Transforming Tele-Ophthalmology: Utilizing Cloud Computing for Remote Eye Care.

BACKGROUND: Tele-ophthalmology is gaining recognition for its role in improving eye care accessibility via cloud-based solutions. The Google Cloud Platform (GCP) Healthcare API enables secure and efficient management of medical image data such as high-resolution ophthalmic images. OBJECTIVES: This study investigates cloud-based solutions' effectiveness in tele-ophthalmology, with a focus on GCP's role in data management, annotation, and integration for a novel imaging device. METHODS: Leveraging the Integrating the Healthcare Enterprise (IHE) Eye Care profile, the cloud platform was utilized as a PACS and integrated with the Open Health Imaging Foundation (OHIF) Viewer for image display and annotation capabilities for ophthalmic images. RESULTS: The setup of a GCP DICOM storage and the OHIF Viewer facilitated remote image data analytics. Prolonged loading times and relatively large individual image file sizes indicated system challenges. CONCLUSION: Cloud platforms have the potential to ease distributed data analytics, as needed for efficient tele-ophthalmology scenarios in research and clinical practice, by providing scalable and secure image management solutions.

Integrating a Novel Eye Imaging System into Clinical Practice: An Open-Source DICOM Simulation Platform.

BACKGROUND: The integration of innovative imaging technologies into clinical workflows requires the utilization of a standardized data exchange format. The "Digital Imaging and Communications in Medicine" (DICOM) standard is widely used in healthcare to process and transfer medical images. However, no simulation environment is ready to use for development. The objective of this paper is to provide an open-source DICOM platform for integrating a novel ocular photography system into a clinical setting. METHODS: After a thorough analysis of the available open-source tools, a subset was selected and aligned with the U-Eyecare Profile of Integrating the Healthcare Enterprise (IHE). RESULTS: Orthanc served as a PACS with a modality worklist and the OHIF-Viewer for image retrieval. Minimal interfaces for the electronic health record and image modality were created. Docker-compose further integrates all components and simulates the network protocols DICOM Message Service Element and DICOMWeb. DISCUSSION: The platform was used to develop and integrate the developed image modality and will be further utilized for teleophthalmology and processing eye images. The platform could be useful for other researchers to integrate an image modality into a clinical environment along IHE.

Degeneration of Melanin-Containing Structures Observed Longitudinally in the Eyes of SOD1-/- Mice Using Intensity, Polarization, and Spectroscopic OCT.

Purpose: Melanin plays an important function in maintaining eye health, however there are few metrics that can be used to study retinal melanin content in vivo. Methods: The slope of the spectral coefficient of variation (SSCoV) is a novel biomarker that measures chromophore concentration by analyzing the local divergence of spectral intensities using optical coherence tomography (OCT). This metric was validated in a phantom and applied in a longitudinal study of superoxide dismutase 1 knockout (SOD1-/-) mice, a model for wet and dry age-related macular degeneration. We also examined a new feature of interest in standard OCT image data, the ratio of maximum intensity in the retinal pigment epithelium to that of the choroid (RC ratio). These new biomarkers were supported by polarization-sensitive OCT and histological analysis. Results: SSCoV correlated well with depolarization metrics both in phantom and in vivo with both metrics decreasing more rapidly in SOD1-/- mice with age (P < 0.05). This finding is correlated with reduced melanin pigmentation in the choroid over time. The RC ratio clearly differentiated the SOD1-/- and control groups (P < 0.0005) irrespective of time and may indicate lower retinal pigment epithelium melanin in the SOD1-/- mice. Histological analysis showed decreased melanin content and potential differences in melanin granule shape in SOD1-/- mice. Conclusions: SSCoV and RC ratio biomarkers provided insights into the changes of retinal melanin in the SOD1-/- model longitudinally and noninvasively. Translational Relevance: These biomarkers were designed with the potential for rapid adoption by existing clinical OCT systems without requiring new hardware.

Data Exchange Standards in Teleophthalmology: Current and Future Developments.

BACKGROUND: Teleophthalmology services are considered capable of supporting screening, early diagnosis, and monitoring of leading causes of blindness on a global scale. Therefore, standards and best practices are needed to seamlessly exchange medical ocular images and related data among relevant stakeholders with maximum interoperability. OBJECTIVES: This paper provides an overview of current standards in the field of store-and-forward teleophthalmology data exchange and further developments in this area. METHODS: A literature review was conducted for healthcare standards with a focus on data exchange in ophthalmology. RESULTS: IHE, HL7 FHIR, DICOM, and clinical terminologies are considered the most important standards, providing distinct concepts, solutions, and guidelines for ophthalmology. CONCLUSION: Available standards provide the necessary base for teleophthalmology on technical and semantic interoperability, but practical use is limited due to missing process interoperability resulting in proprietary interfaces of vendors and rejection by ophthalmologists. Further investigations should analyze processual needs on ophthalmology data exchange standards.

Pulsatile tissue deformation dynamics of the murine retina and choroid mapped by 4D optical coherence tomography.

Irregular ocular pulsatility and altered mechanical tissue properties are associated with some of the most sight-threatening eye diseases. Here we present 4D optical coherence tomography (OCT) for the quantitative assessment and depth-resolved mapping of pulsatile dynamics in the murine retina and choroid. Through a pixel-wise analysis of phase changes of the complex OCT signal, we reveal spatiotemporal displacement characteristics across repeated frame acquisitions. We demonstrate in vivo fundus elastography (FUEL) imaging in wildtype mouse retinas and in a mouse model of retinal neovascularization and uncover subtle structural deformations related to ocular pulsation. Our data in mouse eyes hold promise for a powerful retinal elastography technique that may enable a new paradigm of OCT-based measurements and image contrast.

High-resolution, depth-resolved vascular leakage measurements using contrast-enhanced, correlation-gated optical coherence tomography in mice.

Vascular leakage plays a key role in vision-threatening retinal diseases such as diabetic retinopathy and age-related macular degeneration. Fluorescence angiography is the current gold standard for identification of leaky vasculature in vivo, however it lacks depth resolution, providing only 2D images that complicate precise identification and localization of pathological vessels. Optical coherence tomography (OCT) has been widely adopted for clinical ophthalmology due to its high, micron-scale resolution and rapid volumetric scanning capabilities. Nevertheless, OCT cannot currently identify leaky blood vessels. To address this need, we have developed a new method called exogenous contrast-enhanced leakage OCT (ExCEL-OCT) which identifies the diffusion of tracer particles around leaky vasculature following injection of a contrast agent. We apply this method to a mouse model of retinal neovascularization and demonstrate high-resolution 3D vascular leakage measurements in vivo for the first time.

Improved accuracy of quantitative birefringence imaging by polarization sensitive OCT with simple noise correction and its application to neuroimaging.

Polarization-sensitive optical coherence tomography (PS-OCT) enables three-dimensional imaging of biological tissues based on the inherent contrast provided by scattering and polarization properties. In fibrous tissue such as the white matter of the brain, PS-OCT allows quantitative mapping of tissue birefringence. For the popular PS-OCT layout using a single circular input state, birefringence measurements are based on a straight-forward evaluation of phase retardation data. However, the accuracy of these measurements strongly depends on the signal-to-noise ratio (SNR) and is prone to mapping artifacts when the SNR is low. Here we present a simple yet effective approach for improving the accuracy of PS-OCT phase retardation and birefringence measurements. By performing a noise bias correction of the detected OCT signal amplitudes, the impact of the noise floor on retardation measurements can be markedly reduced. We present simulation data to illustrate the influence of the noise bias correction on phase retardation measurements and support our analysis with real-world PS-OCT image data.

Optical Coherence Tomography Findings in the Retinas of SOD1 Knockout Mice.

Purpose: The retinal phenotype of popular mouse models mimicking ophthalmic diseases, such as the superoxide dismutase 1 (SOD1) knockout (KO) mouse model, has mainly been assessed by ex vivo histology and in vivo fundus photography. We used multifunctional optical coherence tomography (OCT) to characterize the retinas of SOD1 KO mice in vivo. Methods: The custom-made ophthalmoscope featured a combination of conventional OCT, polarization-sensitive OCT, and OCT angiography. Seven SOD1 KO mice and nine age-matched controls were imaged between 6 and 17 months of age. A postprocessing framework was used to analyze total and outer retinal thickness changes. Drusenlike lesions were segmented, and their sizes and the number of lesions were assessed quantitatively. Their appearance in the conventional reflectivity images, as well as in the corresponding polarization-sensitive images, was characterized qualitatively. Results: Drusenlike lesions increased in size and number with age for SOD1 KO mice. Exploiting the multiple contrast channels, the appearance of the lesions was found to resemble pseudodrusen observed in eyes of patients suffering from dry age-related macular degeneration. The total and outer retinal thicknesses were lower on average after 11 months and 7 months in SOD1 KO mice compared with age-matched controls. Neovascularizations were found in one out of seven KO animals. Conclusions: OCT imaging proved beneficial for a detailed in vivo characterization of the pathological changes in SOD1 KO mice. Translational Relevance: Phenotyping of animal models using modern imaging concepts can be conducted with more precision and might also ease the translation of conclusions between clinical and preclinical research.

Improved Diagnostic Imaging of Brain Tumors by Multimodal Microscopy and Deep Learning.

Fluorescence-guided surgery is a state-of-the-art approach for intraoperative imaging during neurosurgical removal of tumor tissue. While the visualization of high-grade gliomas is reliable, lower grade glioma often lack visible fluorescence signals. Here, we present a hybrid prototype combining visible light optical coherence microscopy (OCM) and high-resolution fluorescence imaging for assessment of brain tumor samples acquired by 5-aminolevulinic acid (5-ALA) fluorescence-guided surgery. OCM provides high-resolution information of the inherent tissue scattering and absorption properties of tissue. We here explore quantitative attenuation coefficients derived from volumetric OCM intensity data and quantitative high-resolution 5-ALA fluorescence as potential biomarkers for tissue malignancy including otherwise difficult-to-assess low-grade glioma. We validate our findings against the gold standard histology and use attenuation and fluorescence intensity measures to differentiate between tumor core, infiltrative zone and adjacent brain tissue. Using large field-of-view scans acquired by a near-infrared swept-source optical coherence tomography setup, we provide initial assessments of tumor heterogeneity. Finally, we use cross-sectional OCM images to train a convolutional neural network that discriminates tumor from non-tumor tissue with an accuracy of 97%. Collectively, the present hybrid approach offers potential to translate into an in vivo imaging setup for substantially improved intraoperative guidance of brain tumor surgeries.

Indocyanine green provides absorption and spectral contrast for optical coherence tomography at 840 nm in vivo.

In recent years, there has been growing interest in the application of exogenous contrast agents to supplement the traditional strengths of optical coherence tomography (OCT) and provide additional biological information. In this Letter, we present how indocyanine green, a common fluorescent contrast agent approved by the United States Food and Drug Administration, can provide absorption and spectral contrast for OCT imaging in the mouse eye in vivo. We further demonstrate high stability of spectral contrast measurements for the long-term monitoring of contrast agents in spite of fluctuations in intensity.

Three-dimensional visualization of opacifications in the murine crystalline lens by in vivo optical coherence tomography.

Diagnostic classification techniques used to diagnose cataracts, the world's leading cause of blindness, are currently based on subjective methods. Here, we present optical coherence tomography as a noninvasive tool for volumetric visualization of lesions formed in the crystalline lens. A custom-made swept-source optical coherence tomography (SS-OCT) system was utilized to investigate the murine crystalline lens. In addition to imaging cataractous lesions in aged wildtype mice, we studied the structure and shape of cataracts in a mouse model of Alzheimer's disease. Hyperscattering opacifications in the crystalline lens were observed in both groups. Post mortem histological analysis were performed to correlate findings in the anterior and posterior part of the lens to 3D OCT in vivo imaging. Our results showcase the capability of OCT to rapidly visualize cataractous lesions in the murine lens and suggest that OCT might be a valuable tool that provides additional insight for preclinical studies of cataract formation.

Changes in Retinal Blood Flow in Response to an Experimental Increase in IOP in Healthy Participants as Assessed With Doppler Optical Coherence Tomography.

Purpose: Blood flow autoregulation is an intrinsic mechanism of the healthy retinal vasculature to keep blood flow constant when ocular perfusion pressure (OPP) is changed. In the present study, we set out to investigate retinal blood flow in response to an experimental decrease in OPP in healthy participants using Doppler optical coherence tomography. Methods: Fifteen healthy participants aged between 22 and 31 years (mean, 27 ± 3 years) were included in the present open study. IOP was increased stepwise via the suction cup method to induce a decrease in OPP. Retinal blood flow in arteries and veins was assessed using a custom-built Doppler optical coherence tomography system and pressure-flow relationships were calculated to assess autoregulation. Results: Suction cup application induced a pronounced increase in IOP with a maximum value of 50.5 ± 8.0 mm Hg at the highest level of suction. Pressure-flow relationships revealed that blood flow was autoregulated until the OPP was decreased by approximately 21 mm Hg and started to decrease significantly when the OPP was reduced by 30 mm Hg. Retinal blood flow at the last suction period decreased at a maximum of -57.0 ± 22.3% and 65.2 ± 15.4% in retinal arteries and retinal veins, respectively. These changes in retinal blood flow were less pronounced than the decrease in OPP (-75.2 ± 19.2%), indicating retinal autoregulation. Conclusions: The results of the present study confirm that retinal blood flow is autoregulated in response to changes in the OPP. Doppler optical coherence tomography has the potential to become a clinical tool for the investigation of retinal blood flow autoregulation in the future, because of its ability to assess the blood velocities and diameter of the retinal vessels parallel and therefore also their blood flow in absolute values. (Clinicaltrials.gov number NCT03398616).

Retinal analysis of a mouse model of Alzheimer's disease with multicontrast optical coherence tomography.

Significance. Recent Alzheimer's disease (AD) patient studies have focused on retinal analysis, as the retina is the only part of the central nervous system that can be imaged noninvasively by optical methods. However, as this is a relatively new approach, the occurrence and role of retinal pathological features are still debated. Aim. The retina of an APP/PS1 mouse model was investigated using multicontrast optical coherence tomography (OCT) in order to provide a documentation of what was observed in both transgenic and wild-type mice. Approach. Both eyes of 24 APP/PS1 transgenic mice (age: 45 to 104 weeks) and 15 age-matched wild-type littermates were imaged by the custom-built OCT system. At the end of the experiment, retinas and brains were harvested from a subset of the mice (14 transgenic, 7 age-matched control) in order to compare the in vivo results to histological analysis and to quantify the cortical amyloid beta plaque load. Results. The system provided a combination of standard reflectivity data, polarization-sensitive data, and OCT angiograms. Qualitative and quantitative information from the resultant OCT images was extracted on retinal layer thickness and structure, presence of hyper-reflective foci, phase retardation abnormalities, and retinal vasculature. Conclusions. Although multicontrast OCT revealed abnormal structural properties and phase retardation signals in the retina of this APP/PS1 mouse model, the observations were very similar in transgenic and control mice.

Signal averaging improves signal-to-noise in OCT images: But which approach works best, and when?

The high acquisition speed of state-of-the-art optical coherence tomography (OCT) enables massive signal-to-noise ratio (SNR) improvements by signal averaging. Here, we investigate the performance of two commonly used approaches for OCT signal averaging. We present the theoretical SNR performance of (a) computing the average of OCT magnitude data and (b) averaging the complex phasors, and substantiate our findings with simulations and experimentally acquired OCT data. We show that the achieved SNR performance strongly depends on both the SNR of the input signals and the number of averaged signals when the signal bias caused by the noise floor is not accounted for. Therefore we also explore the SNR for the two averaging approaches after correcting for the noise bias and, provided that the phases of the phasors are accurately aligned prior to averaging, then find that complex phasor averaging always leads to higher SNR than magnitude averaging.

Polarization-sensitive imaging with simultaneous bright- and dark-field optical coherence tomography.

We present a polarization-sensitive (PS) extension for bright- and dark-field (BRAD) optical coherence tomography imaging. Using a few-mode fiber detection scheme, the light backscattered at different angles is separated, and the BRAD images of tissue scattering are generated. A calibration method to correct for the fiber birefringence is proposed. Since particle scattering profiles are polarization dependent, a PS detection extends the capabilities for investigating the scattering properties of biological tissues. Both phantoms consisting of different-sized microparticles and a brain tissue specimen were imaged to validate the system performance and demonstrate the complementary image contrast.

Hyperspectral optical coherence tomography for in vivo visualization of melanin in the retinal pigment epithelium.

Previous studies for melanin visualization in the retinal pigment epithelium (RPE) have exploited either its absorption properties (using photoacoustic tomography or photothermal optical coherence tomography [OCT]) or its depolarization properties (using polarization sensitive OCT). However, these methods are only suitable when the melanin concentration is sufficiently high. In this work, we present the concept of hyperspectral OCT for melanin visualization in the RPE when the concentration is low. Based on white light OCT, a hyperspectral stack of 27 wavelengths (440-700 nm) was created in post-processing for each depth-resolved image. Owing to the size and shape of the melanin granules in the RPE, the variations in backscattering coefficient as a function of wavelength could be identified-a result which is to be expected from Mie theory. This effect was successfully identified both in eumelanin-containing phantoms and in vivo in the low-concentration Brown Norway rat RPE.

Revealing brain pathologies with multimodal visible light optical coherence microscopy and fluorescence imaging.

We present a multimodal visible light optical coherence microscopy (OCM) and fluorescence imaging (FI) setup. Specification and phantom measurements were performed to characterize the system. Two applications in neuroimaging were investigated. First, curcumin-stained brain slices of a mouse model of Alzheimer's disease were examined. Amyloid-beta plaques were identified based on the fluorescence of curcumin, and coregistered morphological images of the brain tissue were provided by the OCM channel. Second, human brain tumor biopsies retrieved intraoperatively were imaged prior to conventional neuropathologic work-up. OCM revealed the three-dimensional structure of the brain parenchyma, and FI added the tumor tissue-specific contrast. Attenuation coefficients computed from the OCM data and the florescence intensity values were analyzed and showed a statistically significant difference for 5-aminolevulinic acid (5-ALA)-positive and -negative brain tissues. OCM findings correlated well with malignant hot spots within brain tumor biopsies upon histopathology. The combination of OCM and FI seems to be a promising optical imaging modality providing complementary contrast for applications in the field of neuroimaging.

Synthetic subaperture-based angle-independent Doppler flow measurements using single-beam line field optical coherence tomography in vivo.

We demonstrate a synthetic subaperture-based angle-independent Doppler flow calculation, using a line field spectral domain optical coherence tomography system. The high speed of the system features a high phase stability over the volume, which is necessary to apply synthetic subapertures in the aperture plane. Thus, the flow component for each subaperture can be reconstructed in postprocessing. Capillary phantom and in vivo retinal imaging experiments were performed to validate and demonstrate angle-independent Doppler flow calculation.

Evaluating cellularity and structural connectivity on whole brain slides using a custom-made digital pathology pipeline.

AIMS: In brain research, the histopathological examination of coronar whole-brain slides provides important insights into spatial disease characteristics. Regarding brain tumor research, this enables visualization of tumor heterogeneity, infiltration patterns and the relationship with the surrounding brain parenchyma. The precise correlation between radiological imaging and post-mortem brains is of special interest. NEW METHOD: We developed a wide-field slide scanner, comprising a microscope, a high-precision remotely controllable x-y-stage, a camera and a computer workstation, for automatically scanning uncommonly large formats. We analyzed whole brain slides of three patients and constructed cellularity heatmaps and fiber tract maps using a custom-made image processing pipeline. RESULTS: The obtained cellularity heatmaps allow for distinguishing compact tumor (5714 ± 1786 cells/mm², mean ± standard deviation) from white matter (3581 ± 828 cells/mm²) and grey matter (2473 ± 716 cells/mm²). Compared to magnetic resonance imaging, the proposed histopathological work-up (i) reveals a larger zone of tumor infiltration around the compact tumor areas and (ii) shows how pre-existing tracts are displaced by the tumor bulk. Moreover, we highlight differences in the histological tumor growth pattern of two different radiological progression subtypes. COMPARISON WITH EXISTING METHOD(S): Compared to existing (commercial) solutions, our slide scanning solution is adaptable and cost-efficient. Moreover, we showcase potential clinical applications by mapping whole brain histology to magnetic resonance imaging. CONCLUSIONS: We herein provide instructions on how to (i) construct a custom-built slide scanner capable of scanning arbitrary slide formats, (ii) automatically evaluate the cell density and (iii) perform fiber tracking on whole brain slides.

Polarization-sensitive optical coherence tomography imaging of the anterior mouse eye.

Polarization-sensitive optical coherence tomography (PS-OCT) enables noninvasive, high-resolution imaging of tissue polarization properties. In the anterior segments of human eyes, PS-OCT allows the visualization of birefringent and depolarizing structures. We present the use of PS-OCT for imaging the murine anterior eye. Using a spectral domain PS-OCT setup operating in the 840-nm regime, we performed in vivo volumetric imaging in anesthetized C57BL/6 mice. The polarization properties of murine anterior eye structures largely replicated those known from human PS-OCT imagery, suggesting that the mouse eye may also serve as a model system under polarization contrast. However, dissimilarities were found in the depolarizing structure of the iris which, as we confirmed in postmortem histological sections, were caused by anatomical differences between both species. In addition to the imaging of tissues in the anterior chamber and the iridocorneal angle, we demonstrate longitudinal PS-OCT imaging of the murine anterior segment during mydriasis as well as birefringence imaging of corneal pathology in an aged mouse.