Ophthalmic Diagnostic Imaging: Retina
The diagnostic efficacy and workflow of retinal diseases has been largely improved by the development of optical coherence tomography (OCT). The availability of cross-sectional, high-resolution images is critical for the assessment of several features ranging from early subtle changes to late severe disruption of the anatomy of the retina. The widespread clinical use of OCT enhances the accurate diagnosis of different retinal and choroidal diseases, including age-related macular degeneration, diabetic retinopathy, vascular occlusions, inflammatory diseases, hereditary diseases. OCT imaging further allows for accurate monitoring of disease progression and treatment efficacy, like anti-vascular endothelium growth factor (VEGF) therapy.
KeywordsAge-related macular degeneration Diabetic retinopathy Macula Myopia Optical coherence tomography Retina Retinal vein occlusion Screening Tumor Uveitis
The first commercially available OCT devices were based on time-domain detection that featured rather low scan rates of 400 A-scans per second leading to possible errors associated with eye motion and reduced measurement accuracy as well as reproducibility (Fig. 4.1a). Nevertheless, it became widely accepted for the assessment of various retinal diseases [3, 4]. Subsequently, the spectral domain (SD) and swept source (SS) imaging technologies have dramatically improved sampling speed and signal-to-noise ratio by using a high-speed spectrometer that measures light interferences from all time delays simultaneously or a tunable frequency swept laser light source (that sequentially emits various frequencies in time) and photodetectors instead of a spectrometer to measure the interference, respectively .
For SD-OCT devices, technical improvements has enabled scan rates up to 250,000 Hz in commercially available devices [6, 7]. The Spectralis® device by Heidelberg Engineering (Heidelberg, Germany) was the first commercially available SD-OCT device that combines the OCT technique with a confocal scanning laser ophthalmoscope (cSLO) using a near-infrared laser light source (815 nm, Fig. 4.1b). The cSLO features simultaneous eye-tracking based on a retinal fundus reflectivity image, enabling accurate and repeatable alignment of OCT images, advanced noise reduction and an auto rescan function for precise placement of follow-up scans .
Commercial SS-OCT devices employ a longer wavelength (>1050 nm) laser light source and have scan rates as fast as 200,000 Hz. The longer wavelengths is thought to enhance visualization of subretinal tissue and choroidal structures (Fig. 4.1c) [9, 10, 11, 12, 13]. Similar effects are aspired by techniques like image averaging and/or enhanced depth imaging (Fig. 4.1d).
The astounding clinical implications and the numerous potential research applications have led to the rapid acceptance and integration of OCT and cSLO technology in the ophthalmic community. Ongoing improvements of the technologies will further deepen the understanding of the physiology and pathophysiology of various retinal conditions as a prerequisite for—the development and approval of new therapeutic approaches. This chapter aims to review the role of OCT diagnostics in retinal conditions, with particular emphasis on differential diagnoses as well as monitoring of progression and therapeutic outcomes.
4.2 Application of OCT in Retinal Diagnostics
OCT technology has revolutionized modern ophthalmology during the last decades. By now, OCT is widely used in clinical practice and trials, as it is a noninvasive, quick and reproducible imaging modality. Advancements in OCT technology have improved the differential diagnosis, the knowledge of the physiopathology, and the ability to monitor disease progression as well as therapeutic effects. Diagnostic capabilities will be reviewed across a range of retinal conditions, including common diseases such as age-related macular degeneration (AMD), diabetic retinopathy, retinal vascular diseases, and rare retinal diseases including hereditary dystrophies. The depth resolution of individual retinal layers allows for localization of altered structures, enabling differentiation of diseases affecting the outer retina from pathologies that primarily impact on the inner retina. The precision and accuracy of the technology further allow for visualization and clinical assessment of subtle structural alterations or different disease stages.
4.2.1 Age-Related Macular Degeneration
In the developed world, AMD is the leading cause of irreversible visual impairment in adults with an age over 60 years . OCT imaging allows for a 3-dimensional visualization and assessment of the integrity or disruption of each individual retinal layer, providing a precise detection of early changes, both in the atrophic and the neovascular spectrum of the disease .
Cuticular drusen were first described as ‘basal laminar drusen’ by Gass in 1974 as numerous, small, round, uniformly sized, yellow, sub-RPE lesions that show early hyperfluorescence on fluorescein angiography resulting in a “starry night” appearance [21, 22]. The ultrastructural and histopathological characteristics of cuticular drusen are similar to those of hard drusen, however, their lifecycle and macular complications are more comparable with those of soft drusen . On OCT, cuticular drusen are classically described as a saw-tooth elevation of the RPE with rippling (and occasional disruption) of the overlying ellipsoid zone band and the external limiting membrane (Fig. 4.2b) .
Reticular pseudodrusen were first described in 1990 as a peculiar yellowish pattern in the fundus of AMD patients, and in 1991 as an ill-defined network of broad interlacing ribbons [25, 26]. OCT enabled an improved characterization of reticular pseudodrusen (Fig. 4.2c) showing that these lesions correspond to granular hyperreflective material between the RPE and the ellipsoid zone band. As a result, the term ‘subretinal drusenoid deposits’ has been proposed .
It has been shown that drusen diameter and volume are a significant risk factor for progression to advanced AMD. Therefore, early and intermediate AMD is differentiated inter alia by smaller and larger than 125 μm drusen size, respectively . As manual analysis of drusen on color fundus images is not reliable and practical, efforts are underway to use OCT for automated detection and quantification of drusen size, area, and volume. This may help to identify patients at high risk of disease progression and to institute appropriate upcoming prophylactic interventions .
4.2.2 Diabetic Retinopathy and Macular Edema
As macular edema is one of the major complications of diabetic retinopathy, well treatable with laser treatment, anti-angiogenic, steroid therapy or a combination of those, a reliable diagnostic and treatment monitoring module is needed . The combination of OCT imaging and fluorescence angiography has become the gold standard imaging strategy in diabetic macular edema, providing high-resolution 3-dimensional retinal information [45, 46, 47].
4.2.3 Retinal Vascular Occlusions and Other Vascular Conditions
4.2.4 Central Serous Chorioretinopathy and Related Diseases
4.2.5 Pathologic Myopia
4.2.6 Inherited Retinal Diseases and Other Macular Conditions
Another disease that might be associated with NV is macular telangiectasia type 2. Using OCT thickness measurements (often in combination with fluorescein angiography), NV lesions are differentiable from degenerative changes that are regularly seen within the natural progression of this disease .
Apart from evaluation of NV and treatment effects, OCT has a significant value in the assessment and differential diagnosis of inherited retinal diseases. Recent studies using OCT have provide a new insight regarding the amount of choroidal involvement in the pathogenesis of retinitis pigmentosa, pseudoxanthoma elasticum (PXE) and Stargardt disease [54, 55, 56]. The latter even provided evidence for a diffusible factor from the RPE sustaining the choroidal structure.
4.2.7 Intraocular Tumors
4.2.8 Inflammatory Diseases, Intermediate and Posterior Uveitis
Intermediate and posterior uveitis may be associated with the development of macular edema, vascular changes in the retina or the choroid, and/or inflammatory lesions. The detection of all these lesions has been enhanced with the use of OCT scans, while providing valuable and reliable information for the challenging follow-up of these patients .
4.2.9 Vitreoretinal Interface
Detection and detailed evaluation of macular holes, epiretinal membranes and tractional changes have been facilitated by OCT images. The International Vitreomacular Traction Study Group classification provided new definitions for vitreomacular adhesion and vitreomacular traction using OCT images . Both can be classified as broad (area of vitreous attachment >1500 μm) or focal (area of vitreous attachment ≤1500 μm). The presence of perifoveal vitreous detachment associated with posterior cortical vitreous attachment within the central 3 mm may be due to vitreomacular adhesion in the absence of retinal abnormalities, or vitreomacular traction when associated with intraretinal cysts, subretinal fluid, or flattening of the foveal contour, but in the absence of full-thickness interruption of all retinal layers .
Full-thickness macular holes are defects of all retinal layers from the inner limiting membrane (ILM) to the photoreceptors with preservation of the RPE located at the level of the fovea. Macular holes are classified as small (≤250 μm), medium (250–400 μm), or large (>400 μm) based on the size (minimum hole width). Visual outcomes of these cases are related to the size of the hole. A lamellar hole is a partial defect with preservation of the photoreceptors. Macular pseudoholes present as changes in the foveal contour that mimic a lamellar macular hole, without retinal layer defects .
Finally, OCT scans allow for visualization and detection of epiretinal membranes as hyperreflective tissue attached to the inner surface of the retina. The location, extension and the evaluation of the outer retinal layers as well as a better planning of the surgical technique is often facilitated by OCT imaging.
4.3 Pitfalls of OCT in Retinal Diagnostics
4.3.1 Acquisition Protocol
Recent advances have led to reliable and fast acquisition of OCT images, providing a broad application in both clinical and experimental settings . The varying indications for use of OCT technology has raised questions concerning the location, density and interpretation of the scans. While the flexibility of scanning is important in order to optimize the scan protocols, an increasing amount of data requires exponentially larger storage drives and fast broadband network systems .
4.3.2 Acquisition Technique
For acquisition of high-quality OCT images, parameters such as alignment of the camera, focus, detector sensitivity and signal strength are important prerequisites. Automatic registration and matching of OCT images of the same retinal location is an essential tool for monitoring subtle changes over time. The same focus should be kept between different imaging sessions and tilting of the head should be avoided during image acquisition in order to minimize artifacts or inaccuracies . Incorrect settings should be identified before a clinician interprets the results. In order to avoid misinterpretations, operators should be adequately trained and instructed to check the quality and completeness of the data directly after the recordings, as an immediate reacquisition might be possible with the subject still in front of the device .
Up to now, no common industry standard has been established for OCT imaging. In addition, device-dependent differences may also occur (e.g. in the appearance of retinal thickness), as OCT B-scans are usually displayed as stretched images in the vertical direction. Accordingly, for better comparability, the same patient should be examined with the same device platform over time. Even by simple software updates, the algorithms and definitions of the automatic segmentation lines may change and, therefore, the comparability of subsequent recordings and their evaluation may be limited .
Projection artefacts may derive from hyperreflective changes in the vitreous (e.g., floaters) or on the surface of the retina (e.g., epiretinal membranes) that may lead to suppression of structures in deeper retinal layers. In such scenarios, comparison with other imaging modalities or ophthalmoscopy is helpful. When applying automatic analysis algorithms, operators and clinicians should evaluate the segmentation of retinal boundaries in each B-scan and, if necessary, manually correct them .
The quantitative evaluation of OCT findings requires precise definition of individual parameters. To date, there is no industry standard or consensus, with different terms being used in parallel. The correct geometric location and segmentation of relevant anatomic landmarks is crucial for meaningful and correct quantitative analysis. But the definition of landmarks such as the fovea may be challenging in the presence of pathologic changes. The OCT interpretation is usually based on the 1:1 pixel presentation mode, in which the image information in the lateral compared to the anteroposterior dimension is compressed depending on the device. It was shown that the quantification of areas or distances in the 1:1 pixel presentation mode is prone to overestimation of values in the anteroposterior dimension. Therefore, measurements should be performed in the 1:1 μm presentation mode [64, 65]. Inaccuracies of measurements within B-scans may further occur if the retinal layers are not orthogonal to the laser beam. To determine correct values, measurements should always be performed parallel to the beam path. Furthermore, the method of scaling must be considered when measured values are specified in the metric system.
In conclusion, while OCT alone should not be the only basis for diagnostic and treatment recommendations, its application in daily clinical practice and for research purposes has become invaluable. It should be regarded as an additional diagnostic procedure in a multimodal imaging assessment including fundoscopy, fluorescence angiography, in association with a careful anamnesis and assessment of patient’s complaints. The latter is known to differ frequently from the severity of OCT findings. In these cases, it is more than mandatory to perform complimentary imaging and diagnostic procedures .
4.4 Summary and Outlook
Many posterior segment ocular diseases involve both the retina and the choroid as the RPE, Bruch’s membrane and the choroid represent a coadjutant functional complex . This may be particularly important in retinal disorders such as AMD, the most common cause of legal blindness in industrialized countries, characterized by abnormal extracellular material deposition either below or above the retinal pigment epithelial layer [68, 69]. Even single gene retinal dystrophies like ABCA4-related retinopathy, that primarily affects the RPE by excessive accumulation of lipofuscin, or pseudoxanthoma elasticum (PXE), which leads to a calcification of the Bruch’s membrane, have been described to reveal choroidal alterations [54, 55, 70, 71]. The combination of shorter and longer wavelength light sources within one gadget might combine the advantages attributed to SD-OCT (i.e., better resolution for the visualization of retinal layers) and SS-OCT (i.e., visualization of the choroid). This might allow for optimum visualization of intraretinal as well as subretinal structures without temporal or spatial separation. In 2017, the first OCT device using different wavelengths of laser light sources was built at the Technical University of Biel and University of Basel, Switzerland. First clinical data and value with the device remain to be demonstrated as well as the possible commercial feasibility.
Since the beginning, continuous improvements have been made to scan rates as well as axial and lateral resolution. Commercial OCT systems achieve scan rates up to 250,000 Hz and an axial resolution of under 7 μm [1, 6]. Faster imaging improves patient comfort and reduces acquisition time, increasing the likelihood of better scan quality. It also enables volumetric as well as 3-dimensional analysis of various pathological features, including choroidal neovascularization and intraretinal fluid. The latter might help in monitoring disease progression and treatment effects . Furthermore, higher quality by improved resolution will further enhance automated segmentation and analysis, a field of rising importance in the view of growing applications of artificial intelligence and machine learning in ophthalmology [73, 74, 75].
During the last decades, OCT technology has revolutionized the retina subspecialty field. OCT imaging now plays a pivotal role in understanding, diagnosing, and monitoring natural history and treatment effects in AMD, diabetic retinopathy, retinal vascular diseases, CSCR, high myopia and many other retinal and choroidal conditions. High resolution and high-quality multimodal assessment in combination with continuous innovations of the OCT imaging modality are aiming to further improve the clinical assessment of retinal and choroidal diseases.
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