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OCT angiography provides noninvasive close-up viewing of retinal vasculature
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Over the past 20 years, OCT has developed rapidly as a noninvasive method of retinal imaging. OCT angiography, or OCTA, is the latest evolution of this technology, allowing extreme close-up imaging of the retinal vasculature for assessing retinal vascular diseases, and holds potential for guiding treatment decisions and monitoring patient responses to therapy.
“The huge progress consists in having both functional and morphological assessment from a single dye-less examination. The rapid and noninvasive nature of the OCTA allows an easier follow-up of morphological and functional changes in prolonged, repetitive and even monthly evaluations.” Gabriel J. Coscas, MD, emeritus professor of ophthalmology at the University of Paris XII in Créteil, France, said.
For many years, in traditional OCT, subretinal or intraretinal fluid accumulation was a test of treatment efficacy to select the best schedule of intravitreal injections. Nevertheless, a large number of patients remained nonresponders or partial responders, despite multiple efforts.
“By directly analyzing activity criteria and blood flow in the CNV network before initial treatment and in the follow-up, OCTA can guide us more effectively in our treatment and re-treatment decisions,” Coscas said.
Image: Coscas GJ
Technological developments
Since the early days of OCT, the work of Rainer A. Leitgeb, PhD, associate professor of medical physics at the Medical University of Vienna, Austria, has been devoted to applications of OCT, particularly functional extensions aimed at visualizing and quantifying blood flow.
The first attempts at angiography were implemented with time domain in the late 1990s, but acquisition speed was too slow, Leitgeb said. Fourier-domain OCT worked at a faster speed of several tens of kHz at the beginning and made flow analysis for a large range of retinal vessels possible by comparison of single consecutive A-scans. With the development of ultra-fast Fourier-domain OCT, shifting A-scan rates of commercial systems to 70 kHz and above, the breakthrough of OCTA was possible. Swept-source OCT operating at one to several hundred thousand of A-scans per second additionally employs light at longer wavelengths that is scattered less and thus yields potentially better contrast for deeper choroidal vasculature.
“OCTA allows us to image blood flow by motion contrast. It takes several tomograms (B-scans) at exactly the same position, and fluctuating red blood cells are visible against the static tissue,” Leitgeb said. “Without any additional contrast agent, the full vascular network is visualized, down to the small capillaries. OCT angiography has been established as a potent tool that can ultimately replace or at least be a very good complement to the gold standard dye-based angiography.”
Leitgeb’s group in Vienna is currently working on several prototypes that are already in use for clinical trials.
“We are aiming at a system that will provide not only structural information but also quantitative blood flow measurement, a very important additional biomarker. Clinical support in our research is provided by the ophthalmology department of Ursula Schmidt-Erfurth, MD, and we do quantitative blood flow studies with Leopold Schmetterer, PhD,” Leitgeb said.
Several other research groups are working on OCTA technology, including groups at Casey Eye Institute in Portland, Oregon, USA, MIT in Cambridge, Massachusetts, USA, and the Department of Bioengineering of the University of Washington in Seattle, USA. Among companies, Zeiss, Heidelberg Engineering, Optovue and Nidek are involved in this new OCT development. The Zeiss AngioPlex and Optovue AngioVue platforms are already available on the market.
Depth-resolved visualization of choroidal neovascularization
Unlike fluorescein angiography, which is a two-dimensional viewing system, OCTA displays a depth-resolved three-dimensional image.
“Therefore, you can peel off layer after layer and look at the blood vessels in each layer,” Nadia K. Waheed, MD, MPH, associate professor of ophthalmology at Tufts University School of Medicine in Boston, USA, said. “We are seeing fine vessels as well as larger vessels. Some of these vessels can be indicative of whether disease is active and in the future may be indicative of how well someone is responding to treatment and the recurrence rates.”
A benefit of AngioPlex OCTA is that it color codes the separate layers of the retina “in a beautiful layout, so that you can see the vessels in the different layers,” Waheed said.
The Spectralis diagnostic imaging platform from Heidelberg Engineering “uses a full-spectrum amplitude decorrelation algorithm to obtain OCTA images and provide images with a very high motion contrast, thus rendering a clear depth-resolved visualization of the different retinal and choroidal vascular layers,” Coscas said.
While automatic segmentation might help in detection, manual segmentation will be more precise for CNV analysis, Coscas said.
He suggested performing “transverse section analysis or horizontally aligned to the retinal pigment epithelium (RPE) profile or Bruch’s membrane (BM) profile, beginning above the RPE to identify pre-epithelial CNV, progressing in 30 µm layers between RPE and BM to image the entire subepithelial CNV network and finally toward the choroidal-scleral interface for feeder and draining vessels and for choroidal vessels and connections.”
An important feature of the Spectralis OCTA system is the TruTrack active eye tracking.
“This represents a very reliable method to acquire OCT volume scans without motion artifacts,” Coscas said. The eye-tracking method is based on the simultaneous acquisition of fundus and OCT images, “making it possible to perform a continuous real-time quality check of the OCT data during the exam. This process ensures that only accurate OCT images are stored.”
The device also allows for “a very precise segmentation of the volume scan, avoiding any risk of superimposed images and obtaining a specific localization of the CNV related to the RPE and BM,” Coscas said.
Coscas was the lead author of a recent article in Retina that compared OCTA using Spectralis with traditional multimodal imaging in patients with exudative AMD for guiding treatment options. The prospective case series of 80 eyes described the use of very thin sections of CNV lesions and the analysis of five criteria of activity or quiescence of CNV in exudative AMD.
“These criteria could be valuable during post-treatment follow-up for evaluating treatment efficacy,” Coscas said. “Coupled with the conventional OCT B-scan, which assesses fluid accumulation, the OCTA may become the choice method to evaluate the activity or quiescence of the lesion and suggest the treatment decision.”
OCTA in diabetes
Likewise, OCTA “shows us in very fine detail and in very high resolution the vascular changes that are taking place in diabetes,” Waheed said. “Unlike fluorescein, which can only show us the superficial layer of blood vessels, OCTA can also show us changes in the deep retinal vessels. We are starting to visualize changes now on imaging that we traditionally were able to see only in pathologic specimens.”
In an article published in Retina, Waheed and colleagues demonstrated that OCTA may be able to detect early microvascular changes, such as foveal avascular zone (FAZ) changes and capillary nonperfusion, in eyes of diabetic individuals before the clinical signs of diabetic retinopathy (DR) appear.
Similar findings were also published in Retina by the group of Yuichiro Ogura, MD, PhD, professor and chair of ophthalmology at Nagoya City University, Japan, using the AngioVue system.
“Diabetic eyes showed statistically significant FAZ enlargement compared with healthy eyes, regardless of the presence of retinopathy,” Ogura said.
“We also found that about 80% of microaneurysms are located in the deep capillary plexus layer and that inside the retinal edema, 91% of microaneurysms are in the deep layer. These results suggest that microaneurysms in the deep capillary plexus might be responsible for the formation of macular edema in DR,” he said.
According to Ogura, it is easy to explain why in diabetes there is more damage in the deep capillaries.
“You have the major retinal vessels on the surface of the retina, and they have connections with superficial capillaries and deep capillaries. Deep capillaries have to go deep and come back to the surface. This is a long way to go, and they can be damaged very easily with the disease,” he said.
Ogura is also studying OCTA use in age-related macular degeneration, myopic CNV and retinal vein occlusion. The use of a dye-less, noninvasive technique has the potential to revolutionize the management of all retinal diseases, he said.
“At present, there are some limitations. Right now the field of view is very narrow, 3 mm × 3 mm or 6 mm × 6 mm, and you cannot go to the periphery, but as technology progresses, over the next 5 years or so, I am expecting that it will replace fluorescein angiography. Currently, we need fluorescein angiography for the periphery,” he said.
“Given time, we have the ability to expand OCTA technology into widefield imaging by stitching together smaller pieces of images to obtain a wide field of view,” Waheed said. “It typically takes 3 to 4 seconds to secure an image, and the overall patient time in the room is probably closer to 10 minutes because you take multiple images.” This is still less time-consuming than fluorescein angiography, which normally takes 15 to 20 minutes.
“Fluorescein and ICG angiography are invasive methods and carry a small risk of adverse reactions. You cannot perform them every week or month, but with OCTA you don’t have such limitations and can perform it every time the patient comes,” Ogura said. “This is an invaluable advantage, the greatest evolution in the field of retina in several years. I am looking forward to the next developments of this technique.” – by Michela Cimberle and Bob Kronemyer
- References:
- Aschinger GC, et al. Biomed Opt Express. 2015;doi:10.1364/BOE.6.001599.
- Coscas GJ, et al. Retina. 2015;doi:10.1097/IAE.0000000000000766.
- de Carlo TE, et al. Retina. 2015;doi:10.1097/IAE.0000000000000882.
- Drexler W, et al. J Biomed Opt. 2014;doi:10.1117/1.JBO.19.7.071412.
- Leitgeb RA, et al. Prog Retin Eye Res. 2014;doi:10.1016/j.preteyeres.2014.03.004.
- Kaneko Y, et al. Invest Ophthalmol Vis Sci. 2014;doi:10.1167/iovs.13-13706.
- Suzuki N, et al. Am J Ophthalmol. 2015;doi:10.1016/j.ajo.2015.09.038.
- Takase N, et al. Retina. 2015;doi:10.1097/IAE.0000000000000849.
- For more information:
- Gabriel J. Coscas, MD, can be reached at Centre Hospitalier Intercommunal de Créteil, 40, Avenue de Verdun, 94010 Créteil, France; email: gabriel.coscas@gmail.com.
- Rainer A. Leitgeb, PhD, can be reached at Medizinische Universität Wien, Zentrum für Medizinische Physik und Biomedizinische Technik, Währinger Gürtel 18-20, A-1090 Vienna, Austria; email: rainer.leitgeb@meduniwien.ac.at.
- Yuichiro Ogura, MD, PhD, can be reached at Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya 467-8601, Japan; email: ogura@med.nagoya-cu.ac.jp.
- Nadia K. Waheed, MD, MPH, can be reached at Tufts Medical Center, 800 Washington St., Box 450, Boston, MA 02111, USA; email: nwaheed@tuftsmedicalcenter.org.
Disclosures: Coscas reports he is a consultant for Heidelberg Engineering. Leitgeb’s research project is partially funded by Carl Zeiss Meditec. Ogura reports no relevant financial disclosures. Waheed reports she has been a consultant for Iconic Therapeutics, a contract researcher for Carl Zeiss Meditec and a member of the speakers bureau for ThromboGenics.
For what retinal conditions would you consider OCTA as a primary modality for monitoring or diagnosing disease, and for what indications would you consider it to be adjunctive?
OCTA already a primary modality in most retinal diseases
OCTA has several advantages, such as 3-D visualization of retinal and choroidal circulations. In addition, injection of a dye is not needed, and we are able to investigate different layers of tissue. Thus, there are several disease entities for which OCTA can become the primary modality for monitoring and diagnosing. Those include macular ischemia in diabetic eyes and other vascular disorders, as well as monitoring of CNV regression after treatment. Diseases that lead to alterations of the choroidal circulation are also candidates for OCTA as a primary modality.
OCTA is only adjunctive if we need data on activities of neovascularization, such as dye leakage, or information on the retinal periphery. Those physiological parameters and the retinal periphery can only be shown by dye-based modalities. We already know that OCTA has limitations if the blood flow is slow, which may occur in CNV due to AMD. In those cases, OCTA can be used as an adjunctive tool rather than a primary modality.
On the other hand, OCTA may provide a primary and unique possibility to study the morphology of occult type 1 neovascular membranes in AMD, especially when fluorescein angiography cannot reveal well-defined CNV. In those cases it has been shown that OCTA guides evaluation and treatment of neovascular AMD. It contributes to the development of improved therapies and gives us a better understanding of the therapeutic effects of both anti-VEGF agents and steroids. Thus, OCTA could become the primary modality and possibility to evaluate the effects of the next generation of such drugs in a clinical trial setting.
Albert Augustin, MD, is a professor and chairman of the department of ophthalmology, Klinikum Karlsruhe, Germany. Disclosure: Augustin reports he is a consultant to Carl Zeiss Meditec.
Promising applications in glaucoma, NAION under investigation
OCTA is becoming a primary modality in all cases of suspected or confirmed choroidal neovascularization, such as AMD and myopic CNV. Added to conventional B-scans and mapping, diagnosis and follow-up are more accurate. It is also useful in cases in which the retinal vasculature is modified, such as diabetic retinopathy or vein occlusion.
Equally promising seems to be the use of OCTA in the evaluation of the peripapillary vasculature in cases of glaucoma and non-arteritic anterior ischemic optic neuropathy. It has recently been evaluated in studies as an adjunct and in correlation with traditional measures of function and structure, and it might give new insights for an enhanced understanding of the pathophysiology of these diseases and assessment of treatment outcomes. Interesting data have emerged that warrant further investigation. Also in this area, OCTA might soon become the primary approach to diagnosis and monitoring.
Jean-François Korobelnik, MD, an OSN Europe Edition Board Member, is a professor and chairman of retina and neuro-ophthalmology services, University of Bordeaux, France. Disclosure: Korobelnik reports he is a consultant to Carl Zeiss Meditec.