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1.  Documentation of Intraretinal Retinal Pigment Epithelium Migration via High Speed Ultrahigh Resolution Optical Coherence Tomography 
Ophthalmology  2010;118(4):687-693.
PURPOSE
To describe the features of intraretinal retinal pigment epithelium (RPE) migration documented on a prototype spectral domain high speed, ultrahigh resolution optical coherence tomography (OCT) device in a group of patients with early to intermediate dry age-related macular degeneration (AMD). To correlate intraretinal RPE migration on OCT to RPE pigment clumping on fundus photographs.
DESIGN
Retrospective, non-comparative, non-interventional case series.
PARTICIPANTS
Fifty-five eyes of 44 patients seen at the New England Eye Center between December 2007 and June 2008 with early to intermediate dry AMD.
METHODS
3D OCT scan sets from all patients were analyzed for presence of intraretinal RPE migration, defined as small discreet hyper-reflective and highly-backscattering lesions within the neurosensory retina. Fundus photographs were also analyzed to determine the presence of RPE pigment clumping, defined as black-colored, often spiculated areas of pigment clumping within the macula. OCT en face images were correlated with fundus photographs to demonstrate correspondence of intraretinal RPE migration on OCT and RPE clumping on fundus photo.
MAIN OUTCOME MEASURES
Drusen, Dry AMD, intraretinal RPE migration, RPE pigment clumping.
RESULTS
54.5% of eyes (61.4% of patients) demonstrated intraretinal RPE migration on OCT scans. 56.4% of the fundus photographs demonstrated RPE pigment clumping. All eyes with intraretinal RPE migration on OCT had corresponding RPE pigment clumping on fundus photographs. RPE pigment migrated most frequently into the outer nuclear layer (66.7% of eyes) and less frequently into more anterior retinal layers. Intraretinal RPE migration mainly occurred above areas of drusen (73.3% of eyes).
CONCLUSIONS
The appearance of intraretinal RPE migration on OCT is a common occurrence in early to intermediate dry AMD, occurring in 54.5% of eyes or 61.4% of patients. The area of intraretinal RPE migration on OCT always correlated to areas of pigment clumping on fundus photography. Conversely, all but one eye with RPE pigment clumping on fundus photography also had areas of intraretinal RPE migration on OCT. The high incidence of intraretinal RPE migration observed above areas of drusen suggests that drusen may play physical and catalytic roles in facilitating intraretinal RPE migration in dry AMD patients.
doi:10.1016/j.ophtha.2010.08.010
PMCID: PMC3070873  PMID: 21093923
2.  Fundus Autofluorescence and Spectral Domain OCT in Central Serous Chorioretinopathy 
Journal of Ophthalmology  2011;2011:706849.
Background. To describe the standard autofluorescence (FAF), the near infrared autofluorescence (NIA) and optical coherence tomography (OCT) patterns in central serous chorioretinopathy, correlating them with fluorescein angiography. Methods. Cross-sectional observational study, in which patients with at least seven months of CSC underwent ophthalmologic examination, fundus photography, FAF, NIA, fluorescein angiography (FA), and spectral-domain OCT. Results. Seventeen eyes of thirteen patients were included. The presentation features were a mottled hyperFAF in the detached area and areas with pigment mottling. NIA images showed areas of hyperNIA similar to FAF and localized areas of hypoNIA, which correlated with the points of leakage in the FA. OCT showed pigment epithelium detachment at the location of these hypoNIA spots. Discussion. FAF showed increased presence of fluorophores in the area of retinal detachment, which is believed to appear secondary to lipofuscin accumulation in the RPE or the presence of debris in the subretinal fluid. NIA has been related to the choroidal melanin content and there were areas of both increased and decreased NIA, which could be explained by damage ahead the retina, basically RPE and choroid. These findings, along with the PEDs found in the areas of hypoNIA, support the notion of a primary choroidal disease in CSC.
doi:10.1155/2011/706849
PMCID: PMC3153919  PMID: 21845214
3.  Quantification of Peripapillary Sparing and Macular Involvement in Stargardt Disease (STGD1) 
Relative structural and functional peripapillary sparing is present with more widespread STGD1 disease. Photoreceptor degeneration may precede RPE atrophy in STGD1 pathogenesis.
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.
doi:10.1167/iovs.11-7693
PMCID: PMC3220414  PMID: 21873672
4.  Analysis of the RPE sheet in the rd10 retinal degeneration model 
Background
The normal RPE sheet in the C57BL/6J mouse is subclassified into two major tiling patterns: a regular generally hexagonal array covering most of the surface and a “soft network” near the ciliary body made of irregularly shaped cells. Physics models predict these two patterns based on contractility and elasticity of the RPE cell, and strength of cellular adhesion between cells.
Hypothesis
We hypothesized and identified major changes in RPE regular hexagonal tiling pattern in rd10 compared to C57BL/6J mice.
Results
In rd10 mice, RPE sheet damage was extensive but occurred later than expected, after most retinal degeneration was complete. RPE sheet changes occur in zones with a bullseye pattern. In the posterior zone, around the optic nerve, RPE cells take on larger irregular and varied shapes to maintain an intact monolayer. In mid periphery, RPE cells have a compressed or convoluted morphology that progress into ingrown layers of RPE under the retina. Cells in the periphery maintain their shape and size until the late stages of the RPE reorganization. The number of neighboring cells varies widely depending on zone and progression. RPE morphology continues to deteriorate after the photoreceptors have degenerated.
Conclusions
The RPE cells are bystanders to photoreceptor degeneration in the rd10 model, and the collateral damage to the RPE results in changes in morphology as early as 30 days old. Quantitative measures of the tiling patterns and histopathology detected here were scripted in a pipeline written in Perl and Cell Profiler (an open source MatLab plugin) and are directly applicable to RPE sheet images from noninvasive fundus autofluorescence (FAF), adaptive optics confocal scanning laser ophthalmoscope (AO-cSLO), and spectral domain optical coherence tomography (SD-OCT) of patients with early stage AMD or RP.
doi:10.1007/978-1-4614-0631-0_81
PMCID: PMC3732179  PMID: 22183388
5.  Fundus Autofluorescence and Optical Coherence Tomography of Congenital Grouped Albinotic Spots 
Retina (Philadelphia, Pa.)  2010;30(8):1217-1222.
Purpose
To describe fundus autofluorescence (FAF) and optical coherence tomography (OCT) in a series of patients with congenital grouped albinotic spots (CGAS).
Methods
Three eyes of three patients with CGAS were evaluated with FAF and OCT imaging to evaluate the nature of the albinotic spots.
Results
In all three eyes with CGAS, FAF imaging revealed 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. FAF imaging of the spots demonstrated decreased general autofluorescence as well as decreased peripheral autofluorescence surrounding central areas of retained or increased autofluorescence. OCT revealed a disruption in signal from the hyper-reflective layer corresponding to the photoreceptor inner and outer segment junction as well as increased signal backscattering from the choroid in the area of the spots. Fluorescein angiography (FA) demonstrated early and stable hyperfluorescence of the spots without leakage.
Conclusion
In this case series, FAF demonstrated decreased autofluorescence of the spots consistent with focal RPE atrophy or abnormal material blocking normal autofluorescence as well as areas of increased autofluorescence suggesting RPE dysfunction. OCT and FA findings suggest photoreceptor and RPE layer abnormalities. FAF and OCT are useful noninvasive diagnostic adjuncts that can aid in the diagnosis of GCAS, help determine extent of disease, and contribute to our understanding of its pathophysiology.
doi:10.1097/IAE.0b013e3181cea5a5
PMCID: PMC2939199  PMID: 20539258
Congenital grouped albinotic spots; Grouped congenital pigmentation of the retina; Fundus autofluorescence; Optical coherence tomography; Polar bear tracks; Bear tracks; White dots
6.  Functional Analysis of Retinal Flecks in Stargardt Disease 
Journal of clinical & experimental ophthalmology  2012;3:10.4172/2155-9570.1000233.
Purpose
To evaluate visual function of flecked areas in a series of patients with Stargardt disease (STGD) and compare them with adjacent non flecked areas.
Methods
Twenty–seven patients with STGD, ABCA4 mutations and yellowish retinal flecks at fundus examination were recruited. Microperimetry with the Nidek MP-1 and fundus autofluorescence imaging (FAF) were performed in all the patients (27 eyes) while spectral-domain optical coherence tomography (SD-OCT) was performed in a subgroup of patients (20 eyes). Visual sensitivity (in dB) for each hyperfluorescent flecked area on FAF was compared with the value of the nearest adjacent non-flecked area in the MP-1 grid and at approximately the same distance from the fovea. Retinal structure in some of the flecked areas tested by microperimetry was analysed with SD-OCT. All patients were screened for mutations in the ABCA4 gene by APEX array and direct sequencing.
Results
A total of 1836 locations (68 locations for each eye with the 10-2 program) were tested with the MP-1 and 97 corresponded to hyperautofluorescent flecks. A repeated measure, linear regression analysis was used to evaluate differences between visual sensitivity associated with the 97 flecked areas with those in the 97 neighbouring non-flecked areas. The difference was statistically significant (p<0.001) (flecked areas 12.89 +/− 3.86 dB vs. non-flecked areas 14.40 +/− 3.53 dB, respectively). SD-OCT in the flecked areas revealed the presence of hyperreflective dome-shaped lesions in the outer retina located at the level of the retinal pigment epithelium (RPE), with dislocation or disruption of the photoreceptor layer.
Conclusions
In STGD hyperfluorescent flecks on FAF are associated with decreased visual sensitivity compared to adjacent non-flecked areas and with an alteration of the photoreceptor layer on OCT. Flecks do not represent only a typical ophthalmoscopic feature but correspond, in some cases, to retinal damage that contributes to patients’ visual loss.
doi:10.4172/2155-9570.1000233
PMCID: PMC3882688  PMID: 24409374
Stargardt disease; Fundus flavimaculatus; Flecks; Fundus autofluorescence; Microperimetry; Spectral domain optical coherence tomography
7.  Spectral-domain optical coherence tomographic and fundus autofluorescence findings in eyes with primary intraocular lymphoma 
Background
The purpose of this study was to evaluate the findings on spectral-domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF) in three eyes with primary intraocular lymphoma (PIOL).
Methods
The medical records of three eyes from three patients with biopsy-proven PIOL and retinal infiltrations were reviewed. The SD-OCT and fluorescein angiographic findings were evaluated in the three eyes and FAF images in two eyes.
Results
The PIOL in the three patients was monocular. Vitreous opacities and retinal infiltrations were observed in the three eyes, and iritis was present in two eyes. The cytologic diagnosis was class V in two eyes and class III in one eye. The interleukin-10/interleukin-6 ratio was >1.0 in the vitreous and aqueous humor of the three eyes. The FAF images for two eyes showed abnormal granular hyperautofluorescence and hypoautofluorescence which were the reverse of the pattern in the fluorescein angiographic images. In all three eyes, SD-OCT showed hyper-reflective infiltrations at the level of the retinal pigment epithelium (RPE), a separation of the Bruch membrane from the RPE, damage to the RPE, disruption of the photoreceptor inner segment/outer segment junction, and multiple hyper-reflective signals in the inner retina.
Conclusion
Because of the characteristic FAF and SD-OCT findings in these eyes with PIOL, we suggest that these noninvasive methods may be used for a rapid diagnosis of PIOL and also for understanding the pathology of PIOL.
doi:10.2147/OPTH.S58114
PMCID: PMC3917953  PMID: 24520190
spectral-domain optical coherence tomography; fundus autofluorescence; primary intraocular lymphoma
8.  Fundus Autofluorescence and Optical Coherence Tomography Findings in Choroidal Melanocytic Lesions 
Purpose:
To establish the characteristics of secondary retinal and retinal pigment epithelial (RPE) changes associated with the presence of choroidal melanoma and choroidal nevus as documented by optical coherence tomography (OCT) and fundus autofluorescence (FAF).
Materials and Methods:
PubMed review of major English publications examining the correlation between clinical characteristics of choroidal melanoma and nevus with OCT and FAF findings.
Results:
The intrinsic properties of choroidal melanoma, as well as overlying RPE changes, drusen, and lipofuscin are best characterized by FAF, while OCT is more sensitive for the identification of subretinal and intraretinal fluid as well as atrophy, degeneration, and photoreceptor loss in the neurosensory retina.
Conclusions:
Secondary retinal changes associated with choroidal melanocytic lesions can be documented by OCT and FAF. OCT-evident changes are observed more often with choroidal melanoma than choroidal nevus. OCT is better suited to identify the overlying retinal detachment and edema, even before these findings are clinically apparent. FAF is most useful in documenting the presence of lipofuscin, a finding that represents one of the important criteria in differentiating small choroidal melanoma from benign choroidal nevus.
doi:10.4103/0974-9233.65489
PMCID: PMC2934710  PMID: 20844674
Autofluorescence; Choroid; Eye; Melanoma; Nevus; Optical Coherence Tomography
9.  Macular dystrophy in Heimler syndrome 
Ophthalmic genetics  2011;32(2):97-100.
Purpose
To describe the retinal imaging findings in the index patient with Heimler syndrome (OMIM #234580).
Design
Non-interventional case report.
Methods
A 29-year-old woman with Heimler syndrome developed bilateral vision loss. Fluorescein angiography (FA), fundus autofluorescence (FAF), spectral domain optical coherence tomography (SD-OCT) and electroretinography (ERG) were performed to assess the retinal anatomy and function.
Results
FA showed mottling of the retinal pigment epithelium (RPE) in the posterior pole and periphery of the retina. FAF revealed hyper and hypoautofluorescent dots corresponding to the RPE mottling observed on FA. SD-OCT documented loss of the inner/outer segments boundary, and RPE thinning. ERG testing excluded generalized rod-cone dysfunction.
Conclusion
We report an adult-onset macular dystrophy in one of the previously reported patients with Heimler syndrome and hypothesize that this syndrome is probably an expression of a ciliopathy.
doi:10.3109/13816810.2010.551797
PMCID: PMC3093430  PMID: 21366429
Amelogenesis imperfecta; Ciliopathy; Deafness; Heimler syndrome; Nail abnormalities; Retina
10.  Multi-modality imaging on multiple evanescent white dot syndrome-A Spectralis Study 
AIM
To present retinal microstructure, metabolism and function abnormalities in the course of multiple evanescent white dot syndrome (MEWDS) by Heidelberg spectralis modality imaging platform and observe its outcome by EDI-SD-OCT and two wavelength autofluorescence.
METHODS
A case of multiple evanescent white dot syndrome in a 23-year-old female presented initially with a 15-day history of floaters and a central scotoma in the right eye. To establish the diagnosis, multimodality imaging was performed, namely, blue light-fundus autofluorescence (BL-FAF, excitation 488nm, emission >500nm), near-infrared fundus autofluorescence (NIR-FAF, excitation 787nm, emission >800nm) using a confocal scanning laser ophthalmoscope, fundus fluorescein angiography (FFA), indocyanine green angiography (ICGA), spectrum-domain enhance depth imaging optical coherence tomography (SD-EDI-OCT), multifocal electroretinography (mf-ERG) and fundus photogragh were performed and followed up at the eighth month after initially visiting.
RESULTS
Optical coherence tomography (OCT) showed a transient disruption of the foveal photoreceptor outer segments in correspondence to foveal granularity. NIR-FAF showed hypoautofluorescent areas, ≤40µm in size, mostly concentrated around the posterior pole and its temporal side less than that in BL-FAF. Mf-ERG show pinnacle disappeared in fovea and macula and responses decreased markedly compared with the follow eye. At the eighth month follow up, hyperfluorescence in BL-FAF were disappear, while, NIR-FAF Hypofluorescent spots in early stage of such lesion were reduced. But OCT demonstrated the structure was recovered in residual Hypofluorescent area in NIR-FAF. The subfoveal choroidal thickness was decreased from 372µm to 307µm slightly and cost line was recovered.
CONCLUSION
MEWDS is a benign self-healing disease and there is no pathological evidence to investigate the natural course of such disease. SD-OCT allows highly detailed images approaching histopathology to certify the microstructural changes. Two-wave length FAF and mf-ERG provide more information about metabolism in outer retina especial RPE and photoreceptor. Spectralis OCT combined with two-wavelength FAF and mf-ERG provide a new way to analyze this disease and offer more details for therapy and follow-up.
doi:10.3980/j.issn.2222-3959.2012.05.21
PMCID: PMC3484713  PMID: 23166880
MEWDS; Spectralis OCT; NIR-FAF; BL-FAF; mf-ERG
11.  Fundus Autofluorescence and Spectral-Domain Optical Coherence Tomography Characteristics in a Rapidly Progressing Form of Geographic Atrophy 
A rapidly progressing geographic atrophy phenotype shows characteristic fundus autofluorescence and SD-OCT features.
Purpose.
To further characterize a previously described phenotypic variant of geographic atrophy (GA) associated with rapid progression and a diffuse-trickling appearance on fundus autofluorescence (FAF).
Methods.
Thirty-six patients (60 eyes; 72.2% women; mean age, 69.4 ± 10.7 years) with this distinct phenotype were examined by simultaneous confocal scanning laser ophthalmoscopy (cSLO) and spectral-domain optical coherence tomography (SD-OCT) imaging. Images were qualitatively and quantitatively analyzed and compared with 60 eyes (38 patients) with non diffuse-trickling GA.
Results.
The atrophic area in the diffuse-trickling phenotype showed a grayish FAF signal and characteristic coalescent lobular configuration at the lesion boundaries. SD-OCT revealed a marked splitting of band 4 (the presumptive retinal pigment epithelium (RPE)/Bruch's membrane (BM) complex) in all 240 analyzed border sections of diffuse-trickling GA eyes (four borders/eye) with a mean distance between the inner and outer parts of band 4 of 23.2 ± 7.5μm. This finding was present in only 13.8% (33/240) of analyzed border sections in non diffuse-trickling GA.
Conclusions.
Patients with the rapidly progressing diffuse-trickling GA phenotype exhibited a characteristic marked separation within the RPE/BM complex on SD-OCT-imaging. The presumed histopathologic correlates are basal laminar deposits. Such deposits may promote RPE cell death and, thus, contribute to rapid GA progression. The persistence of these deposits within the atrophic lesion may account for the distinct grayish FAF appearance, which differs from the markedly reduced signal in other forms of GA. Identification of such alterations based on FAF and SD-OCT imaging may be helpful in future interventional trials directed toward slowing GA progression. (ClinicalTrials.gov number, NCT00393692.)
doi:10.1167/iovs.10-7021
PMCID: PMC3109052  PMID: 21310912
12.  A Comparison of Fundus Autofluorescence and Retinal Structure in Patients with Stargardt Disease 
Purpose
To improve our understanding of Stargardt disease by comparing structural changes seen on spectral domain optical coherence tomography (SD-OCT) to those visible on fundus autofluorescence (FAF).
Methods
FAF and SD-OCT were obtained on 22 eyes of 11 patients with Stargardt disease. SD-OCT images were obtained at the fovea and at the eccentric preferred retinal locus (PRL). The diameters of “absent” (hypo-autofluorescent) and “abnormal” FAF areas were measured. The extent of the transverse defect of the junction between the inner and outer segments of the photoreceptors (IS-OS) was measured in the foveal area. The PRL was evaluated with fundus photography and microperimetry.
Results
Twenty-one of 22 eyes showed defective FAF. For 17 eyes, FAF was absent in the fovea and for 4 eyes the FAF was abnormal. All eyes showed disorganization and/or loss of the IS-OS junction in the foveal area on SD-OCT. The diameter of the absent FAF area was smaller than the measurement of the IS-OS junction loss; the latter was closer to the diameter of the abnormal FAF area. Seventeen eyes had an eccentric PRL associated with a retinal area with no defects on FAF.
Conclusions
For the majority of eyes changes on SD-OCT correlated well with changes on FAF. However for 3 patients, photoreceptor abnormalities were seen in the fovea on SD-OCT without an equivalent abnormality on FAF. This suggests that for these patients, the structural integrity of the photoreceptors may be affected earlier than changes in the RPE at least as detected by FAF.
doi:10.1167/iovs.08-2657
PMCID: PMC2749553  PMID: 19324865
13.  Clinicopathologic findings in Best vitelliform macular dystrophy 
Purpose
To correlate the clinical and histopathologic features of Best vitelliform macular dystrophy (BVMD).
Methods
Two eyes were obtained postmortem from a patient with BVMD. The patient’s clinical information was reviewed. Series sections of the globes were performed and sequentially stained with hematoxylin-eosin, periodic acid-Schiff or Masson trichrome. A section of the left macula was submitted for electron microscopic processing. Histopathologic findings were reconstructed in a scaled two-dimensional map and compared with fundus photography, fundus autofluorescence (FAF), fundus fluorescein angiography (FFA) and optical coherence tomography (OCT) images.
Results
The macular lesion of the right eye was identified as a well-demarcated region with pigment, elevated submacular yellow material and subretinal fluid. This corresponded histopathologically to a well-circumscribed area of RPE hyperplasia, accumulation of lipofuscin in the RPE, deposition of granular material in the photoreceptors, macrophages and drusen. The left eye displayed a 1 disc diameter chorioretinal scar with surrounding shallow fluid and submacular pigment. This corresponded to RPE changes and a fibrocellular proliferation in the choriocapillaris.
Conclusion
Histopathologic mapping revealed retinal edema, RPE abnormalities, drusen and a chorioretinal scar in BVMD that correlated with the fundus, FFA, FAF and OCT findings.
doi:10.1007/s00417-010-1587-3
PMCID: PMC3425361  PMID: 21136072
Best vitelliform macular dystrophy; Optical coherence tomography; Fundus autofluorescence; Fundus fluorescein angiography; Two-dimensional reconstruction; Clinicopathologic correlation
14.  Human RPE Stem Cells Grown into Polarized RPE Monolayers on a Polyester Matrix Are Maintained after Grafting into Rabbit Subretinal Space 
Stem Cell Reports  2014;2(1):64-77.
Summary
Transplantation of the retinal pigment epithelium (RPE) is being developed as a cell-replacement therapy for age-related macular degeneration. Human embryonic stem cell (hESC) and induced pluripotent stem cell (iPSC)-derived RPE are currently translating toward clinic. We introduce the adult human RPE stem cell (hRPESC) as an alternative RPE source. Polarized monolayers of adult hRPESC-derived RPE grown on polyester (PET) membranes had near-native characteristics. Trephined pieces of RPE monolayers on PET were transplanted subretinally in the rabbit, a large-eyed animal model. After 4 days, retinal edema was observed above the implant, detected by spectral domain optical coherence tomography (SD-OCT) and fundoscopy. At 1 week, retinal atrophy overlying the fetal or adult transplant was observed, remaining stable thereafter. Histology obtained 4 weeks after implantation confirmed a continuous polarized human RPE monolayer on PET. Taken together, the xeno-RPE survived with retained characteristics in the subretinal space. These experiments support that adult hRPESC-derived RPE are a potential source for transplantation therapies.
Graphical Abstract
Highlights
•Adult hRPESC-derived RPE had comparable in vitro characteristics to fetal hRPE•hRPE monolayers survived 4 weeks on PET carriers under the rabbit retina•Better xenograft survival may be due to the maintained hRPE cell polarity•Atrophy of the retina overlaying the hRPE xenograft remains a future challenge
Stanzel et al. have transplanted polarized monolayers of human retinal pigment epithelium (hRPE) grown on polyester membranes derived from adult hRPE stem cells or fetal tissue under the rabbit retina. The xeno-RPE survived 4 weeks with retained cell polarity characteristics in the subretinal space. These experiments support that adult hRPESC-derived RPE are a potential source for transplantation therapies.
doi:10.1016/j.stemcr.2013.11.005
PMCID: PMC3916756  PMID: 24511471
15.  The Retinal Disease Screening Study: Prospective Comparison of Nonmydriatic Fundus Photography and Optical Coherence Tomography for Detection of Retinal Irregularities 
Purpose.
To compare the sensitivity of volume scanning with optical coherence tomography (OCT) to nonmydriatic color fundus photography (FP) for the detection of retinal irregularities in asymptomatic populations.
Methods.
Asymptomatic subjects without known ocular disease were recruited over a 6-month period. For each eye, two undilated 45° fundus images and four undilated volume OCT image sets covering the macula and optic nerve were obtained. Color images were evaluated for irregularities both inside and outside the area covered by OCT. OCT image sets were evaluated for internal limiting membrane irregularities, abnormal retinal thickness, hyper/hyporeflective features, and photoreceptor/retinal pigment epithelium (RPE) irregularities. Detection sensitivities were compared and false-negative cases were analyzed.
Results.
A total of 284 eyes (144 subjects) were included, with a mean age of 38.1 years (range 18–77). Among 253 eyes (135 subjects) with gradable images from both FP and OCTs, the detection sensitivities for OCT were higher (96.2% infield and 85.7% in full field) than for FP (19.9% infield and 43.8% in full field) for all irregularities evaluated in the study (including epiretinal irregularities, abnormal retinal thickness, intraretinal hyperreflective/hyporeflective features, and photoreceptor/RPE irregularities). Overall, the presence of definite irregularities on either fundus imaging or OCT by eye in this asymptomatic population was 42.6% (121/284), with 39.4% (112/284) of eyes having RPE irregularities such as drusen.
Conclusions.
For detection of a variety of retinal irregularities evaluated in the current study, volume OCT scanning was more sensitive than nonmydriatic retinal photography in our asymptomatic individuals. OCT detected clinically relevant disease features, such as subretinal fluid, that were missed by FP, and had a lower ungradable image rate. It is likely that OCT will be added to photography screening in the near future for chorioretinal disease.
Volume OCT scanning is significantly more sensitive than nonmydriatic retinal photography for detection of a variety of retinal abnormalities in asymptomatic individuals. OCT may be a more sensitive, comfortable, and adaptable method of screening for chorioretinal disease.
doi:10.1167/iovs.12-10727
PMCID: PMC3597191  PMID: 23322579
16.  Imaging Retinal Pigment Epithelial Proliferation Secondary to PASCAL Photocoagulation In Vivo by Polarization-sensitive Optical Coherence Tomography 
American Journal of Ophthalmology  2013;155(6):1058-1067.e1.
Purpose
To image the retinal pigment epithelium (RPE) after macular laser and to monitor healing responses over time in vivo in patients with diabetic maculopathy using polarization-sensitive optical coherence tomography (OCT).
Design
Prospective, nonrandomized clinical trial.
Methods
In this single-center trial (Department of Ophthalmology and Optometry, Medical University of Vienna, Vienna, Austria), 13 patients (13 eyes) underwent grid photocoagulation for diabetic maculopathy. Retinal healing processes were continuously followed over the course of 3 months. A polarization-sensitive OCT prototype was used, allowing detection and measurement of the RPE changes based on their specific polarization-scrambling qualities.
Results
After 1 day, the intraretinal photocoagulation lesions were sharply demarcated, whereas RPE changes were rather subtle. At 1 week, all lesions exhibited traction of the inner retinal layers toward the RPE and loss of photoreceptor cells. In tissue-sensitive polarization-sensitive OCT imaging, polarization-scrambling columns were found at the level of the RPE. During follow-up, different healing responses were seen in the polarization-scrambling RPE layer, ranging from hyperproliferation to focal atrophy.
Conclusion
Because of the properties of the polarization state of backscattered light, polarization-sensitive OCT revealed specific morphologic changes in the RPE and outer retinal layers secondary to retinal laser treatment undetectable with intensity-based spectral-domain OCT. The increase in polarization-scrambling tissue over the course of 3 months indicates a more intense healing reaction and proliferation of RPE cells than previously characterized in rodent studies.
doi:10.1016/j.ajo.2012.12.017
PMCID: PMC3660624  PMID: 23498853
17.  Drusen Characterization with Multimodal Imaging 
Retina (Philadelphia, Pa.)  2010;30(9):1441-1454.
Summary
Multimodal imaging findings and histological demonstration of soft drusen, cuticular drusen, and subretinal drusenoid deposits provided information used to develop a model explaining their imaging characteristics.
Purpose
To characterize the known appearance of cuticular drusen, subretinal drusenoid deposits (reticular pseudodrusen), and soft drusen as revealed by multimodal fundus imaging; to create an explanatory model that accounts for these observations.
Methods
Reported color, fluorescein angiographic, autofluorescence, and spectral domain optical coherence tomography (SD-OCT) images of patients with cuticular drusen, soft drusen, and subretinal drusenoid deposits were reviewed, as were actual images from affected eyes. Representative histological sections were examined. The geometry, location, and imaging characteristics of these lesions were evaluated. A hypothesis based on the Beer-Lambert Law of light absorption was generated to fit these observations.
Results
Cuticular drusen appear as numerous uniform round yellow-white punctate accumulations under the retinal pigment epithelium (RPE). Soft drusen are larger yellow-white dome-shaped mounds of deposit under the RPE. Subretinal drusenoid deposits are polymorphous light-grey interconnected accumulations above the RPE. Based on the model, both cuticular and soft drusen appear yellow due to the removal of shorter wavelength light by a double pass through the RPE. Subretinal drusenoid deposits, which are located on the RPE, are not subjected to short wavelength attenuation and therefore are more prominent when viewed with blue light. The location and morphology of extracellular material in relationship to the RPE, and associated changes to RPE morphology and pigmentation, appeared to be primary determinants of druse appearance in different imaging modalities.
Conclusion
Although cuticular drusen, subretinal drusenoid deposits, and soft drusen are composed of common components, they are distinguishable by multimodal imaging due to differences in location, morphology, and optical filtering effects by drusenoid material and the RPE.
doi:10.1097/IAE.0b013e3181ee5ce8
PMCID: PMC2952278  PMID: 20924263
cuticular drusen; subretinal drusenoid deposits; reticular pseudodrusen; soft drusen; age-related macular degeneration
18.  Retinal pigment epithelial changes in chronic Vogt-Koyanagi-Harada disease: fundus autofluorescence and spectral domain optical coherence tomography findings 
Retina (Philadelphia, Pa.)  2010;30(1):33-41.
Purpose
To determine whether fundus autofluorescence (FAF) and spectral-domain optical coherence tomography (SD-OCT) imaging allows better assessment of RPE and outer retina (OR) in subjects with chronic VKH compared to examination and angiography alone.
Methods
Cross-sectional analysis of a series of seven consecutive patients with chronic VKH undergoing FAF and SD-OCT. Chronic VKH was defined as during >3 months. Color fundus photographs were correlated to FAF and SD-OCT images. The images were later correlated to fluorescein angiography (FA) and indocyanine green angiography (ICG-A).
Results
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 RPE and involvement of OR 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 OR on SD-OCT and corresponding clinically to areas of RPE proliferation and cystoid macular edema.
Conclusion
Combined use of FAF and SD-OCT imaging allowed noninvasive delineation of RPE/OR changes in patients with chronic VKH, which were consistent with previous histopathological reports. Some of these changes were not apparent on clinical examination.
doi:10.1097/IAE.0b013e3181c5970d
PMCID: PMC2903055  PMID: 20010321
fundus autofluorescence; retinal pigment epithelium; spectral domain optical coherence tomography; Vogt-Koyanagi-Harada disease; uveitis
19.  High-resolution spectral domain optical coherence tomography and fundus autofluorescence correlation in tubercular serpiginouslike choroiditis 
Objective
This study aims to describe changes in high-resolution spectral domain optical coherence tomography (SD-OCT) scans with simultaneous fundus autoflorescence (FAF) signals in tubercular serpiginouslike choroiditis (SLC).
Methods
Simultaneous SD-OCT and FAF imaging of eyes affected with SLC from acute stage until resolution of lesions was obtained using Spectralis HRA+OCT system (Heidelberg Engineering, Heidelberg, Germany).
Patients
Four eyes (three patients) with SLC were prospectively followed.
Results
Acute lesions of SLC (diffusely hyperautofluorescent) corresponded to hyperreflective areas on SD-OCT involving the retinal pigment epithelium (RPE), photoreceptor outer segment tips (POST), inner segment–outer segment (IS/OS) junction, external limiting membrane (ELM), and outer nuclear layer (ONL) with a minimal distortion of inner retinal layers. There was no backscattering from inner choroid. During healing, lesions became discrete with a hypoautofluorescent border and predominant hyperautofluorescence centrally. The hyperreflective fuzzy areas on SD-OCT scans disappeared, and irregular, knobbly elevations of outer retinal layers appeared. The RPE, POST, IS/OS junction, and ELM could not be distinguished. The ONL appeared normal. The choroid showed an increased reflectance. As the lesions healed further over the next 3–6 months, they became predominantly hypoautofluorescent with loss of RPE, POST, IS/OS junction, and ELM in SD-OCT scan.
Conclusion
The SD-OCT provided an insight into the ultrastructural changes in the outer retina during the course of acute SLC lesions. The changes on OCT correlated with abnormal FAF findings.
doi:10.1007/s12348-011-0037-7
PMCID: PMC3223337  PMID: 21847595
Fundus autofluorescence; Spectral domain optical coherence tomography; Tubercular serpiginouslike choroiditis
20.  High-resolution spectral domain optical coherence tomography and fundus autofluorescence correlation in tubercular serpiginouslike choroiditis 
Objective
This study aims to describe changes in high-resolution spectral domain optical coherence tomography (SD-OCT) scans with simultaneous fundus autoflorescence (FAF) signals in tubercular serpiginouslike choroiditis (SLC).
Methods
Simultaneous SD-OCT and FAF imaging of eyes affected with SLC from acute stage until resolution of lesions was obtained using Spectralis HRA+OCT system (Heidelberg Engineering, Heidelberg, Germany).
Patients
Four eyes (three patients) with SLC were prospectively followed.
Results
Acute lesions of SLC (diffusely hyperautofluorescent) corresponded to hyperreflective areas on SD-OCT involving the retinal pigment epithelium (RPE), photoreceptor outer segment tips (POST), inner segment–outer segment (IS/OS) junction, external limiting membrane (ELM), and outer nuclear layer (ONL) with a minimal distortion of inner retinal layers. There was no backscattering from inner choroid. During healing, lesions became discrete with a hypoautofluorescent border and predominant hyperautofluorescence centrally. The hyperreflective fuzzy areas on SD-OCT scans disappeared, and irregular, knobbly elevations of outer retinal layers appeared. The RPE, POST, IS/OS junction, and ELM could not be distinguished. The ONL appeared normal. The choroid showed an increased reflectance. As the lesions healed further over the next 3–6 months, they became predominantly hypoautofluorescent with loss of RPE, POST, IS/OS junction, and ELM in SD-OCT scan.
Conclusion
The SD-OCT provided an insight into the ultrastructural changes in the outer retina during the course of acute SLC lesions. The changes on OCT correlated with abnormal FAF findings.
doi:10.1007/s12348-011-0037-7
PMCID: PMC3223337  PMID: 21847595
Fundus autofluorescence; Spectral domain optical coherence tomography; Tubercular serpiginouslike choroiditis
21.  Epiretinal membrane surgery for combined hamartoma of the retina and retinal pigment epithelium: role of multimodal analysis 
Background
The purpose of this study was to evaluate the role of spectral domain optical coherence tomography (SD-OCT), MP-1 microperimetry, and fundus autofluorescence imaging for planning surgical procedures in combined hamartomas of the retina and retinal pigment epithelium (CHR-RPE) and following epiretinal membrane removal.
Methods
In an interventional retrospective case series, six consecutive subjects with CHR-RPE underwent vitrectomy and epiretinal membrane peeling, with 4 years of follow-up. Each underwent complete ophthalmic examination, including best corrected visual acuity, fundus examination, fundus fluorescein angiography, SD-OCT, MP-1, and fundus autofluorescence at one, 6, 12, and 48 months.
Results
Six eyes from six subjects with CHR-RPE were studied (mean age 31 ± 14 years). All patients were phakic and five were male (83.3%). Lesions were unilateral, ie, three macular, two juxtapapillary and macular, and one pericentral. Preoperative best corrected visual acuity was 0.3 ± 0.08 Snellen, with significant improvement to 0.9 ± 0.17 Snellen (P = 0.001) at 4 years of follow-up. Mean retinal sensitivity within the central 20° field improved from 16.6 ± 1.84 dB to 18.8 ± 0.96 dB (P = 0.07). There was also a statistically significant reduction in the visual defect (P = 0.04). SD-OCT demonstrated that the epiretinal membranes were completely removed in all but one patient, with significantly decreased macular edema on follow-up at one, 6, 12, and 48 months (P = 0.001). A positive correlation was shown between preoperative macular sensitivity and postoperative best corrected visual acuity. Fundus autofluorescence demonstrated a block in background autofluorescence at the site of the lesion, and hyperautofluorescence at the edematous retina overlain by the epiretinal membrane.
Conclusion
Surgery is an effective treatment for CHR-RPE. SD-OCT, fundus autofluorescence, and MP-1 are valuable and noninvasive tools to guide surgical procedures for CHR-RPE. To the best of our knowledge, this study represents the first use of MP-1 in CHR-RPE in conjunction with SD-OCT and fundus autofluorescence imaging for better guided surgery as well as anatomical and functional prognosis.
doi:10.2147/OPTH.S39909
PMCID: PMC3553654  PMID: 23378735
vitrectomy; epiretinal membrane; combined hamartoma of the retina and retinal pigment epithelium
22.  Fundus Autofluorescence Findings in a Mouse Model of Retinal Detachment 
Purpose.
Fundus autofluorescence (fundus AF) changes were monitored in a mouse model of retinal detachment (RD).
Methods.
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.
Conclusions.
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.
Autofluorescent puncta that are a feature of retinal degeneration when imaged by fundus autofluorescence, may reflect retinal folds and/or rosettes within which photoreceptor outer segments form hyperfluorescent cores.
doi:10.1167/iovs.12-9672
PMCID: PMC3416030  PMID: 22786896
23.  Histologic Basis of Variations in Retinal Pigment Epithelium Autofluorescence in Eyes with Geographic Atrophy 
Ophthalmology  2013;120(4):821-828.
Purpose
Lipofuscin contained in the retinal pigment epithelium (RPE) is the main source of fundus auto-fluorescence (FAF), the target of an imaging method useful for estimating the progression of geographic atrophy (GA) in clinical trials. To establish a cellular basis for hyperfluorescent GA border zones, histologic autofluorescence (HAF) was measured at defined stages of RPE pathologic progression.
Design
Experimental study.
Participants and Controls
Ten GA donor eyes (mean age ± standard deviation, 87.1±4.0 years) and 3 age-matched control eyes (mean age ± standard deviation, 84.0±7.2 years) without GA.
Methods
Ten–micrometer-thick sections were divided into zones of RPE morphologic features according to an 8-point scale. Any HAF excited by 488 nm light was imaged by laser confocal microscopy. The HAF intensity summed along vertical lines perpendicular to Bruch’s membrane at 0.2-μm intervals served as a surrogate for FAF. Intensity profiles in 151 zones were normalized to grade 0 at a standard reference location in each eye. Cross-sectional area, mean, and sum autofluorescence for individual RPE cells were measured (cellular autofluorescence [CAF]).
Main Outcome Measures
Statistically significant differences in intensity and localization of HAF and CAF at defined stages of RPE morphologic progression for GA and control eyes.
Results
The RPE morphologic features were most abnormal (cell rounding, sloughing, and layering; grade 2) and HAF intensity profiles were highest and most variable immediately adjacent to atrophic areas. Peaks in HAF intensity frequently were associated with vertically superimposed cells. The HAF value that optimally separated reactive RPE was 0.66 standard deviations more than the mean for uninvolved RPE and was associated with a sensitivity of 75.8% and a specificity of 76.3%. When variable cell area was accounted for, neither mean nor sum CAF differed significantly among the RPE pathologic grades.
Conclusions
Areas with advanced RPE alterations are most likely to exhibit clinically recognizable patterns of elevated FAF around GA, but may not predict cells about to die, because of vertically superimposed cells and cellular fragments. These data do not support a role for lipofuscin-related cell death and call into question the rationale of treatments targeting lipofuscin.
doi:10.1016/j.ophtha.2012.10.007
PMCID: PMC3633595  PMID: 23357621
24.  Atypical features of nanophthalmic macula- a spectral domain OCT study 
BMC Ophthalmology  2012;12:12.
Background
To report atypical features on Spectral domain optical coherence tomography (SD-OCT) in a case of non-familial pure adult nanophthalmos.
Case presentation
A 39 year old male hyperope was found to have biometric and fundus findings typical of nanophthalmos. The additional atypical features included serous pigment epithelial detachment (PED) in right eye and a cuff of subretinal fluid with underlying yellow deposits along superotemporal arcade in the left eye. Fundus flourescein angiogram showed hyperfluorescence due to window defect, dye pooling due to serous PED in right eye and leak superior to disc in right eye and superotemporally in left eye. Cirrus-SD OCT horizontal line scan passing through the fovea showed extensive inner limiting membrane corrugations causing distorted foveal contour in both eyes. A large juxtafoveal serous PED and a small extrafoval PED were seen with folds in the retinal pigment epithelium (RPE)-choriocapillary layer in the right eye.
Conclusion
Structural disruptions in the RPE-choriocapillary complex in the form of folds or juxtafoveal serous PED and RPE folds can be atypical features of nanophthalmic macula better discerned on high resolution OCT.
doi:10.1186/1471-2415-12-12
PMCID: PMC3441246  PMID: 22672150
Nanophthalmos
25.  Fundus autofluorescence and optical coherence tomography in the management of progressive outer retinal necrosis 
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.
doi:10.3928/15428877-20100216-14
PMCID: PMC3265678  PMID: 20337261
Progressive outer retinal necrosis; varicella zoster virus; fundus autofluorescence; optical coherence tomography

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