|SYMPOSIUM - DIABETIC RETINOPATHY UPDATE
|Year : 2014 | Volume
| Issue : 1 | Page : 19-25
Ocular imaging in diabetic retinopathy
Quresh A Mohamed
Department of Ophthalmology, Gloucestershire Hospitals, NHS Foundation Trust, Glos Royal Hospital, Gloucestershire, England, United Kingdom
|Date of Web Publication||3-Mar-2015|
Quresh A Mohamed
Department of Ophthalmology, Gloucestershire Hospitals, NHS Foundation Trust, Glos Royal Hospital, Gloucestershire GL1 3NN, England
Source of Support: None, Conflict of Interest: None
Imaging of the fundus has revolutionized our understanding of the pathogenesis of diabetic retinopathy (DR), allowed standardized grading and follow-up with the ability to evaluate treatments in randomized clinical studies. Ocular imaging provides the tools for screening of diabetic individuals to detect and treat changes before vision loss. Modern instruments allow rapid in vivo imaging of the diabetic fundus using multiple modalities with higher resolution. Images can be transmitted, manipulated, analyzed, and graded with increasing ease. These imaging techniques are now entwined in the paradigms for newer treatments for DR. This paper aimed to provide a brief overview of current imaging modalities including conventional and digital fundus imaging, scanning laser ophthalmoscopy, fluorescein angiography, wide-field retinal imaging, and optical coherence tomography. Future developments in these imaging techniques are discussed.
Keywords: Confocal scanning ophthalmoscopy, diabetic macular edema, diabetic retinopathy, fluorescein angiography, imaging, optical coherence tomography, wide field imaging
|How to cite this article:|
Mohamed QA. Ocular imaging in diabetic retinopathy. Egypt Retina J 2014;2:19-25
| Introduction|| |
It is estimated that almost one in ten individuals in the world will be diabetic by 2030.  The rising tide of diabetes and its associated complications is one of the major healthcare challenges in countries rich and poor. Diabetic retinopathy (DR), a specific microvascular complication of diabetes is the commonest cause of blindness in working age adult's worldwide.  Although the prevalence of diabetes continues to increase, the proportion of diabetics with sight threatening retinopathy is reducing in many regions.  The drop in blind registration among diabetics is in part due to better patient education with tighter glycemic, blood pressure, and lipid control.  However, new advances in ocular imaging have played a vital role.
Imaging of the fundus has revolutionized our understanding of the pathogenesis of DR, allowed standardized grading and follow-up with the ability to evaluate treatments in randomized clinical studies. Ocular imaging provides the tools for screening of diabetic individuals to detect and treat changes before vision loss.
Modern instruments allow rapid in vivo imaging of the diabetic fundus using multiple modalities with higher resolution. Images can be transmitted, manipulated, analyzed, and graded with increasing ease. These imaging techniques are now entwined in the paradigms for newer treatments for DR.
This paper aimed to provide a brief overview of current imaging modalities, and a glimpse at upcoming advances.
| Fundus Photography and Angiography|| |
Historically, retinal abnormalities were depicted by talented medical illustrators.  The advent of photography provided a reliable way to document the fundus in diabetics and chart progression of changes with time. Conventional or film-based cameras use thin plastic covered in a very thin light-sensitive layer consisting billions of sub-micron sized silver halide grains. When one of these grains meets photons of light, a small amount of silver is created. Addition of spectral sensitizers and different silver halides can make the grains more sensitive to blue, green, or red light. Addition of other compounds can increase the light sensitivity of these grains and thus the speed of the film (ISO rating). Multiple thin layers often including gelatine can be sandwiched together to create a film able to image in color at various light conditions and speeds. When the camera shutter is opened, light reflected back from the retina forms a latent image on the film. The more photons or light there on any area of film, the more silver is created. Developing the film by adding developing solution converts any silver halide to silver. This happens much more rapidly in areas where there is already silver present (as silver catalyzes this reaction). Stopping this process at the key moment creates a negative viewable image.
Unlike conventional film, digital imaging stores the image data as a series of numbers. This allows easy accurate duplication, storage, and transmission of images by phone, satellite, cable, electronic storage media or online. Instead of film, digital cameras have sensors that convert light into electrical charges. The image sensor employed by many fundus digital cameras is a charge-coupled device. This sensor converts the light into electrons/voltage, it reads the value (accumulated charge) of each cell in the image. The analog to digital converter then turns each areas value into a digital value by measuring the amount of charge at each photosite and converting that measurement to binary form. This average area is called a photoelement or pixel. The more you split the photo (more pixels), the greater the resolution of the final image.
It can be difficult to accurately compare the resolution of images from digital and conventional film. A good quality conventional film can provide images with a much greater clarity in terms of retinal structures, vascular details than most conventional digital fundus cameras. An image quality with 1024 × 1024 pixels is thought to be adequate to reproduce most of the details of the capillary retinal network seen in conventional film.  Higher resolution images contain more pixels and data points, allow greater magnification without loss of image quality but also require greater storage space and longer time to transmit data over telecommunication or computer networks. The resolution often needed depends on intended use of images. National guidelines and recommendations exist for resolutions needed to detect changes for diabetic eye screening.  Many systems allow various resolutions of images to be obtained.
One of the major advances in diabetic care is the introduction of systematic photographic screening of diabetics. DR is the largest preventable cause of vision loss in working-aged adults. In the UK, the National Health Service Diabetic Eye Screening Program introduced in 2003 invites approximately 2.5 million people for screening every year. Of these, >74,000 were referred to hospital eye services for further investigation in 2013, which resulted in around 4600 diabetic patients being treated to help prevent vision loss.  Before the launch of the diabetic eye program, less than half of the people with diabetes had regular eye screening and even amongst patients screened many were reviewed using handheld ophthalmoscopes with limited view of the fundus and variable quality.
Confocal scanning laser ophthalmoscopy (cSLO) uses laser light instead of a bright flash of white light to illuminate the retina. A focused laser beam scans across the fundus illuminating successive single points in a raster pattern. The reflected light is captured through a small aperture (a confocal pinhole). The confocal pinhole suppresses light reflected or scattered from outside of the focal plane, which otherwise would blur the image. The result is a sharp, high-contrast image of the object layer located at the focal plane.
The advantages of using cSLO over traditional fundus photography include improved image quality, small depth of focus, suppression of scattered light, patient comfort through less bright light, three-dimensional imaging capability, video capability, and effective imaging of patients who do not dilate well. Since diabetics typically do not dilate well cSLO imaging can often produce superior images to conventional cameras.
Some cSLO devices obtain images with multiple lasers typically green and red in the Optos systems and blue, green and infrared in the Heidelberg multicolor providing a pseudo color image. These images can be viewed separately and can provide additional information on changes at various retinal layers; in diabetes this can be helpful identifying areas of previous macular laser treatment and retinal pigment epithelium (RPE) changes.
Since its introduction in the early 1960's, fluorescein angiography (FA) has become an essential tool in the understanding, diagnosis and treatment of retinal disorders including DR. A specialized fundus camera or scanning laser ophthalmoscope fitted with excitation and barrier filters is used captures a sequence of photographs or video image of the retina following an intravenous injection of fluorescein sodium. Blue light (wavelength 465-490 nm) (from laser or white light passed through a blue filter) is used to excite unbound fluorescein molecules. These molecules fluoresce, emitting light with a longer wavelength in the yellow-green spectrum (520-530 nm). A barrier filter blocks any reflected light so that the images capture only light emitted from the fluorescein. In DR, the angiogram is useful in identifying the extent of ischemia, the location of microaneurysms (MA), the presence of neovascularization, and the extent of macular edema.
The earliest visible signs in nonproliferative diabetic retinopathy (NPDR) are MA and retinal hemorrhages. With increasing ischemia, cotton wool spots, venous beading, and intraretinal microvascular abnormalities (IRMA) develop (moderate/severe NPDR).
Vision loss is primarily from the development of abnormal retinal new vessels (NV) (proliferative DR), which can lead to hemorrhage, fibrosis, traction and retinal detachment. Diabetic macular edema (DMO), which can occur at any stage of DR, is characterized by increased vascular permeability, central retinal thickening, and the deposition of hard exudates.
During FA, MA appears as small hyperfluorescent dots. Due to structural alterations in the walls of the MA, fluorescein escapes during the FA to stain the retinal tissue [Figure 1]. FA shows many more MAs than can be seen ophthalmoscopically and can differentiate MA from small retinal hemorrhages.
|Figure 1: Fluorescein angiography image of the eye with diabetic maculopathy showing central microaneurysms adjacent to the foveal avascular zone with some associated leak. Early shots or videos of initial transit of fluorescein dye can show detailed structure and damage to foveal avascular|
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Hard exudates and hemorrhages can mask underlying choroidal fluorescence. Loss of perifoveal capillaries can cause an angiographically visible enlargement of foveal avascular zone. The central capillary network is particularly sensitive to damage due to higher metabolic demand and susceptibility to ischemic damage. Abnormal dilatation of remaining perifoveal capillaries is often seen so that the capillary bed is often more clearly visible during FA.
Diabetes also results in microvascular occlusion leading to areas of retinal capillary nonperfusion. These areas appear dark, and vessels bordering these areas often show increased permeability and leakage of dye due to endothelial cell damage giving an indistinct appearance late in the study.  Retinal vessels/capillaries bordering areas nonperfusion can become widely enlarged and irregular (described as IRMA).
Ischemia induced production of vascular growth factors, most notably vascular endothelial growth factor (VEGF) results in the formation NV. These grow in contrast to IRMA through the internal limiting membrane and onto retinal surface, and with progression can involve the disk, iris and anterior chamber angle.
It can be difficult to distinguish dilated preexisting capillaries from newly formed intraretinal neovascularization clinically, and small NV can be difficult to see by ophthalmoscopy. FA is invaluable at assessing retinal and macular ischemia and differentiating IRMA from retinal NV. Unlike normal vessels or IRMA, retinal NV has fenestrated walls that leak fluorescein and are easily identified on FA.
| Wide Field Imaging|| |
Conventional retinal photography and angiography is limited in its field of view. Most fundus cameras capture only a small portion (typically 30-60°) of the fundus at a time. More peripheral images can be obtained by directing the objective lens at the peripheral retina. Multiple images need to be obtained, and these can then be viewed independently or composited as a montage. Many of the landmarks studies on retinopathy such as the Early Treatment of Diabetic Retinopathy study (ETDRS) used 7 standard fields to allow approximately 75° view of the fundus.  Obtaining these standardized images requires a skilled operator, clear media, adequate pupil dilatation, time, and some patient cooperation. Although the 7 standard fields image the mid-peripheral retina well, they cannot image the far periphery and cannot image the entire retina simultaneously. Peripheral changes and pathology can, therefore, be missed, and this has been demonstrated in patients with DR, sickle cell retinopathy, and vascular occlusions. ,
One of the challenges in obtaining good quality peripheral images (>100°) is the illumination. The Retcam was one of the first portable wide-angle camera systems. It uses a fiberoptic light source and a series of contact lenses providing images out to 130°. The Retcam is widely used in pediatrics but, unfortunately, has limited applicability in adults because illumination is provided through the crystalline lens and even slight lens opacity results in poor quality images.
The increasing use of cSLO imaging (discussed above) has reduced many of the illumination problems. A number of commercial devices use cSLO systems to obtain wide field images. The Heidelberg HRA (Heidelberg Engineering) can be used to create wide-field images if used in conjunction with a wide-angle lens. The Staurenghi lens system can be used to obtain images to 150° with a single shot.  The Staurenghi system relies on a contact lens that has to be applied prior to imaging and requires a trained operator, adequate dilatation and produces an inverted image of the ocular fundus.
More recently Heidelberg has developed an ultra-wide field angiography module with an interchangeable noncontact lens that attaches to the camera head to provide high-contrast, undistorted and evenly illuminated images out to the peripheral retina with much greater ease.
The Optos camera (Optos PLC, Scotland) also employs cSLO and is capable of producing single shot noncontact wide-field image up to 200°. The technology utilizes an ellipsoid mirror to obtain images of the retinal periphery without the need for bright illumination lighting or a contact lens, and can even obtain images in patients with smaller or undilated pupils.
All these systems allow capture of wide field cSLO imaging, FA and on many models wide field fundus autofluorescence images and pseudocolour or multicolor images.
A small comparison of the Optos and Heidelberg noncontact wide field module reported that the Optos consistently imaged a significantly larger total retinal area (single, unsteered images).  However, the images from the Optos were more variable. In particular the Optos use of an ellipsoid mirror to image, the retina resulted in the distortion of images, especially in the far temporal and nasal periphery. The Heidelberg Spectralis noncontact wide field lens in contrast produces an undistorted flat image of the retina. Heidelberg also outperformed the Optos in superior and inferior quadrants field of view and steering the camera head or altering the eye position can obtain wider field images. 
The use of wide-field angiography to image the peripheral retina of patients with DR enhances the clinical evaluation, detects peripheral areas of ischemia and neovascularization missed with standard seven field imaging [Figure 2]. In addition, the wide-field images can help plan surgical or laser treatment. ,
|Figure 2: Wide-field fluorescein angiogram showing areas of peripheral ischemia and retinal neovascularization potentially missed by standard 7 field photography (area typically covered marked centrally by red outlined circles)|
Click here to view
Proponents of wide field angiography suggest targeted retinal photocoagulation to areas of nonperfusion may reduce visual field loss, macular edema, and facilitate treatment in proliferative DR.
| Optical Coherence Tomography|| |
Optical coherence tomography (OCT) is an imaging technique similar to ultrasound, but instead of using sound waves it uses light to achieve much higher resolution images (10-100 times better than ultrasound). The time delay of a beam of light as it is reflected from each optical surface is measured. As light travels quickly and the distances involved are small this is done using low coherence inferometry - the light beam is split and the beam hitting ocular structures is compared to a reference beam by analyzing the interference pattern. This method also allows detection of signals from very small changes in the ocular tissue. Lots of A-scans taken across the retina can be analyzed together to form a cross-sectional or B scan image. Initial commercial OCT devices used time-domain, and the reference arm was moved from the light source allowing imaging at different depths. The speed of this movement limited the axial resolution. The initial Stratus device (Carl Zeiss) acquired approximately 400 A-scans/s using 6 radial slices oriented 30° apart. Because the slices are 30° apart pathology between the slices could be missed.
In Fourier domain OCT, the depth scan is obtained by analyzing the interference signal based on the wavelength of light. This eliminates the need for moving reference mirrors, and the entire axial depth scan is obtained for each point simultaneously. Spectral domain optical coherence tomography (SD-OCT) devices can obtain 20,000-40,000 scans/s. This increased scan rate reduces motion artefact increases resolution from the 10 to 15 μ seen in time-domain optical coherence tomography to 3-5 μ micron resolution and allows imaging of all points in a much larger area.
Optical coherence tomography provides in vivo optical "histology" like images especially of the macular area.
One of the major causes of visual loss in diabetics is the development of macular edema. The ETDRS study showed a reduction of moderate vision loss in patients with clinically significant macular edema with macular laser treatment. More impressive outcomes have been demonstrated following treatment with intravitreal anti-VEGF agents including ranibizumab, bevacizumab, and aflibercept, as well as steroid agents. ,,
Studies comparing OCT diagnosis of macular edema with the clinical gold standard of dilated slit lamp examination using a contact lens showed excellent agreement in patients with thickening >300 μ. 
Similar agreement was seen between OCT and stereo fundus photography. 
One of the major advantages of OCT is the ability to get quantative assessment of DMO, as well as more detailed information on structural alterations. It is well established that treatments that reduce DMO can improve or stabilize visual acuity. ,,, However, the correlation between OCT-measured retinal thickness and visual acuity is variable. ,
Analysis of patients in a DRCRNet study treated with laser showed a linear relationship between central retinal thickness and visual acuity, but there was substantial variation in visual acuities at any given retina thickness.  Many eyes with thickened maculas had excellent visual acuity, and many eyes with maculas of normal thickness had decreased visual acuity.  Suggesting macular thickness is just one of several variables affecting visual acuity. There was a much greater spread in letters read in thicker maculas (>400 microns). Attempts have been made at classifying different patterns of macula edema seen on OCT with visual acuity, response to treatment and angiographic changes like macular ischemia. Previous reports have looked at focal and diffuse patterns of edema, configuration of cystic changes and presence or absence of subretinal fluid.  OCT images in individuals with central DMO typically show a loss of normal foveal depression and multicystic retinal thickening. This thickening may be localized to the outer nuclear layer or extend to involve the entire retina. With time, the cysts coalesce to form larger cystoid spaces and cystoid macular edema. These changes correlate with the petaloid late leakage seen on FA and are thought to herald a poorer visual prognosis. Approximately, 30% have subretinal fluid (between neurosensory retina and RPE)  this may be a sign of more rapid change and in the author's experience is sometimes seen in association with systemic dysfunction such as acute renal dysfunction. Some reports suggest it is not linked to a poorer visual prognosis. Leakage of lipid type material in DMO can lead to deposition of hard exudates. On OCT, these exudates appear initially as small hyperreflective foci in the outer plexiform layers and with greater deposition can appear as large hyperreflective plaques.
Similar hyperreflective areas on OCT images have been documented in areas of retinal ischemia on angiography  [Figure 3].
|Figure 3: Late fluorescein angiogram image and optical coherence tomography scan image of the eye with reduced vision from diabetic macular edema (visual acuity; 6/9). Angiogram shows areas of central and temporal capillary nonperfusion/ischemia with late leak. The corresponding optical coherence tomography shows intraretinal cysts. There are numerous hyper-reflective foci often seen with ischemia and the inner segment/outer segment layer is relatively intact|
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Spectral domain optical coherence tomography devices with their increased resolution allow detailed imaging of outer retinal layers. A hyper reflective line that is thought to correspond to the junction between inner segment/outer photoreceptor segments (junction or ellipsoid zone) can be visualized on SD-OCT. Loss of this layer unsurprisingly seems to correlate with poorer vision and poorer visual prognosis with treatment  [Figure 4].
|Figure 4: Optical coherence tomography scan image showing diabetic macular edema with new central involvement, temporal thickening and intraretinal cysts, and subfoveal subretinal fluid. There is a small microaneurysm with the adjacent area of disruption in the inner segment/outer segment layer and shadowing nasally corresponding to previous macular laser|
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Absence or degradation of this line can be seen in patients with chronic or cystoid type macular edema and in eyes with vision loss secondary to macular ischemia.
| Imaging of the Vitreomacular Interface|| |
There is increasing interest in the role of the vitreomacular interface. In DR, posterior vitreous detachment (PVD) is associated with a decreased rate of neovascularization/proliferative DR and DMO.  Akiba et al. reported that patients with NPDR followed for a mean of 32 months developed retinal neovascularization in 21.5% of cases if the posterior vitreous body was attached and in only 3.4% of cases if PVD was present.  OCT is significantly more sensitive than clinical examination alone in detecting vitreomacular traction. ,
Vitreomacular traction and areas of vitreomacular adhesion are easily visualized on OCT imaging as a low reflective band with focal remaining adherence to the central fovea. Patients with DMO can have associated or secondary epiretinal membrane or vitreomacular traction. These changes can potentiate the DMO and reduce response to treatment. OCT can help identify cases, which may benefit from surgical vitrectomy. 
| Advances in Optical Coherence Tomography Imaging|| |
Standard SD-OCT is set up to give maximal sensitivity in the vitreous and inner retinal layers as these typically have low reflectance. Spaide described a method of positioning the SD-OCT device close enough to the eye to obtain an inverted image of the fundus.  This shift in the sensitivity allows a better view of the choroid and outer retina at the expense of vitreous. This enhanced depth imaging or choroidal imaging mode is now present on many SD-OCT systems. Changes in choroidal thickness have been described in DR with decreased thickness.
Swept source OCT devices use a longer wavelength of light (1050 nm in comparison to 840 nm with SD-OCT) this longer wavelength is scattered less and can penetrate tissues more deeply. The DRI OCT-1 (Topcon) has a fast scanning speed of 100,000 A-scans/s, and using 1050 nm wavelength can penetrate deeper compared to the current conventional OCT's visualizing choroid and sclera. Other advantages include an invisible scanning line, which can reduce patient eye motion and much larger scanned area so that whole disk, macula, choroid, and vitreous are all captured in one shot [Figure 5].
|Figure 5: Unlike conventional spectral domain optical coherence tomography scan, this Swept source optical coherence tomography shows a detailed structure of cortical vitreous, vitreomacular adhesion, and choroid layer in a single image|
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Unlike the axial resolution, the lateral resolution of SD-OCT devices is limited by the eye's optics (monochromatic and chromatic aberrations) and the beam diameter at the eye's pupil (diffraction). Adaptive optics can help correct many of these aberrations. The fundus camera, the cSLO, and the OCT have been combined with adaptive optics allowing much greater resolution of retinal structures. 
With improved cheaper light sources commercially available ultrahigh-resolution OCT devices will become more ubiquitous. Many devices already allow simultaneous OCT with existing imaging modalities such cSLO, fluorescein, indocyanine green angiography, fundus autofluorescence, and microperimetry. Eye tracking technology allows accurate registration of images and follow-up.
Newer imaging modalities such as hyperspectral imaging which can provide information on perfusion,  OCT and phase shift "no dye" retinal angiography,  and photoacoustic ophthalmoscopy  which unlike other methods of imaging measures the photacoustic signal from retinal tissues after a pulse of illuminated laser hold huge promise. They have the potential to view retinal vasculature and RPE in brilliant detail. 
The future is bright. Our understanding and treatment of DR continues to be enhanced. Cheaper nonmydriatic wider field imaging through poor media and automated analysis of images offer scope of offering mass screening to the increasing worldwide population if diabetics, detecting and treating retinopathy before vision loss. The use of adaptive optics, better light sources, increased speed and simultaneous multimodal imaging will give clinicians and researchers much more comprehensive evaluation of functional and structural changes in the diabetic eye with further reductions in the incidence of preventable vision loss.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]