Imaging of the peripheral retina.

The technical progress of the recent years has revolutionized imaging in ophthalmology. Scanning laser ophthalmoscopy (SLO), digital angiography, optical coherence tomography (OCT), and detection of fundus autofluorescence (FAF) have fundamentally changed our understanding of numerous retinal and choroidal diseases. Besides the tremendous advances in macular diagnostics, there is more and more evidence that central pathologies are often directly linked to changes in the peripheral retina. This review provides a brief overview on current posterior segment imaging techniques with a special focus on the peripheral retina.

Retinal vascular diseases such as diabetic retinopathy (DR), retinal vein occlusion (RVO), and neovascular age-related macular degeneration (AMD) are in Europe and the US, as well as in the Middle East main cause of severe vision loss and blindness.[123] Even if central pathologies, such as macular edema are often of primary importance, there is more and more evidence that these central changes are often directly linked to the peripheral retina.[45] Considering the pathogenesis of diabetic macular edema (DME) for example, there are a variety of biochemical changes following diabetes mellitus leading to vascular endothelial damage and a consecutive breakdown of the blood retina barrier in both, the macular region and the peripheral retina. As a final pathway, this results in both, DR and DME, to an increased secretion of vascular endothelial growth factor (VEGF). As a consequence, increased vascular permeability and stimulation of pathological angiogenesis are not only the main causes of retinal neovascularization, but also of macular edema.[67]

Thanks to new treatment options, such as intravitreal anti-VEGF therapy, we do have the opportunity to help many of the patients suffering from macular edema.[89] However, with particular reference to the excessive secretion of growth factors in patients with DR, DME, or RVO; we are often only able to treat more or less in a symptomatic way: Macular edema is located in the center of the posterior pole, but the ischemic retinal areas providing a major stimulus for increased VEGF expression are often located peripherally. In consequence, sole pharmacotherapy will not allow us to treat causally anyhow. Moreover, recent data clearly indicate that for long-term stabilization, the quantification of (peripheral) ischemia is essential, as only this allows us to treat these disease causally and in a comprehensive way (for example, with an additive sectorial or pan-retinal laser therapy)[41011] [Figures 1a and b].

Figure 1

Optomap® ultra-wide-field scanning laser ophthalmoscopy (SLO) color scan (a) and fluorescein angiography (b) of a patient with proliferative diabetic retinopathy (PDR). Fluorescein angiography shows extensive ischemic retinal areas in the periphery

To give us a more comprehensive impression of retinal disease, modern imaging devices are available that are specifically designed to give us an image of the peripheral retina and therefore provide additional valuable information for more comprehensive ophthalmic treatment approaches.

In general, diagnostic fundus imaging has tremendously evolved over the recent years and thereby significantly gained importance. Initially consisting mainly from photographic fundus documentation of central retinal pathologies, supplemented during the 1970s by analog fluorescein angiography; both examination techniques were usually based on analogous single 35-50° photographs of the central of the retina, or, when the focus was set more on peripheral lesions, based on composite images (e.g., Early Treatment Diabetic Retinopathy Study (ETDRS) 7-field fundus photography), put together out of a series of single shots being more or less difficult to achieve and also being strongly operator and patient dependent.

Fortunately, technology has strongly advanced during the last decades and especially during the last few years ophthalmic imaging has made a large step forwards. The technical progress of the recent years has revolutionized imaging in ophthalmology and thereby changed our understanding of numerous retinal and choroidal diseases. In addition, our knowledge about the vitreous and the vitreoretinal interface has largely expanded and improved.

When we talk about imaging of the peripheral retina, particular wide-field scanning laser ophthalmoscopy (SLO), but also digital wide-field angiography have strongly evolved during recent years, and still evolving.[1213] As imaging quality has significantly improved and handling has become easier, both, wide-field SLO and angiography have found their way into broader clinical practice and evidence about the benefits of these imaging techniques is increasing almost from day to day.[12] But also wide-field fundus autofluorescence (FAF) is now becoming more and more clinically available providing completely new insights into peripheral, retinal pathologies.[141516]

A good example for new insight provided by wide-field imaging is given by a recent study that showed clearly that even in the dry AMD, which was primarily seen as a disease of the macula region and the posterior pole, typical peripheral retinal changes commonly occur, allowing the conclusion that AMD must now be better understood as primarily “panretinal” disease.[15] As a consequence, the peripheral retina may provide additional diagnostic information allowing a better understanding of the disease [Figures 2a and b].

Figure 2

Optomap® ultra-wide-field scanning laser ophthalmoscopy (SLO) color scan (a) and fundus autofluorescence (FAF) (b) of a patient with dry age-related macular degeneration (AMD). FAF shows both centrally and peripherally significant changes that are almost invisible on the color image

So, what makes the difference between conventional ophthalmic imaging and modern wide-field imaging devices? In principle, it may be even possible to document peripheral retinal changes with a conventional fundus camera. However, due to the relatively small image angle (usually between 35 and 55°) the implementation as a documentation tool for peripheral retinal changes into daily clinical practice is often technically difficult. Especially when outer peripheral retinal pathologies should be pictured, image quality is highly dependent on the operator's technical skills as well as the patient's collaboration and optical aberrations are often limiting image quality. In certain cases, for example in premature infants for monitoring retinopathy of prematurity, contact fundus cameras, such as the RetCam 120 are a pretty good choice.[1718] However, in systems like this the optical head has to be placed on the surface of the eye and it needs significant experience to handle the device, impeding the spread of these machines into everyday diagnostic routine [Figure 3].

Figure 3

Right eye fundus of a premature infant with retinal hemorrhages, taken with the RetCam® 120 (image courtesy of Prof. Ehrt, LMU Munich)

An approach being more suitable for a widespread clinical use represents noncontact wide-field fundus imaging. There are several systems on the market right now and some of them are even non-mydriatic. They are mostly easy to handle, technically highly developed, and equipped with good image resolution; allowing to accurately reproducing large areas of the central and peripheral retina, being essential for a valid DR screening for example.[31920] In addition, most systems have specific software solutions that provide additional diagnostic functions, such as measuring tools or zooming features that allow to enlarge almost any detail on the fundus in sometimes pretty good image quality. Wide-field fundus imaging systems like this are either available as “stand-alone” devices (such as the Optomap P200Tx system which includes both a color fundus imaging, but also wide-field fluorescein angiography (FA) and FAF allowing to map according to the manufacturer (OPTOS Plc, Dunfermeline, UK) almost 180° of the retina in one scan) or as “add-on” modules for existing imaging devices (e.g., spectralis ultra wide-angle angiography module for Heidelberg Retina Angiograph - 2 (HRA-2), Heidelberg Engineering, Heidelberg, Germany; allowing wide-field FA, but also Indocyanine Green Angiography (ICG) angiography [Figure 4].[1221] These imaging devices open up a host of new diagnostic applications and are increasingly integrated into everyday clinical settings. In (peripheral) retinal vascular disease, such as DR, and also in patients suffering from uveitis and other inflammatory diseases of the retina they have gained a particular area of importance.[31621] Several larger prospective studies for example found that 200°, non-mydriatic, ultra-widefield SLO imaging by Optomap was as effective as ETDRS 7-field stereo color photographs for assessing DR and correlates well with clinical assessment.[319] The authors of one of these studies examined 141 consecutive patients with various levels of DR using Optomap imaging and ETDRS 7-field photography.[3] The level of DR and the presence of clinically significant macular edema (CSME) were graded according to ETDRS classification. As a result, the techniques agreed significantly, with both showing good intergrader reproducibility and correlation with clinical assessment of DR. Of note, Optomap imaging had a lower rate of nongradable images compared with 7-field ETDRS, showing substantial correlation with clinical assessment for detection of CSME.[3] As conclusion of the study the author stated that the results clearly demonstrate that Optomap imaging provides at least similar results for assessment of DR levels and presence of CSME compared with ETDRS 7-field stereo color photographs. They added that Optomap examination does not require much photographer experience and has a fast learning curve; it also can be performed easily by trained medical personnel. Therefore, Optomap provides promising properties for peripheral screening programs and telemedicine in diabetes patients.[319]

Figure 4

Spectralis® Ultra wide-field fluorescein (a) and indocyanine (b) angiography of a patient with choroidal hemangioma. Both retina and choroid show significant abnormalities (courtesy of Prof. Staurenghi, Milan)

The key technology of the past decade in ophthalmology is surely optical coherence tomography (OCT). Since its introduction in 1991, OCT has revolutionized diagnostics in ophthalmology and has become an indispensable tool in both, retina and glaucoma practice. It provides noninvasive high-resolution in vivo imaging of retinal, choroidal, and optic nerve head structures.[8222324] Therefore, OCT is becoming more and more relevant for ophthalmic diagnostics and has increasing impact on therapy. Beside substantial improvements in resolution the increase of scanning speed has led to a wide application in ophthalmology. Furthermore, the evolution of software solutions for image analysis has contributed significantly to make OCT technology an indispensable standard in macular diagnostics. But we still have a different situation in the assessment of peripheral retinal changes. So far, OCT was not really applicable to detect or monitor peripheral retinal pathologies, since there were no OCT systems that owned a sufficiently high scanning speed allowing to asses wide-angle OCT scans and thereby enabling a valid OCT imaging of the peripheral retina. An important step towards this direction has recently been done by a cooperation project of the Institute for Biomolecular Optics of the Ludwig-Maximilians-University (LMU) in Munich and the Department of Ophthalmology at LMU. The development of a novel laser source allowed the development of an ultra-high-speed swept source Fourier domain mode locking (FDML) OCT that was built to improve existing technology.[2526] FDML technology allows ultra-fast, dense isotropic OCT sampling running at 1.68 MHz axial line rate and also enables reconstruction of en-face fundus images out of complete 3D datasets. Thus, using high-resolution OCT technology, wide-field OCT scans can be produced which make it possible to examine peripheral retinal changes in detail [Figures 5a and b]. The availability of this technology, but also by means of commercially available wide-field OCT systems, such as the recently introduced DRI Topcon OCT-1, the assessment of both, central and the peripheral retina with OCT comes closer to every day clinical practice.

Figure 5

Ultra-high-speed Swept Source Fourier domain mode locking (FDML) optical coherence tomography (OCT): ‘En face’ imaging of a left eye with proliferative diabetic retinopathy (PDR) and status post panretinal and macular laser treatment (a), and a left eye of a patient with central serous retinopathy (unprocessed data, without image averaging) (b). Due to the large angle covered, FDML OCT technology allows to image both, optic nerve and macular on one scan

In summary, besides all the progresses in macular diagnostics and treatment, the technological advances of the last years have brought the peripheral retina once again back in the focus and a more comprehensive look at the ocular fundus steps into everyday clinical practice. Even if not all interrelations between the central and the peripheral retina are completely understood, new imaging technologies allow now to display both, the macular and peripheral retina, and thereby providing new insights that have the potential to further improve our understanding of retinal disease.