Review for Disease of the Year Clinical Features and Ocular Imaging in Intermediate Uveitis and Pars Planitis.

Intermediate uveitis is a relatively common form of intraocular inflammation that can be seen at any age. The vitreous is the primary site of inflammation; and the presence of snowballs or snowbank defines its subtype, pars planitis. Since it is a clinical diagnosis, it is important to recognize the typical clinical features and associated ocular complications. Recent advances in ocular imaging have made significant contributions to the clinical appraisal and studies of intermediate uveitis. This narrative review includes clinical signs, ocular complications, and ocular imaging of intermediate uveitis and pars planitis.

Optical coherence tomography imaging of the peripheral retina.

This review critically assesses the applicability of retinal periphery imaging technology, scrutinizing its practical limitations and potential advancements within ophthalmology. It underscores the significant costs and the need to evaluate the clinical utility of optical coherence tomography (OCT) and OCT angiography devices. It emphasizes how clinicians should consider their practice-specific use-cases while investing in devices with capabilities like ultra-widefield OCT, autofluorescence imaging, and angiography. The paper also highlights the challenges associated with image acquisition, such as artifact management and patient cooperation for extended fixation periods. This review outlines the utility of these modalities in various retinal pathologies, as well as their contribution to telemedicine and personalized care, facilitated by artificial intelligence for improved image processing, quantification, and interpretation. These techniques potentially offer a more comprehensive understanding of peripheral retinal conditions and associated pathologies, thus influencing clinical decision-making, particularly in remote regions with limited specialist access.

The protocol for an observational Australian cohort study of CADASIL: The AusCADASIL study.

Introduction: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a rare genetic condition with a broad phenotypic presentation. This study aims to establish the first Australian cohort of individuals affected by CADASIL (AusCADASIL) and examine its clinical features and longitudinal course, and to investigate neuroimaging and blood biomarkers to assist in early diagnosis and identify disease progression. Methods: Participants will be recruited from six study centres across Australia for an observational study of CADASIL. We aim to recruit 150 participants with diagnosed CADASIL, family history of CADASIL or suspected CADASIL symptoms, and 150 cognitively normal NOTCH3 negative individuals as controls. Participants will complete: 1) online questionnaires on medical and family history, mental health, and wellbeing; 2) neuropsychological evaluation; 3) neurological examination and brain MRI; 4) ocular examination and 5) blood sample donation. Participants will have annual follow-up for 4 years to assess their progression and will be asked to invite a study partner to corroborate their self-reported cognitive and functional abilities.Primary outcomes include cognitive function and neuroimaging abnormalities. Secondary outcomes include investigation of genetics and blood and ocular biomarkers. Data from the cohort will contribute to an international consortium, and cohort participants will be invited to access future treatment/health intervention trials. Discussion: AusCADASIL will be the first study of an Australian cohort of individuals with CADASIL. The study will identify common pathogenic variants in this cohort, and characterise the pattern of clinical presentation and longitudinal progression, including imaging features, blood and ocular biomarkers and cognitive profile.

A Pilot Study to Evaluate the Usefulness of Optical Coherence Tomography for Staging Iris Pigmented Lesions in Cats.

This study investigated the utility of optical coherence tomography (OCT) for staging iris pigmented lesions in cats. Eighteen cats that underwent OCT examination for unilateral iris pigmented lesion were included. The cats were either suspected of melanosis due to clinical features (n = 8) or had been definitively diagnosed through histopathology with iris melanosis (n = 3), early feline diffuse iris melanoma (FDIM) (n = 4), or mid-stage or advanced FDIM (n = 3). From OCT images, mean iris thickness (MIT) was measured, and the ratio of pigmented lesion to normal iris (PN) was calculated. OCT images depicted the entire iris layer in all eyes with suspected melanosis, iris melanosis, and early FDIM, but observing the entire lesion in mid-stage/advanced FDIM was challenging. No significant difference in MIT was observed among the groups. Conversely, PN ratio was significantly higher (p < 0.05) in early FDIM (1.29 ± 0.16) than in suspected melanosis (1.02 ± 0.10) or iris melanosis (0.99 ± 0.09). Furthermore, OCT imaging revealed hyperreflective lines in 75% of eyes with suspected melanosis and in all the eyes with iris melanosis, corresponding to the pigmented lesions. Our results demonstrate that OCT is capable of detecting subtle differences in iris thickness and features in early-stage FDIM, indicating its potential utility in distinguishing between iris melanosis and early FDIM. Further study is warranted to verify the reliability of such OCT findings.

Optical coherence tomography angiography in the diagnosis of ocular disease.

Clinical imaging provided by optical coherence tomography (OCT) and its variant, OCT-angiography (OCT-A), has revolutionised eyecare practice. The imaging techniques allow for the identification and quantification of ocular structures, supporting the diagnosis and prognosis of eye disease. In this review, an overview of the usefulness of OCT-A imaging in the diagnosis and management of a range of ocular conditions is provided when used in isolation or in combination with other imaging modalities and measures of visual function (visual field results). OCT-A imaging has the capacity to identify and quantify ocular vasculature non-invasively, thereby assisting the clinician in the diagnosis or to determine the efficacy of intervention in ocular conditions impacting retinal vasculature. Thus, additional clinically useful information can be obtained in eye diseases involving conditions such as those impacting retinal vessel occlusion, in diabetic retinopathy, inherited retinal dystrophy, age-related macular degeneration, choroidal neovascularisation and optic nerve disorders. Through a clinical case series, various ocular conditions are reviewed, and the impact of OCT-A imaging is discussed. Although OCT-A imaging has great promise and is already used in clinical management, there is a lack of set standards to characterise altered vascular features in disease and consequently for prognostication, primarily due to a lack of large-scale clinical trials and variability in OCT-A algorithms when generating quantitative parameters.

Two-Photon and Multiphoton Microscopy in Anterior Segment Diseases of the Eye.

Two-photon excitation microscopy (TPM) and multiphoton fluorescence microscopy (MPM) are advanced forms of intravital high-resolution functional microscopy techniques that allow for the imaging of dynamic molecular processes and resolve features of the biological tissues of interest. Due to the cornea's optical properties and the uniquely accessible position of the globe, it is possible to image cells and tissues longitudinally to investigate ocular surface physiology and disease. MPM can also be used for the in vitro investigation of biological processes and drug kinetics in ocular tissues. In corneal immunology, performed via the use of TPM, cells thought to be intraepithelial dendritic cells are found to resemble tissue-resident memory T cells, and reporter mice with labeled plasmacytoid dendritic cells are imaged to understand the protective antiviral defenses of the eye. In mice with limbal progenitor cells labeled by reporters, the kinetics and localization of corneal epithelial replenishment are evaluated to advance stem cell biology. In studies of the conjunctiva and sclera, the use of such imaging together with second harmonic generation allows for the delineation of matrix wound healing, especially following glaucoma surgery. In conclusion, these imaging models play a pivotal role in the progress of ocular surface science and translational research.

Anterior-Segment Optical Coherence Tomography Unlocks Novel Perspectives: Lacking Iris Anterior Limiting Layer Signal in Uveitis.

Chronic uveitis, a challenging intraocular inflammatory condition, presents complexities in diagnosis and management due to its diverse etiologies and manifestations. Anterior-segment optical coherence tomography (AS-OCT) has emerged as a pivotal tool in evaluating uveitis, offering high-resolution imaging of anterior segment structures. We present the case of a 49-year-old man diagnosed with neurosarcoidosis and chronic intermediate uveitis, where AS-OCT revealed unique findings. Clinical examination identified a Koeppe nodule. AS-OCT evaluation unveiled hyperreflectivity in the iris stroma and the adjacent nodule. Notably, AS-OCT documented the absence of the hyperreflective anterior limiting layer signal, a novel observation in uveitis assessment. This unprecedented finding underscores the significance of AS-OCT in elucidating uveitis pathophysiology and emphasizes its potential in refining diagnostic and therapeutic strategies for this complex ocular condition.

Non-Invasive High-Resolution Imaging of In Vivo Human Myelinated Axons.

This work aims to reveal the microscopic (2-3 micrometer resolution) appearance of human myelinated nerve fibers in vivo for the first time. We analyzed the myelinated retinal nerve fibers of a male patient without other neurological disorders in a non-invasive way using the transscleral optical phase imaging method with adaptive optics. We also analyzed the fellow eye with non-myelinated nerve fibers and compared the results with traditional ocular imaging methods such as optical coherence tomography. We documented the microscopic appearance of human myelin and myelinated axons in vivo. This method allowed us to obtain better details than through traditional ocular imaging methods. We hope these findings will be useful to the scientific community to evaluate neuro-retinal structures through new imaging techniques and more accurately document nerve anatomy and the pathophysiology of this disease.

Progression of Rare Inherited Retinal Dystrophies May Be Monitored by Adaptive Optics Imaging.

Inherited retinal dystrophies (IRDs) are bilateral genetic conditions of the retina, leading to irreversible vision loss. This study included 55 eyes afflicted with IRDs affecting the macula. The diseases examined encompassed Stargardt disease (STGD), cone dystrophy (CD), and cone-rod dystrophy (CRD) using adaptive optics (Rtx1™; Imagine Eyes, Orsay, France). Adaptive optics facilitate high-quality visualisation of retinal microstructures, including cones. Cone parameters, such as cone density (DM), cone spacing (SM), and regularity (REG), were analysed. The best corrected visual acuity (BCVA) was assessed as well. Examinations were performed twice over a 6-year observation period. A significant change was observed in DM (1282.73/mm2 vs. 10,073.42/mm2, p< 0.001) and SM (9.83 µm vs. 12.16 µm, p< 0.001) during the follow-up. BCVA deterioration was also significant (0.16 vs. 0.12, p = 0.001), albeit uncorrelated with the change in cone parameters. No significant difference in REG was detected between the initial examination and the follow-up (p = 0.089).

Optical Coherence Tomography: Imaging Visual System Structures in Mice.

Optical coherence tomography (OCT) enables micron-scale resolution of structural anatomy, thereby making OCT a valuable tool for addressing ophthalmologic and neurologic inquiries. Although the murine eye and its structures are very small and offers challenges for OCT imaging, OCT can be used to monitor retinal layer thickness in healthy and diseased retinas in murine lines in vivo longitudinally. Thus, OCT can provide insights into disease severity and treatment efficacy. This chapter describes the use of OCT as a powerful non-invasive imaging technology for high-resolution retinal imaging and retinal thickness quantification in rodents.

Akimba Proliferative Diabetic Retinopathy Model: Understanding Molecular Mechanism and Drug Screening for the Progression of Diabetic Retinopathy.

As the prevalence of diabetes has reached epidemic proportions worldwide, diabetic retinopathy incidence is increasing rapidly. An advanced diabetic retinopathy (DR) stage can lead to a sight-threatening form. There is growing evidence showing diabetes causes a range of metabolic changes that subsequently lead to pathological modifications in the retina and retinal blood vessels. To understand the complex mechanism of the pathophysiology of DR, a precise model is not readily available. By crossbreeding the Akita and Kimba strains, a suitable proliferative DR model was acquired. This new Akimba strain manifests marked hyperglycemia and vascular changes, which resemble the early and advanced stage of DR.Here, we describe the breeding method, colony screening for experiments, and imaging techniques widely used to investigate the DR progression in this model. We elaborate step-by-step protocols to set up and perform fundus, fluorescein angiography, optical coherence tomography, and optical coherence tomography-angiogram to study retinal structural changes and vascular abnormalities. In addition, we show a method to label the leukocytes with fluorescence and laser speckle flowgraphy to examine the inflammation in the retina and retinal vessel blood flow speed, respectively. Lastly, we describe electroretinogram to evaluate the functional aspect of the DR transformations.

Renally Clearable Ultraminiature Chain-Like Gold Nanoparticle Clusters for Multimodal Molecular Imaging of Choroidal Neovascularization.

Currently, available gold nanoparticles (GNPs) typically accumulate in the liver and spleen, leading to concerns for their long-term biosafety. To address this long-standing problem, ultraminiature chain-like gold nanoparticle clusters (GNCs) are developed. Via self-assembly of 7-8 nm GNP monomers, GNCs provide redshifted optical absorption and scattering contrast in the near-infrared window. After disassembly, GNCs turn back to GNPs with a size smaller than the renal glomerular filtration size cutoff, allowing their excretion via urine. A one-month longitudinal study in a rabbit eye model demonstrates that GNCs facilitate multimodal molecular imaging of choroidal neovascularization (CNV) in vivo, non-invasively, with excellent sensitivity and spatial resolution. GNCs targeting αv ß3  integrins enhance photoacoustic and optical coherence tomography (OCT) signals from CNV by 25.3-fold and 150%, respectively. With excellent biosafety and biocompatibility demonstrated, GNCs render a first-of-its-kind nanoplatform for biomedical imaging.

Fibrosis in neovascular age-related macular degeneration: A review of definitions based on clinical imaging.

Despite the success of antiangiogenic therapy in controlling exudation in neovascular age-related macular degeneration (nAMD), the involvement of the outer retina in fibrosis results in gradual vision loss over time. The development of drugs that prevent or ameliorate fibrosis in nAMD requires that it is accurately detected and quantified with reliable endpoints and identification of robust biomarkers. Achievement of such an aim is currently challenging due to the lack of a consensus definition of fibrosis in nAMD. As a first step towards the establishment of a clear definition of fibrosis, we provide an extensive overview of the imaging modalities and criteria used to characterize fibrosis in nAMD. We observed variety in the selection of individual and combinations of imaging modalities, and criteria for detection. We also observed heterogeneity in classification systems and severity scales for fibrosis. The most commonly used imaging modalities were color fundus photography, fluorescein angiography and optical coherence tomography (OCT). A multimodal approach was frequently utilized. Our review suggests that OCT offers a more detailed, objective and sensitive characterization than color fundus photography/fluorescein angiography. Thus, we recommend it as a primary modality for fibrosis evaluation. This review provides a basis for future discussions to reach a consensus definition using standardized terms based on a detailed characterization of fibrosis, its presence and evolution, and taking into consideration impact on visual function. Achieving this goal is of paramount importance for the development of antifibrotic therapies.

Endpoints for clinical trials in ophthalmology.

With the identification of novel targets, the number of interventional clinical trials in ophthalmology has increased. Visual acuity has for a long time been considered the gold standard endpoint for clinical trials, but in the recent years it became evident that other endpoints are required for many indications including geographic atrophy and inherited retinal disease. In glaucoma the currently available drugs were approved based on their IOP lowering capacity. Some recent findings do, however, indicate that at the same level of IOP reduction, not all drugs have the same effect on visual field progression. For neuroprotection trials in glaucoma, novel surrogate endpoints are required, which may either include functional or structural parameters or a combination of both. A number of potential surrogate endpoints for ophthalmology clinical trials have been identified, but their validation is complicated and requires solid scientific evidence. In this article we summarize candidates for clinical endpoints in ophthalmology with a focus on retinal disease and glaucoma. Functional and structural biomarkers, as well as quality of life measures are discussed, and their potential to serve as endpoints in pivotal trials is critically evaluated.

Functional Carbon Quantum Dots for Ocular Imaging and Therapeutic Applications.

Carbon quantum dots (CDs) are a class of emerging carbonaceous nanomaterials that have received considerable attention due to their excellent fluorescent properties, extremely small size, ability to penetrate cells and tissues, ease of synthesis, surface modification, low cytotoxicity, and superior water dispersion. In light of these properties, CDs are extensively investigated as candidates for bioimaging probes, efficient drug carriers, and disease diagnostics. Functionalized CDs represent a promising therapeutic candidate for ocular diseases. Here, this work reviews the potential use of functionalized CDs in the diagnosis and treatment of eye-related diseases, including the treatment of macular and anterior segment diseases, as well as targeting Aß amyloids in the retina.

Federated Learning in Ocular Imaging: Current Progress and Future Direction.

Advances in artificial intelligence deep learning (DL) have made tremendous impacts on the field of ocular imaging over the last few years. Specifically, DL has been utilised to detect and classify various ocular diseases on retinal photographs, optical coherence tomography (OCT) images, and OCT-angiography images. In order to achieve good robustness and generalisability of model performance, DL training strategies traditionally require extensive and diverse training datasets from various sites to be transferred and pooled into a "centralised location". However, such a data transferring process could raise practical concerns related to data security and patient privacy. Federated learning (FL) is a distributed collaborative learning paradigm which enables the coordination of multiple collaborators without the need for sharing confidential data. This distributed training approach has great potential to ensure data privacy among different institutions and reduce the potential risk of data leakage from data pooling or centralisation. This review article aims to introduce the concept of FL, provide current evidence of FL in ocular imaging, and discuss potential challenges as well as future applications.

Ophthalmic imaging in diabetic retinopathy: A review.

Retinal imaging has been a key tool in the diagnosis, evaluation, management and documentation of diabetic retinopathy (DR) and diabetic macular oedema (DMO) for many decades. Imaging technologies have rapidly evolved over the last few decades, yielding images with higher resolution and contrast with less time, effort and invasiveness. While many retinal imaging technologies provide detailed insight into retinal structure such as colour reflectance photography and optical coherence tomography (OCT), others such as fluorescein or OCT angiography and oximetry provide dynamic and functional information. Many other novel imaging technologies are in development and are poised to further enhance our evaluation of patients with DR.

Normative data of retinal arteriolar and venular calibre measurements determined using confocal scanning laser ophthalmoscopy system - Importance and implications for study of cardiometabolic disorders.

Purpose: To determine and validate retinal vascular caliber measurements by using the confocal scanning laser ophthalmoscopy system. Retinal vasculature changes are often regarded as clinical markers for systemic disease. Methods: It was a prospective observational study conducted on 600 eyes of 300 normal subjects with no systemic or ocular illness from January 1, 2016 to June 30, 2017 in a tertiary referral eye center. Non-mydriatic infrared reflectance, blue reflectance, and blue peak blue autofluorescence fundus imaging were done on the confocal scanning laser ophthalmoscopy system. The dimensions of the retinal vessels were measured using inbuilt calipers at 1800 µm from the center of the optic disc. Internal and external dimensions were measured. Observer variation and its comparison using Image J software were assessed. Results: The median age was 29 years (18-50 years). Mean internal and external diameters for arterioles were 85.1 ± 12.4 µm and 105.0 ± 12.0 µm, and for venules were 133.8 ± 16.6 µm and 145.4 ± 16.1 µm, respectively. The mean internal and external wall thicknesses were 19.7 ± 8.0 µm and 11.0 ± 5.6 µm, and wall thickness-to-lumen ratios were 0.3 ± 0.1 and 0.1 ± 0.1, respectively. Arteriolar-to-venular ratio for lumen and vessel was 0.66 ± 0.1 and 0.74 ± 0.1, respectively. There was no statistically significant difference between age groups. Both inter- and intra-observer reproducibility was >95%. The Bland-Altman plot showed that the difference between measurements using both confocal scanning laser ophthalmoscopy and Image J software lies within the limits of agreement approximately 95% of the time. Conclusion: This is the first effort to develop a normative database by using a simple non-invasive confocal scanning laser ophthalmoscopy system with high observer reproducibility.