Adopting and Adapting Imaging Tools for Clinical Use

It’s no secret that we live in a society that yearns for technology, as evidenced by the long lines outside Apple stores last month. We adopt new technology almost as fast as it’s available; in fact, you may even be reading this on the new Retina Today iPad App. This desire for the latest and greatest is no different in the medical field, and although advances in imaging and image analysis for the back of the eye have paralleled the advances in other technology, implementing new technology into clinical trials and practice is not so easy. Even more difficult, however, is actually understanding the structural measurements and endpoints the device is capable of and integrating these new device technologies into clinical trial protocols. Additionally, prospective sites will need to obtain the technology, and the staff and study personal must be properly trained to use the devices. These hurdles are certainly not insurmountable, but must be taken into consideration from the beginning of the development process.

With that said, advances in retinal imaging are taking the industry to the next level. Imaging advances are providing entirely new ways of capturing the human eye and visualizing ocular structures and disorders. We are now able to see retinal structure with unprecedented precision, transforming the diagnosis and treatment of a number of retinal diseases. Ultimately, better structural imaging technology may take us 1 step closer to correlating structural and functional changes.

Adaptive Optics Scanning Laser Ophthalmoscope (AO-SLO)

The scanning laser ophthalmoscope (SLO) was invented by Webb et al in the 1980s.Webb RH, Hughes GW. Scanning laser ophthalmoscope. IEEE Trans Biomed Eng. 1981;28(7):488-492. This imaging modality offered a unique view of the living human eye with improved effectiveness in light gathering and real-time imaging. Further, the addition of a confocal pinhole provided higher contrast images in comparison to conventional imaging intsrutments.Webb RH, Hughes GW, Delori FC. Confocal scanning laser ophthalmoscope. Appl Opt. 1987;26(8):1492-1499. Although the SLO has the ability to optically section the retina, aberrations of the eye created primarily from the tear film, cornea, and lens affect the ultimate image resolution.

More recently, adaptive optics (AO) has been used to compensate for ocular aberrations and is considered an indispensable mechanism for high quality optical imaging. Reducing aberrations improves both lateral and axial resolution to approximately 2.5 μm lateral and better than 100 μm axial,Roorda A, Romero-Borja F, Donnelly Iii W, Queener H, Hebert T, Campbell M. Adaptive optics scanning laser ophthalmoscopy. Opt Express. 2002;10(9):405-412. a reduction over conventional SLOs, which have a typical resolution of 5 μm lateral and 300 μm axial. The use of AO-SLO by Roorda, et al generated microscopic real-time views of the living human retina, and produced the first real-time images of individual photoreceptors and blood flow.3 This is useful in clinical studies as a surrogate evaluation of drug efficacy—selection, monitoring, and analysis of a specific area prone to disease progression can be tracked over time and may be advantageous in predicting whether the drug prevents progression of cell death. Although the full clinical utility of AO-SLO is still under investigation, clinical researchers have set out to explore its place in the retinal arena. One study found that AO-SLO images revealed mosaics of retinal pigment epithelial (RPE) cells in patients with hereditary retinal diseases.Roorda A, Zhang Y, Duncan JL. High-resolution in vivo imaging of the RPE mosaic in eyes with retinal disease. Invest Ophthalmol Vis Sci. 2007;48(5):2297-2303. In these patients, visualization of RPE cells in areas where cones were missing was observed. Another study designed to investigate macular photoreceptor structure with AO in patients with inherited retinal degeneration found that AO-SLO images can be used to study macular cones in subjects with healthy eyes and in patients with 2 types of retinal degenerative disease, retinitis pigmentosa (RP) and cone-rod dystrophy (CRD). AO-SLO cone spacing measures correlated significantly with foveal threshold, visual acuity, and multifocal electroretinogram (mfERG) amplitude.Duncan JL, Zhang Y, Gandhi J, et al. High-resolution imaging with adaptive optics in patients with inherited retinal degeneration. Invest Ophthalmol Vis Sci. 2007;48(7):3283-3291. And so, the use of AO-SLO to image macular cones with high resolution suggests that the technology may be useful in monitoring cones during disease progression and in response to treatment.

Imaging advances are providing entirely new ways of capturing the human eye and visualizing ocular structures and disorders.

 

Ultra-WideField Fluorescein Angiography

Since the first report in 1961, fluorescein angiography (FA) has been monumental in the assessment and management of retinal diseases, particularly by the evaluation of blood vessels and circulation within the eye.Novotny HR, Alvis DL. A method of photographing fluorescence in circulating blood in the human retina. Circulation. 1961;24:82-86. Patterns of hyper- and hypofluorescence in lesions and structures associated with retinal disease are useful in identifying the pathophysiologic processes at work. Still, to capture the periphery and the posterior pole at the same time has long been desired by retina specialists, as standard FA captures an image only 30º across, requiring multiple images to be taken for a complete picture of posterior health.

The development of ultra-widefield fluorescein angiography has allowed for a more comprehensive assessment of the extent of disease process. Ultra-widefield FA images provide high-resolution posterior pole images as well as identification of peripheral pathology. Hyperfluorescence caused by leakage, transmission defects, or staining, and hypofluorescence from hypoperfusion or blockage are clearly imaged with ultra-widefield views. The Optos ultra-widefield retinal imaging systems (Optos PLC), for example, utilizes SLO technology, in addition to an ellipsoidal mirror that provides 2 conjugate focal points, and is capable of producing widefield fundus images of up to 200º in breadth.Kaines A, Oliver S, Reddy S, Schwartz SD. Ultrawide angle angiography for the detection and management of diabetic retinopathy. Int Ophthalmol Clin. 2009;49(2):53-59. The model uses a green (532 nm) laser and a red (633 nm) laser to image the retina and inner retinal pigment epithelium (RPE), and outer RPE and choroid, respectively. In a recent single-site, prospective, instrument validation study, nonmydriatic stereoscopic ultra-widefield images using an Optos P200MA device were compared with dilated stereoscopic ETDRS photography and clinical examination for determining diabetic retinopathy (DR) and diabetic macular edema (DME) severity.Silva PS, Cavallerano JD, Sun JK, Noble J, Aiello LM, Aiello LP. Nonmydriatic ultrawide field retinal imaging compared with dilated standard 7-field 35-mm photography and retinal specialist examination for evaluation of diabetic retinopathy. Am J Ophthalmol. 2012;154(3):549-559 e542. The ultra-widefield images compared favorably with ETDRS photography and dilated fundus examination, but were acquired more rapidly, and also provided the additional benefits of easier operation and no pupil dilation. Although these results must be confirmed across diverse sites and broader diabetic populations, ultra-widefield imaging may be beneficial in both research and clinical settings.8

The incorporation of ultra-widefield FA into clinical studies may enable evaluation of diabetic disease of the peripheral retina and assessment of drug efficacy in these patients. In addition to more precisely classifying patients with diabetic macular edema, the use of ultra-widefield FA can be useful for the detection of peripheral abnormalities and subsequently treating peripheral nonperfusion or late leakage from peripheral vessels.Kaines A, Tsui I, Sarraf D, Schwartz S. The use of ultra wide field fluorescein angiography in evaluation and management of uveitis. Semin Ophthalmol. 2009;24(1):19-24. Therapeutic interventions can also be monitored and adjusted according to a patient’s specific condition.

Conclusion

It’s no doubt that the past few decades have unveiled significant advancements in retinal imaging. The ability to view a single photoreceptor in a live human eye is surely a sign of the incredible development of optical tools and instrumentation in the retinal space. It seems as though that this rapid pace of discovery in ophthalmic imaging devices is only the beginning. Although the challenges to integrate these newer technologies into clinical trial protocols remains, the better resolution provided by these novel imaging devices offers detailed structural information that may, with time, be able to be correlated with visual function.