OCT Angiography Opens Eyes

JAMES SCHLETT, EDITOR, james.schlett@photonics.com

Dr. Daniela Ferrara, an assistant professor of ophthalmology at Tufts University School of Medicine in Boston, began researching retinal diseases in 1998. Age-related macular degeneration (AMD), a leading cause of blindness in elderly individuals of European descent, has been a recurring topic in her research. However, it was not until about two years ago — when Ferrara started testing prototype optical coherence tomography angiography (OCT-A) devices — that she saw just how much at the back of her patients’ eyes had been escaping her own eyes.

For example, Ferrara identified choroidal neovascularization (CNV) in the OCT-A scan of an elderly patient long before it would have been noticeable in a conventional OCT scan or with indocyanine green angiography (ICGA). She could not believe it was possible to see the CNV — a condition marked by abnormal blood vessels stemming from the choroid and an indicator of AMD — so early (Figure 1).

“I don’t think we knew what we were missing,” said Ferrara.

Figure 1. The abnormal vasculature arising from a choroidal net in the outer retina is clearly visualized in yellow, distinct from the red colorization of the choroidal layer. Also present are the vessels from the superficial capillary plexus slab (in white), which is used as a reference. Courtesy of Optovue.

U.S. market opens to OCT-A

A growing number of ophthalmologists, like Ferrara, are also starting to see what they have been missing as the first wave of OCT-A devices hit the U.S. market. Although Ferrara and her colleagues were able to run scans on patients who had consented to the study with the prototype OCT-A devices, it was only last summer that Dublin, Calif.-based Carl Zeiss Meditec Inc. became the first company to receive U.S. Food and Drug Administration (FDA) clearance to market the technology in the United States. Last summer also saw the Oregon Health and Science University (OHSU) in Portland, Ore., host the first international Optical Coherence Tomography Angiography Summit.

Figure 2. Optovue’s AngioVue OCT-A system. Courtesy of Optovue.

By the time Zeiss’ AngioPlex OCT-A technology for its CIRRUS HD-OCT system received FDA clearance, such technology was already commercially available outside the U.S. For example, in September 2014, Fremont, Calif.-based Optovue Inc. introduced its AngioVue Imaging System to non-U.S. markets and by last March the OCT-A system was in daily clinical use at over 550 sites worldwide (Figure 2). Optovue last November also received FDA clearance for the AngioVue. Other OCT-A system developments include:

• December 2015: Gamagori, Japan-based Nidek Co. Ltd. released OCT-A software for its RS-3000 Advance OCT system.

• December 2015: Heidelberg, Germany-based Heidelberg Engineering GmbH announced its plans to launch an OCT-A feature in 2016 for its SPECTRALIS diagnostic imaging platform (Figure 4).

• February 2016: Tokyo-based Topcon Corp. launched its SS-OCT Angio in Canada and Latin America for the company’s OCT DRI OCT Triton series system.

• March 2016: Logan, Utah-based Wasatch Photonics Inc. announced the launch of its MicroAngio OCT-A technology.

By last June, neither Wasatch, Topcon, Nidek nor Heidelberg’s OCT-A technologies had received FDA approval. Instead of focusing on a clinical application, Wasatch’s MicroAngio is geared toward several medical research applications related to animal model imaging in ophthalmology, dermatology, oncology and other areas, according to the company.

“It [OCT-A] is a major game changer since it provides for the first time rapid, noninvasive access to vascular imaging, which can be done at every visit, if necessary, without concerns for the morbidity of intravascular contrast administration,” said Dr. Richard B. Rosen, who is the vice chair and director of ophthalmology research, as well as the surgeon director and chief of retinal services for the New York Eye and Ear Infirmary of Mount Sinai in New York.

In addition to detecting the CNV associated with AMD, OCT-A can also show the presence of microaneurysms, which are swelling retinal blood vessels, and areas of where there is insufficient blood flow, referred to as ischemia — signatures of diabetic retinopathy (Figure 3). OCT-A can also show the blockages of retinal arteries and affected areas of ischemia associated with branch retinal vein occlusion¹.

Figure 3. Areas of capillary dropout and the microaneurysms associated with diabetic retinopathy are visualized in this Angiovue image of macular region. Note the enlarged and irregular FAZ border. Courtesy of Optovue.

OCT + angiography

OCT is an optical imaging acquisition technique that has been evolving since its inception at the Massachusetts Institute of Technology in 1991². It can create 3D, layered, cross-sectional images of the retina through the use of light waves, similarly to how ultrasound uses sound waves to map areas. In contrast, angiography is a medical imaging technique that traditionally has relied on dyes to view blood vessels.

Long before OCT revolutionized ophthalmology, in 1930 Kunimaro Kikai published the first paper describing how retinal vessels could be viewed through the injection of intravenous fluorescein. Thirty-one years later, Harold R. Novotny and David L. Alvis revealed in Circulation a method of photographing fluorescence in circulating blood in the retina³. This method, known as fluorescein angiography (FA), and ICGA, another dye-based method that dates back to the 1950s⁴, have become the gold standard for initial retinal disease diagnosis. OCT, too, is commonly relied upon for diagnosis and clinical management.

Figure 4. A patient during a noninvasive OCT examination with Heidelberg Engineering GmbH’s SPECTRALIS diagnostic imaging platform, which soon will be able to support OCT-A scans. The company’s OCT-A technology is currently under development and not commercially available. Courtesy of Heidelberg Engineering.

“OCT-A measures changes in the reflectance characteristics of tissue. These changes are based on the motion of material reflecting the ‘OCT light signal,’” said Jörg Pintaske, head of marketing at Heidelberg Engineering. “This means everything that moves can be detected by OCT-A. It’s like a moving car observed from a distance: If the car moves too slowly it is perceived as standing still. This is what happens with leakages, the flow is too slow for OCT-A. Similarly, by the way, too fast flow would not be detected either.”

While some OCT-A systems are for spectral-domain (SD) platforms, such as Optovue’s AngioVue, others are for swept source (SS) platforms, such as Topcon’s Triton. Rosen, who worked with Optovue on the AngioVue, said swept source systems are faster — and more expensive — than spectral-domain systems, which have higher axial resolution and are currently more stable.

Unlike SD technology, which uses a superluminescent diode and spectrometer, Topcon’s 1050-nm SS light source uses a tunable laser and photodetector. They help provide the speed advantage. According to Topcon’s vice president of product planning and management, Robert Gibson, and OCT product manager, Thai Do, the SS laser’s longer wavelength “provides better penetration through media opacities and hemorrhages, and [the laser] is not seen by the patient, which can be less distracting.”

While OCT has proved to be a versatile technology, finding applications in, among others, cardiology, dentistry and dermatology, OCT-A’s reach may not be so broad. It can, however, have a profound impact in the life sciences because “vasculature and angiogenesis play such a critical role in everything,” said Yali Jia, an assistant professor of ophthalmology and biomedical engineering at the OHSU School of Medicine.

“I think OCT-A has the potential to have broad impact. … There is a lot of work in animal models looking at vasculature changes in the brain, particularly after stroke. There is also work in otolaryngology looking at the microvasculature of the stria vascularis,” said Jia, who also helped develop the split-spectrum amplitude decorrelation angiography (SSADA) algorithm that was licensed to Optovue for its OCT-A system.

Not a standard of care … yet

OCT-A, at least in its current stage of development, will not replace FA or ICGA in the near future. Without formal treatment protocols solely based on OCT-A, ophthamologists will defer to FA, ICGA or OCT when trying to determine how to treat a patient, Ferrara said. The need to avoid invasive methods such as FA and ICGA stems from the adverse effects they can have on predominately elderly patients, such as nausea and anxiety.

“Since it is a new imaging modality and clinicians are just getting comfortable with it, it will take time for them to recognize some of the disease entities they were used to diagnosing with FA or ICG. Over time they will learn to use it alone, but may still need contrast for select complex cases,” said Mount Sinai’s Rosen.

Pintaske similarly predicted FA and ICG “will maintain a gold standard for the initial diagnosis,” though he foresaw “the more frequent follow-ups will be replaced by noninvasive procedures.” At the World Ophthalmology Congress in Guadalajara, Mexico, last February, Ferrara also spoke on ICGA’s enduring value amid the emergence of OCT-A. She does, however, acknowledge that OCT-A’s 3D imaging and high resolution in the order of microns, does allow it to detect lesions that do not show up on OCT or ICGA (Figure 5).

Figure 5. OCT-A is powerful and fast, but it cannot yet outperform older diagnostic tools. In these images of a patient with pseudoxanthoma elasticum with concomitant geographic atrophy (GA) and choroidal neovascularization, OCT-A clearly shows the extent of neovascularization. However, the BluePeak autofluorescence image best identifies the area of GA. Also shown are fluorescein angiography (FA) and indocyanine green angiography (ICGA) images. Courtesy of Heidelberg Engineering.

“It [OCT-A] is a very exciting technology, but it’s under development and a lot of refinement is needed,” Ferrara said.

Some of those areas that need improvement include projection artifacts, segmentation issues produced by variation in macular anatomy due to edema and vascular lesions, limitations in field size, and movement artifacts due to fixation demands in patients with central lesions, according to Rosen. In comparison to FA, which images the entire retina, OCT-A scans are relatively small. According to Optovue, the largest single OCT-A scan size available is 8 × 8 mm. However, technology is available to “stitch” two images together, which increases the size. Optovue also notes that OCT-A, unlike FA, cannot consistently detect certain ocular vasculature features that exhibit slow or no blood flow, such as leakage, pooling or microaneurysms.

Rosen sees OCT-A playing a key role in differentiating types of glaucoma, particularly those that are pressure-driven or more vascular in nature. That “may help identify which glaucoma suspects are more [at] risk than others for progression,” he said. OCT-A can also help neurologists and neuro-ophthalmologists determine whether immediate intervention actions are necessary in cases, for example, where there is perfusion risk of swollen nerves. However, Jia cautioned that it will take time for physicians to realize OCT-A’s full potential as a clinical tool.

“People should be prepared for a long learning curve for any new method. OCT-A also requires this learning curve. It should have more attracting advantages than FA, once people know it very well,” said Jia.

References

1. Zeiss Medical Technology. AngioPlex OCT Angiography. Product Web page. Accessed at www.zeiss.com/meditec/en_us/c/oct-angiography.html.

2. J. G. Fujimoto et al. (January 2000). Optical coherence tomography: An emerging technology for biomedical imaging and optical biopsy. Neoplasia, Vol. 2, pp. 9–25.

3. R. F. Spaide et al. (January 2015). Retinal vascular layers imaged by fluorescein angiography and optical coherence tomography angiography. JAMA Ophthalmol, Vol. 133, pp. 45-50.

4. T. E. de Carlo et al. (April 2015). A review of optical coherence tomography angiography (OCTA). Int J of Retina and Vitreous, Vol. 1, pp. 1-15.

5. Zeiss Medical Technology. Zeiss sets the pace in OCT innovation with first FDA 510(k) clearance of OCT angiography technology. Press release, Sept. 1, 2015. Accessed at www.zeiss.com/meditec/en_us/media-and-news/latest-news/zeiss-sets-the-pace-in-oct-innovation-with-first-fda-510-k-clearance-of-oct-angiography-technology.html.

OCT-A Literature: A Glimpse into the ‘New Era’ of Ophthalmology

When Dublin, Calif.-based Carl Zeiss Meditec Inc. announced last September that it had become the first company to receive U.S. Food and Drug Administration marketing clearance for optical coherence tomography angiography (OCT-A) technology, Dr. Carmen Puliafito, dean of the Keck School of Medicine at the University of Southern California, said, “OCT angiography ushers in a new era in the evaluation of the retina in diabetic retinopathy and macular degeneration.” Puliafito, one of the co-inventors of optical coherence tomography (OCT), added, “This unique capability promises to revolutionize clinical decision making in retinal pharmacotherapy⁵.”

This revolution has been years in the making. OCT-A’s origins, at least in scientific literature, can be traced to papers on Doppler OCT and the quantification of blood flow in large vessels, which started appearing in journals in the early 2000s, according to Yali Jia, Oregon Health and Science University (OHSU) assistant professor of ophthalmology and biomedical engineering. Such research evolved into OCT-A methods to visualize the microvasculature, with papers on this topic starting to appear in journals in 2007.

Since 2012, the body of scientific, peer-reviewed papers on OCT-A, which provide glimpses of the “new era” in ophthalmology, have grown exponentially. For example, a Google Scholar query finds only eight journal articles with titles including the phrases “optical coherence angiography” or “OCT angiography” in 2012, compared to 166 in 2015.

Below is a sampling of articles that are either widely cited or singled out by OCT-A experts at Optovue Inc. and OHSU at the request of Photonics Media: