vectors. However, few studies have investigated the effects of subretinal injections alone on the structure and function of the healthy or diseased retina, particularly in models of oxygen-induced retinopathy (OIR). We report on the effects of subretinal injections in a rat OIR model, which is used to study mechanisms of retinopathy of prematurity. Within 6 h of birth, neonatal rat pups were exposed to repeated cycles of oxygen between 50% and 10% O 2 every 24 h for 14 days and subsequently moved to room air. On postnatal day 8 (P8), animals were treated in both eyes with advancement of the injection needle into the vitreous (pilot-treated) or with a subretinal PBS injection (sPBS-treated) or were left untreated (untreated). Additional control animals were exposed to microscope light after eyelid opening only (light-treated). Retinal fundus images were recorded on P26. Areas of the avascular retina and intravitreal neovascularization were determined in flat mounted retinas stained with isolectin B4 on P32. Retinal function of the respective eyes was assessed with the Ganzfeld electroretinogram (ERG) on P31 or P32 and with focal ERG in the central retina on P28 or P29. The thickness of the retinal layers was measured with spectral domain optical coherence tomography (OCT) on P30 and in opsin- and TO-PRO 3-stained retinal cryosections from pups euthanized on P32. Two sections were analyzed in each pup. For each section, three images of three different locations were analyzed accounting for 18 thickness measurements per pup. Compared to untreated animals, the avascular area of the retina was greater in the pilot-treated (p<0.05) and sPBS-treated eyes (p<0.01), and the sPBS-treated eyes had a greater avascular retinal area compared to the pilot-treated eyes (p<0.01). The intravitreal neovascular area was larger in the sPBS-treated eyes compared to the untreated eyes (p<0.01). The outer nuclear and outer segment layers were thinner in the pilot- (p<0.01) and sPBS-treated eyes (p<0.05) compared to the untreated eyes as measured with OCT and immunohistochemical staining of the retinal cryosections. Compared to the untreated eyes, the amplitudes of the scotopic a- and b-waves in the Ganzfeld ERG were reduced in the pilot-treated eyes (p<0.001 and p<0.01, respectively), but only the a-wave was reduced in the sPBS-treated eyes (p<0.001). The a-wave amplitude in the focal ERG was reduced in the pilot- and sPBS-treated eyes, and no difference was seen in the b-wave amplitude between any of the groups. There was no difference between the light-treated and untreated eyes in the areas of the avascular retina or intravitreal neovascularization or Ganzfeld or focal ERG. Pilot injections alone without injection into the subretinal space resulted in an increased avascular retinal area, reduced thickness of the photoreceptors, and reduced ERG function compared to the untreated animals. Although subretinal PBS injections further increased the areas of avascular retina and intravitreal neovascularization and resulted in similar retinal thinning compared to the pilot treatment, inner retinal function was improved, as evidenced by higher Ganzfeld b-wave amplitudes. Differences in the Ganzfeld and focal ERGs may indicate that the peripheral retina is more susceptible to remote beneficial effects from potential protective mechanisms induced by subretinal injection. This study stresses the importance of appropriate controls in experiments with subretinal delivery of agents.

The Edge Detectors Suitable for Retinal OCT Image Segmentation

PubMed Central

Yang, Jing; Gao, Qian; Zhou, Sheng

2017-01-01

Retinal layer thickness measurement offers important information for reliable diagnosis of retinal diseases and for the evaluation of disease development and medical treatment responses. This task critically depends on the accurate edge detection of the retinal layers in OCT images. Here, we intended to search for the most suitable edge detectors for the retinal OCT image segmentation task. The three most promising edge detection algorithms were identified in the related literature: Canny edge detector, the two-pass method, and the EdgeFlow technique. The quantitative evaluation results show that the two-pass method outperforms consistently the Canny detector and the EdgeFlow technique in delineating the retinal layer boundaries in the OCT images. In addition, the mean localization deviation metrics show that the two-pass method caused the smallest edge shifting problem. These findings suggest that the two-pass method is the best among the three algorithms for detecting retinal layer boundaries. The overall better performance of Canny and two-pass methods over EdgeFlow technique implies that the OCT images contain more intensity gradient information than texture changes along the retinal layer boundaries. The results will guide our future efforts in the quantitative analysis of retinal OCT images for the effective use of OCT technologies in the field of ophthalmology. PMID:29065594

Reduction of foveal bulges and other anatomical changes in fellow eyes of patients with unilateral idiopathic macular hole without vitreomacular pathologic changes.

PubMed

Delas, Barbara; Julio, Gemma; Fernández-Vega, Álvaro; Casaroli-Marano, Ricardo P; Nadal, Jeroni

2017-11-01

To compare the foveal characteristics in fellow eyes (FE) of patients with unilateral idiopathic macular hole without vitreomacular pathologic changes with eyes of healthy controls. Forty-seven FE and 52 eyes of 52 age- and sex-matched healthy controls were studied. Quantitative assessment of the dome-shaped appearance of the hyperreflective lines that represent external limiting membrane (ELM_bulge) and inner outer segment junctions (IS/OS_bulge) were made by optical coherence tomography (OCT) images. Inner retinal complex thickness (IRCT) was quantitatively assessed at 1000 and 2000 μm of the foveal center in nasal and temporal quadrants. Presence of alterations in the inner retinal outer layers and central foveal thickness (CFT) were also analyzed. Significantly lower ELM_bulge (p < 0.0001; Mann-Whitney test) and IS/OS_bulge (p < 0.001; student t test) and higher cases with COST alterations, expressed as a diffuse line (p < 0.006; Chi 2 test) were found in FE than control eyes. IRCT were significantly reduced in FE at all the studied locations when comparing to control eyes (p < 0.05; student t test), maintaining anatomical proportionality among locations. FE without pathologic vitreomacular interactions seems to present some central cone alterations that may be related to other causes than vitreomacular traction.

Safety and efficacy of intravitreal injection of recombinant erythropoietin for protection of photoreceptor cells in a rat model of retinal detachment

PubMed Central

Xie, Z; Chen, F; Wu, X; Zhuang, C; Zhu, J; Wang, J; Ji, H; Wang, Y; Hua, X

2012-01-01

Purpose To elucidate the safety and efficacy of exogenous erythropoietin (EPO) for the protection of photoreceptor cells in a rat model of retinal detachment (RD). Methods Recombinant rat EPO (400 ng) was injected into the vitreous cavity of normal rats to observe the eye manifestations. Retinal function was assessed by flash electroretinograms. Histopathological examination of retinal tissue was performed at 14 days and 2 months after injection, respectively. To investigate the inhibitory effect of EPO on photoreceptor cell apoptosis in RD rats, 100, 200, or 400 ng EPO was injected into the vitreous cavity immediately after RD model establishment. Apoptosis of photoreceptor cells was determined at 3 days after injection. Caspase-3 activation was measured by western blot analysis and immunofluorescence, respectively, and the level of Bcl-XL expression was analyzed by western blot. Results Intravitreal injection of EPO 400 ng into normal rats had no significant impact on retinal function, morphology, or structure. Apoptosis of retinal photoreceptor cells apparently increased after RD and was significantly reduced following EPO treatment. The thickness of the outer nuclear layer in the RD+400 ng group was significantly thicker than that in other experimental RD groups both at 14 days and at 2 months after RD (P<0.05). Western blot and immunofluorescence analyses showed decreased caspase-3 activation and increased Bcl-XL expression following EPO treatment. Conclusion Intravitreal injection of EPO 400 ng is safe, and EPO may suppress caspase-3 activation and enhance Bcl-XL expression, resulting in inhibition of apoptosis and protection of photoreceptor cells. PMID:22020175

Neuroprotective effect of subretinal implants in the RCS rat.

PubMed

Pardue, Machelle T; Phillips, Michael J; Yin, Hang; Sippy, Brian D; Webb-Wood, Sarah; Chow, Alan Y; Ball, Sherry L

2005-02-01

Retinal prosthetics have been designed to interface with the neural retina by electrically stimulating the remaining retinal circuits after photoreceptor degeneration. However, the electrical stimulation provided by the subretinal implant may also stimulate neurotrophic factors that provide neuroprotection to the retina. This study was undertaken to determine whether electrical stimulation from a subretinal photodiode-based implant has a neuroprotective effect on photoreceptors in the RCS rat, a model of photoreceptor degeneration. Eyes of RCS rats were implanted with an active or inactive device or underwent sham surgery before photoreceptor degeneration. Outer retinal function was assessed with electroretinogram (ERG) recordings weekly until 8 weeks after surgery, at which time retinal tissue was collected and processed for morphologic assessment, including photoreceptor cell counts and retinal layer thickness. At 4 to 6 weeks after surgery, the ERG responses in the active-implant eyes were 30% to 70% greater in b-wave amplitude than the responses from eyes implanted with inactive devices, those undergoing sham surgery, or the nonsurgical control eyes. At 8 weeks after surgery the ERG responses from active-implant eyes were not significantly different from the control groups. However, the number of photoreceptors in eyes implanted with the active or inactive device was significantly greater in the regions over and around the implant versus sham-surgical and nonsurgical control eyes. These results suggest that subretinal electrical stimulation provides temporary preservation of retinal function in the RCS rat. In addition, implantation of an active or inactive device into the subretinal space causes morphologic preservation of photoreceptors in the RCS rat until 8 weeks after surgery. Further studies are needed to determine whether the correlation of neuropreservation with subretinal implantation is due to electrical stimulation and/or a mechanical presence of the implant in the subretinal space.

Ratiometric analysis of in vivo retinal layer thicknesses in multiple sclerosis

NASA Astrophysics Data System (ADS)

Bhaduri, Basanta; Nolan, Ryan M.; Shelton, Ryan L.; Pilutti, Lara A.; Motl, Robert W.; Boppart, Stephen A.

2016-09-01

We performed ratiometric analysis of retinal optical coherence tomography images for the first time in multiple sclerosis (MS) patients. The ratiometric analysis identified differences in several retinal layer thickness ratios in the cohort of MS subjects without a history of optic neuritis (ON) compared to healthy control (HC) subjects, and there was no difference in standard retinal nerve fiber layer thickness (RNFLT). The difference in such ratios between HC subjects and those with mild MS-disability, without a difference in RNFLT, further suggests the possibility of using layer ratiometric analysis for detecting early retinal changes in MS. Ratiometric analysis may be useful and potentially more sensitive for detecting disease changes in MS.

Sarcocystis neurona retinochoroiditis in a sea otter (Enhydra lutris kenyoni).

PubMed

Dubey, J P; Thomas, N J

2011-12-29

Sarcocystis neurona is an important cause of fatal disease in sea otters in the USA. Encephalitis is the predominant lesion and parasites are confined to the central nervous system and muscles. Here we report retinochoroiditis in a sea otter (Enhydra lutris kenyoni) found dead on Copalis Beach, WA, USA. Salient lesions were confined to the brain and eye. Multifocal nonsuppurative meningoencephalitis was present in the cerebrum and cerebellum associated with S. neurona schizonts. The retina of one eye had a focus of inflammation that contained numerous S. neurona schizonts and merozoites. The focus extended from the retinal pigment epithelium inward through all layers of the retina, but inflammation was most concentrated at the inner surface of the tapetum and the outer retina. The inner and outer nuclear layers of the retina were disorganized and irregular at the site of inflammation. There was severe congestion and mild hemorrhage in the choroid, and mild hemorrhage into the vitreous body. Immunohistochemistry with S. neurona-specific polyclonal rabbit antibodies stained schizonts and merozoites. To our knowledge this is the first report of S. neurona-associated retinochoroiditis in any naturally infected animal. Copyright © 2011 Elsevier B.V. All rights reserved.

Sarcocystis neurona retinochoroiditis in a sea otter (Enhydra lutris kenyoni)

USGS Publications Warehouse

Dubey, J.P.; Thomas, N.J.

2011-01-01

Sarcocystis neurona is an important cause of fatal disease in sea otters in the USA. Encephalitis is the predominant lesion and parasites are confined to the central nervous system and muscles. Here we report retinochoroiditis in a sea otter (Enhydra lutris kenyoni) found dead on Copalis Beach, WA, USA. Salient lesions were confined to the brain and eye. Multifocal nonsuppurative meningoencephalitis was present in the cerebrum and cerebellum associated with S. neurona schizonts. The retina of one eye had a focus of inflammation that contained numerous S. neurona schizonts and merozoites. The focus extended from the retinal pigment epithelium inward through all layers of the retina, but inflammation was most concentrated at the inner surface of the tapetum and the outer retina. The inner and outer nuclear layers of the retina were disorganized and irregular at the site of inflammation. There was severe congestion and mild hemorrhage in the choroid, and mild hemorrhage into the vitreous body. Immunohistochemistry with S. neurona-specific polyclonal rabbit antibodies stained schizonts and merozoites. To our knowledge this is the first report of S. neurona-associated retinochoroiditis in any naturally infected animal. ?? 2011 Elsevier B.V.

Pediatric Bilateral Blue Laser Pointer-Induced Maculopathy

PubMed Central

Raevis, Joseph; Shrier, Eric

2017-01-01

Background We report the first case of pediatric bilateral blue laser pointer maculopathy with complete resolution of visual symptoms. Case A 12-year-old boy presented with bilateral decreased visual acuity and central scotomata after blue laser pointer exposure. He was treated with a Medrol Dosepak and topical nonsteroidal anti-inflammatory drug (NSAID), with gradual visual acuity improved from 20/40 OU to 20/20 OU over 22 weeks, but with persistent evidence of outer retinal layer disruption from the external limiting membrane to the interdigitation zone. Conclusion Oral steroids and topical NSAIDs may be effective in improving visual outcomes in laser pointer maculopathy in the pediatric population. PMID:28611647

The retina visual cycle is driven by cis retinol oxidation in the outer segments of cones

PubMed Central

Sato, Shinya; Frederiksen, Rikard; Cornwall, M. Carter; Kefalov, Vladimir J.

2017-01-01

Vertebrate rod and cone photoreceptors require continuous supply of chromophore for regenerating their visual pigments after photoactivation. Cones, which mediate our daytime vision, demand a particularly rapid supply of 11-cis retinal chromophore in order to maintain their function in bright light. An important contribution to this process is thought to be the chromophore precursor 11-cis retinol, which is supplied to cones from Müller cells in the retina and subsequently oxidized to 11-cis retinal as part of the retina visual cycle. However, the molecular identity of the cis retinol oxidase in cones remains unclear. Here, as a first step in characterizing this enzymatic reaction, we sought to determine the subcellular localization of this activity in salamander red cones. We found that the onset of dark adaptation of isolated salamander red cones was substantially faster when exposing directly their outer vs. their inner segment to 9-cis retinol, an analogue of 11-cis retinol. In contrast, this difference was not observed when treating the outer vs. inner segment with 9-cis retinal, a chromophore analogue which can directly support pigment regeneration. These results suggest, surprisingly, that the cis-retinol oxidation occurs in the outer segments of cone photoreceptors. Confirming this notion, pigment regeneration with exogenously added 9-cis retinol was directly observed in the truncated outer segments of cones, but not in rods. We conclude that the enzymatic machinery required for the oxidation of recycled cis retinol as part of the retina visual cycle is present in the outer segments of cones. PMID:28359344

Changes in Retinal and Choroidal Vascular Blood Flow after Oral Sildenafil: An Optical Coherence Tomography Angiography Study.

PubMed

Berrones, David; Salcedo-Villanueva, Guillermo; Morales-Cantón, Virgilio; Velez-Montoya, Raul

2017-01-01

To describe changes in the retina and choroidal flow by optical coherence tomography angiography (OCT-A) after a single dose of oral sildenafil. A case-control study. Patients in the study group received 50 mg of oral sildenafil. Patients in the control group received a sham pill. Retinal and choroidal images were obtained at baseline (before pill ingestion) and 1 hour after ingestion. Central macular and choroidal thickness, choroidal and outer retina flow, and the retinal and choroidal vascular density were compared using a Mann-Whitney U test. Twenty eyes were enrolled into the study group and 10 eyes in the control group. There was a significant difference in central choroidal thickness and outer retina blood flow between groups after 1 hour of sildenafil ingestion ( p < 0.01). There were no differences in central macular thickness, choroidal flow, and retinal vascular density among groups. A single dose of oral sildenafil increases choroidal thickness, probably due to sildenafil-induced vasodilation.

Changes in Retinal and Choroidal Vascular Blood Flow after Oral Sildenafil: An Optical Coherence Tomography Angiography Study

PubMed Central

Berrones, David; Morales-Cantón, Virgilio

2017-01-01

Purpose To describe changes in the retina and choroidal flow by optical coherence tomography angiography (OCT-A) after a single dose of oral sildenafil. Method A case-control study. Patients in the study group received 50 mg of oral sildenafil. Patients in the control group received a sham pill. Retinal and choroidal images were obtained at baseline (before pill ingestion) and 1 hour after ingestion. Central macular and choroidal thickness, choroidal and outer retina flow, and the retinal and choroidal vascular density were compared using a Mann-Whitney U test. Results Twenty eyes were enrolled into the study group and 10 eyes in the control group. There was a significant difference in central choroidal thickness and outer retina blood flow between groups after 1 hour of sildenafil ingestion (p < 0.01). There were no differences in central macular thickness, choroidal flow, and retinal vascular density among groups. Conclusions A single dose of oral sildenafil increases choroidal thickness, probably due to sildenafil-induced vasodilation. PMID:29129998

Photoreceptor Cells With Profound Structural Deficits Can Support Useful Vision in Mice

PubMed Central

Thompson, Stewart; Blodi, Frederick R.; Lee, Swan; Welder, Chris R.; Mullins, Robert F.; Tucker, Budd A.; Stasheff, Steven F.; Stone, Edwin M.

2014-01-01

Purpose. In animal models of degenerative photoreceptor disease, there has been some success in restoring photoreception by transplanting stem cell–derived photoreceptor cells into the subretinal space. However, only a small proportion of transplanted cells develop extended outer segments, considered critical for photoreceptor cell function. The purpose of this study was to determine whether photoreceptor cells that lack a fully formed outer segment could usefully contribute to vision. Methods. Retinal and visual function was tested in wild-type and Rds mice at 90 days of age (RdsP90). Photoreceptor cells of mice homozygous for the Rds mutation in peripherin 2 never develop a fully formed outer segment. The electroretinogram and multielectrode recording of retinal ganglion cells were used to test retinal responses to light. Three distinct visual behaviors were used to assess visual capabilities: the optokinetic tracking response, the discrimination-based visual water task, and a measure of the effect of vision on wheel running. Results. RdsP90 mice had reduced but measurable electroretinogram responses to light, and exhibited light-evoked responses in multiple types of retinal ganglion cells, the output neurons of the retina. In optokinetic and discrimination-based tests, acuity was measurable but reduced, most notably when contrast was decreased. The wheel running test showed that RdsP90 mice needed 3 log units brighter luminance than wild type to support useful vision (10 cd/m2). Conclusions. Photoreceptors that lack fully formed outer segments can support useful vision. This challenges the idea that normal cellular structure needs to be completely reproduced for transplanted cells to contribute to useful vision. PMID:24569582

Retinal nerve fiber layer changes after LASIK evaluated with optical coherence tomography.

PubMed

Dementyev, Dmitriy D; Kourenkov, Vyacheslav V; Rodin, Alexander S; Fadeykina, Tatyana L; Diaz Martines, Tatyana E

2005-01-01

To determine whether the increase in intraocular pressure (IOP) during LASIK suction can induce a decrease in retinal nerve fiber layer thickness assessed by optical coherence tomography (OCT). Nineteen patients (38 eyes) were enrolled in the study. Intraocular pressure was normal at all pre- and postoperative examinations. Retinal nerve fiber layer thickness was measured using OCT-3 Stratus prior to and 1 week and 3 months after LASIK. Laser in situ keratomileusis was performed using the Bausch & Lomb Hansatome microkeratome and the NIDEK EC-5000 excimer laser. Optical coherence tomography mean retinal nerve fiber layer thickness values before and after LASIK were compared using the Student paired t test. Mean patient age was 27.8 years (range: 18 to 33 years). Mean preoperative spherical equivalent refractive error was -4.9 diopters (D) (range: -2.0 to -8.5 D). Mean time of microkeratome suction was 30 seconds (range: 20 to 50 seconds). Preoperatively, the mean retinal nerve fiber layer thickness obtained by OCT was 104.2+/-9.0 microm; at 1 week postoperatively the mean thickness was 101.9+/-6.9 microm, and 106.7+/-6.1 microm at 3 months postoperatively. Mean retinal nerve fiber layer thicknesses obtained by OCT were not significantly different between preoperative and 1 week and 3 months after LASIK (P > or = .05). Laser in situ keratomileusis performed on young myopic patients does not have a significant effect on retinal nerve fiber layer thickness determined by OCT. Further studies are required to reveal the risk of possible optic nerve or retinal nerve fiber layer damage by elevated IOP during LASIK.

The RNA-binding protein Musashi-1 is produced in the developing and adult mouse eye.

PubMed

Raji, B; Dansault, A; Leemput, J; de la Houssaye, G; Vieira, V; Kobetz, A; Arbogast, L; Masson, C; Menasche, M; Abitbol, M

2007-08-10

Musashi-1 (Msi1) is an RNA-binding protein produced in various types of stem cells including neural stem/progenitor cells and astroglial progenitor cells in the vertebrate central nervous system. Other RNA-binding proteins such as Pumilio-1, Pumilio-2, Staufen-1, and Staufen-2 have been characterized as potential markers of several types of stem or progenitor cells. We investigated the involvement of Msi1 in mouse eye development and adult mouse eye functions by analyzing the profile of Msi1 production in all ocular structures during development and adulthood. We studied Msi1 production by in situ hybridization and immunohistochemistry of ocular tissue sections and by semi-quantitative RT-PCR and western blot analysis from the embryonic stage of 12.5 days post coitum (E12.5 dpc) when the first retinal ganglion cells (RGCs) begin to appear to the adult stage when all retinal cell types are present. Msi1 mRNA was present at all studied stages of eye development. Msi1 protein was detected in the primitive neuroblastic layer (NbL), the ganglion cell layer (GCL), and in all major differentiated neurons of postnatal developing and adult retinae. During postnatal developing stages, faint diffuse Msi1 protein staining is converted to a more specific distribution once mouse retina is fully differentiated. The most striking result of our study concerns the large amounts of Msi1 protein and mRNA in several unexpected sites of adult mouse eyes including the corneal epithelium and endothelium, stromal keratocytes, progenitor cells of the limbus, equatorial lens stem cells, differentiated lens epithelial cells, and differentiating lens fibers. Msi1 was also found in the pigmented and nonpigmented cells of the ciliary processes, the melanocytes of the ciliary body, the retinal pigment epithelium, differentiated retinal neurons, and most probably in the retinal glial cells such as Müller glial cells, astrocytes, and the oligodendocytes surrounding the axons of the optic nerve. Msi1 expression was detected in the outer plexiform layer, the inner plexiform layer, and the nerve fiber layer of fully differentiated adult retina. We provide here the first demonstration that the RNA-binding protein, Msi1, is produced in mouse eyes from embryonic stages until adulthood. The relationship between the presence of Msi1 in developing ocular compartments and the possible stem/progenitor cell characteristics of these compartments remains unclear. Finally, the expression of Msi1 in several different cell types in the adult eye is extremely intriguing and should lead to further attempts to unravel the role of Msi1 in cellular and subcellular RNA metabolism and in the control of translational processes in adult eye cells particularly in adult neuronal dendrites, axons, and synapses.

Correlation of retinal nerve fibre layer and macular thickness with serum uric acid among type 2 diabetes mellitus.

PubMed

Vinuthinee-Naidu, Munisamy-Naidu; Zunaina, Embong; Azreen-Redzal, Anuar; Nyi-Nyi, Naing

2017-06-14

Uric acid is a final breakdown product of purine catabolism in humans. It's a potent antioxidant and can also act as a pro-oxidant that induces oxidative stress on the vascular endothelial cells, thus mediating progression of diabetic related diseases. Various epidemiological and experimental evidence suggest that uric acid has a role in the etiology of type 2 diabetes mellitus. We conducted a cross-sectional study to evaluate the correlation of retinal nerve fibre layer (RNFL) and macular thickness with serum uric acid in type 2 diabetic patients. A cross-sectional study was conducted in the Eye Clinic, Hospital Universiti Sains Malaysia, Kelantan between the period of August 2013 till July 2015 involving type 2 diabetes mellitus patients with no diabetic retinopathy and with non-proliferative diabetic retinopathy (NPDR). An evaluation for RNFL and macular thickness was measured using Spectralis Heidelberg optical coherence tomography. Six ml of venous blood was taken for the measurement of serum uric acid and glycosylated haemoglobin (HbA1 C ). A total of 180 diabetic patients were recruited (90 patients with no diabetic retinopathy and 90 patients with NPDR) into the study. The mean level of serum uric acid for both the groups was within normal range and there was no significance difference between the two groups. Based on gender, both male and female gender showed significantly higher level of mean serum uric acid in no diabetic retinopathy group (p = 0.004 respectively). The mean serum uric acid was significantly higher in patient with HbA1 C  < 6.5% (p < 0.031). Patients with NPDR have thicker RNFL and macular thickness compared to patients with no diabetic retinopathy. However, only the RNFL thickness of the temporal quadrant and the macular thickness of the superior outer, inferior outer and temporal outer subfields were statistically significant (p = 0.038, p = 0.004, 0.033 and <0.001 respectively). There was poor correlation between RNFL and macular thickness with serum uric acid in both the groups. Serum uric acid showed a poor correlation with RNFL and macular thickness among type 2 diabetic patients.

Retinal Degeneration in a Rodent Model of Smith-Lemli-Opitz Syndrome

PubMed Central

Fliesler, Steven J.; Peachey, Neal S.; Richards, Michael J.; Nagel, Barbara A.; Vaughan, Dana K.

2010-01-01

Objective To assess the electrophysiologic, histologic, and biochemical features of an animal model of Smith-Lemli-Opitz syndrome (SLOS). Methods Sprague-Dawley rats were treated with AY9944, a selective inhibitor of 3β-hydroxysterol-Δ7-reductase (the affected enzyme in SLOS). Dark- and light-adapted electroretinograms were obtained from treated and control animals. From each animal, 1 retina was analyzed by microscopy, and the contralateral retina plus serum samples were analyzed for sterol composition. The main outcome measures were rod and cone electroretinographic amplitudes and implicit times, outer nuclear layer (ONL) thickness, rod outer segment length, pyknotic ONL nucleus counts, and the 7-dehydrocholesterol/ cholesterol mole ratio in the retina and serum. Results By 10 weeks’ postnatal age, rod and cone electroretinographic wave amplitudes in AY9944-treated animals were significantly reduced and implicit times were significantly increased relative to controls. Maximal rod photoresponse and gain values were reduced approximately 2-fold in treated animals relative to controls. The ONL thickness and average rod outer segment length were reduced by approximately 18% and 33%, respectively, and ONL pyknotic nucleus counts were approximately 4.5-fold greater in treated animals relative to controls. The retinal pigment epithelium of treated animals contained massive amounts of membranous/lipid inclusions not routinely observed in controls. The 7-dehydrocholesterol/cholesterol mole ratios in treated retinas and serum samples were approximately 5:1 and 9:1, respectively, whereas the ratios in control tissues were essentially zero. Conclusions This rodent model exhibits the key biochemical hallmarks associated with SLOS and displays electrophysiologic deficits comparable to or greater than those observed in the human disease. Clinical Relevance These results predict retinal degeneration in patients with SLOS, particularly those with the more severe (type II) form of the disease, and may be more broadly relevant to other inborn errors of cholesterol biosynthesis. This animal model may also be of use in evaluating therapeutic treatments for SLOS and in understanding the slow phototransduction kinetics observed in patients with SLOS. PMID:15302661

Relationship between photoreceptor outer segment length and visual acuity in diabetic macular edema.

PubMed

Forooghian, Farzin; Stetson, Paul F; Meyer, Scott A; Chew, Emily Y; Wong, Wai T; Cukras, Catherine; Meyerle, Catherine B; Ferris, Frederick L

2010-01-01

The purpose of this study was to quantify photoreceptor outer segment (PROS) length in 27 consecutive patients (30 eyes) with diabetic macular edema using spectral domain optical coherence tomography and to describe the correlation between PROS length and visual acuity. Three spectral domain-optical coherence tomography scans were performed on all eyes during each session using Cirrus HD-OCT. A prototype algorithm was developed for quantitative assessment of PROS length. Retinal thicknesses and PROS lengths were calculated for 3 parameters: macular grid (6 x 6 mm), central subfield (1 mm), and center foveal point (0.33 mm). Intrasession repeatability was assessed using coefficient of variation and intraclass correlation coefficient. The association between retinal thickness and PROS length with visual acuity was assessed using linear regression and Pearson correlation analyses. The main outcome measures include intrasession repeatability of macular parameters and correlation of these parameters with visual acuity. Mean retinal thickness and PROS length were 298 mum to 381 microm and 30 microm to 32 mum, respectively, for macular parameters assessed in this study. Coefficient of variation values were 0.75% to 4.13% for retinal thickness and 1.97% to 14.01% for PROS length. Intraclass correlation coefficient values were 0.96 to 0.99 and 0.73 to 0.98 for retinal thickness and PROS length, respectively. Slopes from linear regression analyses assessing the association of retinal thickness and visual acuity were not significantly different from 0 (P > 0.20), whereas the slopes of PROS length and visual acuity were significantly different from 0 (P < 0.0005). Correlation coefficients for macular thickness and visual acuity ranged from 0.13 to 0.22, whereas coefficients for PROS length and visual acuity ranged from -0.61 to -0.81. Photoreceptor outer segment length can be quantitatively assessed using Cirrus HD-OCT. Although the intrasession repeatability of PROS measurements was less than that of macular thickness measurements, the stronger correlation of PROS length with visual acuity suggests that the PROS measures may be more directly related to visual function. Photoreceptor outer segment length may be a useful physiologic outcome measure, both clinically and as a direct assessment of treatment effects.

Loss of MAP3K1 enhances proliferation and apoptosis during retinal development

PubMed Central

Mongan, Maureen; Wang, Jingcai; Liu, Hongshan; Fan, Yunxia; Jin, Chang; Kao, Winston Y.-W.; Xia, Ying

2011-01-01

Precise coordination of progenitor cell proliferation and differentiation is essential for proper organ morphogenesis and function during mammalian development. The mitogen-activated protein kinase kinase kinase 1 (MAP3K1) has a well-established role in anterior eyelid development, as Map3k1-knockout mice have defective embryonic eyelid closure and an `eye-open at birth' (EOB) phenotype. Here, we show that MAP3K1 is highly expressed in the posterior of the developing eye and is required for retina development. The MAP3K1-deficient mice exhibit increased proliferation and apoptosis, and Müller glial cell overproduction in the developing retinas. Consequently, the retinas of these mice show localized rosette-like arrangements in the outer nuclear layer, and develop abnormal vascularization, broken down retinal pigment epithelium, photoreceptor loss and early onset of retinal degeneration. Although the retinal defect is associated with increased cyclin D1 and CDK4/6 expression, and RB phosphorylation and E2F-target gene upregulation, it is independent of the EOB phenotype and of JNK. The retinal developmental defect still occurs in knockout mice that have undergone tarsorrhaphy, but is absent in compound mutant Map3k1+/ΔKDJnk1–/– and Map3k1+/ΔKDJnk+/–Jnk2+/– mice that have EOB and reduced JNK signaling. Our results unveil a novel role for MAP3K1 in which it crosstalks with the cell cycle regulatory pathways in the prevention of retina malformation and degeneration. PMID:21862560

Characterization of an Early-Onset, Autosomal Recessive, Progressive Retinal Degeneration in Bengal Cats

PubMed Central

Ofri, Ron; Reilly, Christopher M.; Maggs, David J.; Fitzgerald, Paul G.; Shilo-Benjamini, Yael; Good, Kathryn L.; Grahn, Robert A.; Splawski, Danielle D.; Lyons, Leslie A.

2015-01-01

Purpose A form of retinal degeneration suspected to be hereditary was discovered in a family of Bengal cats. A breeding colony was established to characterize disease progression clinically, electrophysiologically, and morphologically, and to investigate the mode of inheritance. Methods Affected and related cats were donated by owners for breeding trials and pedigree analysis. Kittens from test and complementation breedings underwent ophthalmic and neuro-ophthalmic examinations and ERG, and globes were evaluated using light microscopy. Results Pedigree analysis, along with test and complementation breedings, indicated autosomal recessive inheritance and suggested that this disease is nonallelic to a retinal degeneration found in Persian cats. Mutation analysis confirmed the disease is not caused by CEP290 or CRX variants found predominantly in Abyssinian and Siamese cats. Ophthalmoscopic signs of retinal degeneration were noted at 9 weeks of age and became more noticeable over the next 4 months. Visual deficits were behaviorally evident by 1 year of age. Electroretinogram demonstrated reduced rod and cone function at 7 and 9 weeks of age, respectively. Rod responses were mostly extinguished at 14 weeks of age; cone responses were minimal by 26 weeks. Histologic degeneration was first observed at 8 weeks, evidenced by reduced photoreceptor numbers, then rapid deterioration of the photoreceptor layer and, subsequently, severe outer retinal degeneration. Conclusions A recessively inherited primary photoreceptor degeneration was characterized in the Bengal cat. The disease is characterized by early onset, with histologic, ophthalmoscopic, and electrophysiological signs evident by 2 months of age, and rapid progression to blindness. PMID:26258614

Half-Fluence Photodynamic Therapy for Chronic Central Serous Chorioretinopathy: Predisposing Factors for Visual Acuity Outcomes.

PubMed

Matušková, Veronika; Vysloužilová, Daniela; Uher, Michal

2017-12-18

Central serous chorioretinopathy (CSC) is characterised by a serous detachment of the neurosensory retina in the macula. Chronic CSC tends to affect older individuals with a less favourable visual outcome. Photodynamic therapy (PDT) with verteporfin is a possible therapeutic approach in cases of CSC with no tendency for spontaneous resorption. PDT has shown good anatomic and functional results in treating chronic CSC. For the purpose of diminishing side effects, modifications of the standard protocol were used. This is a retrospective study of 32 eyes with CSC of 32 patients treated by half-fluence PDT. The patients underwent complete ophthalmology examination. On optical coherence tomography (OCT) we measured central retinal thickness (CRT), the outer nuclear layer (ONL), presence of subfoveolar detachment of retinal pigment epithelium (PED), disturbance of external limiting membrane (ELM), morphological changes in the inner segment/outer segment (IS/OS) line and retinal pigment epithelium (RPE) atrophy. We evaluated at baseline, 3 and 12 months after PDT. The mean BCVA at baseline was 0.41 ± 0.23 log MAR, the mean BCVA at 3 months was 0.24 ± 0.20 and at the end of the follow-up it was 0.23 ± 0.200. We observed statistically significant improvements of visual acuity after 3 and 12 months (p < 0.001, Wilcoxon test). The mean central retinal thickness at baseline was 373 ± 87 µm, the mean CRT after 3 months was 234 ± 42 µm and after 12 months 223 ± 39 µm. A significant reduction from baseline was seen after 3 months and 12 months (p < 0.001, Wilcoxon test). Baseline ONL reached 80 ± 27 µm, after 3 months it was 78 ± 20 and after 12 months it was 74 ± 20 µm. We observed a statistically significant change in diminishing the amount of PED after PDT after 3 months and after 12 months (p = 0.021, McNemar's test). We observed that in patients with RPE ablation, there is lower chance for the restitution of the IS/OS layer (p = 0.045, Mann-Whitney test). We observed a negative association between the improvement of visual acuity after 12 months and the presence of RPE ablation (p = 0.031, Mann-Whitney test). Restitution of ELM was significantly more often in patients with shorter duration of symptoms, (p = 0.027 after 3 months, p = 0.033 after 12 months after PDT, Spearman correlation). Neither ocular nor systemic adverse effects were observed during the follow-up period. Half-fluence PDT treatment has shown to be a usually safe and often effective therapy in patients with chronic CSC. This study suggests that the most important predictive factor is baseline visual acuity. The important anatomical change detected using OCT is a thinning of the outer nuclear layer. Nonetheless, other studies with a larger number of patients and a longer follow-up are required.

Layer-specific blood-flow MRI of retinitis pigmentosa in RCS rats☆

PubMed Central

Li, Guang; Garza, Bryan De La; Shih, Yen-Yu I.; Muir, Eric R.; Duong, Timothy Q.

2013-01-01

The Royal College of Surgeons (RCS) rat is an established animal model of retinitis pigmentosa, a family of inherited retinal diseases which starts with loss of peripheral vision and progresses to eventual blindness. Blood flow (BF), an important physiological parameter, is intricately coupled to metabolic function under normal physiological conditions and is perturbed in many neurological and retinal diseases. This study reports non-invasive high-resolution MRI (44 × 44 × 600 μm) to image quantitative retinal and choroidal BF and layer-specific retinal thicknesses in RCS rat retinas at different stages of retinal degeneration compared with age-matched controls. The unique ability to separate retinal and choroidal BF was made possible by the depth-resolved MRI technique. RBF decreased with progressive retinal degeneration, but ChBF did not change in RCS rats up to post-natal day 90. We concluded that choroidal and retinal circulations have different susceptibility to progressive retinal degeneration in RCS rats. Layer-specific retinal thickness became progressively thinner and was corroborated by histological analysis in the same animals. MRI can detect progressive anatomical and BF changes during retinal degeneration with laminar resolution. PMID:22721720

Layer-specific blood-flow MRI of retinitis pigmentosa in RCS rats.

PubMed

Li, Guang; De La Garza, Bryan; Shih, Yen-Yu I; Muir, Eric R; Duong, Timothy Q

2012-08-01

The Royal College of Surgeons (RCS) rat is an established animal model of retinitis pigmentosa, a family of inherited retinal diseases which starts with loss of peripheral vision and progresses to eventual blindness. Blood flow (BF), an important physiological parameter, is intricately coupled to metabolic function under normal physiological conditions and is perturbed in many neurological and retinal diseases. This study reports non-invasive high-resolution MRI (44 × 44 × 600 μm) to image quantitative retinal and choroidal BF and layer-specific retinal thicknesses in RCS rat retinas at different stages of retinal degeneration compared with age-matched controls. The unique ability to separate retinal and choroidal BF was made possible by the depth-resolved MRI technique. RBF decreased with progressive retinal degeneration, but ChBF did not change in RCS rats up to post-natal day 90. We concluded that choroidal and retinal circulations have different susceptibility to progressive retinal degeneration in RCS rats. Layer-specific retinal thickness became progressively thinner and was corroborated by histological analysis in the same animals. MRI can detect progressive anatomical and BF changes during retinal degeneration with laminar resolution. Copyright © 2012 Elsevier Ltd. All rights reserved.

Fundus autofluorescence and optical coherence tomography of congenital grouped albinotic spots.

PubMed

Kim, David Y; Hwang, John C; Moore, Anthony T; Bird, Alan C; Tsang, Stephen H

2010-09-01

The purpose of this study was to describe the findings of fundus autofluores-cence (FAF) and optical coherence tomography in a series of patients with congenital grouped albinotic spots. Three eyes of three patients with congenital grouped albinotic spots were evaluated with FAF and optical coherence tomography imaging to evaluate the nature of the albinotic spots. In all three eyes with congenital grouped albinotic spots, FAF imaging showed autofluorescent spots corresponding to the albinotic spots seen on stereo biomicroscopy. One eye also had additional spots detected on FAF imaging that were not visible on stereo biomicroscopy or color fundus photographs. Fundus autofluorescence imaging of the spots showed decreased general autofluorescence and decreased peripheral autofluorescence surrounding central areas of retained or increased autofluorescence. Optical coherence tomography showed a disruption in signal from the hyperreflective layer corresponding to the inner and outer segment junction and increased signal backscattering from the choroid in the area of the spots. Fluorescein angiography showed early and stable hyperfluorescence of the spots without leakage. In this case series, FAF showed decreased autofluorescence of the spots consistent with focal retinal pigment epithelium atrophy or abnormal material blocking normal autofluorescence and areas of increased autofluorescence suggesting retinal pigment epithelium dysfunction. The findings of optical coherence tomography and fluorescein angiography suggest photoreceptor and retinal pigment epithelium layer abnormalities. Fundus autofluorescence and optical coherence tomography are useful noninvasive diagnostic adjuncts that can aid in the diagnosis of congenital grouped albinotic spots, help determine extent of disease, and contribute to our understanding of its pathophysiology.

Demonstration of anatomical development of the human macula within the first 5 years of life using handheld OCT.

PubMed

Alabduljalil, Talal; Westall, Carol A; Reginald, Arun; Farsiu, Sina; Chiu, Stephanie J; Arshavsky, Alec; Toth, Cynthia A; Lam, Wai-Ching

2018-06-23

To demonstrate the anatomical development of the human macula using handheld spectral domain optical coherence tomography (SD-OCT) during the first 5 years of life. This study is a cross-sectional, observational case series. Thirty-five normal eyes of 35 full-term/late preterm infants and children under 5 years of age were included. Handheld SD-OCT was used to image the macula of each eye. The data were analyzed using the Duke OCT Retinal Analysis Program v17 software. Retinal thickness maps were generated for the total retinal thickness (TRT), the inner retinal layers thickness (IRL), and the photoreceptor layer thickness (PRL). Based on the early treatment diabetic retinopathy study macular map, average thickness measurements were taken at 4 circles centered on the fovea (diameter): the foveal center (0.5 mm), sector 1 (S1) (1 mm), sector 2 (S2) (3 mm), sector 3 (S3) (6 mm). The median age at participation was 24 months (range 5-52 months). The TRT increased throughout the first 5 years of life, and this increase was statistically significant at the foveal center and S1 (p = 0.01, p = 0.016, respectively). The IRL did not show any significant change in thickness from birth and throughout the first 5 years of life. The PRL thickness showed thickening in the first 24 months of age at the foveal center and S1 which was statistically significant at S1 (p = 0.066, p = 0.016, respectively). Interestingly, this PRL thickness increase plateaus beyond 24 months of age. The photoreceptors inner segment/outer segment (IS/OS) band was identified as a distinct layer in all our subjects. Our findings conform with the literature that the anatomical development of the macular IRL completes before 5 months of age and hence before the PRL. We also identify 24 months of age as an important developmental milestone for photoreceptors development in the human macula.

[Retinal whitening following vitrectomy for epiretinal macular membrane].

PubMed

Uemura, A

1993-09-01

To investigate the clinical pictures of retinal whitening following epiretinal membrane dissection. I studied retrospectively the records of 18 eyes which had undergone vitrectomy. Two types of retinal whitening were observed: cotton wool-like spots within the superficial retinal layers and a linear or dendritic pattern within the deep retinal layers. The spots were mainly noted in idiopathic cases and resolved completely in a few weeks, and the pattern was observed in macular pucker cases after retinal detachment surgery and persisted for a long time after vitrectomy.

Turbine airfoil with a compliant outer wall

DOEpatents

Campbell, Christian X [Oviedo, FL; Morrison, Jay A [Oviedo, FL

2012-04-03

A turbine airfoil usable in a turbine engine with a cooling system and a compliant dual wall configuration configured to enable thermal expansion between inner and outer layers while eliminating stress formation in the outer layer is disclosed. The compliant dual wall configuration may be formed a dual wall formed from inner and outer layers separated by a support structure. The outer layer may be a compliant layer configured such that the outer layer may thermally expand and thereby reduce the stress within the outer layer. The outer layer may be formed from a nonplanar surface configured to thermally expand. In another embodiment, the outer layer may be planar and include a plurality of slots enabling unrestricted thermal expansion in a direction aligned with the outer layer.

Maculopathy due to drug inhalation.

PubMed

Asensio-Sánchez, V M; Gonzalez-Buendia, L; Marcos-Fernández, M

2014-08-01

A case of maculopathy due to "poppers" is described. Poppers is a drug composed of various forms of alkyl nitrite. A 39 year-old man, who had been using poppers for years, was seen in the clinic with phosphenes, reduced visual acuity and central scotoma. The SD-OCT in the right eye showed disruption at the level of the IS/OS junction line. The SD-OCT scan in the left eye showed an outer rectangular retinal hole and an outer retinal cyst. Copyright © 2012 Sociedad Española de Oftalmología. Published by Elsevier Espana. All rights reserved.

Multimodal imaging of the disease progression of birdshot chorioretinopathy.

PubMed

Teussink, Michel M; Huis In Het Veld, Paulien I; de Vries, Lieuwe A M; Hoyng, Carel B; Klevering, B Jeroen; Theelen, Thomas

2016-12-01

To study outer retinal deterioration in relation to clinical disease activity in patients with birdshot chorioretinopathy using fundus autofluorescence and spectral-domain optical coherence tomography (OCT). A single-centre retrospective cohort study was carried out on 42 eyes of 21 patients with birdshot disease, using a multimodal imaging approach including fundus autofluorescence, OCT, fluorescein angiography and indocyanine green angiography in combination with a patient chart review. The patients' overall clinical activity of retinal vasculitis during the follow-up period was determined by periods of clinical activity as indicated by fluorescein angiography and associated treatment decisions. Image analysis was performed to examine the spatial correspondence between autofluorescence changes and disruption of the photoreceptor inner segment ellipsoid zone on OCT. Three common types of outer retinal lesions were observed in fovea-centred images of 43% of patients: circular patches of chorioretinal atrophy, ellipsoid zone disruption on OCT, and outer retinal atrophy on autofluorescence and OCT. There was good spatial correspondence between ellipsoid zone disruption and areas of diffuse hyper-autofluorescence outside the fovea. Interestingly, the ellipsoid zone disruption recovered in four out of seven patients upon intensified therapeutic immunosuppression. Most patients only developed peripapillary atrophy and occasional perivascular hypo-autofluorescence. A multimodal imaging approach with autofluorescence imaging and OCT may help to detect ellipsoid zone disruption in the central retina of patients with birdshot disease. Our results suggest that ellipsoid zone disruption may be related to both the activity and duration of retinal vasculitis, and could help to determine therapeutic success in birdshot disease. © 2016 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

Rod Photopigment Kinetics After Photodisruption of the Retinal Pigment Epithelium

PubMed Central

Masella, Benjamin D.; Hunter, Jennifer J.; Williams, David R.

2014-01-01

Purpose. Advances in retinal imaging have led to the discovery of long-lasting retinal changes caused by light exposures below published safety limits, including disruption of the RPE. To investigate the functional consequences of RPE disruption, we combined adaptive optics ophthalmoscopy with retinal densitometry. Methods. A modified adaptive optics scanning light ophthalmoscope (AOSLO) measured the apparent density and regeneration rate of rhodopsin in two macaques before and after four different 568-nm retinal radiant exposures (RREs; 400–3200 J/cm2). Optical coherence tomography (OCT) was used to measure the optical path length through the photoreceptor outer segments before and after RPE disruption. Results. All tested RREs caused visible RPE disruption. Apparent rhodopsin density was significantly reduced following 1600 (P = 0.01) and 3200 J/cm2 (P = 0.007) exposures. No significant change in apparent density was observed in response to 800 J/cm2. Surprisingly, exposure to 400 J/cm2 showed a significant increase in apparent density (P = 0.047). Rhodopsin recovery rate was not significantly affected by these RREs. Optical coherence tomography measurements showed a significant decrease in the optical path length through the photoreceptor outer segments for RREs above 800 J/cm2 (P < 0.001). Conclusions. At higher RREs, optical path length through the outer segments was reduced. However, the rate of photopigment regeneration was unchanged. While some ambiguity remains as to the correlation between measured reflectivity and absolute rhodopsin density; at the lowest RREs, RPE disruption appears not to be accompanied by a loss of apparent rhodopsin density, which would have been indicative of functional loss. PMID:25316724

Defining the Catalytic Activity of Nanoceria in the P23H-1 Rat, a Photoreceptor Degeneration Model

PubMed Central

Wong, Lily L.; Pye, Quentin N.; Chen, Lijuan; Seal, Sudipta; McGinnis, James F.

2015-01-01

Purpose Inorganic catalytic nanoceria or cerium oxide nanoparticles (CeNPs) are bona fide antioxidants that possess regenerative radical scavenging activities in vitro. Previously, we demonstrated that CeNPs had neuroprotective and anti-angiogenic properties in rodent retinal degeneration and neovascularization models. However, the cellular mechanisms and duration of the catalytic activity of CeNPs in preventing photoreceptor cell loss are still unknown. In this study, we sought to answer these questions using the P23H-1 rat, an autosomal dominant retinitis pigmentosa (adRP) model. Methods A single dose of either saline or CeNPs was delivered intravitreally into the eyes of P23H-1 rats at 2–3 weeks of age. Retinal functions were examined at 3 to 7 weeks post injection. We quantified retinal proteins by Western blot analyses and counted the number of apoptotic (TUNEL+) profiles in the outer nuclear layer (ONL) of retinal sections. We measured free 8-isoprostanes to quantify lipid peroxidation in retinal tissues. Results We observed increased rod and cone cell functions up to three weeks post injection. Apoptotic cells were reduced by 46%, 56%, 21%, and 24% at 3, 7, 14, 21 days, respectively, after CeNPs injection compared to saline. Additionally, reduction of lipid peroxidation in the retinas of CeNPs-treated vs saline-treated animals was detected 14 days post injection. Conclusions We validated that CeNPs were effective in delaying loss of photoreceptor cell function in an adRP rat model. This represents the fourth rodent retinal disease model that shows delay in disease progression after a single application of CeNPs. We further demonstrated that CeNPs slowed the rate of photoreceptor cell death. We deduced that the catalytic activity of CeNPs in vivo in this rat model to be undiminished for at least 7 days and then declined over the next 14 days after CeNPs administration. PMID:25822196

Clearance of apoptotic photoreceptors: elimination of apoptotic debris into the subretinal space and macrophage-mediated phagocytosis via phosphatidylserine receptor and integrin alphavbeta3.

PubMed

Hisatomi, Toshio; Sakamoto, Taiji; Sonoda, Koh-Hei; Tsutsumi, Chikako; Qiao, Hong; Enaida, Hiroshi; Yamanaka, Ichiro; Kubota, Toshiaki; Ishibashi, Tatsuro; Kura, Shinobu; Susin, Santos A; Kroemer, Guido

2003-06-01

The effective phagocytotic clearance of apoptotic debris is fundamental to the maintenance of neural tissues during apoptosis. Retinal photoreceptors undergo apoptosis after retinal detachment. Although their induction phase of apoptosis has been well discussed, their phagocytotic process remains quite unclear. We herein demonstrate that apoptotic photoreceptors are selectively eliminated from their physiological localization, the outer nuclear layer, to the subretinal space, and then phagocytosed by monocyte-derived macrophages. This could be shown by an ultrastructural and immunophenotypic analysis. Moreover, in chimera mice expressing transgenic green fluorescent protein in bone marrow-derived cells, the local infiltration of macrophages could be detected after retinal detachment-induced photoreceptor apoptosis. The local injection of an antibody blocking the phosphatidylserine receptor (PSR) or a peptide (GRGDSP)-blocking integrin alphavbeta3 revealed that phagocytotic clearance involves the PSR as well as integrin alphavbeta3 in vivo. Importantly, the level of blockade obtained with these reagents was different. Although anti-PSR increased the frequency of apoptotic cells that fail to bind to macrophages, GRGDSP prevented the engulfment (but not the recognition) of apoptotic photoreceptor cells by macrophages. To our knowledge, this is the first report describing the mechanisms through which apoptotic photoreceptors are selectively eliminated via a directional process in the subretinal space.

OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY SHOWS INNER CHOROIDAL ISCHEMIA IN ACUTE POSTERIOR MULTIFOCAL PLACOID PIGMENT EPITHELIOPATHY.

PubMed

Dolz-Marco, Rosa; Sarraf, David; Giovinazzo, Vincent; Freund, K Bailey

2017-01-01

To describe multimodal imaging findings of an evolving case of acute posterior multifocal placoid pigment epitheliopathy occurring in a young healthy male. Case report of a patient with acute posterior multifocal placoid pigment epitheliopathy including comprehensive systemic and ocular examinations. Ultra-widefield autofluorescence, fluorescein angiography, indocyanine green angiography, and serial optical coherence tomography angiography were performed. A 34-year-old male presented with acute vision loss in his left eye for 2 weeks. His best-corrected visual acuity was 20/20 in his right eye and 20/200 in his left eye. Dilated funduscopic examination revealed multiple creamy white deep retinal lesions showing macular involvement of the left eye with a diffuse area of pigmentary changes. The presence of multiple areas of hypoperfusion of the inner choroid were demonstrated with fluorescein and indocyanine green angiography. Serial optical coherence tomography angiography showed multiple evolving areas of decreased flow at the level of the inner choroid. Although the pathogenesis of acute posterior multifocal placoid pigment epitheliopathy remains unknown, there is growing evidence of a primary choroidal involvement with secondary damage to the overlying retinal pigment epithelium and the outer retinal layers. Optical coherence tomography angiography may provide valuable information for the diagnosis and follow-up of this condition avoiding invasive angiographic procedures.

Clearance of Apoptotic Photoreceptors

PubMed Central

Hisatomi, Toshio; Sakamoto, Taiji; Sonoda, Koh-hei; Tsutsumi, Chikako; Qiao, Hong; Enaida, Hiroshi; Yamanaka, Ichiro; Kubota, Toshiaki; Ishibashi, Tatsuro; Kura, Shinobu; Susin, Santos A.; Kroemer, Guido

2003-01-01

The effective phagocytotic clearance of apoptotic debris is fundamental to the maintenance of neural tissues during apoptosis. Retinal photoreceptors undergo apoptosis after retinal detachment. Although their induction phase of apoptosis has been well discussed, their phagocytotic process remains quite unclear. We herein demonstrate that apoptotic photoreceptors are selectively eliminated from their physiological localization, the outer nuclear layer, to the subretinal space, and then phagocytosed by monocyte-derived macrophages. This could be shown by an ultrastructural and immunophenotypic analysis. Moreover, in chimera mice expressing transgenic green fluorescent protein in bone marrow-derived cells, the local infiltration of macrophages could be detected after retinal detachment-induced photoreceptor apoptosis. The local injection of an antibody blocking the phosphatidylserine receptor (PSR) or a peptide (GRGDSP)-blocking integrin αvβ3 revealed that phagocytotic clearance involves the PSR as well as integrin αvβ3 in vivo. Importantly, the level of blockade obtained with these reagents was different. Although anti-PSR increased the frequency of apoptotic cells that fail to bind to macrophages, GRGDSP prevented the engulfment (but not the recognition) of apoptotic photoreceptor cells by macrophages. To our knowledge, this is the first report describing the mechanisms through which apoptotic photoreceptors are selectively eliminated via a directional process in the subretinal space. PMID:12759244

Short-wavelength cone-opponent retinal ganglion cells in mammals.

PubMed

Marshak, David W; Mills, Stephen L

2014-03-01

In all of the mammalian species studied to date, the short-wavelength-sensitive (S) cones and the S-cone bipolar cells that receive their input are very similar, but the retinal ganglion cells that receive synapses from the S-cone bipolar cells appear to be quite different. Here, we review the literature on mammalian retinal ganglion cells that respond selectively to stimulation of S-cones and respond with opposite polarity to longer wavelength stimuli. There are at least three basic mechanisms to generate these color-opponent responses, including: (1) opponency is generated in the outer plexiform layer by horizontal cells and is conveyed to the ganglion cells via S-cone bipolar cells, (2) inputs from bipolar cells with different cone inputs and opposite response polarity converge directly on the ganglion cells, and (3) inputs from S-cone bipolar cells are inverted by S-cone amacrine cells. These are not mutually exclusive; some mammalian ganglion cells that respond selectively to S-cone stimulation seem to utilize at least two of them. Based on these findings, we suggest that the small bistratified ganglion cells described in primates are not the ancestral type, as proposed previously. Instead, the known types of ganglion cells in this pathway evolved from monostratified ancestral types and became bistratified in some mammalian lineages.

Investigation of alterations in multifractality in optical coherence tomographic images of in vivo human retina

NASA Astrophysics Data System (ADS)

Das, Nandan Kumar; Mukhopadhyay, Sabyasachi; Ghosh, Nirmalya; Chhablani, Jay; Richhariya, Ashutosh; Divakar Rao, Kompalli; Sahoo, Naba Kishore

2016-09-01

Optical coherence tomography (OCT) enables us to monitor alterations in the thickness of the retinal layer as disease progresses in the human retina. However, subtle morphological changes in the retinal layers due to early disease progression often may not lead to detectable alterations in the thickness. OCT images encode depth-dependent backscattered intensity distribution arising due to the depth distributions of the refractive index from tissue microstructures. Here, such depth-resolved refractive index variations of different retinal layers were analyzed using multifractal detrended fluctuation analysis, a special class of multiresolution analysis tools. The analysis extracted and quantified microstructural multifractal information encoded in normal as well as diseased human retinal OCT images acquired in vivo. Interestingly, different layers of the retina exhibited different degrees of multifractality in a particular retina, and the individual layers displayed consistent multifractal trends in healthy retinas of different human subjects. In the retinal layers of diabetic macular edema (DME) subjects, the change in multifractality manifested prominently near the boundary of the DME as compared to the normal retinal layers. The demonstrated ability to quantify depth-resolved information on multifractality encoded in OCT images appears promising for the early diagnosis of diseases of the human eye, which may also prove useful for detecting other types of tissue abnormalities from OCT images.

Vitrectomy for optic disk pit with macular schisis and outer retinal dehiscence.

PubMed

Shukla, Dhananjay; Kalliath, Jay; Tandon, Manish; Vijayakumar, Balakrishnan

2012-07-01

To describe the outcomes of vitrectomy for optic disc pit-related maculopathy with central outer retinal dehiscence. This prospective interventional case series included seven patients with optic disc pit with macular schisis and central outer retinal dehiscence who underwent vitrectomy with internal limiting membrane peeling, barrage laser photocoagulation, and gas tamponade and were followed for at least 6 months. The surgical outcomes in terms of restoration of macular anatomy and visual improvement were recorded at each visit by fundus photography and optical coherence tomography. The mean age of the patients was 21.3 ± 8.6 years (range, 10-35 years), and the mean duration of defective vision was 6.7 ± 8.5 months (range, 1-24 months). Preoperatively, the median best-corrected visual acuity (BCVA) was 20/60 (range, 20/40 to 20/120). Full-thickness macular holes were noticed in 4 patients 1 month postoperatively. Gas tamponade was repeated in two patients with large macular holes. By the final follow-up, macular holes had closed and BCVA improved in all patients except one. Final mean central macular thickness was 176.83 ± 55.74 μ, the range being 109 μ to 256 μ. The median postoperative BCVA was 20/30 (range, 20/20 to 20/80). Six of 7 patients (85.7%) had improvement in BCVA postoperatively (mean, +2 lines; range, 1-4 lines). Five patients (71%) achieved a postoperative BCVA of ≥20/30. Best-corrected visual acuity dropped by one line in the patient with persistent macular hole. Vitrectomy with internal limiting membrane peeling can achieve excellent final surgical outcomes in optic pit maculopathy with outer retinal dehiscence despite the potential for macular hole formation.

Loss of ift122, a Retrograde Intraflagellar Transport (IFT) Complex Component, Leads to Slow, Progressive Photoreceptor Degeneration Due to Inefficient Opsin Transport.

PubMed

Boubakri, Meriam; Chaya, Taro; Hirata, Hiromi; Kajimura, Naoko; Kuwahara, Ryusuke; Ueno, Akiko; Malicki, Jarema; Furukawa, Takahisa; Omori, Yoshihiro

2016-11-18

In the retina, aberrant opsin transport from cell bodies to outer segments leads to retinal degenerative diseases such as retinitis pigmentosa. Opsin transport is facilitated by the intraflagellar transport (IFT) system that mediates the bidirectional movement of proteins within cilia. In contrast to functions of the anterograde transport executed by IFT complex B (IFT-B), the precise functions of the retrograde transport mediated by IFT complex A (IFT-A) have not been well studied in photoreceptor cilia. Here, we analyzed developing zebrafish larvae carrying a null mutation in ift122 encoding a component of IFT-A. ift122 mutant larvae show unexpectedly mild phenotypes, compared with those of mutants defective in IFT-B. ift122 mutants exhibit a slow onset of progressive photoreceptor degeneration mainly after 7 days post-fertilization. ift122 mutant larvae also develop cystic kidney but not curly body, both of which are typically observed in various ciliary mutants. ift122 mutants display a loss of cilia in the inner ear hair cells and nasal pit epithelia. Loss of ift122 causes disorganization of outer segment discs. Ectopic accumulation of an IFT-B component, ift88, is observed in the ift122 mutant photoreceptor cilia. In addition, pulse-chase experiments using GFP-opsin fusion proteins revealed that ift122 is required for the efficient transport of opsin and the distal elongation of outer segments. These results show that IFT-A is essential for the efficient transport of outer segment proteins, including opsin, and for the survival of retinal photoreceptor cells, rendering the ift122 mutant a unique model for human retinal degenerative diseases. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Loss of ift122, a Retrograde Intraflagellar Transport (IFT) Complex Component, Leads to Slow, Progressive Photoreceptor Degeneration Due to Inefficient Opsin Transport*

PubMed Central

Boubakri, Meriam; Chaya, Taro; Hirata, Hiromi; Kajimura, Naoko; Kuwahara, Ryusuke; Ueno, Akiko; Malicki, Jarema; Furukawa, Takahisa; Omori, Yoshihiro

2016-01-01

In the retina, aberrant opsin transport from cell bodies to outer segments leads to retinal degenerative diseases such as retinitis pigmentosa. Opsin transport is facilitated by the intraflagellar transport (IFT) system that mediates the bidirectional movement of proteins within cilia. In contrast to functions of the anterograde transport executed by IFT complex B (IFT-B), the precise functions of the retrograde transport mediated by IFT complex A (IFT-A) have not been well studied in photoreceptor cilia. Here, we analyzed developing zebrafish larvae carrying a null mutation in ift122 encoding a component of IFT-A. ift122 mutant larvae show unexpectedly mild phenotypes, compared with those of mutants defective in IFT-B. ift122 mutants exhibit a slow onset of progressive photoreceptor degeneration mainly after 7 days post-fertilization. ift122 mutant larvae also develop cystic kidney but not curly body, both of which are typically observed in various ciliary mutants. ift122 mutants display a loss of cilia in the inner ear hair cells and nasal pit epithelia. Loss of ift122 causes disorganization of outer segment discs. Ectopic accumulation of an IFT-B component, ift88, is observed in the ift122 mutant photoreceptor cilia. In addition, pulse-chase experiments using GFP-opsin fusion proteins revealed that ift122 is required for the efficient transport of opsin and the distal elongation of outer segments. These results show that IFT-A is essential for the efficient transport of outer segment proteins, including opsin, and for the survival of retinal photoreceptor cells, rendering the ift122 mutant a unique model for human retinal degenerative diseases. PMID:27681595

[Early macular edema after phacoemulsification and suspected overdose of cefuroxime: report of six cases].

PubMed

Le Dû, B; Pierre-Kahn, V

2014-03-01

Antibiotic prophylaxis by intracameral cefuroxime injection, 1mg/0.1 mL after cataract surgery is increasing in popularity. Several cases of early postoperative macular edema have recently been reported after cefuroxime injection, most of them due to accidental cefuroxime overdose. We report six additional cases of macular involvement after cataract surgery, with intracameral cefuroxime injection imputed to cause retinal toxicity. Formal proof of cefuroxime overdose has never been possible, due to rapid wash-out in a few hours and the diagnosis of the macular edema the day after surgery or within a few days. Thus, this strong suspicion is based on clinical, pharmacokinetic, tomographic and retinographic criteria. In our series of six cases, the first four patients involved the same surgeon in the same hospital, and two of them on the same day. For the sixth case, the diagnosis was made retrospectively and based on history and medium-term tomographic characteristics. All the patients underwent optical coherence tomography (OCT) relatively early. As early as day one after surgery, there is macular edema predominantly in the outer retinal layers associated with serous retinal detachment, similar to the cases described in the literature. In the late stage, three patients had functional impairment related to photoreceptor damage on OCT. Three cases are described with additional retinal imaging (angiography, autofluorescence) to better characterize this macular toxicity associated with cefuroxime. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Structural recovery of the retina in a retinoschisin-deficient mouse after gene replacement therapy by solid lipid nanoparticles.

PubMed

Apaolaza, P S; Del Pozo-Rodríguez, A; Solinís, M A; Rodríguez, J M; Friedrich, U; Torrecilla, J; Weber, B H F; Rodríguez-Gascón, A

2016-06-01

X-linked juvenile retinoschisis (XLRS) is a retinal degenerative disorder caused by mutations in the RS1 gene encoding a protein termed retinoschisin. The disease is an excellent candidate for gene replacement therapy as the majority of mutations have been shown to lead to a complete deficiency of the secreted protein in the retinal structures. In this work, we have studied the ability of non-viral vectors based on solid lipid nanoparticles (SLN) to induce the expression of retinoschisin in photoreceptors (PR) after intravitreal administration to Rs1h-deficient mice. We designed two vectors prepared with SLN, protamine, and dextran (DX) or hyaluronic acid (HA), bearing a plasmid containing the human RS1 gene under the control of the murin opsin promoter (mOPS). In vitro, the nanocarriers were able to induce the expression of retinoschisin in a PR cell line. After injection into the murine vitreous, the formulation prepared with HA induced a higher transfection level in PR than the formulation prepared with DX. Moreover, the level of retinoschisin in the inner nuclear layer (INL), where bipolar cells are located, was also higher. Two weeks after vitreal administration into Rs1h-deficient mice, both formulations showed significant improvement of the retinal structure by inducing a decrease of cavities and PR loss, and an increase of retinal and outer nuclear layer (ONL) thickness. HA-SLN resulted in a significant higher increase in the thickness of both retina and ONL, which can be explained by the higher transfection level of PR. In conclusion, we have shown the structural improvement of the retina of Rs1h-deficient mice with PR specific expression of the RS1 gene driven by the specific promoter mOPS, after successful delivery via SLN-based non-viral vectors. Copyright © 2016 Elsevier Ltd. All rights reserved.

MICROSTRUCTURAL ABNORMALITIES IN MEWDS DEMONSTRATED BY ULTRAHIGH RESOLUTION OPTICAL COHERENCE TOMOGRAPHY

PubMed Central

NGUYEN, MY HANH T.; WITKIN, ANDRE J.; REICHEL, ELIAS; KO, TONY H.; FUJIMOTO, JAMES G.; SCHUMAN, JOEL S.; DUKER, JAY S.

2007-01-01

Background Histopathological studies of acute multiple evanescent white dot syndrome (MEWDS) have not been reported because of the transient and benign nature of the disease. Ultrahigh resolution optical coherence tomography (UHR-OCT), capable of high resolution in vivo imaging, offers a unique opportunity to visualize retinal microstructure in the disease. Methods UHR-OCT images of the maculae of five patients with MEWDS were obtained and analyzed. Diagnosis was based on clinical presentation, examination, visual field testing, and angiography. Results UHR-OCT revealed disturbances in the photoreceptor inner/outer segment junction (IS/OS) in each of the five patients (six eyes) with MEWDS. In addition, thinning of the outer nuclear layer was seen in the case of recurrent MEWDS, suggesting that repeated episodes of MEWDS may result in photoreceptor atrophy. Conclusions Subtle disruptions of the photoreceptor IS/OS are demonstrated in all eyes affected by MEWDS. UHR-OCT may be a useful adjunct to diagnosis and monitoring of MEWDS. PMID:17420691

Tissue inhibitor of metalloproteinases 1 enhances rod survival in the rd1 mouse retina.

PubMed

Kim, Hwa Sun; Vargas, Andrew; Eom, Yun Sung; Li, Justin; Yamamoto, Kyra L; Craft, Cheryl Mae; Lee, Eun-Jin

2018-01-01

Retinitis pigmentosa (RP), an inherited retinal degenerative disease, is characterized by a progressive loss of rod photoreceptors followed by loss of cone photoreceptors. Previously, when tissue inhibitor of metalloproteinase 1 (TIMP1), a key extracellular matrix (ECM) regulator that binds to and inhibits activation of Matrix metallopeptidase 9 (MMP9) was intravitreal injected into eyes of a transgenic rhodopsin rat model of RP, S334ter-line3, we discovered cone outer segments are partially protected. In parallel, we reported that a specific MMP9 and MMP2 inhibitor, SB-3CT, interferes with mechanisms leading to rod photoreceptor cell death in an MMP9 dependent manner. Here, we extend our initial rat studies to examine the potential of TIMP1 as a treatment in retinal degeneration by investigating neuroprotective effects in a classic mouse retinal degeneration model, rdPde6b-/- (rd1). The results clearly demonstrate that intravitreal injections of TIMP1 produce extended protection to delay rod photoreceptor cell death. The mean total number of rods in whole-mount retinas was significantly greater in TIMP-treated rd1 retinas (postnatal (P) 30, P35 (P<0.0001) and P45 (P<0.05) than in saline-treated rd1 retinas. In contrast, SB-3CT did not delay rod cell death, leading us to further investigate alternative pathways that do not involve MMPs. In addition to inducing phosphorylated ERK1/2, TIMP1 significantly reduces BAX activity and delays attenuation of the outer nuclear layer (ONL). Physiological responses using scotopic electroretinograms (ERG) reveal b-wave amplitudes from TIMP1-treated retinas are significantly greater than from saline-treated rd1 retinas (P<0.05). In later degenerative stages of rd1 retinas, photopic b-wave amplitudes from TIMP1-treated rd1 retinas are significantly larger than from saline-treated rd1 retinas (P<0.05). Our findings demonstrate that TIMP1 delays photoreceptor cell death. Furthermore, this study provides new insights into how TIMP1 works in the mouse animal model of RP.

Postnatal development of retinal projections in the brushtailed possum, Trichosurus vulpecula.

PubMed

Sanderson, K J; Dixon, P G; Pearson, L J

1982-10-01

The postnatal development of retinal projections was studied in the brushtailed possum, Trichosurus vulpecula. [3H]proline was injected into one eye of 13 young possums aged 24-84 days in order to trace retinal pathways. The dorsal lateral geniculate nucleus (LGNd) can be identified in Nissl material at 19 days but not at 9-10 days. By 40 days some cytoarchitectural lamination of the LGNd is apparent and by 71 days the adult pattern of cell layers is present. At 24 days retinal fibers occupy by lateral part of the LGNd on both sides of the brain. By 38-40 days the retinal fibers fill be contralateral LGNd and the binocular part of the ipsilateral LGNd and there is a beginning of the segregation of retinal fibers into left and right eye territories. By 49-50 days a partial segregation is achieved, and complete segregation by 71 days. At 9-10 days the superior colliculus is not differentiated into layers and there is a thick zone of cell proliferation around the ventricle. By 23 days the superior colliculus has well-defined cell layers and there is still some indication of cell proliferation around the ventricle. By 40 days, the superior colliculus shows little evidence of cell proliferation. At 24 days retinal fibers fill the superficial layers of the contralateral optic tectum and are lightly distributed through the superficial layers of the rostral half of the ipsilateral tectum. By 38 days the ipsilateral retinal input is restricted to the deeper layers of the tectum. These results show that the adult pattern of retinal projections to the LGNd and optic tectum develops a number of weeks before eye opening occurs (at 90-120 days).

High-resolution optical coherence tomography, autofluorescence, and infrared reflectance imaging in Sjögren reticular dystrophy.

PubMed

Schauwvlieghe, Pieter-Paul; Torre, Kara Della; Coppieters, Frauke; Van Hoey, Anneleen; De Baere, Elfride; De Zaeytijd, Julie; Leroy, Bart P; Brodie, Scott E

2013-01-01

To describe the phenotype of three cases of Sjögren reticular dystrophy in detail, including high-resolution optical coherence tomography, autofluorescence imaging, and near-infrared reflectance imaging. Two unrelated teenagers were independently referred for ophthalmologic evaluation. Both underwent a full ophthalmologic workup, including electrophysiologic and extensive imaging with spectral-domain optical coherence tomography, autofluorescence imaging, and near-infrared reflectance imaging. In addition, mutation screening of ABCA4, PRPH2, and the mitochondrial tRNA gene was performed in Patient 1. Subsequently, the teenage sister of Patient 2 was examined. Strikingly similar phenotypes were present in these three patients. Fundoscopy showed bilateral foveal pigment alterations, and a lobular network of deep retinal, pigmented deposits throughout the posterior pole, tapering toward the midperiphery, with relative sparing of the immediate perifoveal macula and peripapillary area. This network is mildly to moderately hyperautofluorescent on autofluorescence and bright on near-infrared reflectance imaging. Optical coherence tomography showed abnormalities of the retinal pigment epithelium-Bruch membrane complex, photoreceptor outer segments, and photoreceptor inner/outer segment interface. The results of retinal function test were entirely normal. No molecular cause was detected in Patient 1. Imaging suggested that the lobular network of deep retinal deposits in Sjögren reticular dystrophy is the result of accumulation of both pigment and lipofuscin between photoreceptors and retinal pigment epithelium, as well as within the retinal pigment epithelium.

Segmentation of the macular choroid in OCT images acquired at 830nm and 1060nm

NASA Astrophysics Data System (ADS)

Lee, Sieun; Beg, Mirza F.; Sarunic, Marinko V.

2013-06-01

Retinal imaging with optical coherence tomography (OCT) has rapidly advanced in ophthalmic applications with the broad availability of Fourier domain (FD) technology in commercial systems. The high sensitivity afforded by FD-OCT has enabled imaging of the choroid, a layer of blood vessels serving the outer retina. Improved visualization of the choroid and the choroid-sclera boundary has been investigated using techniques such as enhanced depth imaging (EDI), and also with OCT systems operating in the 1060-nm wavelength range. We report on a comparison of imaging the macular choroid with commercial and prototype OCT systems, and present automated 3D segmentation of the choroid-scleral layer using a graph cut algorithm. The thickness of the choroid is an important measurement to investigate for possible correlation with severity, or possibly early diagnosis, of diseases such as age-related macular degeneration.

Retinal degeneration in cats fed casein. IV. The early receptor potential.

PubMed

Berson, E L; Watson, G; Grasse, K L; Szamier, R B

1981-08-01

Electroretinographic studies of casein-fed cats with retinal taurine deficiency revealed that the early receptor potential (ERP) was initially normal in amplitude at a time when the a-wave and b-wave of the electroretinogram were substantially reduced or even nondetectable. The preserved ERP's in these taurine-deficient cats could be correlated with the histologic finding that their outer segments were relatively intact over 90% of the retinal area subtended by the test flash. The sequence of electroretinographic changes in these taurine-deficient cats was also consistent with previous biochemical studies on the normal cat retina that have shown a relatively low concentration of taurine at the level of the outer segments and a higher concentration at the level of the inner segments. The responses in early stages from taurine-deficient cats differed from the responses obtained from vitamin A--deficient cats but resembled those from cats that received an intravitreal injection of ouabain. Similarities and a difference between the responses of taurine-deficient cats and those of patients with early retinitis pigmentosa are considered.

Automated detection of retinal layers from OCT spectral-domain images of healthy eyes

NASA Astrophysics Data System (ADS)

Giovinco, Gaspare; Savastano, Maria Cristina; Ventre, Salvatore; Tamburrino, Antonello

2015-12-01

Optical coherence tomography (OCT) has become one of the most relevant diagnostic tools for retinal diseases. Besides being a non-invasive technique, one distinguished feature is its unique capability of providing (in vivo) cross-sectional view of the retina. Specifically, OCT images show the retinal layers. From the clinical point of view, the identification of the retinal layers opens new perspectives to study the correlation between morphological and functional aspects of the retinal tissue. The main contribution of this paper is a new method/algorithm for the automated segmentation of cross-sectional images of the retina of healthy eyes, obtained by means of spectral-domain optical coherence tomography (SD-OCT). Specifically, the proposed segmentation algorithm provides the automated detection of different retinal layers. Tests on experimental SD-OCT scans performed by three different instruments/manufacturers have been successfully carried out and compared to a manual segmentation made by an independent ophthalmologist, showing the generality and the effectiveness of the proposed method.

Optical coherence tomography in retinitis pigmentosa: reproducibility and capacity to detect macular and retinal nerve fiber layer thickness alterations.

PubMed

Garcia-Martin, Elena; Pinilla, Isabel; Sancho, Eva; Almarcegui, Carmen; Dolz, Isabel; Rodriguez-Mena, Diego; Fuertes, Isabel; Cuenca, Nicolas

2012-09-01

To evaluate the ability of time-domain and Fourier-domain optical coherence tomographies (OCTs) to detect macular and retinal nerve fiber layer atrophies in retinitis pigmentosa (RP). To test the intrasession reproducibility using three OCT instruments (Stratus, Cirrus, and Spectralis). Eighty eyes of 80 subjects (40 RP patients and 40 healthy subjects) underwent a visual field examination, together with 3 macular scans and 3 optic disk evaluations by the same experienced examiner using 3 OCT instruments. Differences between healthy and RP eyes were compared. The relationship between measurements with each OCT instrument was evaluated. Repeatability was studied by intraclass correlation coefficients and coefficients of variation. Macular and retinal nerve fiber layer atrophies were detected in RP patients for all OCT parameters. Macular and retinal nerve fiber layer thicknesses, as determined by the different OCTs, were correlated but significantly different (P < 0.05). Reproducibility was moderately high using Stratus, good using Cirrus and Spectralis, and excellent using the Tru-track technology of Spectralis. In RP eyes, measurements showed higher variability compared with healthy eyes. Differences in thickness measurements existed between OCT instruments, despite there being a high degree of correlation. Fourier-domain OCT can be considered a valid and repeatability technique to detect retinal nerve fiber layer atrophy in RP patients.

Biochemical Measurements of Free Opsin in Macular Degeneration Eyes: Examining the 11-CIS Retinal Deficiency Hypothesis of Delayed Dark Adaptation (An American Ophthalmological Society Thesis).

PubMed

Hanneken, Anne; Neikirk, Thomas; Johnson, Jennifer; Kono, Masahiro

2017-08-01

To test the hypothesis that delayed dark adaptation in patients with macular degeneration is due to an excess of free unliganded opsin (apo-opsin) and a deficiency of the visual chromophore, 11 -cis retinal, in rod outer segments. A total of 50 human autopsy eyes were harvested from donors with and without macular degeneration within 2-24 hrs. postmortem. Protocols were developed which permitted dark adaptation of normal human eyes after death and enucleation. Biochemical methods of purifying rod outer segments were optimized and the concentration of rhodopsin and apo-opsin was measured with UV-visible scanning spectroscopy. The presence of apo-opsin was calculated by measuring the difference in the rhodopsin absorption spectra before and after the addition of 11 -cis retinal. A total of 20 normal eyes and 16 eyes from donors with early, intermediate and advanced stages of macular degeneration were included in the final analysis. Dark adaptation was achieved by harvesting whole globes in low light, transferring into dark (light-proof) canisters and dissecting the globes using infrared light and image converters for visualization. Apo-opsin was readily detected in positive controls after the addition of 11 -cis retinal. Normal autopsy eyes showed no evidence of apo-opsin. Eyes with macular degeneration also showed no evidence of apo-opsin, regardless of the severity of disease. Methods have been developed to study dark adaptation in human autopsy eyes. Eyes with age-related macular degeneration do not show a deficiency of 11 -cis retinal or an excess of apo-opsin within rod outer segments.

Age, Sex, and Ethnic Variations in Inner and Outer Retinal and Choroidal Thickness on Spectral-Domain Optical Coherence Tomography.

PubMed

Bafiq, Rinoza; Mathew, Raeba; Pearce, Elizabeth; Abdel-Hey, Ahmed; Richardson, Matthew; Bailey, Thomas; Sivaprasad, Sobha

2015-11-01

To evaluate age, sex, and ethnic variations in inner and outer retinal and choroidal thickness and foveal pit, using spectral-domain optical coherence tomography (SD OCT). Single-center observational cross-sectional study. Ninety randomly selected, healthy individuals of white, black, and South Asian origin underwent SD OCT raster and enhanced depth imaging scan. Manual measurements of inner and outer retinal thickness and choroidal thickness up to 3 mm nasal and temporal to the fovea were performed. The age, sex, and ethnic differences in these parameters were analyzed. The mean inner retinal thickness was lower by approximately 12 μm in black subjects across the central retina compared to white subjects (P < .05). The central foveal thickness below the foveal pit was lower in eyes of blacks compared to South Asians (12 μm, P = .035) and white subjects (18 μm, P < .0001). The fovea was also significantly wider in eyes of black and South Asian subjects compared to white individuals. The inner retinal thickness decreased by 0.5 μm per year of age of subjects and was thinner by 6.1 μm (P < .02) in female compared to male subjects. The subfoveal choroidal thickness did not vary between ethnic groups but the temporal choroid was significantly thinner in black subjects (P < .05). The choroid showed an age-related decline in thickness of 2 μm per year of age of the subjects. Interethnic differences include wider fovea, lower central foveal thickness, and thinner inner retina in eyes of black subjects compared to their white and South Asian counterparts. Copyright © 2015 Elsevier Inc. All rights reserved.

Administration of novel dyes for intraocular surgery: an in vivo toxicity animal study.

PubMed

Schuettauf, Frank; Haritoglou, Christos; May, Christian A; Rejdak, Robert; Mankowska, Anna; Freyer, Wolfgang; Eibl, Kirsten; Zrenner, Eberhart; Kampik, Anselm; Thaler, Sebastian

2006-08-01

To investigate the effect of intravitreal injections of new vital dyes on the retina, the retinal pigment epithelium (RPE) and the choroid in an in vivo rat model. Rats were injected intravitreally with four dyes: light-green SF yellowish (LGSF), copper(II)phthalocyanine-tetrasulfonic acid (E68), bromphenol blue (BPB), and Chicago blue (CB) dissolved in physiologic saline solution (PSS) at concentrations of 0.5% and 0.02%. PSS served as the control. Additional animals were treated with single injections of 0.5%, 0.02%, 0.002%, and 0.0002% ICG or 0.002% E68 into one eye. Adverse effects on anterior and posterior segments were evaluated by slit lamp biomicroscopy and ophthalmoscopy. Retinal toxicity was assessed by histology and retinal ganglion cell (RGC) quantification 7 days after dye administration. Eyes treated with 0.5% E68, 0.5% ICG, or 0.5% CB showed discrete staining of both cornea and lens not seen at lower concentrations or with other dyes. Histology revealed dose-dependent reactions after E68 administration. ICG 0.5% induced significant thinning of inner retinal layers compared with PSS. ICG 0.02% caused focal degenerative changes of the outer retina in three of seven eyes, whereas 0.002% and 0.0002% ICG did not. CB led to heterogeneous morphologic alterations. BPB- or LGSF-treated eyes showed normal retinal morphology. ICG at all tested concentrations induced significant RGC loss, as did E68 at 0.5% but not at lower concentrations. BPB or LGSF produced no significantly detectable toxic effects on the retina in vivo. The safety of these new dyes must be established in other models and/or in preclinical studies before the clinical use of any of these dyes.

Correlation of Cytokine Levels and Microglial Cell Infiltration during Retinal Degeneration in RCS Rats

PubMed Central

Liu, Yong; Yang, Xuesen; Utheim, Tor Paaaske; Guo, Chenying; Xiao, Mingchun; Liu, Yan; Yin, Zhengqin; Ma, Jie

2013-01-01

Microglial cells, which are immunocompetent cells, are involved in all diseases of the central nervous system. During their activation in various diseases, a variety of soluble factors are released. In the present study, the correlation between cytokine levels and microglial cell migration in the course of retinal degeneration of Royal College of Surgeons (RCS) rats was evaluated. MFG-E8 and CD11b were used to confirm the microglial cells. In the retina of RCS rats, the mRNA expression of seven genes (MFG-E8 and its integrins αυ and ß5, CD11b and the cytokines TNF-α, IL-1ß, and MCP-1) formed almost similar bimodal peak distributions, which were centred at P7 and P45 to P60. In contrast, in rdy rats, which comprised the control group, a unimodal peak distribution centred at P14 was observed. The gene expression accompanied the activation and migration of microglial cells from the inner to the outer layer of the retina during the process of degeneration. Principal component analysis and discriminant function analysis revealed that the expression of these seven genes, especially TNF-α and CD11b, positively correlated with retinal degeneration and microglial activity during retinal degeneration in RCS rats, but not in the control rats. Furthermore, linear regression analysis demonstrated a significant correlation between the expression of these genes and the activation of microglial cells in the dystrophic retina. Our findings suggest that the suppression of microglial cells and the blockade of their cytotoxic effects may constitute a novel therapeutic strategy for treating photoreceptor death in various retinal disorders. PMID:24349184

Correlation of cytokine levels and microglial cell infiltration during retinal degeneration in RCS rats.

PubMed

Liu, Yong; Yang, Xuesen; Utheim, Tor Paaaske; Guo, Chenying; Xiao, Mingchun; Liu, Yan; Yin, Zhengqin; Ma, Jie

2013-01-01

Microglial cells, which are immunocompetent cells, are involved in all diseases of the central nervous system. During their activation in various diseases, a variety of soluble factors are released. In the present study, the correlation between cytokine levels and microglial cell migration in the course of retinal degeneration of Royal College of Surgeons (RCS) rats was evaluated. MFG-E8 and CD11b were used to confirm the microglial cells. In the retina of RCS rats, the mRNA expression of seven genes (MFG-E8 and its integrins αυ and ß5, CD11b and the cytokines TNF-α, IL-1ß, and MCP-1) formed almost similar bimodal peak distributions, which were centred at P7 and P45 to P60. In contrast, in rdy rats, which comprised the control group, a unimodal peak distribution centred at P14 was observed. The gene expression accompanied the activation and migration of microglial cells from the inner to the outer layer of the retina during the process of degeneration. Principal component analysis and discriminant function analysis revealed that the expression of these seven genes, especially TNF-α and CD11b, positively correlated with retinal degeneration and microglial activity during retinal degeneration in RCS rats, but not in the control rats. Furthermore, linear regression analysis demonstrated a significant correlation between the expression of these genes and the activation of microglial cells in the dystrophic retina. Our findings suggest that the suppression of microglial cells and the blockade of their cytotoxic effects may constitute a novel therapeutic strategy for treating photoreceptor death in various retinal disorders.

Integrity of the Cone Photoreceptor Mosaic in Oligocone Trichromacy

PubMed Central

Rha, Jungtae; Dees, Elise W.; Baraas, Rigmor C.; Wagner-Schuman, Melissa L.; Mollon, John D.; Dubis, Adam M.; Andersen, Mette K. G.; Rosenberg, Thomas; Larsen, Michael; Moore, Anthony T.

2011-01-01

Purpose. Oligocone trichromacy (OT) is an unusual cone dysfunction syndrome characterized by reduced visual acuity, mild photophobia, reduced amplitude of the cone electroretinogram with normal rod responses, normal fundus appearance, and normal or near-normal color vision. It has been proposed that these patients have a reduced number of normal functioning cones (oligocone). This paper has sought to evaluate the integrity of the cone photoreceptor mosaic in four patients previously described as having OT. Methods. Retinal images were obtained from two brothers (13 and 15 years) and two unrelated subjects, one male (47 years) and one female (24 years). High-resolution images of the cone mosaic were obtained using high-speed adaptive optics (AO) fundus cameras. Visible structures were analyzed for density using custom software. Additional retinal images were obtained using spectral domain optical coherence tomography (SD-OCT), and the four layers of the photoreceptor-retinal pigment epithelium complex (ELM, IS/OS, RPE1, RPE2) were evaluated. Cone photoreceptor length and the thickness of intraretinal layers were measured and compared to previously published normative data. Results. The adult male subject had infantile onset nystagmus while the three other patients did not. In the adult male patient, a normal appearing cone mosaic was observed. However, the three other subjects had a sparse mosaic of cones remaining at the fovea, with no structure visible outside the central fovea. On SD-OCT, the adult male subject had a very shallow foveal pit, with all major retinal layers being visible, and both inner segment (IS) and outer segment (OS) length were within normal limits. In the other three patients, while all four layers were visible in the central fovea and IS length was within normal limits, the OS length was significantly decreased. Peripherally the IS/OS layer decreased in intensity, and the RPE1 layer was no longer discernable, in keeping with the lack of cone structure observed on AO imaging outside the central fovea. Conclusions. Findings are consistent with the visual deficits being caused by a reduced number of healthy cones in the two brothers and the adult female. In the unrelated adult subject, no structural basis for the disorder was found. These data suggest two distinct groups on the basis of structural imaging. It is proposed that the former group with evidence of a reduction in cone numbers is more in keeping with typical OT, with the latter group representing an OT-like phenotype. These two groups may be difficult to readily discern on the basis of phenotypic features alone, and high-resolution imaging may be an effective way to distinguish between these phenotypes. PMID:21436275

Progressive Outer Retinal Necrosis Combined with Vitreous Hemorrhage in a Patient with Acquired Immunodeficiency Syndrome

PubMed Central

You, Yong Sung; Lee, Sung Jin; Lee, Sung Ho; Park, Chang Hyun

2007-01-01

Purpose To describe an unusual case of rapidly progressive outer retinal necrosis (PORN) with vitreous hemorrhage in a 41-year-old woman with acquired immunodeficiency syndrome (AIDS), who had retinitis developed from what was probably varicellar-zoster virus combined with cytomegalovirus (CMV) and herpes simplex type 1,2, as proven by the polymerase chain reaction restriction fragment length polymorphism method (PCR-RFLP). Methods This study is a case report detailing clinical follow-up and an aqueous humor test by PCR-RFLP. Results The deep, white retinal lesions coalesced and progressively expanded in a circumferential manner, with sparing of the perivascular retina. However, retinal and vitreous hemorrhages, unusual findings for PORN, could be noted around the optic nerve. Varicellar-zoster virus (VZV), cytomegalovirus (CMV), and herpes simplex types 1,2 (HSV-1,2) were detected in the aqueous humor by PCR. Conclusions PORN has been described as a variant of necrotizing herpetic retinopathy, occurring particularly in patients with AIDS. Although the etiologic agent has been reported to be VZV, concurrent or combined etiologic agents can include HSV-1, HSV-2, and CMV in AIDS patients. Therefore, combined antiviral therapy with acyclovir and ganciclovir could be more reasonable as an initial therapy. PMID:17460434

Synaptic remodeling generates synchronous oscillations in the degenerated outer mouse retina

PubMed Central

Haq, Wadood; Arango-Gonzalez, Blanca; Zrenner, Eberhart; Euler, Thomas; Schubert, Timm

2014-01-01

During neuronal degenerative diseases, neuronal microcircuits undergo severe structural alterations, leading to remodeling of synaptic connectivity. The functional consequences of such remodeling are mostly unknown. For instance, in mutant rd1 mouse retina, a common model for Retinitis Pigmentosa, rod bipolar cells (RBCs) establish contacts with remnant cone photoreceptors (cones) as a consequence of rod photoreceptor cell death and the resulting lack of presynaptic input. To assess the functional connectivity in the remodeled, light-insensitive outer rd1 retina, we recorded spontaneous population activity in retinal wholemounts using Ca2+ imaging and identified the participating cell types. Focusing on cones, RBCs and horizontal cells (HCs), we found that these cell types display spontaneous oscillatory activity and form synchronously active clusters. Overall activity was modulated by GABAergic inhibition from interneurons such as HCs and/or possibly interplexiform cells. Many of the activity clusters comprised both cones and RBCs. Opposite to what is expected from the intact (wild-type) cone-ON bipolar cell pathway, cone and RBC activity was positively correlated and, at least partially, mediated by glutamate transporters expressed on RBCs. Deletion of gap junctional coupling between cones reduced the number of clusters, indicating that electrical cone coupling plays a crucial role for generating the observed synchronized oscillations. In conclusion, degeneration-induced synaptic remodeling of the rd1 retina results in a complex self-sustained outer retinal oscillatory network, that complements (and potentially modulates) the recently described inner retinal oscillatory network consisting of amacrine, bipolar and ganglion cells. PMID:25249942

Barrier properties of cultured retinal pigment epithelium.

PubMed

Rizzolo, Lawrence J

2014-09-01

The principal function of an epithelium is to form a dynamic barrier that regulates movement between body compartments. Each epithelium is specialized with barrier functions that are specific for the tissues it serves. The apical surface commonly faces a lumen, but the retinal pigment epithelium (RPE) appears to be unique by a facing solid tissue, the sensory retina. Nonetheless, there exists a thin (subretinal) space that can become fluid filled during pathology. RPE separates the subretinal space from the blood supply of the outer retina, thereby forming the outer blood-retinal barrier. The intricate interaction between the RPE and sensory retina presents challenges for learning how accurately culture models reflect native behavior. The challenge is heightened by findings that detail the variation of RPE barrier proteins both among species and at different stages of the life cycle. Among the striking differences is the expression of claudin family members. Claudins are the tight junction proteins that regulate ion diffusion across the spaces that lie between the cells of a monolayer. Claudin expression by RPE varies with species and life-stage, which implies functional differences among commonly used animal models. Investigators have turned to transcriptomics to supplement functional studies when comparing native and cultured tissue. The most detailed studies of the outer blood-retinal barrier have focused on human RPE with transcriptome and functional studies reported for human fetal, adult, and stem-cell derived RPE. Copyright © 2014 Elsevier Ltd. All rights reserved.

Culture of adult transgenic zebrafish retinal explants for live-cell imaging by multiphoton microscopy

PubMed Central

Lahne, Manuela; Gorsuch, Ryne A; Nelson, Craig M; Hyde, David R

2017-01-01

An endogenous regeneration program is initiated by Müller glia in the adult zebrafish (Danio rerio) retina following neuronal damage and death. The Müller glia re-enter the cell cycle and produce neuronal progenitor cells that undergo subsequent rounds of cell divisions and differentiate into the lost neuronal cell types. Both Müller glia and neuronal progenitor cell nuclei replicate their DNA and undergo mitosis in distinct locations of the retina i.e. they migrate between the basal inner nuclear layer (INL) and the outer nuclear layer (ONL), respectively, in a process described as interkinetic nuclear migration (INM). INM has predominantly been studied in the developing retina. To examine the dynamics of INM in the adult regenerating zebrafish retina in detail, live-cell imaging of fluorescently-labeled Müller glia/neuronal progenitor cells is required. Here, we provide the conditions to isolate and culture dorsal retinas from Tg[gfap:nGFP]mi2004 zebrafish that were exposed to constant intense light for 35 h. We also show that these retinal cultures are viable to perform live-cell imaging experiments, continuously acquiring z-stack images throughout the thickness of the retinal explant for up to 8 h using multiphoton microscopy to monitor the migratory behavior of gfap:nGFP-positive cells. In addition, we describe the details to perform post-imaging analysis to determine the velocity of apical and basal INM. To summarize, we established conditions to study the dynamics of INM in an adult model of neuronal regeneration. This will advance our understanding of this crucial cellular process and allow us to determine the mechanisms that control INM. PMID:28287581

Culture of Adult Transgenic Zebrafish Retinal Explants for Live-cell Imaging by Multiphoton Microscopy.

PubMed

Lahne, Manuela; Gorsuch, Ryne A; Nelson, Craig M; Hyde, David R

2017-02-24

An endogenous regeneration program is initiated by Müller glia in the adult zebrafish (Danio rerio) retina following neuronal damage and death. The Müller glia re-enter the cell cycle and produce neuronal progenitor cells that undergo subsequent rounds of cell divisions and differentiate into the lost neuronal cell types. Both Müller glia and neuronal progenitor cell nuclei replicate their DNA and undergo mitosis in distinct locations of the retina, i.e. they migrate between the basal Inner Nuclear Layer (INL) and the Outer Nuclear Layer (ONL), respectively, in a process described as Interkinetic Nuclear Migration (INM). INM has predominantly been studied in the developing retina. To examine the dynamics of INM in the adult regenerating zebrafish retina in detail, live-cell imaging of fluorescently-labeled Müller glia/neuronal progenitor cells is required. Here, we provide the conditions to isolate and culture dorsal retinas from Tg[gfap:nGFP] mi2004 zebrafish that were exposed to constant intense light for 35 h. We also show that these retinal cultures are viable to perform live-cell imaging experiments, continuously acquiring z-stack images throughout the thickness of the retinal explant for up to 8 h using multiphoton microscopy to monitor the migratory behavior of gfap:nGFP-positive cells. In addition, we describe the details to perform post-imaging analysis to determine the velocity of apical and basal INM. To summarize, we established conditions to study the dynamics of INM in an adult model of neuronal regeneration. This will advance our understanding of this crucial cellular process and allow us to determine the mechanisms that control INM.

Cobalamin C Deficiency Shows a Rapidly Progressing Maculopathy With Severe Photoreceptor and Ganglion Cell Loss.

PubMed

Bonafede, Lucas; Ficicioglu, Can H; Serrano, Leona; Han, Grace; Morgan, Jessica I W; Mills, Monte D; Forbes, Brian J; Davidson, Stefanie L; Binenbaum, Gil; Kaplan, Paige B; Nichols, Charles W; Verloo, Patrick; Leroy, Bart P; Maguire, Albert M; Aleman, Tomas S

2015-12-01

To describe in detail the retinal structure and function of a group of patients with cobalamin C (cblC) disease. Patients (n = 11, age 4 months to 15 years) with cblC disease (9/11, early onset) diagnosed by newborn screening underwent complete ophthalmic examinations, fundus photography, near-infrared reflectance imaging, and spectral-domain optical coherence tomography (SD-OCT). Electroretinograms (ERGs) were performed in a subset of patients. Patients carried homozygous or compound heterozygote mutations in the methylmalonic aciduria and homocystinuria type C (MMACHC) gene. Late-onset patients had a normal exam. All early-onset patients showed a maculopathy; older subjects had a retina-wide degeneration (n = 4; >7 years of age). In general, retinal changes were first observed before 1 year of age and progressed within months to a well-established maculopathy. Pseudocolobomas were documented in three patients. Measurable visual acuities ranged from 20/200 to 20/540. Nystagmus was present in 8/11 patients; 5/6 patients had normal ERGs; 1/6 had reduced rod-mediated responses. Spectral-domain OCT showed macular thinning, with severe ganglion cell layer (GCL) and outer nuclear layer (ONL) loss. Inner retinal thickening was observed in areas of total GCL/ONL loss. A normal lamination pattern in the peripapillary nasal retina was often seen despite severe central and/or retina-wide disease. Patients with early-onset cblC and MMACHC mutations showed an early-onset, unusually fast-progressing maculopathy with severe central ONL and GCL loss. An abnormally thickened inner retina supports a remodeling response to both photoreceptor and ganglion cell degeneration and/or an interference with normal development in early-onset cblC.

Cobalamin C Deficiency Shows a Rapidly Progressing Maculopathy With Severe Photoreceptor and Ganglion Cell Loss

PubMed Central

Bonafede, Lucas; Ficicioglu, Can H.; Serrano, Leona; Han, Grace; Morgan, Jessica I. W.; Mills, Monte D.; Forbes, Brian J.; Davidson, Stefanie L.; Binenbaum, Gil; Kaplan, Paige B.; Nichols, Charles W.; Verloo, Patrick; Leroy, Bart P.; Maguire, Albert M.; Aleman, Tomas S.

2015-01-01

Purpose To describe in detail the retinal structure and function of a group of patients with cobalamin C (cblC) disease. Methods Patients (n = 11, age 4 months to 15 years) with cblC disease (9/11, early onset) diagnosed by newborn screening underwent complete ophthalmic examinations, fundus photography, near-infrared reflectance imaging, and spectral-domain optical coherence tomography (SD-OCT). Electroretinograms (ERGs) were performed in a subset of patients. Results Patients carried homozygous or compound heterozygote mutations in the methylmalonic aciduria and homocystinuria type C (MMACHC) gene. Late-onset patients had a normal exam. All early-onset patients showed a maculopathy; older subjects had a retina-wide degeneration (n = 4; >7 years of age). In general, retinal changes were first observed before 1 year of age and progressed within months to a well-established maculopathy. Pseudocolobomas were documented in three patients. Measurable visual acuities ranged from 20/200 to 20/540. Nystagmus was present in 8/11 patients; 5/6 patients had normal ERGs; 1/6 had reduced rod-mediated responses. Spectral-domain OCT showed macular thinning, with severe ganglion cell layer (GCL) and outer nuclear layer (ONL) loss. Inner retinal thickening was observed in areas of total GCL/ONL loss. A normal lamination pattern in the peripapillary nasal retina was often seen despite severe central and/or retina-wide disease. Conclusions Patients with early-onset cblC and MMACHC mutations showed an early-onset, unusually fast-progressing maculopathy with severe central ONL and GCL loss. An abnormally thickened inner retina supports a remodeling response to both photoreceptor and ganglion cell degeneration and/or an interference with normal development in early-onset cblC. PMID:26658511

Conditional ablation of the choroideremia gene causes age-related changes in mouse retinal pigment epithelium.

PubMed

Wavre-Shapton, Silène T; Tolmachova, Tanya; Lopes da Silva, Mafalda; da Silva, Mafalda Lopes; Futter, Clare E; Seabra, Miguel C

2013-01-01

The retinal pigment epithelium (RPE) is a pigmented monolayer of cells lying between the photoreceptors and a layer of fenestrated capillaries, the choriocapillaris. Choroideremia (CHM) is an X-linked progressive degeneration of these three layers caused by the loss of function of Rab Escort protein-1 (REP1). REP1 is involved in the prenylation of Rab proteins, key regulators of membrane trafficking. To study the pathological consequences of chronic disruption of membrane traffic in the RPE we used a cell type-specific knock-out mouse model of the disease, where the Chm/Rep1 gene is deleted only in pigmented cells (Chm(Flox), Tyr-Cre+). Transmission electron microscopy (TEM) was used to quantitate the melanosome distribution in the RPE and immunofluorescent staining of rhodopsin was used to quantitate phagocytosed rod outer segments in retinal sections. The ultrastructure of the RPE and Bruch's membrane at different ages was characterised by TEM to analyse age-related changes occurring as a result of defects in membrane traffic pathways. Chm/Rep1 gene knockout in RPE cells resulted in reduced numbers of melanosomes in the apical processes and delayed phagosome degradation. In addition, the RPE accumulated pathological changes at 5-6 months of age similar to those observed in 2-year old controls. These included the intracellular accumulation of lipofuscin-containing deposits, disorganised basal infoldings and the extracellular accumulation of basal laminar and basal linear deposits. The phenotype of the Chm(Flox), Tyr-Cre+ mice suggests that loss of the Chm/Rep1 gene causes premature accumulation of features of aging in the RPE. Furthermore, the striking similarities between the present observations and some of the phenotypes reported in age-related macular degeneration (AMD) suggest that membrane traffic defects may contribute to the pathogenesis of AMD.

Mutation of ATF6 causes autosomal recessive achromatopsia.

PubMed

Ansar, Muhammad; Santos-Cortez, Regie Lyn P; Saqib, Muhammad Arif Nadeem; Zulfiqar, Fareeha; Lee, Kwanghyuk; Ashraf, Naeem Mahmood; Ullah, Ehsan; Wang, Xin; Sajid, Sundus; Khan, Falak Sher; Amin-ud-Din, Muhammad; Smith, Joshua D; Shendure, Jay; Bamshad, Michael J; Nickerson, Deborah A; Hameed, Abdul; Riazuddin, Saima; Ahmed, Zubair M; Ahmad, Wasim; Leal, Suzanne M

2015-09-01

Achromatopsia (ACHM) is an early-onset retinal dystrophy characterized by photophobia, nystagmus, color blindness and severely reduced visual acuity. Currently mutations in five genes CNGA3, CNGB3, GNAT2, PDE6C and PDE6H have been implicated in ACHM. We performed homozygosity mapping and linkage analysis in a consanguineous Pakistani ACHM family and mapped the locus to a 15.12-Mb region on chromosome 1q23.1-q24.3 with a maximum LOD score of 3.6. A DNA sample from an affected family member underwent exome sequencing. Within the ATF6 gene, a single-base insertion variant c.355_356dupG (p.Glu119Glyfs*8) was identified, which completely segregates with the ACHM phenotype within the family. The frameshift variant was absent in public variant databases, in 130 exomes from unrelated Pakistani individuals, and in 235 ethnically matched controls. The variant is predicted to result in a truncated protein that lacks the DNA binding and transmembrane domains and therefore affects the function of ATF6 as a transcription factor that initiates the unfolded protein response during endoplasmic reticulum (ER) stress. Immunolabeling with anti-ATF6 antibodies showed localization throughout the mouse neuronal retina, including retinal pigment epithelium, photoreceptor cells, inner nuclear layer, inner and outer plexiform layers, with a more prominent signal in retinal ganglion cells. In contrast to cytoplasmic expression of wild-type protein, in heterologous cells ATF6 protein with the p.Glu119Glyfs*8 variant is mainly confined to the nucleus. Our results imply that response to ER stress as mediated by the ATF6 pathway is essential for color vision in humans.

Study on choroidal neovascularization with anti-VEGF treatment in the mouse retina using optical coherence tomography angiography (Conference Presentation)

NASA Astrophysics Data System (ADS)

Park, Jang Ryul; Choi, WooJhon; Kim, Jaeryung; Hong, Hye Kyong; Kim, Yongjoo; Hwang, Yoonha; Park, Sang Jun; Woo, Se Joon; Kim, Pilhan; Park, Kyu Hyung; Koh, Gou Young; Oh, Wang-Yuhl

2017-02-01

To understand the pathogenesis of ophthalmic disease, utilizing small animal models such as mouse is necessary because of their ease of maintenance and availability. For identifying pathophysiology and drug development of retinal diseases in mouse model, optical coherence tomography angiography (OCTA) is promising imaging modality visualizing not only microstructure but also microvasculature. In this study, we serially imaged 3D structure and angiography of laser-induced choroidal neovascularization (CNV) in the mouse retina with/without anti-VEGF treatment. Also, the volume changes of CNV and avascular region in choroid layer are measured for identifying effects of anti-VEGF. A lab-built high-speed OCTA prototype using the wavelength-swept laser centered at 1040 nm with 230 kHz A-scan rate acquired 3-D volumetric data consisted of 1024 x 1024 x 3 A-scans. The OCTA scanned 1.7 mm x 1.7 mm area around ONH. For obtaining angiography, amplitude decorrelation from 3 consecutive B-scans at each position was generated. Seven days after the laser photocoagulation at mouse retina for generation of the laser-induced CNV, intravitreal administration of Fc and VEGF-Trap was given in the therapeutic arm. The OCTA were performed at 6, 14, 21 and 35 days after laser photocoagulation. Vasculatures of inner retina, outer retina and choroid layers were separately visualized after RPE flattening and layer segmentation. To investigate therapeutic effects of anti-VEGF treatment, the relative area and volume of CNV in outer retina layer is measured. Also, total volume of avascular zone surrounding the laser injury site in choroid layer is also analyzed.

Characteristics of eyes with inner retinal cleavage.

PubMed

Hwang, Young Hoon; Kim, Yong Yeon; Kim, Hwang Ki; Sohn, Yong Ho

2015-02-01

Inner retinal cleavage can be misdiagnosed as a glaucomatous retinal nerve fiber layer (RNFL) defect. This study was performed to characterize eyes with inner retinal cleavage. Inner retinal cleavage is defined as the appearance of a dark spindle-shaped space between the nerve fibers. Patients who presented at our institution with inner retinal cleavage were enrolled in the study. All participants were evaluated by fundus examination, visual field testing with standard automated perimetry, and optical coherence tomography (OCT) imaging. A total of 15 eyes of 11 subjects with inner retinal cleavage were included in the study. The median age of the subjects was 57 years (age range, 30-67 years). In each case, inner retinal cleavage was located adjacent to retinal blood vessels. Tissue bridging the cleavage area was observed in ten eyes. Six eyes had epiretinal membranes (ERMs), two eyes had glaucoma, and one eye had ERM in addition to glaucoma. Six eyes with inner retinal cleavage without combined ocular abnormalities had highly myopic refractive error (-6.50 to -8.50 diopters). Cross-sectional OCT images of the areas of inner retinal cleavage demonstrated defects with irregular margins and empty spaces in the inner layers of the retina. During the follow-up period, no eye showed changes in inner retinal layer cleavage or visual field sensitivity. Inner retinal cleavage was found in eyes with high myopia or ERMs. Inner retinal cleavage was associated with structural changes distinct from those associated with glaucomatous RNFL defects.

The Contribution of L-Type Cav1.3 Channels to Retinal Light Responses

PubMed Central

Shi, Liheng; Chang, Janet Ya-An; Yu, Fei; Ko, Michael L.; Ko, Gladys Y.-P.

2017-01-01

L-type voltage-gated calcium channels (LTCCs) regulate tonic neurotransmitter release from sensory neurons including retinal photoreceptors. There are three types of LTCCs (Cav1.2, Cav1.3, and Cav1.4) expressed in the retina. While Cav1.2 is expressed in all retinal cells including the Müller glia and neurons, Cav1.3 and Cav1.4 are expressed in the retinal neurons with Cav1.4 exclusively expressed in the photoreceptor synaptic terminals. Mutations in the gene encoding Cav1.4 cause incomplete X-linked congenital stationary night blindness in humans. Even though Cav1.3 is present in the photoreceptor inner segments and the synaptic terminals in various vertebrate species, its role in vision is unclear, since genetic alterations in Cav1.3 are not associated with severe vision impairment in humans or in Cav1.3-null (Cav1.3−/−) mice. However, a failure to regulate Cav1.3 was found in a mouse model of Usher syndrome, the most common cause of combined deafness and blindness in humans, indicating that Cav1.3 may contribute to retinal function. In this report, we combined physiological and morphological data to demonstrate the role of Cav1.3 in retinal physiology and function that has been undervalued thus far. Through ex vivo and in vivo electroretinogram (ERG) recordings and immunohistochemical staining, we found that Cav1.3 plays a role in retinal light responses and synaptic plasticity. Pharmacological inhibition of Cav1.3 decreased ex vivo ERG a- and b-wave amplitudes. In Cav1.3−/− mice, their dark-adapted ERG a-, b-wave, and oscillatory potential amplitudes were significantly dampened, and implicit times were delayed compared to the wild type (WT). Furthermore, the density of ribbon synapses was reduced in the outer plexiform layer of Cav1.3−/− mice retinas. Hence, Cav1.3 plays a more prominent role in retinal physiology and function than previously reported. PMID:29259539

The Contribution of L-Type Cav1.3 Channels to Retinal Light Responses.

PubMed

Shi, Liheng; Chang, Janet Ya-An; Yu, Fei; Ko, Michael L; Ko, Gladys Y-P

2017-01-01

L-type voltage-gated calcium channels (LTCCs) regulate tonic neurotransmitter release from sensory neurons including retinal photoreceptors. There are three types of LTCCs (Ca v 1.2, Ca v 1.3, and Ca v 1.4) expressed in the retina. While Ca v 1.2 is expressed in all retinal cells including the Müller glia and neurons, Ca v 1.3 and Ca v 1.4 are expressed in the retinal neurons with Ca v 1.4 exclusively expressed in the photoreceptor synaptic terminals. Mutations in the gene encoding Ca v 1.4 cause incomplete X-linked congenital stationary night blindness in humans. Even though Ca v 1.3 is present in the photoreceptor inner segments and the synaptic terminals in various vertebrate species, its role in vision is unclear, since genetic alterations in Ca v 1.3 are not associated with severe vision impairment in humans or in Ca v 1.3-null (Ca v 1.3 -/- ) mice. However, a failure to regulate Ca v 1.3 was found in a mouse model of Usher syndrome, the most common cause of combined deafness and blindness in humans, indicating that Ca v 1.3 may contribute to retinal function. In this report, we combined physiological and morphological data to demonstrate the role of Ca v 1.3 in retinal physiology and function that has been undervalued thus far. Through ex vivo and in vivo electroretinogram (ERG) recordings and immunohistochemical staining, we found that Ca v 1.3 plays a role in retinal light responses and synaptic plasticity. Pharmacological inhibition of Ca v 1.3 decreased ex vivo ERG a- and b-wave amplitudes. In Ca v 1.3 -/- mice, their dark-adapted ERG a-, b-wave, and oscillatory potential amplitudes were significantly dampened, and implicit times were delayed compared to the wild type (WT). Furthermore, the density of ribbon synapses was reduced in the outer plexiform layer of Ca v 1.3 -/- mice retinas. Hence, Ca v 1.3 plays a more prominent role in retinal physiology and function than previously reported.

Treatment of dry age-related macular degeneration with dobesilate

PubMed Central

Cuevas, P; Outeiriño, L A; Angulo, J; Giménez-Gallego, G

2012-01-01

The authors present anatomical and functional evidences of dry age-macular degeneration improvement, after intravitreal treatment with dobesilate. Main outcomes measures were normalisation of retinal structure and function, assessed by optical coherence tomography, fundus-monitored microperimetry, electrophysiology and visual acuity. The effect might be related to the normalisation of the outer retinal architecture. PMID:22729337

Light-Emitting Diodes and Cool White Fluorescent Light Similarly Suppress Pineal Gland Melatonin and Maintain Retinal Function and Morphology in the Rat. Part 1

NASA Technical Reports Server (NTRS)

Holley, Daniel C.; Heeke, D.; Mele, G.

1999-01-01

Currently, the light sources most commonly used in animal habitat lighting are cool white fluorescent or incandescent lamps. We evaluated a novel light-emitting diode (LED) light source for use in animal habitat lighting by comparing its effectiveness to cool white fluorescent light (CWF) in suppressing pineal gland melatonin and maintaining normal retinal physiology and morphology in the rat. Results of pineal melatonin suppression experiments showed equal suppression of pineal melatonin concentrations for LED light and CWF light at five different light illuminances (100, 40, 10, 1 and 0.1 lux). There were no significant differences in melatonin suppression between LED and CWF light when compared to unexposed controls. Retinal physiology was evaluated using electroretinography. Results show no differences in a-wave implicit times and amplitudes or b-wave implicit times and amplitudes between 100-lux LED-exposed rats and 100-lux CWF-exposed rats. Results of retinal histology assessment show no differences in retinal thickness rod outer segment length and number of rod nuclei between rats exposed to 100-lux LED and 100-lux CWF for days. Furthermore, the retinal pigmented epithelium and rod outer segments of all eyes observed were in good condition and of normal thickness. This study indicates that LED light does not cause retinal damage and can suppress pineal melatonin at similar intensities as a conventional CWF light source. These data suggest that LED light sources may be suitable replacements for conventional light sources used in the lighting of rodent vivariums while providing many mechanical and economical advantages.

ARL2BP, a protein linked to Retinitis Pigmentosa, is needed for normal photoreceptor cilia doublets and outer segment structure.

PubMed

Moye, Abigail R; Singh, Ratnesh; Kimler, Victoria A; Dilan, Tanya L; Munezero, Daniella; Saravanan, Thamaraiselvi; Goldberg, Andrew F X; Ramamurthy, Visvanathan

2018-05-02

The outer segment (OS) of photoreceptor cells is an elaboration of a primary cilium with organized stacks of membranous discs that contain the proteins needed for phototransduction and vision. Though cilia formation and function has been well characterized, little is known about the role of cilia in the development of photoreceptor OS. Nevertheless, progress has been made by studying mutations in ciliary proteins which often result in malformed outer segments and lead to blinding diseases. To investigate how ciliary proteins contribute to outer segment formation, we generated a knockout mouse model for ARL2BP, a ciliary protein linked to Retinitis Pigmentosa. The knockout mice display an early and progressive reduction in visual response. Prior to photoreceptor degeneration we observed disorganization of the photoreceptor OS, with vertically aligned discs and shortened axonemes. Interestingly, ciliary doublet microtubule structure was also impaired, displaying open B-tubule doublets, paired with loss of singlet microtubules. Based on results from this study, we conclude that ARL2BP is necessary for photoreceptor cilia doublet formation and axoneme elongation, which is required for outer segment morphogenesis and vision.

Experimental chloroquine retinopathy.

PubMed

Matsumura, M; Ohkuma, M; Tsukahara, I

1986-01-01

Chloroquine retinopathy was produced experimentally in the eye of the albino corydoras (one of the tropical fish) by daily administration of chloroquine (0.1 mg per os). The enucleated eyes were examined from the 14th day to 3 months after the beginning of drug administration under light and electron microscopy. The first change of retina was the appearance of membraneous cytoplasmic body (MCB) in the cytoplasm of ganglion, amacrine, bipolar and horizontal cells. MCB might be degenerated lysosome. They showed lamellar figures or crystalline lattice-like structures. Secondarily, these MCB appeared in the inner segments of photoreceptor cells. The outer segments of rod cells disappeared, and then those of cone cells. Although photoreceptor cells were diminished in number in advanced degeneration, the cells of inner nuclear layer and ganglion cells were maintained in number. The presence of MCB dose not mean death of cells. The retinal pigment epithelial cells contained MCB in its cytoplasm only in severe degenerative cases, and did not show other remarkable changes. MCB also appeared in the cytoplasm of pericytes of retinal vessels. Chloroquine is considered to damage directly photoreceptor cells most severely.

Protective effect of basic fibroblast growth factor on laser induced retinopathy

PubMed Central

Kartal, Unal; Koptagel, Emel; Bulut, H. Eray; Erdogan, Haydar

2013-01-01

AIM To investigate the side effects of the commonly used laser treatment along with testing the neuroprotective effect of bFGF on a potential retinal impairment. METHODS To do this, 30 chinchilla pigmented adult male rabbits were divided into the control and experimental groups. The control and experimental groups underwent both laser application and bFGF treatment. The retinal tissue impairment and its renewal rate were tested under the light and electron microscopical levels. RESULTS The focal laser application on rabbit eyes caused morphological alterations both in the application region and in the neighbouring areas. In the damaged areas, the outer nuclear layer of the neural retina was almost disappeared, retina pigment epithelium was interrupted, the retina pigment epithelium migrated intraretinally, and the damaged region along with neighbouring areas seemed to be not separated. bFGF application just after the laser photocoagulation, revealed better results in application areas. CONCLUSION It could be suggested that the bFGF application following laser photocoagulation might have protective, repairing and wound healing effects on the retina. PMID:24392319

Diabetic choroidopathy. Light and electron microscopic observations of seven cases.

PubMed

Hidayat, A A; Fine, B S

1985-04-01

The choroid of seven young patients (ages 20-29 years), who had had diabetes mellitus for many years (14-23 years) was studied by light and electron microscopy. The eight enucleated eyes were blind and painful as a complication of diabetes mellitus. Histopathologically, the choriocapillaris and other small choroidal blood vessels disclosed marked basement membrane thickening of their walls. Periodic acid-Schiff-positive homogeneous acellular nodules were present and resembled those of diabetic glomerulosclerosis (Kimmelsteil-Wilson disease). Some choroidal arteries were arteriosclerotic. Choroidal compromise was suggested by luminal narrowing of the capillaries, capillary dropout, and focal scarring. Choroidal neovascularization with subretinal fibrovascular membranes occurred in two patients at the midperiphery and periphery, and resembled those of retinitis proliferans. Leakage of proteinaceous fluid into the choroidal stroma and beneath the focally detached pigment epithelium was suggested by the electron microscopic observations. Choroidal vasculopathy in diabetes mellitus is similar to much of what has been described in other tissues of the eye and body, and suggests an important role in the pathogenesis of diabetic retinopathy since the outer retinal layers are largely dependent on the choroid for their nutrition and oxygenation.

Automated detection of the retinal from OCT spectral domain images of healthy eyes

NASA Astrophysics Data System (ADS)

Giovinco, Gaspare; Savastano, Maria Cristina; Ventre, Salvatore; Tamburrino, Antonello

2015-06-01

Optical coherence tomography (OCT) has become one of the most relevant diagnostic tools for retinal diseases. Besides being a non-invasive technique, one distinguished feature is its unique capability of providing (in vivo) cross-sectional view of the retinal. Specifically, OCT images show the retinal layers. From the clinical point of view, the identification of the retinal layers opens new perspectives to study the correlation between morphological and functional aspects of the retinal tissue. The main contribution of this paper is a new method/algorithm for the automated segmentation of cross-sectional images of the retina of healthy eyes, obtained by means of spectral domain optical coherence tomography (SD-OCT). Specifically, the proposed segmentation algorithm provides the automated detection of different retinal layers. Tests on experimental SD-OCT scans performed by three different instruments/manufacturers have been successfully carried out and compared to a manual segmentation made by an independent ophthalmologist, showing the generality and the effectiveness of the proposed method.

RETINAL DEEP CAPILLARY ISCHEMIA ASSOCIATED WITH AN OCCLUDED CONGENITAL RETINAL MACROVESSEL.

PubMed

Hasegawa, Taiji; Ogata, Nahoko

2017-01-01

To report the case of a patient with an occluded congenital retinal macrovessel accompanied by retinal deep capillary ischemia. A 38-year-old woman presented with a 2-day history of a paracentral scotoma of her right eye. Fundus photograph showed a dilated congenital retinal macrovessel with arteriovenous anastomosis, an intravascular white region indicating the thrombus at arteriovenous anastomotic region, and an area of retinal whitening temporal to the fovea. The spectral domain optical coherence tomography images through the area of retinal whitening showed a thickening and highly reflectivity at the level of the inner nuclear layer, which is likely due to the deep capillary ischemia. After 6 weeks, spectral domain optical coherence tomography images through the same area demonstrated a thinning and atrophy of only the inner nuclear layer, and the patient's paracentral scotoma persisted. Acute capillary hemodynamic changes caused deep capillary ischemia. The spectral domain optical coherence tomography showed a highly reflective lesion at the level of the inner nuclear layer in the acute phase.

Photoreceptor neuroprotection in RCS rats via low-dose intravitreal sustained-delivery of fluocinolone acetonide.

PubMed

Glybina, Inna V; Kennedy, Alexander; Ashton, Paul; Abrams, Gary W; Iezzi, Raymond

2009-10-01

To study the neuroprotective effects of intravitreal fluocinolone acetonide (FA) in Royal College of Surgeons (RCS) rats. Five-week-old RCS rats were divided into four groups: 0.5 microg/d FA-loaded intravitreal drug-delivery implant (IDDI); 0.2 microg/d FA-loaded IDDI; inactive IDDI; and nonsurgical control. Electroretinography (ERG) and intraocular pressure (IOP) measurements were performed before surgery and weekly thereafter. Thicknesses of the retinal outer (ONL) and inner (INL) nuclear layers were evaluated at 9 weeks of age. ED-1-labeled activated microglia were counted. Total microglial cell counts were made by using Iba-1 antibody labeling. At 9 weeks, control groups demonstrated an 80% reduction in ERG amplitudes (P < 0.001 for both groups). FA-treated groups demonstrated no statistically significant attenuation of ERG amplitudes at the end of the study, compared with the initial ERGs. Intraocular pressure (IOP) remained normal in all groups. ONL thickness in FA 0.2 microg/d-treated eyes was 2.1 +/- 0.5 times greater than in nonsurgical eyes (P < 0.001) and 3.4 +/- 0.7 times greater than in inactive IDDI-treated eyes (P < 0.0001). In FA 0.5 microg/d-treated eyes, ONL thickness was 1.5 +/- 0.1 times higher than in nonsurgical controls (P < 0.05) and 2.4 +/- 0.4 times higher than in inactive IDDI-treated eyes (P < 0.01). INL thickness was not different among groups. FA-treated eyes demonstrated significantly fewer activated microglia (P < 0.001) and overall number of microglia in the photoreceptor and outer debris zone layers (P < 0.001), compared with control groups. Chronic intravitreal infusion of FA is neuroprotective in RCS rats, preserves ONL morphology and ERG amplitudes and reduces retinal neuroinflammation. These findings may have a therapeutic role in human photoreceptor cell degenerations.

Extra-mitochondrial aerobic metabolism in retinal rod outer segments: new perspectives in retinopathies.

PubMed

Panfoli, I; Calzia, D; Ravera, S; Morelli, A M; Traverso, C E

2012-04-01

Vertebrate retinal rods are photoreceptors for dim-light vision. They display extreme sensitivity to light thanks to a specialized subcellular organelle, the rod outer segment. This is filled with a stack of membranous disks, expressing the proteins involved in visual transduction, a very energy demanding process. Our previous proteomic and biochemical studies have shed new light on the chemical energy processes that supply ATP to the outer segment, suggesting the presence of an extra-mitochondrial aerobic metabolism in rod outer segment, devoid of mitochondria, which would account for a quantitatively adequate ATP supply for phototransduction. Here the functional presence of an oxidative phosphorylation in the rod outer limb is examined for its relationship to many physiological and pathological data on the rod outer segment. We hypothesize that the rod outer limb is at risk of oxidative stress, in any case of impairment in the respiratory chain functioning, or of blood supply. In fact, the electron transfer chain is a major source of reactive O(2) species, known to produce severe alteration to the membrane lipids, especially those of the outer segment that are rich in polyunsaturated fatty acids. We propose that the disk membrane may become the target of reactive oxygen species that may be released by the electron transport chain under pathologic conditions. For example, during aging reactive oxygen species production increases, while cellular antioxidant capacity decreases. Also the apoptosis of the rod observed after exposure to bright or continuous illumination can be explained considering that an overfunctioning of phototransduction may damage the disk membrane to a point at which cytochrome c escapes from the intradiskal space, where it is presently supposed to be, activating a putative caspase 9 and the apoptosome. A pathogenic mechanism for many inherited and acquired retinal degenerations, representing a major problem in clinical ophthalmology, is proposed: a number of rod pathologies would be promoted by impairment of energy supply and/or oxidative stress in the rod outer segment. In conclusion we suppose that the damaging role of oxygen, be it hypoxia or hyperoxia invoked in most of the blinding diseases, acquired and even hereditary is to be seeked for inside the photoreceptor outer segment that would conceal a potential for cell death that is still to be recognized. Copyright © 2012 Elsevier Ltd. All rights reserved.

Cone Structure in Patients With Usher Syndrome Type III and Mutations in the Clarin 1 Gene

PubMed Central

Ratnam, Kavitha; Västinsalo, Hanna; Roorda, Austin; Sankila, Eeva-Marja K.; Duncan, Jacque L.

2015-01-01

Objective To study macular structure and function in patients with Usher syndrome type III (USH3) caused by mutations in the Clarin 1 gene (CLRN1). Methods High-resolution macular images were obtained by adaptive optics scanning laser ophthalmoscopy and spectral domain optical coherence tomography in 3 patients with USH3 and were compared with those of age-similar control subjects. Vision function measures included best-corrected visual acuity, kinetic and static perimetry, and full-field electroretinography. Coding regions of the CLRN1 gene were sequenced. Results CLRN1 mutations were present in all the patients; a 20-year-old man showed compound heterozygous mutations (p.N48K and p.S188X), and 2 unrelated women aged 25 and 32 years had homozygous mutations (p.N48K). Best-corrected visual acuity ranged from 20/16 to 20/40, with scotomas beginning at 3° eccentricity. The inner segment-outer segment junction or the inner segment ellipsoid band was disrupted within 1° to 4° of the fovea, and the foveal inner and outer segment layers were significantly thinner than normal. Cones near the fovea in patients 1 and 2 showed normal spacing, and the preserved region ended abruptly. Retinal pigment epithelial cells were visible in patient 3 where cones were lost. Conclusions Cones were observed centrally but not in regions with scotomas, and retinal pigment epithelial cells were visible in regions without cones in patients with CLRN1 mutations. High-resolution measures of retinal structure demonstrate patterns of cone loss associated with CLRN1 mutations. Clinical Relevance These findings provide insight into the effect of CLRN1 mutations on macular cone structure, which has implications for the development of treatments for USH3. Trial Registration clinicaltrials.gov Identifier: NCT00254605 PMID:22964989

Current perspectives of herpesviral retinitis and choroiditis.

PubMed

Madhavan, H N; Priya, K; Biswas, J

2004-10-01

Vision-threatening viral retinitis are primarily caused by members of the herpesvirus family. The biology and molecular characterization of herpesviruses, clinical presentations of retinopathies, pathology and pathogenesis including the host responses, epidemiology and the laboratory methods of aetiological diagnosis of these diseases are described. Clinical syndromes are acute retinal necrosis (ARN), progressive outer retinal necrosis (PORN), cytomegalovirus (CMV) retinitis, multifocal choroiditis and serpiginous choroiditis besides other viral retinopathies. Herpes simplex virus (HSV) retinitis is more common in immunocompetent persons while varicella zoster virus (VZV) affects both immunocompetent and immunosuppressed patients equally. CMV retinitis is most common among patients with AIDS. The currently employed laboratory methods of antigen detection, virus isolation and antibody detection by enzyme linked immuno-sorbent assay (ELISA) have low sensitivity. Polymerase chain reaction (PCR) has increased the value of diagnosis due to its high clinical sensitivity and absolute specificity in detection of herpesviruses in intraocular specimens.

Vessel density, retinal thickness, and choriocapillaris vascular flow in myopic eyes on OCT angiography.

PubMed

Milani, Paolo; Montesano, Giovanni; Rossetti, Luca; Bergamini, Fulvio; Pece, Alfredo

2018-06-06

To investigate foveal avascular zone area, macular vascular density, choroidal thickness, and outer retina and choriocapillaris flow in myopic eyes by OCT angiography. Automated macular maps and flow calculations were retrospectively evaluated in 42 myopic and in 40 control eyes. Myopic eyes presented lower whole superficial vessel density (46.4 ± 4.9 vs. 51.6 ± 3.6%, P < 0.0001) and higher flow area in the outer retina (1.3 ± 0.2 vs. 1.1 ± 0.3 mm 2 , P = 0.0012). Between the myopic and non-myopic eyes, no significant differences could be detected in the choriocapillaris perfusion area (1.9 ± 0.07 vs. 1.9 ± 0.05 mm 2 , respectively; P = 0.55) and in the foveal avascular zone area (0.23 ± 0.1 vs. 0.26 ± 0.1 mm 2 , respectively; P = 0.12). The spherical correction positively correlated with superficial vessel density and negatively correlated with outer retina perfusion (P ≤ 0.0021). The superficial vessel density and the local retinal thickness positively correlated at all macular locations (P < 0.005), especially in the foveal region (P < 0.0001). Eyes with high myopia present reduced superficial vascular density and increased outer retina flow. Superficial vascular density and retinal thickness appear to be significantly correlated.

Long-term preservation of retinal function in the RCS rat model of retinitis pigmentosa following lentivirus-mediated gene therapy.

PubMed

Tschernutter, M; Schlichtenbrede, F C; Howe, S; Balaggan, K S; Munro, P M; Bainbridge, J W B; Thrasher, A J; Smith, A J; Ali, R R

2005-04-01

The Royal College of Surgeons (RCS) rat is a well-characterized model of autosomal recessive retinitis pigmentosa (RP) due to a defect in the retinal pigment epithelium (RPE). It is homozygous for a null mutation in the gene encoding , a receptor tyrosine kinase found in RPE cells, that is required for phagocytosis of shed photoreceptor outer segments. The absence of Mertk results in accumulation of outer segment debris. This subsequently leads to progressive loss of photoreceptor cells. In order to evaluate the efficacy of lentiviral-mediated gene replacement therapy in the RCS rat, we produced recombinant VSV-G pseudotyped HIV-1-based lentiviruses containing a murine Mertk cDNA driven by a spleen focus forming virus (SFFV) promoter. The vector was subretinally injected into the right eye of 10-day-old RCS rats; the left eye was left untreated as an internal control. Here, we present a detailed assessment of the duration and extent of the morphological rescue and the resulting functional benefits. We examined animals at various time points over a period of 7 months by light and electron microscopy, and electroretinography. We observed correction of the phagocytic defect, slowing of photoreceptor cell loss and preservation of retinal function for up to 7 months. This study demonstrates the potential of gene therapy approaches for the treatment of retinal degenerations caused by defects specific to the RPE and supports the use of lentiviral vectors for the treatment of such disorders.

Effects of Combined Ketamine/Xylazine Anesthesia on Light Induced Retinal Degeneration in Rats

PubMed Central

Bolz, Sylvia; Eslava-Schmalbach, Javier; Willmann, Gabriel; Zhour, Ahmad; Zrenner, Eberhart; Fischer, M. Dominik; Gekeler, Florian

2012-01-01

Objectives To explore the effect of ketamine-xylazine anesthesia on light-induced retinal degeneration in rats. Methods Rats were anesthetized with ketamine and xylazine (100 and 5 mg, respectively) for 1 h, followed by a recovery phase of 2 h before exposure to 16,000 lux of environmental illumination for 2 h. Functional assessment by electroretinography (ERG) and morphological assessment by in vivo imaging (optical coherence tomography), histology (hematoxylin/eosin staining, TUNEL assay) and immunohistochemistry (GFAP and rhodopsin staining) were performed at baseline (ERG), 36 h, 7 d and 14 d post-treatment. Non-anesthetized animals treated with light damage served as controls. Results Ketamine-xylazine pre-treatment preserved retinal function and protected against light-induced retinal degeneration. In vivo retinal imaging demonstrated a significant increase of outer nuclear layer (ONL) thickness in the non-anesthetized group at 36 h (p<0.01) and significant reduction one week (p<0.01) after light damage. In contrast, ketamine-xylazine pre-treated animals showed no significant alteration of total retinal or ONL thickness at either time point (p>0.05), indicating a stabilizing and/or protective effect with regard to phototoxicity. Histology confirmed light-induced photoreceptor cell death and Müller cells gliosis in non-anesthetized rats, especially in the superior hemiretina, while ketamine-xylazine treated rats showed reduced photoreceptor cell death (TUNEL staining: p<0.001 after 7 d), thicker ONL and longer IS/OS. Fourteen days after light damage, a reduction of standard flash induced a-wave amplitudes and a-wave slopes (p = 0.01) and significant alterations in parameters of the scotopic sensitivity function (e.g. Vmax of the Naka Rushton fit p = 0.03) were observed in non-treated vs. ketamine-xylazine treated animals. Conclusions Our results suggest that pre-treatment with ketamine-xylazine anesthesia protects retinas against light damage, reducing photoreceptor cell death. These data support the notion that anesthesia with ketamine-xylazine provides neuroprotective effects in light-induced cell damage. PMID:22558200

A method and technical equipment for an acute human trial to evaluate retinal implant technology

NASA Astrophysics Data System (ADS)

Hornig, Ralf; Laube, Thomas; Walter, Peter; Velikay-Parel, Michaela; Bornfeld, Norbert; Feucht, Matthias; Akguel, Harun; Rössler, Gernot; Alteheld, Nils; Lütke Notarp, Dietmar; Wyatt, John; Richard, Gisbert

2005-03-01

This paper reports on methods and technical equipment to investigate the epiretinal stimulation of the retina in blind human subjects in acute trials. Current is applied to the retina through a thin, flexible microcontact film (microelectrode array) with electrode diameters ranging from 50 to 360 µm. The film is mounted in a custom-designed surgical tool that is hand-held by the surgeon during stimulation. The eventual goal of the work is the development of a chronically implantable retinal prosthesis to restore a useful level of vision to patients who are blind with outer retinal degenerations, specifically retinitis pigmentosa and macular degeneration.

Progressive outer retinal necrosis presenting as cherry red spot.

PubMed

Yiu, Glenn; Young, Lucy H

2012-10-01

To report a case of progressive outer retinal necrosis (PORN) presenting as a cherry red spot. Case report. A 53-year-old woman with recently diagnosed HIV and varicella-zoster virus (VZV) aseptic meningitis developed rapid sequential vision loss in both eyes over 2 months. Her exam showed a "cherry red spot" in both maculae with peripheral atrophy and pigmentary changes, consistent with PORN. Due to her late presentation and the rapid progression of her condition, she quickly developed end-stage vision loss in both eyes. PORN should be considered within the differential diagnosis of a "cherry red spot." Immune-deficient patients with a history of herpetic infection who present with visual loss warrant prompt ophthalmological evaluation.

Ganglion cell-inner plexiform layer and retinal nerve fibre layer changes within the macula in retinitis pigmentosa: a spectral domain optical coherence tomography study.

PubMed

Yoon, Chang Ki; Yu, Hyeong Gon

2018-03-01

To investigate how macular ganglion cell-inner plexiform layer (GCIPL) and retinal nerve fibre layer (RNFL) thicknesses within the macula change with retinitis pigmentosa (RP) severity. Spectral domain optical coherence tomography (SD-OCT) was used to examine 177 patients with RP and 177 normal controls. An optical coherence tomography (OCT) line scan was used to grade RP severity. Retinitis pigmentosa (RP) was categorized as more advanced if there was no identifiable inner segment ellipsoid (ISe) band (NISE) and as less advanced if an ISe band could be identified and peripheral loss of ISe was apparent (IISE). Ganglion cell-inner plexiform layer (GCIPL) and RNFL thicknesses were manually measured on OCT images and analysed. Pearson's correlation analyses were used to examine correlations between GCIPL thickness, RNFL thickness, visual acuity (VA) and visual field extent in patients and controls. Ganglion cell-inner plexiform layer (GCIPL) was significantly thicker in IISE than in control eyes (p < 0.001), but significantly thinner in NISE than in IISE eyes (p < 0.001) in both horizontal and vertical OCT scans. Retinal nerve fibre layer (RNFL) was significantly thicker in eyes with IISE and NISE than in control eyes in both horizontal and vertical meridians (all p < 0.001). Ganglion cell-inner plexiform layer (GCIPL) thickness showed a weak positive correlation with vision, and RNFL thickness showed a weak negative correlation with vision and visual field extent. Based on these results, the inner retina, including the GCIPL and RNFL, maintains its gross integrity longer than the photoreceptor layer in RP. Additionally, thickening of the inner retina may have some functional implications in patients with RP. © 2017 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

Intra-retinal segmentation of optical coherence tomography images using active contours with a dynamic programming initialization and an adaptive weighting strategy

NASA Astrophysics Data System (ADS)

Gholami, Peyman; Roy, Priyanka; Kuppuswamy Parthasarathy, Mohana; Ommani, Abbas; Zelek, John; Lakshminarayanan, Vasudevan

2018-02-01

Retinal layer shape and thickness are one of the main indicators in the diagnosis of ocular diseases. We present an active contour approach to localize intra-retinal boundaries of eight retinal layers from OCT images. The initial locations of the active contour curves are determined using a Viterbi dynamic programming method. The main energy function is a Chan-Vese active contour model without edges. A boundary term is added to the energy function using an adaptive weighting method to help curves converge to the retinal layer edges more precisely, after evolving of curves towards boundaries, in final iterations. A wavelet-based denoising method is used to remove speckle from OCT images while preserving important details and edges. The performance of the proposed method was tested on a set of healthy and diseased eye SD-OCT images. The experimental results, compared between the proposed method and the manual segmentation, which was determined by an optometrist, indicate that our method has obtained an average of 95.29%, 92.78%, 95.86%, 87.93%, 82.67%, and 90.25% respectively, for accuracy, sensitivity, specificity, precision, Jaccard Index, and Dice Similarity Coefficient over all segmented layers. These results justify the robustness of the proposed method in determining the location of different retinal layers.

Recent developments in the management of dry age-related macular degeneration

PubMed Central

Buschini, Elisa; Fea, Antonio M; Lavia, Carlo A; Nassisi, Marco; Pignata, Giulia; Zola, Marta; Grignolo, Federico M

2015-01-01

Dry age-related macular degeneration (AMD), also called geographic atrophy, is characterized by the atrophy of outer retinal layers and retinal pigment epithelium (RPE) cells. Dry AMD accounts for 80% of all intermediate and advanced forms of the disease. Although vision loss is mainly due to the neovascular form (75%), dry AMD remains a challenge for ophthalmologists because of the lack of effective therapies. Actual management consists of lifestyle modification, vitamin supplements, and supportive measures in the advanced stages. The Age-Related Eye Disease Study demonstrated a statistically significant protective effect of dietary supplementation of antioxidants (vitamin C, vitamin E, beta-carotene, zinc, and copper) on dry AMD progression rate. It was also stated that the consumption of omega-3 polyunsaturated fatty acids, such as docosahexaenoic acid and eicosapentaenoic acid, has protective effects. Other antioxidants, vitamins, and minerals (such as crocetin, curcumin, and vitamins B9, B12, and B6) are under evaluation, but the results are still uncertain. New strategies aim to 1) reduce or block drusen formation, 2) reduce or eliminate inflammation, 3) lower the accumulation of toxic by-products from the visual cycle, 4) reduce or eliminate retinal oxidative stress, 5) improve choroidal perfusion, 6) replace/repair or regenerate lost RPE cells and photoreceptors with stem cell therapy, and 7) develop a target gene therapy. PMID:25878491

Fundus autofluorescence findings in a mouse model of retinal detachment.

PubMed

Secondi, Roberta; Kong, Jian; Blonska, Anna M; Staurenghi, Giovanni; Sparrow, Janet R

2012-08-07

Fundus autofluorescence (fundus AF) changes were monitored in a mouse model of retinal detachment (RD). RD was induced by transscleral injection of hyaluronic acid (Healon) or sterile balanced salt solution (BSS) into the subretinal space of 4-5-day-old albino Abca4 null mutant and Abca4 wild-type mice. Images acquired by confocal scanning laser ophthalmoscopy (Spectralis HRA) were correlated with spectral domain optical coherence tomography (SD-OCT), infrared reflectance (IR), fluorescence spectroscopy, and histologic analysis. Results. In the area of detached retina, multiple hyperreflective spots in IR images corresponded to punctate areas of intense autofluorescence visible in fundus AF mode. The puncta exhibited changes in fluorescence intensity with time. SD-OCT disclosed undulations of the neural retina and hyperreflectivity of the photoreceptor layer that likely corresponded to histologically visible photoreceptor cell rosettes. Fluorescence emission spectra generated using flat-mounted retina, and 488 and 561 nm excitation, were similar to that of RPE lipofuscin. With increased excitation wavelength, the emission maximum shifted towards longer wavelengths, a characteristic typical of fundus autofluorescence. In detached retinas, hyper-autofluorescent spots appeared to originate from photoreceptor outer segments that were arranged within retinal folds and rosettes. Consistent with this interpretation is the finding that the autofluorescence was spectroscopically similar to the bisretinoids that constitute RPE lipofuscin. Under the conditions of a RD, abnormal autofluorescence may arise from excessive production of bisretinoid by impaired photoreceptor cells.

Effects of heavy ions on visual function and electrophysiology of rodents: the ALTEA-MICE project

NASA Technical Reports Server (NTRS)

Sannita, W. G.; Acquaviva, M.; Ball, S. L.; Belli, F.; Bisti, S.; Bidoli, V.; Carozzo, S.; Casolino, M.; Cucinotta, F.; De Pascale, M. P.;

Guidelines for the Management of Wet Age-Related Macular Degeneration: Recommendations from a Panel of Greek Experts.

PubMed

Androudi, Sofia; Dastiridou, Anna; Pharmakakis, Nikolaos; Stefaniotou, Maria; Kalogeropoulos, Christos; Symeonidis, Chrysanthos; Charonis, Alexandros; Tsilimbaris, Miltiadis

2016-05-01

To propose guidelines for the management of patients with wet age-related macular degeneration (wAMD), taking into account the results of large multicenter studies and clinical experience of retina experts. A team of retina experts developed a consensus paper after three consecutive meetings. The group was focused on guidelines to help clinical decision-making around the definition of successful treatment and the definition of non-response to therapy. Parameters suggestive of a successful response to treatments included: any gain in best corrected visual acuity (BCVA) or vision loss that is less than 5-10 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, reduction of central retinal thickness, partial or complete absorption of subretinal fluid (SRF), reduction of intraretinal fluid, reduction of pigment epithelial detachment or restoration of the anatomy of outer retinal layers. Non-response to current treatment was considered in the case of loss of BCVA greater than 10 ETDRS letters, increased retinal edema or increase of SRF as evidenced by optical coherence tomography or new bleeding in biomicroscopy. The introduction of anti-VEGF agents revolutionized the treatment of wAMD. Given the complexity of the disease, the emerging new agents and the difference of cases recruited in clinical trials compared to those appearing in every-day practice, it is essential to individualize treatment options taking into account the results of clinical trials.

Superpixel guided active contour segmentation of retinal layers in OCT volumes

NASA Astrophysics Data System (ADS)

Bai, Fangliang; Gibson, Stuart J.; Marques, Manuel J.; Podoleanu, Adrian

2018-03-01

Retinal OCT image segmentation is a precursor to subsequent medical diagnosis by a clinician or machine learning algorithm. In the last decade, many algorithms have been proposed to detect retinal layer boundaries and simplify the image representation. Inspired by the recent success of superpixel methods for pre-processing natural images, we present a novel framework for segmentation of retinal layers in OCT volume data. In our framework, the region of interest (e.g. the fovea) is located using an adaptive-curve method. The cell layer boundaries are then robustly detected firstly using 1D superpixels, applied to A-scans, and then fitting active contours in B-scan images. Thereafter the 3D cell layer surfaces are efficiently segmented from the volume data. The framework was tested on healthy eye data and we show that it is capable of segmenting up to 12 layers. The experimental results imply the effectiveness of proposed method and indicate its robustness to low image resolution and intrinsic speckle noise.

Exploring photoreceptor reflectivity via multimodal imaging of outer retinal tubulation in advanced age-related macular degeneration

PubMed Central

Litts, Katie M.; Wang, Xiaolin; Clark, Mark E.; Owsley, Cynthia; Freund, K. Bailey; Curcio, Christine A.; Zhang, Yuhua

2016-01-01

Purpose To investigate the microscopic structure of outer retinal tubulation (ORT) and optical properties of cone photoreceptors in vivo, we studied ORT appearance by multimodal imaging, including spectral domain optical coherence tomography (SD-OCT) and adaptive optics scanning laser ophthalmoscopy (AOSLO). Methods Four eyes of 4 subjects with advanced AMD underwent color fundus photography, infrared reflectance imaging, SD-OCT, and AOSLO with a high-resolution research instrument. ORT was identified in closely spaced (11 μm) SD-OCT volume scans. Results ORT in cross-sectional and en face SD-OCT was a hyporeflective area representing a lumen surrounded by a hyperreflective border consisting of cone photoreceptor mitochondria and external limiting membrane, per previous histology. In contrast, ORT by AOSLO was a hyporeflective structure of the same shape as in en face SD-OCT but lacking visualizable cone photoreceptors. Conclusion Lack of ORT cone reflectivity by AOSLO indicates that cones have lost their normal directionality and waveguiding property due to loss of outer segments and subsequent retinal remodeling. Reflective ORT cones by SD-OCT, in contrast, may depend partly on mitochondria as light scatterers within inner segments of these degenerating cells, a phenomenon enhanced by coherent imaging. Multimodal imaging of ORT provides insight into cone degeneration and reflectivity sources in OCT. PMID:27584549

Optical Coherence Tomography as a Biomarker for Diagnosis, Progression, and Prognosis of Neurodegenerative Diseases

PubMed Central

Otin, Sofia; Fuertes, Maria I.; Vilades, Elisa; Gracia, Hector; Ara, Jose R.; Alarcia, Raquel; Polo, Vicente; Larrosa, Jose M.; Pablo, Luis E.

2016-01-01

Neurodegenerative diseases present a current challenge for accurate diagnosis and for providing precise prognostic information. Developing imaging biomarkers for multiple sclerosis (MS), Parkinson disease (PD), and Alzheimer's disease (AD) will improve the clinical management of these patients and may be useful for monitoring treatment effectiveness. Recent research using optical coherence tomography (OCT) has demonstrated that parameters provided by this technology may be used as potential biomarkers for MS, PD, and AD. Retinal thinning has been observed in these patients and new segmentation software for the analysis of the different retinal layers may provide accurate information on disease progression and prognosis. In this review we analyze the application of retinal evaluation using OCT technology to provide better understanding of the possible role of the retinal layers thickness as biomarker for the detection of these neurodegenerative pathologies. Current OCT analysis of the retinal nerve fiber layer and, specially, the ganglion cell layer thickness may be considered as a good biomarker for disease diagnosis, severity, and progression. PMID:27840739

In situ cell surface proteomics reveals differentially expressed membrane proteins in retinal pigment epithelial cells during autoimmune uveitis.

PubMed

Uhl, P B; Szober, C M; Amann, B; Alge-Priglinger, C; Ueffing, M; Hauck, S M; Deeg, C A

2014-09-23

Retinal pigment epithelium (RPE) builds the outer blood-retinal barrier of the eye and plays an important role in pathogenesis of the sight threatening disease equine recurrent uveitis (ERU). ERU is a spontaneous autoimmune mediated inflammatory disease characterised by the breakdown of the outer blood-retinal barrier and an influx of autoaggressive T-cells into the inner eye. Therefore, identification of molecular mechanisms contributing to changed function of blood-retinal barrier in ERU is important for the understanding of pathophysiology. Cell surface proteins of RPE collected from healthy horses and horses with ERU were captured by in situ biotinylation and analysed with high resolution mass spectrometry coupled to liquid chromatography (LC-MS/MS) to identify differentially expressed proteins. With label free differential proteomics, a total of 27 differently expressed cell surface proteins in diseased RPE could be detected. Significant down-regulation of three very interesting proteins, synaptotagmin 1, basigin and collectrin was verified and further characterised. We applied an innovative and successful method to detect changes in the plasma cell surface proteome of RPE cells in a spontaneous inflammatory eye disease, serving as a valuable model for human autoimmune uveitis. We were able to identify 27 differentially expressed plasma cell membrane proteins, including synaptotagmin 1, basigin and collectrin, which play important roles in cell adhesion, transport and cell communication. Copyright © 2014 Elsevier B.V. All rights reserved.

The Cellular Origins of the Outer Retinal Bands in Optical Coherence Tomography Images

PubMed Central

Jonnal, Ravi S.; Kocaoglu, Omer P.; Zawadzki, Robert J.; Lee, Sang-Hyuck; Werner, John S.; Miller, Donald T.

2014-01-01

Purpose. To test the recently proposed hypothesis that the second outer retinal band, observed in clinical OCT images, originates from the inner segment ellipsoid, by measuring: (1) the thickness of this band within single cone photoreceptors, and (2) its respective distance from the putative external limiting membrane (band 1) and cone outer segment tips (band 3). Methods. Adaptive optics-optical coherence tomography images were acquired from four subjects without known retinal disease. Images were obtained at foveal (2°) and perifoveal (5°) locations. Cone photoreceptors (n = 9593) were identified and segmented in three dimensions using custom software. Features corresponding to bands 1, 2, and 3 were automatically identified. The thickness of band 2 was assessed in each cell by fitting the longitudinal reflectance profile of the band with a Gaussian function. Distances between bands 1 and 2, and between 2 and 3, respectively, were also measured in each cell. Two independent calibration techniques were employed to determine the depth scale (physical length per pixel) of the imaging system. Results. When resolved within single cells, the thickness of band 2 is a factor of three to four times narrower than in corresponding clinical OCT images. The distribution of band 2 thickness across subjects and eccentricities had a modal value of 4.7 μm, with 48% of the cones falling between 4.1 and 5.2 μm. No significant differences were found between cells in the fovea and perifovea. The distance separating bands 1 and 2 was found to be larger than the distance between bands 2 and 3, across subjects and eccentricities, with a significantly larger difference at 5° than 2°. Conclusions. On the basis of these findings, we suggest that ascription of the outer retinal band 2 to the inner segment ellipsoid is unjustified, because the ellipsoid is both too thick and proximally located to produce the band. PMID:25324288

Inner Blood-Retinal Barrier Dominantly Expresses Breast Cancer Resistance Protein: Comparative Quantitative Targeted Absolute Proteomics Study of CNS Barriers in Pig.

PubMed

Zhang, Zhengyu; Uchida, Yasuo; Hirano, Satoshi; Ando, Daisuke; Kubo, Yoshiyuki; Auriola, Seppo; Akanuma, Shin-Ichi; Hosoya, Ken-Ichi; Urtti, Arto; Terasaki, Tetsuya; Tachikawa, Masanori

2017-11-06

The purpose of this study was to determine absolute protein expression levels of transporters at the porcine inner blood-retinal barrier (BRB) and to compare the transporter protein expression quantitatively among the inner BRB, outer BRB, blood-brain barrier (BBB), and blood-cerebrospinal fluid barrier (BCSFB). Crude membrane fractions of isolated retinal capillaries (inner BRB) and isolated retinal pigment epithelium (RPE, outer BRB) were prepared from porcine eyeballs, while plasma membrane fractions were prepared from isolated porcine brain capillaries (BBB) and isolated choroid plexus (BCSFB). Protein expression levels of 32 molecules, including 16 ATP-binding-cassette (ABC) transporters and 13 solute-carrier (SLC) transporters, were measured using a quantitative targeted absolute proteomic technique. At the inner BRB, five molecules were detected: breast cancer resistance protein (BCRP, ABCG2; 22.8 fmol/μg protein), multidrug resistance protein 1 (MDR1, ABCB1; 8.70 fmol/μg protein), monocarboxylate transporter 1 (MCT1, SLC16A1; 4.83 fmol/μg protein), glucose transporter 1 (GLUT1, SLC2A1; 168 fmol/μg protein), and sodium-potassium adenosine triphosphatase (Na + /K + -ATPase; 53.7 fmol/μg protein). Other proteins were under the limits of quantification. Expression of MCT1 was at least 17.6-, 11.0-, and 19.2-fold greater than those of MCT2, 3, and 4, respectively. The transporter protein expression at the inner BRB was most highly correlated with that at the BBB (R 2 = 0.8906), followed by outer BRB (R 2 = 0.7988) and BCSFB (R 2 = 0.4730). Sodium-dependent multivitamin transporter (SMVT, SLC5A6) and multidrug resistance-associated protein 1 (MRP1, ABCC1) were expressed at the outer BRB (0.378 and 1.03 fmol/μg protein, respectively) but were under the limit of quantification at the inner BRB. These findings may be helpful for understanding differential barrier function.

Differential Modulation of Retinal Degeneration by Ccl2 and Cx3cr1 Chemokine Signalling

PubMed Central

Luhmann, Ulrich F. O.; Lange, Clemens A.; Robbie, Scott; Munro, Peter M. G.; Cowing, Jill A.; Armer, Hannah E. J.; Luong, Vy; Carvalho, Livia S.; MacLaren, Robert E.; Fitzke, Frederick W.; Bainbridge, James W. B.; Ali, Robin R.

2012-01-01

Microglia and macrophages are recruited to sites of retinal degeneration where local cytokines and chemokines determine protective or neurotoxic microglia responses. Defining the role of Ccl2-Ccr2 and Cx3cl1-Cx3cr1 signalling for retinal pathology is of particular interest because of its potential role in age-related macular degeneration (AMD). Ccl2, Ccr2, and Cx3cr1 signalling defects impair macrophage trafficking, but have, in several conflicting studies, been reported to show different degrees of age-related retinal degeneration. Ccl2/Cx3cr1 double knockout (CCDKO) mice show an early onset retinal degeneration and have been suggested as a model for AMD. In order to understand phenotypic discrepancies in different chemokine knockout lines and to study how defects in Ccl2 and/or Cx3cr1 signalling contribute to the described early onset retinal degeneration, we defined primary and secondary pathological events in CCDKO mice. To control for genetic background variability, we compared the original phenotype with that of single Ccl2, Cx3cr1 and Ccl2/Cx3cr1 double knockout mice obtained from backcrosses of CCDKO with C57Bl/6 mice. We found that the primary pathological event in CCDKO mice develops in the inferior outer nuclear layer independently of light around postnatal day P14. RPE and vascular lesions develop secondarily with increasing penetrance with age and are clinically similar to retinal telangiectasia not to choroidal neovascularisation. Furthermore, we provide evidence that a third autosomal recessive gene causes the degeneration in CCDKO mice and in all affected re-derived lines and subsequently demonstrated co-segregation of the naturally occurring RD8 mutation in the Crb1 gene. By comparing CCDKO mice with re-derived CCl2−/−/Crb1Rd8/RD8, Cx3cr1−/−/Crb1Rd8/RD8 and CCl2−/−/Cx3cr1−/−/Crb1Rd8/RD8 mice, we observed a differential modulation of the retinal phenotype by genetic background and both chemokine signalling pathways. These findings indicate that CCDKO mice are not a model of AMD, but a model for an inherited retinal degeneration that is differentially modulated by Ccl2-Ccr2 and Cx3cl1-Cx3cr1 chemokine signalling. PMID:22545116

Formation of the outer layer of the Dictyostelium spore coat depends on the inner-layer protein SP85/PsB.

PubMed

Metcalf, Talibah; Kelley, Karen; Erdos, Gregory W; Kaplan, Lee; West, Christopher M

2003-02-01

The Dictyostelium spore is surrounded by a 220 microm thick trilaminar coat that consists of inner and outer electron-dense layers surrounding a central region of cellulose microfibrils. In previous studies, a mutant strain (TL56) lacking three proteins associated with the outer layer exhibited increased permeability to macromolecular tracers, suggesting that this layer contributes to the coat permeability barrier. Electron microscopy now shows that the outer layer is incomplete in the coats of this mutant and consists of a residual regular array of punctate electron densities. The outer layer is also incomplete in a mutant lacking a cellulose-binding protein associated with the inner layer, and these coats are deficient in an outer-layer protein and another coat protein. To examine the mechanism by which this inner-layer protein, SP85, contributes to outer-layer formation, various domain fragments were overexpressed in forming spores. Most of these exert dominant negative effects similar to the deletion of outer-layer proteins, but one construct, consisting of a fusion of the N-terminal and Cys-rich C1 domain, induces a dense mat of novel filaments at the surface of the outer layer. Biochemical studies show that the C1 domain binds cellulose, and a combination of site-directed mutations that inhibits its cellulose-binding activity suppresses outer-layer filament induction. The results suggest that, in addition to a previously described early role in regulating cellulose synthesis, SP85 subsequently contributes a cross-bridging function between cellulose and other coat proteins to organize previously unrecognized structural elements in the outer layer of the coat.

Relationship Between Foveal Cone Specialization and Pit Morphology in Albinism

PubMed Central

Wilk, Melissa A.; McAllister, John T.; Cooper, Robert F.; Dubis, Adam M.; Patitucci, Teresa N.; Summerfelt, Phyllis; Anderson, Jennifer L.; Stepien, Kimberly E.; Costakos, Deborah M.; Connor, Thomas B.; Wirostko, William J.; Chiang, Pei-Wen; Dubra, Alfredo; Curcio, Christine A.; Brilliant, Murray H.; Summers, C. Gail; Carroll, Joseph

2014-01-01

Purpose. Albinism is associated with disrupted foveal development, though intersubject variability is becoming appreciated. We sought to quantify this variability, and examine the relationship between foveal cone specialization and pit morphology in patients with a clinical diagnosis of albinism. Methods. We recruited 32 subjects with a clinical diagnosis of albinism. DNA was obtained from 25 subjects, and known albinism genes were analyzed for mutations. Relative inner and outer segment (IS and OS) lengthening (fovea-to-perifovea ratio) was determined from manually segmented spectral domain-optical coherence tomography (SD-OCT) B-scans. Foveal pit morphology was quantified for eight subjects from macular SD-OCT volumes. Ten subjects underwent imaging with adaptive optics scanning light ophthalmoscopy (AOSLO), and cone density was measured. Results. We found mutations in 22 of 25 subjects, including five novel mutations. All subjects lacked complete excavation of inner retinal layers at the fovea, though four subjects had foveal pits with normal diameter and/or volume. Peak cone density and OS lengthening were variable and overlapped with that observed in normal controls. A fifth hyper-reflective band was observed in the outer retina on SD-OCT in the majority of the subjects with albinism. Conclusions. Foveal cone specialization and pit morphology vary greatly in albinism. Normal cone packing was observed in the absence of a foveal pit, suggesting a pit is not required for packing to occur. The degree to which retinal anatomy correlates with genotype or visual function remains unclear, and future examination of larger patient groups will provide important insight on this issue. PMID:24845642

The rod-driven a-wave of the dark-adapted mammalian electroretinogram.

PubMed

Robson, John G; Frishman, Laura J

2014-03-01

The a-wave of the electroretinogram (ERG) reflects the response of photoreceptors to light, but what determines the exact waveform of the recorded voltage is not entirely understood. We have now simulated the trans-retinal voltage generated by the photocurrent of dark-adapted mammalian rods, using an electrical model based on the in vitro measurements of Hagins et al. (1970) and Arden (1976) in rat retinas. Our simulations indicate that in addition to the voltage produced by extracellular flow of photocurrent from rod outer to inner segments, a substantial fraction of the recorded a-wave is generated by current that flows in the outer nuclear layer (ONL) to hyperpolarize the rod axon and synaptic terminal. This current includes a transient capacitive component that contributes an initial negative "nose" to the trans-retinal voltage when the stimulus is strong. Recordings in various species of the a-wave, including the peak and initial recovery towards the baseline, are consistent with simulations showing an initial transient primarily related to capacitive currents in the ONL. Existence of these capacitive currents can explain why there is always a substantial residual transient a-wave when post-receptoral responses are pharmacologically inactivated in rodents and nonhuman primates, or severely genetically compromised in humans (e.g. complete congenital stationary night blindness) and nob mice. Our simulations and analysis of ERGs indicate that the timing of the leading edge and peak of dark-adapted a-waves evoked by strong stimuli could be used in a simple way to estimate rod sensitivity. Copyright © 2013 Elsevier Ltd. All rights reserved.

Use of bioreactors for culturing human retinal organoids improves photoreceptor yields.

PubMed

Ovando-Roche, Patrick; West, Emma L; Branch, Matthew J; Sampson, Robert D; Fernando, Milan; Munro, Peter; Georgiadis, Anastasios; Rizzi, Matteo; Kloc, Magdalena; Naeem, Arifa; Ribeiro, Joana; Smith, Alexander J; Gonzalez-Cordero, Anai; Ali, Robin R

2018-06-13

The use of human pluripotent stem cell-derived retinal cells for cell therapy strategies and disease modelling relies on the ability to obtain healthy and organised retinal tissue in sufficient quantities. Generating such tissue is a lengthy process, often taking over 6 months of cell culture, and current approaches do not always generate large quantities of the major retinal cell types required. We adapted our previously described differentiation protocol to investigate the use of stirred-tank bioreactors. We used immunohistochemistry, flow cytometry and electron microscopy to characterise retinal organoids grown in standard and bioreactor culture conditions. Our analysis revealed that the use of bioreactors results in improved laminar stratification as well as an increase in the yield of photoreceptor cells bearing cilia and nascent outer-segment-like structures. Bioreactors represent a promising platform for scaling up the manufacture of retinal cells for use in disease modelling, drug screening and cell transplantation studies.

Varicella Zoster Virus Necrotizing Retinitis in Two Patients with Idiopathic CD4 Lymphocytopenia.

PubMed

Gupta, Meenakashi; Jardeleza, Maria Stephanie R; Kim, Ivana; Durand, Marlene L; Kim, Leo; Lobo, Ann-Marie

2016-10-01

Progressive outer retinal necrosis (PORN) associated with varicella zoster virus (VZV) is usually diagnosed in HIV positive or immunosuppressed patients. We report two cases of immunocompetent patients with necrotizing viral retinitis found to have idiopathic CD4 lymphocytopenia. Clinical presentation, examination, imaging, and laboratory testing of two patients with VZV retinitis are presented. An HIV negative patient with history of herpes zoster presented with rapid loss of vision and examination consistent with PORN. PCR testing confirmed VZV. Lymphocytopenia was noted with a CD4 count of 25/mm(3). A second HIV negative patient presented with blurred vision and lid swelling and was found to have peripheral VZV retinitis confirmed by PCR. Laboratory workup revealed lymphocytopenia with a CD4 count of 133/mm(3). VZV necrotizing retinitis classic for PORN can occur in HIV negative patients. Idiopathic CD4 lymphocytopenia should be considered healthy patients who develop ocular infections seen in the immunocompromised.

Correction of the retinal dystrophy phenotype of the RCS rat by viral gene transfer of Mertk.

PubMed

Vollrath, D; Feng, W; Duncan, J L; Yasumura, D; D'Cruz, P M; Chappelow, A; Matthes, M T; Kay, M A; LaVail, M M

2001-10-23

The Royal College of Surgeons (RCS) rat is a widely studied animal model of retinal degeneration in which the inability of the retinal pigment epithelium (RPE) to phagocytize shed photoreceptor outer segments leads to a progressive loss of rod and cone photoreceptors. We recently used positional cloning to demonstrate that the gene Mertk likely corresponds to the retinal dystrophy (rdy) locus of the RCS rat. In the present study, we sought to determine whether gene transfer of Mertk to a RCS rat retina would result in correction of the RPE phagocytosis defect and preservation of photoreceptors. We used subretinal injection of a recombinant replication-deficient adenovirus encoding rat Mertk to deliver the gene to the eyes of young RCS rats. Electrophysiological assessment of animals 30 days after injection revealed an increased sensitivity of treated eyes to low-intensity light. Histologic and ultrastructural assessment demonstrated substantial sparing of photoreceptors, preservation of outer segment structure, and correction of the RPE phagocytosis defect in areas surrounding the injection site. Our results provide definitive evidence that mutation of Mertk underlies the RCS retinal dystrophy phenotype, and that the phenotype can be corrected by treatment of juvenile animals. To our knowledge, this is the first demonstration of complementation of both a functional cellular defect (phagocytosis) and a photoreceptor degeneration by gene transfer to the RPE. These results, together with the recent discovery of MERTK mutations in individuals with retinitis pigmentosa, emphasize the importance of the RCS rat as a model for gene therapy of diseases that arise from RPE dysfunction.

Laser-induced retinal nerve fiber layer injury in the nonhuman primate

NASA Astrophysics Data System (ADS)

Zwick, Harry; Belkin, Michael; Zuclich, Joseph A.; Lund, David J.; Schuschereba, Steven T.; Scales, David K.

1996-04-01

We have evaluated the acute effects of Argon laser injury to the retinal nerve fiber layer (NFL) in the non-human primate. Single Argon laser exposures of 150 millijoules were employed to induce retinal NFL injury. Retinal NFL injury is not acute; unlike its parallel in retinal disease it has two components that emanate from the acute retinal injury site. The ascending component is more visible, primarily because it is ascending toward the disk, representing ganglion cell axons cut off from their nutrient base, the ganglion cell body; the descending component may require up to 3 weeks to develop. Its characterization depends on the distribution of retinal NFL and the slower degeneration of the ganglion cell bodies. Fluorescein angiography suggest a retinal capillary loss that occurs in the capillary bed of the retinal NFL defect. It may reflect a reduced capillary vascular requirement of the NFL as well as a possible reduction of activity in the axonal transport mechanisms in the ascending NFL defect.

Identification of endogenous flurophores in the layered retina

NASA Astrophysics Data System (ADS)

Xu, Gaixia; Chen, Danni; Sun, Yiwen; Qu, Junle; Lin, Ziyang; Ding, Zhihua; Niu, Hanben

2007-05-01

In this paper, we measured and analyzed the characteristic of endogenous fluorophores in porcine layered retina by using advanced fluorescence spectroscopy and microscopy imaging technology. It was found that there were obvious contrasts corresponding to the different layers of retina, which may be important for fundus disease diagnosis. The retinal pigment epithelium cells exhibited strong autofluorescence with as emission peak of 600+/-10nm when excited with 860-nm light. The emission peak of photoreceptors was at 652+/-5nm, and the emission peak of retinal vessels layer was weak and at 640~700nm, when excited with 488-nm light. Autofluorescence images of three layers of retina were obtained using the same setup. We concluded that the main endogenous fluorophore in PRE was lipofuscin and that in retinal vessels was porphyrin. What's more, the FMHW (full width at half. maximum) of retinal fluorescence spectrum was broad, which suggested that there wasn't only one endogenous fluorophores of tissues excited.

Chromatic discrimination: differential contributions from two adapting fields

PubMed Central

Cao, Dingcai; Lu, Yolanda H.

2012-01-01

To test whether a retinal or cortical mechanism sums contributions from two adapting fields to chromatic discrimination, L/M discrimination was measured with a test annulus surrounded by an inner circular field and an outer rectangular field. A retinal summation mechanism predicted that the discrimination pattern would not change with a change in the fixation location. Therefore, the fixation was set either in the inner or the outer field in two experiments. When one of the adapting fields was “red” and the other was “green,” the adapting field where the observer fixated always had a stronger influence on chromatic discrimination. However, when one adapting field was “white” and the other was red or green, the white field always weighted more heavily than the other adapting field in determining discrimination thresholds, whether the white field or the fixation was in the inner or outer adapting field. These results suggest that a cortical mechanism determines the relative contributions from different adapting fields. PMID:22330364

Chromatic discrimination: differential contributions from two adapting fields.

PubMed

Cao, Dingcai; Lu, Yolanda H

2012-02-01

To test whether a retinal or cortical mechanism sums contributions from two adapting fields to chromatic discrimination, L/M discrimination was measured with a test annulus surrounded by an inner circular field and an outer rectangular field. A retinal summation mechanism predicted that the discrimination pattern would not change with a change in the fixation location. Therefore, the fixation was set either in the inner or the outer field in two experiments. When one of the adapting fields was "red" and the other was "green," the adapting field where the observer fixated always had a stronger influence on chromatic discrimination. However, when one adapting field was "white" and the other was red or green, the white field always weighted more heavily than the other adapting field in determining discrimination thresholds, whether the white field or the fixation was in the inner or outer adapting field. These results suggest that a cortical mechanism determines the relative contributions from different adapting fields. © 2012 Optical Society of America

Influence of bacterial toxins on the GTPase activity of transducin from bovine retinal rod outer segments

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rybin, V.O.; Gureeva, A.A.

1986-05-10

The action of cholera toxin, capable of ADP-ribosylation of the activator N/sub s/ protein, and pertussis toxin, capable of ADP-ribosylation of the inhibitor N/sub i/ protein of the adenylate cyclase complex, on transducin, the GTP-binding protein of the rod outer segments of the retina, was investigated. It was shown that under the action of pertussis and cholera toxins, the GTPase activity of transducin is inhibited. Pertussin toxin inhibits the GTPase of native retinal rod outer segments by 30-40%, while GTPase of homogeneous transducin produces a 70-80% inhibition. The action of toxins on transducin depends on the presence and nature ofmore » the guanylic nucleotide with which incubation is performed. On the basis of the data obtained it is suggested that pertussis toxin interacts with pretransducin and with the transducin-GDP complex, while cholera toxin ADP-ribosylates the transducin-GTP complex and does not act on transducin lacking GTP.« less

Spectral-Domain Optical Coherence Tomography Staging and Autofluorescence Imaging in Achromatopsia

PubMed Central

Greenberg, Jonathan P.; Sherman, Jerome; Zweifel, Sandrine A.; Chen, Royce W. S.; Duncker, Tobias; Kohl, Susanne; Baumann, Britta; Wissinger, Bernd; Yannuzzi, Lawrence A.; Tsang, Stephen H.

2015-01-01

Importance Evidence is mounting that achromatopsia is a progressive retinal degeneration, and treatments for this condition are on the horizon. Objectives To categorize achromatopsia into clinically identifiable stages using spectral-domain optical coherence tomography and to describe fundus autofluorescence imaging in this condition. Design, Setting, and Participants A prospective observational study was performed between 2010 and 2012 at the Edward S. Harkness Eye Institute, New York-Presbyterian Hospital. Participants included 17 patients (aged 10-62 years) with full-field electroretinography-confirmed achromatopsia. Main outcomes and Measures Spectral-domain optical coherence tomography features and staging system, fundus autofluorescence and near-infrared reflectance features and their correlation to optical coherence tomography, and genetic mutations served as the outcomes and measures. Results Achromatopsia was categorized into 5 stages on spectral-domain optical coherence tomography: stage 1 (2 patients [12%]), intact outer retina; stage 2 (2 patients [12%]), inner segment ellipsoid line disruption; stage 3 (5 patients [29%]), presence of an optically empty space; stage 4 (5 patients [29%]), optically empty space with partial retinal pigment epithelium disruption; and stage 5 (3 patients [18%]), complete retinal pigment epithelium disruption and/or loss of the outer nuclear layer. Stage 1 patients showed isolated hyperreflectivity of the external limiting membrane in the fovea, and the external limiting membrane was hyperreflective above each optically empty space. On near infrared reflectance imaging, the fovea was normal, hyporeflective, or showed both hyporeflective and hyperreflective features. All patients demonstrated autofluorescence abnormalities in the fovea and/or parafovea: 9 participants (53%) had reduced or absent autofluorescence surrounded by increased autofluorescence, 4 individuals (24%) showed only reduced or absent autofluorescence, 3 patients (18%) displayed only increased autofluorescence, and 1 individual (6%) exhibited decreased macular pigment contrast. Inner segment ellipsoid line loss generally correlated with the area of reduced autofluorescence, but hyperautofluorescence extended into this region in 2 patients (12%). Bilateral coloboma-like atrophic macular lesions were observed in 1 patient (6%). Five novel mutations were identified (4 in the CNGA3 gene and 1 in the CNGB3 gene). Conclusions and Relevance Achromatopsia often demonstrates hyperautofluorescence suggestive of progressive retinal degeneration. The proposed staging system facilitates classification of the disease into different phases of progression and may have therapeutic implications. PMID:24504161

Spectral-domain optical coherence tomography staging and autofluorescence imaging in achromatopsia.

PubMed

Greenberg, Jonathan P; Sherman, Jerome; Zweifel, Sandrine A; Chen, Royce W S; Duncker, Tobias; Kohl, Susanne; Baumann, Britta; Wissinger, Bernd; Yannuzzi, Lawrence A; Tsang, Stephen H

2014-04-01

IMPORTANCE Evidence is mounting that achromatopsia is a progressive retinal degeneration, and treatments for this condition are on the horizon. OBJECTIVES To categorize achromatopsia into clinically identifiable stages using spectral-domain optical coherence tomography and to describe fundus autofluorescence imaging in this condition. DESIGN, SETTING, AND PARTICIPANTS A prospective observational study was performed between 2010 and 2012 at the Edward S. Harkness Eye Institute, New York-Presbyterian Hospital. Participants included 17 patients (aged 10-62 years) with full-field electroretinography-confirmed achromatopsia. MAIN OUTCOMES AND MEASURES Spectral-domain optical coherence tomography features and staging system, fundus autofluorescence and near-infrared reflectance features and their correlation to optical coherence tomography, and genetic mutations served as the outcomes and measures. RESULTS Achromatopsia was categorized into 5 stages on spectral-domain optical coherence tomography: stage 1 (2 patients [12%]), intact outer retina; stage 2 (2 patients [12%]), inner segment ellipsoid line disruption; stage 3 (5 patients [29%]), presence of an optically empty space; stage 4 (5 patients [29%]), optically empty space with partial retinal pigment epithelium disruption; and stage 5 (3 patients [18%]), complete retinal pigment epithelium disruption and/or loss of the outer nuclear layer. Stage 1 patients showed isolated hyperreflectivity of the external limiting membrane in the fovea, and the external limiting membrane was hyperreflective above each optically empty space. On near infrared reflectance imaging, the fovea was normal, hyporeflective, or showed both hyporeflective and hyperreflective features. All patients demonstrated autofluorescence abnormalities in the fovea and/or parafovea: 9 participants (53%) had reduced or absent autofluorescence surrounded by increased autofluorescence, 4 individuals (24%) showed only reduced or absent autofluorescence, 3 patients (18%) displayed only increased autofluorescence, and 1 individual (6%) exhibited decreased macular pigment contrast. Inner segment ellipsoid line loss generally correlated with the area of reduced autofluorescence, but hyperautofluorescence extended into this region in 2 patients (12%). Bilateral coloboma-like atrophic macular lesions were observed in 1 patient (6%). Five novel mutations were identified (4 in the CNGA3 gene and 1 in the CNGB3 gene). CONCLUSIONS AND RELEVANCE Achromatopsia often demonstrates hyperautofluorescence suggestive of progressive retinal degeneration. The proposed staging system facilitates classification of the disease into different phases of progression and may have therapeutic implications.

Retinal nerve fiber layer thickness measured with optical coherence tomography is related to visual function in glaucomatous eyes.

PubMed

El Beltagi, Tarek A; Bowd, Christopher; Boden, Catherine; Amini, Payam; Sample, Pamela A; Zangwill, Linda M; Weinreb, Robert N

2003-11-01

To determine the relationship between areas of glaucomatous retinal nerve fiber layer thinning identified by optical coherence tomography and areas of decreased visual field sensitivity identified by standard automated perimetry in glaucomatous eyes. Retrospective observational case series. Forty-three patients with glaucomatous optic neuropathy identified by optic disc stereo photographs and standard automated perimetry mean deviations >-8 dB were included. Participants were imaged with optical coherence tomography within 6 months of reliable standard automated perimetry testing. The location and number of optical coherence tomography clock hour retinal nerve fiber layer thickness measures outside normal limits were compared with the location and number of standard automated perimetry visual field zones outside normal limits. Further, the relationship between the deviation from normal optical coherence tomography-measured retinal nerve fiber layer thickness at each clock hour and the average pattern deviation in each visual field zone was examined by using linear regression (R(2)). The retinal nerve fiber layer areas most frequently outside normal limits were the inferior and inferior temporal regions. The least sensitive visual field zones were in the superior hemifield. Linear regression results (R(2)) showed that deviation from the normal retinal nerve fiber layer thickness at optical coherence tomography clock hour positions 6 o'clock, 7 o'clock, and 8 o'clock (inferior and inferior temporal) was best correlated with standard automated perimetry pattern deviation in visual field zones corresponding to the superior arcuate and nasal step regions (R(2) range, 0.34-0.57). These associations were much stronger than those between clock hour position 6 o'clock and the visual field zone corresponding to the inferior nasal step region (R(2) = 0.01). Localized retinal nerve fiber layer thinning, measured by optical coherence tomography, is topographically related to decreased localized standard automated perimetry sensitivity in glaucoma patients.

Peripapillary retinal nerve fiber layer thickness in a population of 6-year-old children: findings by optical coherence tomography.

PubMed

Huynh, Son C; Wang, Xiu Ying; Rochtchina, Elena; Mitchell, Paul

2006-09-01

To study the distribution of retinal nerve fiber layer (RNFL) thickness by ocular and demographic variables in a population-based study of young children. Population-based cross-sectional study. One thousand seven hundred sixty-five of 2238 (78.9%) eligible 6-year-old children participated in the Sydney Childhood Eye Study between 2003 and 2004. Mean age was 6.7 years (50.9% boys). Detailed examination included cycloplegic autorefraction and measurement of axial length. Retinal nerve fiber layer scans using an optical coherence tomographer were performed with a circular scan pattern of 3.4-mm diameter. Multivariate analyses were performed to examine the distribution of RNFL parameters with gender, ethnicity, axial length, and refraction. Peripapillary RNFL thickness and RNFL(estimated integral) (RNFL(EI)), which measures the total cross-sectional area of ganglion cell axons converging onto the optic nerve head. Peripapillary RNFL thickness and RNFL(EI) were normally distributed. The mean+/-standard deviation RNFL average thickness was 103.7+/-11.4 microm and RNFL(EI) was 1.05+/-0.12 mm2. Retinal nerve fiber layer thickness was least for the temporal quadrant (75.7+/-14.7 microm), followed by the nasal (81.7+/-19.6 microm), inferior (127.8+/-20.5 microm), and superior (129.5+/-20.6 microm) quadrants. Multivariate adjusted RNFL average thickness was marginally greater in boys than in girls (104.7 microm vs. 103.2 microm; P = 0.007) and in East Asian than in white children (107.7 microm vs. 102.7 microm; P<0.0001). The RNFL was thinner with greater axial length (P(trend)<0.0001) and less positive spherical equivalent refractions (P(trend) = 0.004). Retinal nerve fiber layer average thickness and RNFL(EI) followed a normal distribution. Retinal nerve fiber layer thickness varied marginally with gender, but differences were more marked between white and East Asian children. Retinal nerve fiber layer thinning was associated with increasing axial length and less positive refractions.

Protection of retinal function by sulforaphane following retinal ischemic injury.

PubMed

Ambrecht, Lindsay A; Perlman, Jay I; McDonnell, James F; Zhai, Yougang; Qiao, Liang; Bu, Ping

2015-09-01

Sulforaphane, a precursor of glucosinolate in cruciferous vegetables such as broccoli and cauliflower, has been shown to protect brain ischemic injury. In this study, we examined the effect of systemic administration of sulforaphane on retinal ischemic reperfusion injury. Intraocular pressure was elevated in two groups of C57BL/6 mice (n = 8 per group) for 45 min to induce retinal ischemic reperfusion injury. Following retinal ischemic reperfusion injury, vehicle (1% DMSO saline) or sulforaphane (25 mg/kg/day) was administered intraperitoneally daily for 5 days. Scotopic electroretinography (ERG) was used to quantify retinal function prior to and one-week after retinal ischemic insult. Retinal morphology was examined one week after ischemic insult. Following ischemic reperfusion injury, ERG a- and b-wave amplitudes were significantly reduced in the control mice. Sulforaphane treatment significantly attenuated ischemic-induced loss of retinal function as compared to vehicle treated mice. In vehicle treated mice, ischemic reperfusion injury produced marked thinning of the inner retinal layers, but the thinning of the inner retinal layers appeared significantly less with sulforaphane treatment. Thus, sulforaphane may be beneficial in the treatment of retinal disorders with ischemic reperfusion injury. Copyright © 2015 Elsevier Ltd. All rights reserved.

Topographic and age-related changes of the retinal epithelium and Bruch's membrane of rhesus monkeys.

PubMed

Gouras, Peter; Ivert, Lena; Neuringer, Martha; Mattison, Julie A

2010-07-01

To examine structural differences in the retinal pigmented epithelium (RPE) and Bruch's membrane of rhesus monkeys (Macaca mulatta) as a function of topography and age. The retinas of two old (24 and 26 years old) and two young (1 and 6 years old) female monkeys were examined by light fluorescence and electron microscopy at the macula, equator, and ora serrata. All monkeys lacked fluorescence and lipofuscin granules in the RPE at the ora serrata where photoreceptors are absent. The equator and macula showed intense fluorescence and many lipofuscin granules in the RPE of the old but not the young monkeys. At the ora, the RPE contained many dense round melanin granules throughout the cell. At the equator and macula, melanin granules were more apical, less frequent, and often elongated. Mitochondria were clustered at the basal side of the RPE cell near infolds of the plasma membrane. Both mitochondria and infolds tended to increase toward the macula. In all regions, the basal lamina of the RPE did not penetrate the extracellular space adjacent to infolds. The elastin layer of Bruch's membrane was wide at the ora and equator and thinner at the macula. In the old monkeys, drusen were found at all retinal regions between the basal lamina and the internal collagen layer of Bruch's membrane. The drusen were often membrane-bound with a basal lamina and contained material resembling structures in the RPE. Lack of fluorescence and lipofuscin in the RPE at the ora serrata, where photoreceptors are absent, confirms that RPE fluorescence occurs only where outer segments are phagocytized. Mitochondrial clustering indicates that the basal side of the RPE cell uses the most energy and this becomes maximal at the macula. The presence of age-related degenerative changes and drusen at all retinal locations in the older monkeys, even at the ora where RPE lipofuscin was absent, indicates that these processes are not dependent on local lipofuscin accumulation. Therefore lipofuscin toxicity may not be the sole cause of age-related RPE degeneration.

Adhesion Failures Determine the Pattern of Choroidal Neovascularization in the Eye: A Computer Simulation Study

PubMed Central

Shirinifard, Abbas; Glazier, James Alexander; Swat, Maciej; Gens, J. Scott; Family, Fereydoon; Jiang, Yi; Grossniklaus, Hans E.

2012-01-01

Choroidal neovascularization (CNV) of the macular area of the retina is the major cause of severe vision loss in adults. In CNV, after choriocapillaries initially penetrate Bruch's membrane (BrM), invading vessels may regress or expand (CNV initiation). Next, during Early and Late CNV, the expanding vasculature usually spreads in one of three distinct patterns: in a layer between BrM and the retinal pigment epithelium (sub-RPE or Type 1 CNV), in a layer between the RPE and the photoreceptors (sub-retinal or Type 2 CNV) or in both loci simultaneously (combined pattern or Type 3 CNV). While most studies hypothesize that CNV primarily results from growth-factor effects or holes in BrM, our three-dimensional simulations of multi-cell model of the normal and pathological maculae recapitulate the three growth patterns, under the hypothesis that CNV results from combinations of impairment of: 1) RPE-RPE epithelial junctional adhesion, 2) Adhesion of the RPE basement membrane complex to BrM (RPE-BrM adhesion), and 3) Adhesion of the RPE to the photoreceptor outer segments (RPE-POS adhesion). Our key findings are that when an endothelial tip cell penetrates BrM: 1) RPE with normal epithelial junctions, basal attachment to BrM and apical attachment to POS resists CNV. 2) Small holes in BrM do not, by themselves, initiate CNV. 3) RPE with normal epithelial junctions and normal apical RPE-POS adhesion, but weak adhesion to BrM (e.g. due to lipid accumulation in BrM) results in Early sub-RPE CNV. 4) Normal adhesion of RBaM to BrM, but reduced apical RPE-POS or epithelial RPE-RPE adhesion (e.g. due to inflammation) results in Early sub-retinal CNV. 5) Simultaneous reduction in RPE-RPE epithelial binding and RPE-BrM adhesion results in either sub-RPE or sub-retinal CNV which often progresses to combined pattern CNV. These findings suggest that defects in adhesion dominate CNV initiation and progression. PMID:22570603

Lipofuscin and N-Retinylidene-N-Retinylethanolamine (A2E) Accumulate in Retinal Pigment Epithelium in Absence of Light Exposure

PubMed Central

Boyer, Nicholas P.; Higbee, Daniel; Currin, Mark B.; Blakeley, Lorie R.; Chen, Chunhe; Ablonczy, Zsolt; Crouch, Rosalie K.; Koutalos, Yiannis

2012-01-01

The age-dependent accumulation of lipofuscin in the retinal pigment epithelium (RPE) has been associated with the development of retinal diseases, particularly age-related macular degeneration and Stargardt disease. A major component of lipofuscin is the bis-retinoid N-retinylidene-N-retinylethanolamine (A2E). The current model for the formation of A2E requires photoactivation of rhodopsin and subsequent release of all-trans-retinal. To understand the role of light exposure in the accumulation of lipofuscin and A2E, we analyzed RPEs and isolated rod photoreceptors from mice of different ages and strains, reared either in darkness or cyclic light. Lipofuscin levels were determined by fluorescence imaging, whereas A2E levels were quantified by HPLC and UV-visible absorption spectroscopy. The identity of A2E was confirmed by tandem mass spectrometry. Lipofuscin and A2E levels in the RPE increased with age and more so in the Stargardt model Abca4−/− than in the wild type strains 129/sv and C57Bl/6. For each strain, the levels of lipofuscin precursor fluorophores in dark-adapted rods and the levels and rates of increase of RPE lipofuscin and A2E were not different between dark-reared and cyclic light-reared animals. Both 11-cis- and all-trans-retinal generated lipofuscin-like fluorophores when added to metabolically compromised rod outer segments; however, it was only 11-cis-retinal that generated such fluorophores when added to metabolically intact rods. The results suggest that lipofuscin originates from the free 11-cis-retinal that is continuously supplied to the rod for rhodopsin regeneration and outer segment renewal. The physiological role of Abca4 may include the translocation of 11-cis-retinal complexes across the disk membrane. PMID:22570475

Optical coherence tomography angiography indicates associations of the retinal vascular network and disease activity in multiple sclerosis.

PubMed

Feucht, Nikolaus; Maier, Mathias; Lepennetier, Gildas; Pettenkofer, Moritz; Wetzlmair, Carmen; Daltrozzo, Tanja; Scherm, Pauline; Zimmer, Claus; Hoshi, Muna-Miriam; Hemmer, Bernhard; Korn, Thomas; Knier, Benjamin

2018-01-01

Patients with multiple sclerosis (MS) and clinically isolated syndrome (CIS) may show alterations of retinal layer architecture as measured by optical coherence tomography. Little is known about changes in the retinal vascular network during MS. To characterize retinal vessel structures in patients with MS and CIS and to test for associations with MS disease activity. In all, 42 patients with MS or CIS and 50 healthy controls underwent retinal optical coherence tomography angiography (OCT-A) with analysis of the superficial and deep vascular plexuses and the choriocapillaries. We tested OCT-A parameters for associations with retinal layer volumes, history of optic neuritis (ON), and the retrospective disease activity. Inner retinal layer volumes correlated positively with the density of both the superficial and deep vascular plexuses. Eyes of MS/CIS patients with a history of ON revealed reduced vessel densities of the superficial and deep vascular plexuses as compared to healthy controls. Higher choriocapillary vessel densities were associated with ongoing inflammatory disease activity during 24 months prior to OCT-A examination in MS and CIS patients. Optic neuritis is associated with rarefaction of the superficial and deep retinal vessels. Alterations of the choriocapillaries might be linked to disease activity in MS.

Automated retinal layer segmentation and characterization

NASA Astrophysics Data System (ADS)

Luisi, Jonathan; Briley, David; Boretsky, Adam; Motamedi, Massoud

2014-05-01

Spectral Domain Optical Coherence Tomography (SD-OCT) is a valuable diagnostic tool in both clinical and research settings. The depth-resolved intensity profiles generated by light backscattered from discrete layers of the retina provide a non-invasive method of investigating progressive diseases and injury within the eye. This study demonstrates the application of steerable convolution filters capable of automatically separating gradient orientations to identify edges and delineate tissue boundaries. The edge maps were recombined to measure thickness of individual retinal layers. This technique was successfully applied to longitudinally monitor changes in retinal morphology in a mouse model of laser-induced choroidal neovascularization (CNV) and human data from age-related macular degeneration patients. The steerable filters allow for direct segmentation of noisy images, while novel recombination of weaker segmentations allow for denoising post-segmentation. The segmentation before denoising strategy allows the rapid detection of thin retinal layers even under suboptimal imaging conditions.

Quantifying retinal microvascular changes in uveitis using spectral domain optical coherence tomography angiography (SD-OCTA)

PubMed Central

Kim, Alice Y.; Rodger, Damien C.; Shahidzadeh, Anoush; Chu, Zhongdi; Koulisis, Nicole; Burkemper, Bruce; Jiang, Xuejuan; Pepple, Kathryn L.; Wang, Ruikang K.; Puliafito, Carmen A.; Rao, Narsing A.; Kashani, Amir H.

2016-01-01

Purpose To quantify retinal capillary density and morphology in uveitis using SD-OCTA. Design Cross-sectional, observational study Methods Healthy and uveitic subjects were recruited from two tertiary care eye centers. Prototype SD-OCTA devices (Cirrus, Carl Zeiss Meditec, Inc., Dublin, CA) were used to generate 3×3 mm2 OCTA images centered on the fovea. Subjects were placed into 3 groups based on the type of optical microangiography (OMAG) algorithm used for image processing (intensity-and/or phase) and type of retinal segmentation (automatic or manual). A semi-automated method was used to calculate skeleton density (SD), vessel density (VD), fractal dimension (FD), and vessel diameter index (VDI). Retinal vasculature was assessed in the superficial retinal layer (SRL), deep retinal layer (DRL), and non-segmented retinal layer (NS-RL). A generalized estimating equations model was used to analyze associations between the OCTA measures and disease status within each retinal layer. A P value < 0.05 was accepted as significant. Reproducibility and repeatability were assessed using the Intraclass Correlation Coefficient (ICC). Results The SD, VD, and FD of the parafoveal capillaries were lower in uveitic eyes compared to healthy eyes in all retinal segments. In addition, SD and VD were significantly lower in the DRL of subjects with uveitic macular edema. There was no correlation in any capillary parameters and anatomic classification of uveitis. Conclusions Quantitative analysis of parafoveal capillary density and morphology in uveitis demonstrates significantly lower capillary density and complexity. SD-OCTA algorithms are robust enough to detect these changes and can provide a novel diagnostic index of disease for uveitis subjects. PMID:27594138

A novel platform for minimally invasive delivery of cellular therapy as a thin layer across the subretina for treatment of retinal degeneration

NASA Astrophysics Data System (ADS)

Rotenstreich, Ygal; Tzameret, Adi; Kalish, Sapir E.; Belkin, Michael; Meir, Amilia; Treves, Avraham J.; Nagler, Arnon; Sher, Ifat

2015-03-01

Incurable retinal degenerations affect millions worldwide. Stem cell transplantation rescued visual functions in animal models of retinal degeneration. In those studies cells were transplanted in subretinal "blebs", limited number of cells could be injected and photoreceptor rescue was restricted to areas in proximity to the injection sites. We developed a minimally-invasive surgical platform for drug and cell delivery in a thin layer across the subretina and extravascular spaces of the choroid. The novel system is comprised of a syringe with a blunt-tipped needle and an adjustable separator. Human bone marrow mesenchymal stem cells (hBM-MSCs) were transplanted in eyes of RCS rats and NZW rabbits through a longitudinal triangular scleral incision. No immunosuppressants were used. Retinal function was determined by electroretinogram analysis and retinal structure was determined by histological analysis and OCT. Transplanted cells were identified as a thin layer across the subretina and extravascular spaces of the choroid. In RCS rats, cell transplantation delayed photoreceptor degeneration across the entire retina and significantly enhanced retinal functions. No retinal detachment or choroidal hemorrhages were observed in rabbits following transplantation. This novel platform opens a new avenue for drug and cell delivery, placing the transplanted cells in close proximity to the damaged RPE and retina as a thin layer, across the subretina and thereby slowing down cell death and photoreceptor degeneration, without retinal detachment or choroidal hemorrhage. This new transplantation system may increase the therapeutic effect of other cell-based therapies and therapeutic agents. This study is expected to directly lead to phase I/II clinical trials for autologous hBM-MSCs transplantation in retinal degeneration patients.

Outer Retinal Changes Including the Ellipsoid Zone Band in Usher Syndrome 1B due to MYO7A Mutations.

PubMed

Sumaroka, Alexander; Matsui, Rodrigo; Cideciyan, Artur V; McGuigan, David B; Sheplock, Rebecca; Schwartz, Sharon B; Jacobson, Samuel G

2016-07-01

To study transition zones from normal to abnormal retina in Usher syndrome IB (USH1B) caused by myosin 7A (MYO7A) mutations. Optical coherence tomography (OCT) scattering layers in outer retina were segmented in patients (n = 16, ages 2-42; eight patients had serial data, average interval 4.5 years) to quantify outer nuclear layer (ONL) and outer segments (OS) as well as the locus of EZ (ellipsoid zone) edge and its extent from the fovea. Static perimetry was measured under dark-adapted (DA) and light-adapted (LA) conditions. Ellipsoid zone edge in USH1B-MYO7A could be located up to 23° from the fovea. Ellipsoid zone extent constricted at a rate of 0.51°/year with slower rates at smaller eccentricities. A well-defined EZ line could be associated with normal or abnormal ONL and/or OS thickness; detectable ONL extended well beyond EZ edge. At the EZ edge, the local slope of LA sensitivity loss was 2.6 (±1.7) dB/deg for central transition zones. At greater eccentricities, the local slope of cone sensitivity loss was shallower (1.1 ± 0.4 dB/deg for LA) than that of rod sensitivity loss (2.8 ± 1.2 dB/deg for DA). In USH1B-MYO7A, constriction rate of EZ extent depends on the initial eccentricity of the transition. Ellipsoid zone edges in the macula correspond to large local changes in cone vision, but extramacular EZ edges show more pronounced losses on rod-based vision tests. It is advisable to use not only the EZ line but also other structural and functional parameters for estimating natural history of disease and possible therapeutic effects in future clinical trials of USH1B-MYO7A.

Impact of MCT1 Haploinsufficiency on the Mouse Retina.

PubMed

Peachey, Neal S; Yu, Minzhong; Han, John Y S; Lengacher, Sylvain; Magistretti, Pierre J; Pellerin, Luc; Philp, Nancy J

2018-01-01

The monocarboxylate transporter 1 (MCT1) is highly expressed in the outer retina, suggesting that it plays a critical role in photoreceptors. We examined MCT1 +/- heterozygotes, which express half of the normal complement of MCT1. The MCT1 +/- retina developed normally and retained normal function, indicating that MCT1 is expressed at sufficient levels to support outer retinal metabolism.

Orbital exenteration after transarterial embolization in a patient with Wyburn-Mason syndrome: pathological findings.

PubMed

Matsuo, Toshihiko; Yanai, Hiroyuki; Sugiu, Kenji; Tominaga, Susumu; Kimata, Yoshihiro

2008-01-01

We present the pathological findings at orbital exenteration in a patient with Wyburn-Mason syndrome who underwent transarterial embolization. A 31-year-old man with a 10-year history of gradual exacerbation of left exophthalmos and left cheek swelling was found to have facial and orbital arteriovenous malformations on the left side. There was no vascular malformation in the brain. The feeding arteries derived from the left internal maxillary artery, facial artery, and ophthalmic artery. He underwent several courses of transarterial embolization of the feeding arteries from the left internal maxillary artery and then from the facial artery, resulting in no reduction of the arteriovenous malformation. He finally elected to undergo ophthalmic artery embolization in the expectation of a reduction and with the understanding that he would lose sight in his left eye. Two years later, he requested lid-sparing orbital exenteration and reconstruction with cutaneous flap transfer and prosthesis for cosmetic reasons. Pathologically, orbital vascular channels of varying sizes were filled with embolizing glue and had degenerating vascular wall cells surrounded by inflammatory cell infiltration. The central retinal artery in the optic nerve was also filled with the embolizing glue, and the retina lost the ganglion cell layer and inner nuclear layer but maintained the outer nuclear layer and outer segments. Marked anastomoses and hence incomplete embolization among the feeding arteries of facial and orbital vascular malformations in Wyburn-Mason syndrome do not respond well to attempts at feeding vessel embolization, which result in unsuccessful closure of the malformation.

Thinner retinal layers are associated with changes in the visual pathway: A population-based study.

PubMed

Mutlu, Unal; Ikram, Mohammad K; Roshchupkin, Gennady V; Bonnemaijer, Pieter W M; Colijn, Johanna M; Vingerling, Johannes R; Niessen, Wiro J; Ikram, Mohammad A; Klaver, Caroline C W; Vernooij, Meike W

2018-06-23

Increasing evidence shows that thinner retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL), assessed on optical coherence tomography (OCT), are reflecting global brain atrophy. Yet, little is known on the relation of these layers with specific brain regions. Using voxel-based analysis, we aimed to unravel specific brain regions associated with these retinal layers. We included 2,235 persons (mean age: 67.3 years, 55% women) from the Rotterdam Study (2007-2012) who had gradable retinal OCT images and brain magnetic resonance imaging (MRI) scans, including diffusion tensor (DT) imaging. Thicknesses of peripapillary RNFL and perimacular GCL were measured using an automated segmentation algorithm. Voxel-based morphometry protocols were applied to process DT-MRI data. We investigated the association between retinal layer thickness with voxel-wise gray matter density and white matter microstructure by performing linear regression models. We found that thinner RNFL and GCL were associated with lower gray matter density in the visual cortex, and with lower fractional anisotropy and higher mean diffusivity in white matter tracts that are part of the optic radiation. Furthermore, thinner GCL was associated with lower gray matter density of the thalamus. Thinner RNFL and GCL are associated with gray and white matter changes in the visual pathway suggesting that retinal thinning on OCT may be specifically associated with changes in the visual pathway rather than with changes in the global brain. These findings may serve as a basis for understanding visual symptoms in elderly patients, patients with Alzheimer's disease, or patients with posterior cortical atrophy. © 2018 Wiley Periodicals, Inc.

Ischaemia-reperfusion injury in central retinal artery occlusion.

PubMed

Saxena, Sandeep; Mishra, Nibha; Meyer, Carsten H; Akduman, Levent

2013-10-21

A 53-year-old man presented with sudden painless diminution of vision in his right eye for 3 days. His fundus examination showed diffuse whitening of the retina with a cherry red spot at the fovea with cilioretinal artery sparing. On fluorescein angiography delayed arteriovenous transit was observed. Three-dimensional spectral domain optical coherence tomography was used to assess retinal nerve fibre layer thickness and average macular central subfield thickness on days 3, 7, 30 and 90. Marked retinal oedema due to ischaemia was observed on day 3 of occurrence of central retinal artery occlusion. On day 7, significant decrease in retinal nerve fibre thickness and macular thickness was noted suggestive of acute reperfusion injury. Retinal nerve fibre layer thickness and macular thickness returned to near normal on day 30 due to restoration of blood supply with wash out of stress mediators. Retinal atrophy was observed on day 90.

Ischaemia-reperfusion injury in central retinal artery occlusion

PubMed Central

Saxena, Sandeep; Mishra, Nibha; Meyer, Carsten H; Akduman, Levent

2013-01-01

A 53-year-old man presented with sudden painless diminution of vision in his right eye for 3 days. His fundus examination showed diffuse whitening of the retina with a cherry red spot at the fovea with cilioretinal artery sparing. On fluorescein angiography delayed arteriovenous transit was observed. Three-dimensional spectral domain optical coherence tomography was used to assess retinal nerve fibre layer thickness and average macular central subfield thickness on days 3, 7, 30 and 90. Marked retinal oedema due to ischaemia was observed on day 3 of occurrence of central retinal artery occlusion. On day 7, significant decrease in retinal nerve fibre thickness and macular thickness was noted suggestive of acute reperfusion injury. Retinal nerve fibre layer thickness and macular thickness returned to near normal on day 30 due to restoration of blood supply with wash out of stress mediators. Retinal atrophy was observed on day 90. PMID:24145508

OCT as a convenient tool to assess the quality and application of organotypic retinal samples

NASA Astrophysics Data System (ADS)

Gater, Rachel; Khoshnaw, Nicholas; Nguyen, Dan; El Haj, Alicia J.; Yang, Ying

2016-03-01

Eye diseases such as macular degeneration and glaucoma have profound consequences on the quality of human life. Without treatment, these diseases can lead to loss of sight. To develop better treatments for retinal diseases, including cell therapies and drug intervention, establishment of an efficient and reproducible 3D native retinal tissue system, enabled over a prolonged culture duration, will be valuable. The retina is a complex tissue, consisting of ten layers with a different density and cellular composition to each. Uniquely, as a light transmitting tissue, retinal refraction of light differs among the layers, forming a good basis to use optical coherence tomography (OCT) in assessing the layered structure of the retina and its change during the culture and treatments. In this study, we develop a new methodology to generate retinal organotypic tissues and compare two substrates: filter paper and collagen hydrogel, to culture the organotypic tissue. Freshly slaughtered pig eyes have been obtained for use in this study. The layered morphology of intact organotypic retinal tissue cultured on two different substrates has been examined by spectral domain OCT. The viability of the tissues has been examined by live/dead fluorescence dye kit to cross validate the OCT images. For the first time, it is demonstrated that the use of a collagen hydrogel supports the viability of retinal organotypic tissue, capable of prolonged culture up to 2 weeks. OCT is a convenient tool for appraising the quality and application of organotypic retinal samples and is important in the development of current organotypic models.

Fundus autofluorescence findings in central serous chorioretinopathy using two different confocal scanning laser ophthalmoscopes: correlation with functional and structural status.

PubMed

Shin, Joo Youn; Choi, Hun Jin; Lee, Jonghyun; Choi, Moonjung; Chung, Byunghoon; Byeon, Suk Ho

2016-08-01

To compare autofluorescence (AF) findings using wide-field (Optomap) and conventional (HRA-AF) confocal scanning laser ophthalmoscopy (cSLO) systems in patients with central serous chorioretinopathy (CSC), and to investigate the correlations between AF findings and functional and anatomical status. Optical coherence tomography (OCT) and AF images were compared in 73 eyes with serous retinal detachment (SRD) (group A) and 30 eyes without SRD (group B). We evaluated AF findings from the SRD region, atrophic area, and foveola. Correlations between AF findings and outer retinal abnormalities in OCT and visual acuity (VA) were analyzed. Optomap-AF was more effective than HRA-AF in identifying the margins of a detached area (P = 0.001) in group A, and for monitoring mild outer retinal damage (P = 0.041) in group B. The foveolar AF grades in both instruments were significantly correlated with VA and central foveal thickness (CFT) in both group A (Optomap, VA r s = 0.33, P = 0.012; CFT r s = -0.38, P = 0.002; HRA, VA r s = 0.62, P < 0.001; CFT r s = -0.70, P < 0.001) and group B (Optomap, VA r s = 0.71, P < 0.001, CFT r s = -0.78, P < 0.001; HRA, VA r s = 0.40, P = 0.026, CFT r s = -0.40, P = 0.030). Optomap-AF was found to be advantageous for monitoring subretinal status in eyes with SRD, and more accurately reflected mild outer retinal changes in eyes without SRD. Foveolar AF grades of both imaging modalities were significantly correlated with functional and anatomical status.

Rod outer segment retinol formation is independent of Abca4, arrestin, rhodopsin kinase, and rhodopsin palmitylation.

PubMed

Blakeley, Lorie R; Chen, Chunhe; Chen, Ching-Kang; Chen, Jeannie; Crouch, Rosalie K; Travis, Gabriel H; Koutalos, Yiannis

2011-06-01

The reactive aldehyde all-trans retinal is released in rod photoreceptor outer segments by photoactivated rhodopsin and is eliminated through reduction to all-trans retinol. This study was undertaken to determine whether all-trans retinol formation depends on Abca4, arrestin, rhodopsin kinase, and the palmitylation of rhodopsin, all of which are factors that affect the release and sequestration of all-trans retinal. Experiments were performed in isolated retinas and single living rods derived from 129/sv wild-type mice and Abca4-, arrestin-, and rhodopsin kinase-deficient mice and in genetically modified mice containing unpalmitylated rhodopsin. Formation of all-trans retinol was measured by imaging its fluorescence and by HPLC of retina extracts. The release of all-trans retinal from photoactivated rhodopsin was measured in purified rod outer segment membranes according to the increase in tryptophan fluorescence. All experiments were performed at 37°C. The kinetics of all-trans retinol formation in the different types of genetically modified mice are in reasonable agreement with those in wild-type animals. The kinetics of all-trans retinol formation in 129/sv mice are similar to those in C57BL/6, although the latter are known to regenerate rhodopsin much more slowly. The release of all-trans retinal from rhodopsin in purified membranes is significantly faster than the formation of all-trans retinol in intact cells and is independent of the presence of the palmitate groups. The regeneration of rhodopsin and the recycling of its chromophore are not strongly coupled. Neither the activities of Abca4, rhodopsin kinase, and arrestin, nor the palmitylation of rhodopsin affects the formation of all-trans retinol.