Time-Resolved Ultra–High Resolution Optical Coherence Tomography for Real-Time Monitoring of Selective Retina Therapy

Purpose: Selective retina therapy (SRT) is a novel treatment for retinal pathologies, solely targeting the retinal pigment epithelium (RPE). During SRT, the detection of an immediate tissue reaction is challenging as tissue effects remain limited to intracellular RPE photodisruption. Time-resolved ultra-high axial resolution optical coherence tomography (OCT) is thus evaluated for the monitoring of dynamic optical changes at and around the RPE during SRT. Methods: An experimental OCT system with an ultra-high axial resolution of 1.78 µm was combined with an SRT system and time-resolved OCT M-scans of the target area were recorded from four patients undergoing SRT. OCT scans were analyzed and OCT morphology was correlated with findings in fluorescein angiography, fundus photography and cross-sectional OCT. Results: In cases where the irradiation caused RPE damage proven by fluorescein angiography, the lesions were well discernible in time-resolved OCT images but remained invisible in fundus photography and cross-sectional OCT acquired after treatment. If RPE damage was introduced, all applied SRT pulses led to detectable signal changes in the time-resolved OCT images. The extent of optical signal variation seen in the OCT data appeared to scale with the applied SRT pulse energy. Conclusion: The first clinical results proved that successful SRT irradiation induces detectable changes in the OCT M-scan signal while it remains invisible in conventional ophthalmoscopic imaging. Thus, real-time high-resolution OCT is a promising modality to monitor and analyze tissue effects introduced by selective retina therapy and may be used to guide SRT in an automatic feedback mode.

Quantitative Analysis of Mouse Retinal Layers Using Automated Segmentation of Spectral Domain Optical Coherence Tomography Images.

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(+)Prph2(Rd2) /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.

Imaging of the Sclera in Patients with Scleritis and Episcleritis using Anterior Segment Optical Coherence Tomography

PURPOSE To evaluate the sclera and episclera in patients with scleritis and episcleritis using anterior segment optical coherence tomography (AS-OCT). METHODS Cross-sectional prospective case series of 11 consecutive patients with episcleral or scleral inflammatory disease located anterior to the equator. The thickness of the ocular wall (sclera and the episclera) was measured using AS-OCT and compared to the contralateral healthy eye. RESULTS Eleven patients with a mean age of 49.5 years presented with symptomatic scleritis or episcleritis. The mean thickness of the ocular wall in the affected eye was 982 ± 56 μm compared to 790 ± 23 μm (p < 0.05) in the fellow eye. Enhanced-depth AS-OCT showed that the thickening occurred mainly in the episcleral layer in both scleritis and episcleritis. CONCLUSION Enhanced-depth AS-OCT may be a useful tool for imaging scleritis or episcleritis and may serve to monitor therapeutic success in these patients.

Mechanisms of Very Late Drug-Eluting Stent Thrombosis Assessed by Optical Coherence Tomography.

BACKGROUND The pathomechanisms underlying very late stent thrombosis (VLST) after implantation of drug-eluting stents (DES) are incompletely understood. Using optical coherence tomography, we investigated potential causes of this adverse event. METHODS AND RESULTS Between August 2010 and December 2014, 64 patients were investigated at the time point of VLST as part of an international optical coherence tomography registry. Optical coherence tomography pullbacks were performed after restoration of flow and analyzed at 0.4 mm. A total of 38 early- and 20 newer-generation drug-eluting stents were suitable for analysis. VLST occurred at a median of 4.7 years (interquartile range, 3.1-7.5 years). An underlying putative cause by optical coherence tomography was identified in 98% of cases. The most frequent findings were strut malapposition (34.5%), neoatherosclerosis (27.6%), uncovered struts (12.1%), and stent underexpansion (6.9%). Uncovered and malapposed struts were more frequent in thrombosed compared with nonthrombosed regions (ratio of percentages, 8.26; 95% confidence interval, 6.82-10.04; P<0.001 and 13.03; 95% confidence interval, 10.13-16.93; P<0.001, respectively). The maximal length of malapposed or uncovered struts (3.40 mm; 95% confidence interval, 2.55-4.25; versus 1.29 mm; 95% confidence interval, 0.81-1.77; P<0.001), but not the maximal or average axial malapposition distance, was greater in thrombosed compared with nonthrombosed segments. The associations of both uncovered and malapposed struts with thrombus were consistent among early- and newer-generation drug-eluting stents. CONCLUSIONS The leading associated findings in VLST patients in descending order were malapposition, neoatherosclerosis, uncovered struts, and stent underexpansion without differences between patients treated with early- and new-generation drug-eluting stents. The longitudinal extension of malapposed and uncovered stent was the most important correlate of thrombus formation in VLST.

Differentiation of Diabetic Macular Edema From Pseudophakic Cystoid Macular Edema by Spectral-Domain Optical Coherence Tomography.

PURPOSE: To differentiate diabetic macular edema (DME) from pseudophakic cystoid macular edema (PCME) based solely on spectral-domain optical coherence tomography (SD-OCT). METHODS: This cross-sectional study included 134 participants: 49 with PCME, 60 with DME, and 25 with diabetic retinopathy (DR) and ME after cataract surgery. First, two unmasked experts classified the 25 DR patients after cataract surgery as either DME, PCME, or mixed-pattern based on SD-OCT and color-fundus photography. Then all 134 patients were divided into two datasets and graded by two masked readers according to a standardized reading-protocol. Accuracy of the masked readers to differentiate the diseases based on SD-OCT parameters was tested. Parallel to the masked readers, a computer-based algorithm was established using support vector machine (SVM) classifiers to automatically differentiate disease entities. RESULTS: The masked readers assigned 92.5% SD-OCT images to the correct clinical diagnose. The classifier-accuracy trained and tested on dataset 1 was 95.8%. The classifier-accuracy trained on dataset 1 and tested on dataset 2 to differentiate PCME from DME was 90.2%. The classifier-accuracy trained and tested on dataset 2 to differentiate all three diseases was 85.5%. In particular, higher central-retinal thickness/retinal-volume ratio, absence of an epiretinal-membrane, and solely inner nuclear layer (INL)-cysts indicated PCME, whereas higher outer nuclear layer (ONL)/INL ratio, the absence of subretinal fluid, presence of hard exudates, microaneurysms, and ganglion cell layer and/or retinal nerve fiber layer cysts strongly favored DME in this model. CONCLUSIONS: Based on the evaluation of SD-OCT, PCME can be differentiated from DME by masked reader evaluation, and by automated analysis, even in DR patients with ME after cataract surgery. The automated classifier may help to independently differentiate these two disease entities and is made publicly available.

RETICULAR PSEUDODRUSEN ON INFRARED IMAGING ARE TOPOGRAPHICALLY DISTINCT FROM SUBRETINAL DRUSENOID DEPOSITS ON EN FACE OPTICAL COHERENCE TOMOGRAPHY.

PURPOSE: To evaluate the quantitative and topographic relationship between reticular pseudodrusen (RPD) on infrared reflectance (IR) and subretinal drusenoid deposits (SDD) on en face volumetric spectral domain optical coherence tomography. METHODS: Reticular pseudodrusen were marked on IR images by a masked observer. Subretinal drusenoid deposits were visualized on en face sections of spectral domain optical coherence tomography below the external limiting membrane and identified by a semiautomated technique. Control RPD lesions were generated in a random distribution for each IR image. Binary maps of control and experimental RPD and SDD were merged and analyzed in terms of topographic localization and quantitative drusen load comparison. RESULTS: A total of 54 eyes of 41 patients diagnosed with RPD were included in this study. The average number of RPD lesions on IR images was 320 ± 44.62 compared with 127 ± 26.02 SDD lesions on en face (P < 0.001). The majority of RPD lesions did not overlap with SDD lesions and were located >30 μm away (92%). The percentage of total SDD lesions overlapping RPD was 2.91 ± 0.87% compared with 1.73 ± 0.68% overlapping control RPD lesions (P < 0.05). The percentage of total SDD lesions between 1 and 3 pixels of the nearest RPD lesion was 5.08 ± 1.40% compared with 3.33 ± 1.07% between 1 and 3 pixels of the nearest control RPD lesion (P < 0.05). CONCLUSION: This study identified significantly more RPD lesions on IR compared with SDD lesions on en face spectral domain optical coherence tomography and found that a large majority of SDD (>90% of lesions) were >30 μm away from the nearest RPD. Together, our findings indicate that RPD and SDD are two entities that are only occasionally topographically associated, suggesting that at some stage in their development, they may be pathologically related.

Detection and Differentiation of Intraretinal Hemorrhage in Spectral Domain Optical Coherence Tomography.

PURPOSE The purpose of this study was to classify and detect intraretinal hemorrhage (IRH) in spectral domain optical coherence tomography (SD-OCT). METHODS Initially the presentation of IRH in BRVO-patients in SD-OCT was described by one reader comparing color-fundus (CF) and SD-OCT using dedicated software. Based on these established characteristics, the presence and the severity of IRH in SD-OCT and CF were assessed by two other masked readers and the inter-device and the inter-observer agreement were evaluated. Further the area of IRH was compared. RESULTS About 895 single B-scans of 24 eyes were analyzed. About 61% of SD-OCT scans and 46% of the CF-images were graded for the presence of IRH (concordance: 73%, inter-device agreement: k = 0.5). However, subdivided into previously established severity levels of dense (CF: 21.3% versus SD-OCT: 34.7%, k = 0.2), flame-like (CF: 15.5% versus SD-OCT: 45.5%, k = 0.3), and dot-like (CF: 32% versus SD-OCT: 24.4%, k = 0.2) IRH, the inter-device agreement was weak. The inter-observer agreement was strong with k = 0.9 for SD-OCT and k = 0.8 for CF. The mean area of IRH detected on SD-OCT was significantly greater than on CF (SD-OCT: 11.5 ± 4.3 mm(2) versus CF: 8.1 ± 5.5 mm(2), p = 0.008). CONCLUSIONS IRH seems to be detectable on SD-OCT; however, the previously established severity grading agreed weakly with that assessed by CF.

Enhanced depth imaging optical coherence tomography of congenital cavitary optic disc anomaly (CODA).

AIM To report the finding of extension of the 4th hyper-reflective band and retinal tissue into the optic disc in patients with cavitary optic disc anomalies (CODAs). METHODS In this observational study, 10 patients (18 eyes) with sporadic or autosomal dominant CODA were evaluated with enhanced depth imaging optical coherence tomography (EDI-OCT) and colour fundus images for the presence of 4th hyper-reflective band extension into the optic disc. RESULTS Of 10 CODA patients (18 eyes), five patients (8 eyes) showed a definite 4th hyper-reflective band (presumed retinal pigment epithelium (RPE)) extension into the optic disc. In these five patients (seven eyes), the inner retinal layers also extended with the 4th hyper-reflective band into the optic disc. Best corrected visual acuity ranged from 20/20 to 20/200. In three patients (four eyes), retinal splitting/schisis was present and in two patients (two eyes), the macula was involved. In all cases, the 4th hyper-reflective band extended far beyond the termination of the choroid into the optic disc. The RPE extension was found either temporally or nasally in areas of optic nerve head excavation, most often adjacent to peripapillary pigment. Compared with eyes without RPE extension, eyes with RPE extension were more myopic (mean dioptres -0.9±2.6 vs -8.8±5, p=0.043). CONCLUSIONS The RPE usually stops near the optic nerve border separated by a border tissue. With CODA, extension of this hyper-reflective band and retinal tissue into the disc is possible and best evaluable using EDI-OCT or analogous image modalities. Whether this is a finding specific for CODA, linked to specific gene loci or is also seen in patients with other optic disc abnormalities needs further evaluation.

Spectral-domain optical coherence tomography study of macular structure as prognostic and determining factor for macular hole surgery outcome

Purpose: To evaluate postoperative spectral-domain optical coherence tomography findings after macular hole surgery. Methods: Retrospective, interventional, nonrandomized study. Overall, 164 eyes of 157 patients diagnosed with macular hole were operated on by vitrectomy and internal limiting membrane peeling. Preoperative and postoperative best-corrected visual acuity and spectral-domain optical coherence tomography images were obtained. Two groups were considered on the basis of the postoperative integrity of the back reflection line from the ellipsoid portion of the photoreceptor inner segment: group A (disruption of ellipsoid portion of the inner segment line, 60 eyes) and group B (restoration of ellipsoid portion of the inner segment line, 104 eyes). Results: Logarithm of the minimum angle of resolution best-corrected visual acuity improved significantly after the surgery of macular hole from a mean preoperative value of 0.79 ± 0.37 (range, 0.15–2.00) to a mean postoperative value of 0.35 ± 0.31 (range, 0.00–1.30) at the last follow-up visit (P < 0.01). Best-corrected visual acuity improved significantly in the 2 groups analyzed (all P < 0.01). A larger improvement was found in group B than in group A (P < 0.01). Conclusion: Ellipsoid portion of the inner segment line reconstruction seems to be a good prognostic factor for visual rehabilitation after macular hole surgery.

Long time remodeling during retinal degeneration evaluated by optical coherence tomography, immunocytochemistry and fundus autofluorescence

Purpose: To characterize the relationship between fundus autofluorescence (FAF), Optical Coherence Tomography (OCT) and immunohistochemistry (IHC) over the course of chronic retinal degeneration in the P23H rat. Methods: Homozygous albino P23H rats, Sprague–Dawley (SD) rats as controls and pigmented Long Evans (LE) rats were used. A Spectralis HRA OCT system was used for scanning laser ophthalmoscopy (SLO) imaging OCT and angiography. To determine FAF, fluorescence was excited using diode laser at 488 nm. A fast retina map OCT was performed using the optic nerve as a landmark. IHC was performed to correlate with the findings of OCT and FAF changes. Results: During the course of retinal degeneration, the FAF pattern evolved from some spotting at 2 months old to a mosaic of hyperfluorescent dots in rats 6 months and older. Retinal thicknesses progressively diminished over the course of the disease. At later stages of degeneration, OCT documented changes in the retinal layers, however, IHC better identified the cell loss and remodeling changes. Angiography revealed attenuation of the retinal vascular plexus with time. Conclusion: We provide for the first time a detailed long-term analysis of the course of retinal degeneration in P23H rats using a combination of SLO and OCT imaging, angiography, FAF and IHC. Although, the application of noninvasive methods enables longitudinal studies and will decrease the number of animals needed for a study, IHC is still an essential tool to identify retinal changes at the cellular level.

SPECTRAL DOMAIN-OPTICAL COHERENCE TOMOGRAPHY IMAGE CONTRAST AND BACKGROUND COLOR SETTINGS INFLUENCE IDENTIFICATION OF RETINAL STRUCTURES.

PURPOSE To evaluate image contrast and color setting on assessment of retinal structures and morphology in spectral-domain optical coherence tomography. METHODS Two hundred and forty-eight Spectralis spectral-domain optical coherence tomography B-scans of 62 patients were analyzed by 4 readers. B-scans were extracted in 4 settings: W + N = white background with black image at normal contrast 9; W + H = white background with black image at maximum contrast 16; B + N = black background with white image at normal contrast 12; B + H = black background with white image at maximum contrast 16. Readers analyzed the images to identify morphologic features. Interreader correlation was calculated. Differences between Fleiss-kappa correlation coefficients were examined using bootstrap method. Any setting with significantly higher correlation coefficient was deemed superior for evaluating specific features. RESULTS Correlation coefficients differed among settings. No single setting was superior for all respective spectral-domain optical coherence tomography parameters (P = 0.3773). Some variables showed no differences among settings. Hard exudates and subretinal fluid were best seen with B + H (κ = 0.46, P = 0.0237 and κ = 0.78, P = 0.002). Microaneurysms were best seen with W + N (κ = 0.56, P = 0.025). Vitreomacular interface, enhanced transmission signal, and epiretinal membrane were best identified using all color/contrast settings together (κ = 0.44, P = 0.042, κ = 0.57, P = 0.01, and κ = 0.62, P ≤ 0.0001). CONCLUSION Contrast and background affect the evaluation of retinal structures on spectral-domain optical coherence tomography images. No single setting was superior for all features, though certain changes were best seen with specific settings.

Functional Optical Coherence Tomography: In Vivo Applications in Dermatology and Neuroscience

Thesis (Ph.D.)--University of Washington, 2016-06

Fourier-domain optical coherence tomography: optimization of signal-to-noise ratio in full space

Optical coherence tomography (OCT) is an emerging coherence-domain technique capable of in vivo imaging of sub-surface structures at millimeter-scale depth. Its steady progress over the last decade has been galvanized by a breakthrough detection concept, termed spectral-domain OCT, which has resulted in a dramatic improvement of the OCT signal-to-noise ratio of 150 times demonstrated for weakly scattering objects at video-frame-rates. As we have realized, however, an important OCT sub-system remains sub-optimal: the sample arm traditionally operates serially, i.e. in flying-spot mode. To realize the full-field image acquisition, a Fourier holography system illuminated with a swept-source is employed instead of a Michelson interferometer commonly used in OCT. The proposed technique, termed Fourier-domain OCT, offers a new leap in signal-to-noise ratio improvement, as compared to flying-spot OCT systems, and represents the main thrust of this paper. Fourier-domain OCT is described, and its basic theoretical aspects, including the reconstruction algorithm, are discussed. (C) 2004 Elsevier B.V. All rights reserved.

Image reconstruction in full-field Fourier-domain optical coherence tomography

Full-field Fourier-domain optical coherence tomography (3F-OCT) is a full-field version of spectral domain/swept source optical coherence tomography. A set of two-dimensional Fourier holograms is recorded at discrete wavenumbers spanning the swept source tuning range. The resultant three-dimensional data cube contains comprehensive information on the three-dimensional spatial properties of the sample, including its morphological layout and optical scatter. The morphological layout can be reconstructed in software via three-dimensional discrete Fourier transformation. The spatial resolution of the 3F-OCT reconstructed image, however, is degraded due to the presence of a phase cross-term, whose origin and effects are addressed in this paper. We present a theoretical and experimental study of the imaging performance of 3F-OCT, with particular emphasis on elimination of the deleterious effects of the phase cross-term.

Signal-to-noise ratio study of full-field Fourier-domain optical coherence tomography

We report a new approach in optical coherence tomography (OCT) called full-field Fourier-domain OCT (3F-OCT). A three-dimensional image of a sample is obtained by digital reconstruction of a three-dimensional data cube, acquired with a Fourier holography recording system, illuminated with a swept source. We present a theoretical and experimental study of the signal-to-noise ratio of the 3F-OCT approach versus serial image acquisition (flying-spot OCT) approach. (c) 2005 Optical Society of America.