American Academy of Ophthalmology Web Site: www.aao.org
Sharpening The Picture
Ophthalmic Imaging Advances With Ultra-Wide-Angle FA, SD-OCT and Fundus Autofluorescence.
Among medical specialties, ophthalmology enjoys a big advantage: Much of the eye’s anatomy is rendered quite visible by the transparent media of aqueous and vitreous. Now a number of 21st-century technologies are “looking” beyond even the eye’s own transparency to divine the signs of health and disease.
Contemporary imaging advances are permitting the visualization of ocular structures and disorders as never before—producing ever more detailed images that can capture the subtlest of pathologies. These technologies—spectral-domain optical coherence tomography, fundus autofluorescence and ultra-wide-angle fluorescein angiography—were, at first, considered to be the purview of retina specialists. But now glaucoma and anterior segment surgeons are benefiting as well, using these imaging techniques to scrutinize the corneal and lenticular zones of the eye. What follows is a bird’s-eye view of these technologies and their ophthalmic applications.
Spectral or Fourier-domain OCT (SD-OCT) is an improvement over conventional or time-domain OCT (TD-OCT) because of its three-dimensional, high-speed, high-resolution capabilities, which offer a “virtual biopsy” of ocular structures. “Because it’s able to capture more information at a faster rate of speed and at a higher resolution, we can see much more detail than in time-domain OCT—enabling us to display the retina in a three-dimensional format and to isolate layers, both en face and cross-sectionally,” said Michael P. Kelly, CPT, manager of Duke Eye Center Labs at Duke University. SD-OCT machines also provide a two-dimensional fundus image that correlates exactly with the cross-sectional image.
Enhanced sensitivity. The most common use of SD-OCT is in diagnosing and treating age-related macular degeneration. The acquisition speed and the detail of SD-OCT can capture pathology that’s not evident with TD-OCT, and it produces fewer artifacts, according to Todd J. Purkiss, MD, PhD, in private practice at Kentucky Eye Care in Louisville. Dr. Purkiss recalls the case of a patient with bilateral retinal angiomatous proliferation in which a clinical exam on the left eye revealed no blood or obvious thickening of the retina, although the patient’s vision was reduced in the right eye from a recent hemorrhage. By using SD-OCT along with a fluorescein videoangiogram, Dr. Purkiss was able to pinpoint an area of thickening corresponding to a vascular abnormality in the asymptomatic left eye—an early angiomatous lesion. The same lesion was missed by a TD-OCT scan obtained at another facility.
Visit-to-visit tracking. The Heidelberg Spectralis SD-OCT also has software with eye tracking capabilities, enabling comparisons between scans of patients at different follow-up visits. “The software and the speed of the scans in SD-OCT allow you to align scans from visit to visit, and you can track response to treatment much more accurately than with time-domain OCT,” Dr. Purkiss said. Because SD-OCT scans are so quick, patients don’t have to keep their eyes still and open for as long a time, and fewer scans need to be taken in order to obtain accurate images of retinal pathology, he added.
Front-of-the-eye capability. Some SD-OCT devices can be used to image the anterior segment of the eye—to look at the curvature and thickness of the cornea, to identify pathology within it, such as growing tumors, and to analyze outcomes for patients who’ve had corneal surgery, for instance. “It’s a very powerful noninvasive tool that will become more widely used as the advantages become better known among ophthalmologists in the community,” Dr. Purkiss said.
Value for glaucoma monitoring. SD-OCT is also being used by some ophthalmologists to identify structural and functional abnormalities in glaucoma. Researchers are asking if it can provide a means of demonstrating early nerve fiber layer loss or early ganglion cell loss in patients who are glaucoma suspects. “If we could identify these very early losses, then we can catch glaucoma at an early stage and treat it before it becomes advanced,” said Sanjay G. Asrani, MD, associate professor of ophthalmology at Duke University.
Using reproducible measurements of the retinal nerve fiber layer (RNFL) and the ganglion cell layer from SD-OCT could also help clinicians establish much more accurately than visual field tests whether glaucoma is progressing, Dr. Asrani said. “We are looking into the questions of what is the earliest stage of glaucoma and the smallest change or loss of tissue that SD-OCT machines can pick up.” Dr. Asrani’s research indicates that measurements of the RNFL and ganglion cell layer in the eyes of patients with glaucoma are highly accurate and reproducible. Yet he noted that SD-OCT may not be useful in some glaucoma patients, such as those who have coexisting macular degeneration or diabetic retinopathy and have already developed macular thickening or swelling that makes it difficult to diagnose glaucoma-related retinal loss.
Using SD-OCT in research development, Dr. Asrani and colleagues at Duke were able to image Schlemm’s canal and the trabecular meshwork in six healthy subjects and six with glaucoma in an observational cross-sectional study.1 The study was the first to show that SD-OCT could be used to image the full depth of the anterior chamber.
These images could be very useful in expanding an understanding of pupillary block syndrome, plateau iris syndrome and possibly malignant glaucoma, Dr. Asrani said. They could also help clinicians accurately distinguish between open-angle and angle-closure glaucoma. Some patients appear to have open-angle glaucoma on standard testing, but after undergoing SD-OCT, the angles actually are shown to be narrow, Dr. Asrani said. By using SD-OCT, the root cause could be correctly identified, avoiding the complications of treating the “wrong” etiology.
Accurate imaging of the trabecular meshwork and Schlemm’s canal could also help researchers understand the pathogenesis of open-angle glaucoma, Dr. Asrani said. He predicts that SD-OCT systems could eventually be adapted to operating microscopes to allow easier, more accurate and more efficient surgeries on structures such as Schlemm’s canal. Those systems will not, however, be able to see behind the iris to the ciliary body, which is important in addressing plateau iris syndrome and malignant glaucoma.
Fundus autofluorescence (FAF) has recently pole-vaulted from a research tool to a real clinical application. Autofluorescence is a means by which both the retina’s morphology and metabolic changes can be assessed. It can be used to determine lipofuscin accumulation—a key clue to the health of the retinal pigment epithelium, especially in diseases such as AMD. “Those areas that image as dark or black (hypo-autofluorescence) indicate an area of atrophy in the retinal pigment epithelium, while normal retinal pigment epithelium appears gray overall,” Mr. Kelly said. “By contrast, with hyper-autofluorescence we know we are delineating an area under stress and at very high risk.”
Spotting dry degeneration. Autofluorescence can also identify the geographic atrophy typical of dry AMD. With autofluorescence, the high-contrast difference between atrophic and nonatrophic areas of the retina permits accurate assessment of the progression of atrophy and could be important in studying new interventions for dry AMD, according to Lawrence A. Yannuzzi, MD, professor of clinical ophthalmology at Columbia University.
Targeting genetic dystrophies. Autofluorescence can be used to pick up abnormalities within the retinal pigment epithelium that are typical of genetic disorders, such as Stargardt disease and cone dystrophies. “With autofluorescence, we can recognize cells at risk and document those that are no longer viable and have become atrophic,” Dr. Yannuzzi said. “The delineation of these cells is very precise.” Autofluorescent imaging may allow noninvasive assistance in diagnosis and help to monitor the rate of progression in genetic and cone dystrophies, he added.
Catching PEDS. Another application of autofluorescence is documentation of pigment epithelial detachments (PEDs) secondary to age-related macular degeneration, according to a report published in Retina.2 “Most PEDs have a corresponding marked, evenly distributed increase of the FAF signal over the lesion surrounded by a well-defined, less autofluorescent halo delineating the entire border of the lesion,” the authors write. They note that more work is needed to categorize the appearance of PEDs on FAF, and how to correlate these with fluorescein angiography and OCT.
Cornering chorioretinopathy. Central serous chorioretinopathy, a condition that can lead to serous retinal detachment, can also be documented by autofluorescence, since the condition is associated with atrophic and degenerative changes in the retinal pigment epithelium, according to the authors of the same report. They note that patients with acute progressive central serous chorioretinopathy show an irregular pattern of increased autofluorescence while those with chronic disease show irregular autofluorescence with decreased intensity over areas of atrophy. Autofluorescence patterns around the leaks in the retinal pigment epithelium that occur with central serous chorioretinopathy also show changes over time, as the condition progresses.
Ultra-wide-angle fluorescein angiography is another tool for assessing the health of the retina. Some ultra-wide-angle fluorescein angiography units can visualize as much as 82 percent of the retina in one view, Mr. Kelly said. In contrast, standard fundus cameras can visualize only 11 percent of the retina—meaning that many photographs must be taken to get a full documentation of the retina. With ultra-wide-angle fluorescein angiography, the periphery and the posterior pole can be visualized at the same time and in the same frame.
Multiple uses. Developers who are marketing ultra-wide-angle FA include Heidelberg Engineering—which makes both the Spectralis and the HRA2 units—and Optos, as well as RetCam for pediatric patients. The technology is helpful in the diagnosis and follow-up of patients with diabetic retinopathy or vascular occlusions, as well as those with AMD, intraocular tumors such as choroidal melanoma and sickle-cell retinopathy, according to Mr. Kelly. “With standard fluorescein angiography, we’ve always studied the microangiopathy at the posterior pole down to details of the perifoveal capillary net; we now can do the same all the way out to the far periphery—similar to ‘Google-Earth’ zooming in to assess areas of capillary nonperfusion and retinal neovascularization.”
Using standard fluorescein angiography devices to visualize the entire retina requires a skilled photographer, a cooperative patient and wide dilation of the pupil to see outside the macula, said Ivan J. Suner, MD, a retina specialist in private practice in Tampa, Fla. “Ultra-wide-angle fluorescein angiography allows us to better classify patients in terms of what is really happening in the retina—whether these patients have diabetic retinopathy, vein occlusions or inflammatory conditions.” Because ultra-wide-angle fluorescein angiography has a wide depth of field, the images are sharper than those of standard fluorescein angiography.
DME. Dr. Suner said that while some patients with diabetic macular edema have leakage in the macula, others have leakage caused by peripheral nonperfusion. As a response to peripheral nonperfusion, the eye upregulates VEGF production, and the blood vessels become more permeable. So Dr. Suner is using ultra-wide-angle fluorescein angiography to classify patients with DME, and to test a new treatment for those with peripheral nonperfusion.
In a clinical trial sponsored by Genentech, those with peripheral nonperfusion will be randomized to treatment with macular laser and steroid (the standard therapy) or to peripheral laser in combination with ranibizumab (Lucentis). “By treating the areas of peripheral nonperfusion, we’re hoping to change the underlying biologic driver of the diabetic macular edema—ischemia—that affects these patients and provide more permanent results than standard therapies, which often require multiple retreatments,” Dr. Suner said.
By assessing the degree of peripheral perfusion in diabetic macular edema, clinicians can stratify patients and better choose the best intervention, said Scott W. Cousins, MD, professor of ophthalmology and director of the Duke Center for Macular Disease at Duke University. “If there’s poor peripheral perfusion, we assume that comes from too much VEGF production, and we can use anti-VEGF therapy as an initial therapy. We’ll also consider doing scatter laser of their nonperfused retina rather than grid laser. But if we see diffuse leakage and good peripheral perfusion, then we’ll consider a steroid injection first,” he said. With good peripheral perfusion but lots of microaneurysms in the macula, the traditional grid laser or focal grid laser would be the initial approach, and then a secondary treatment would be steroid injections, he added. “It’s a different way of managing diabetic macular edema than what is currently used in the standard approach, and stratification of patients for different types of treatment is made possible by the images produced by ultra-wide-angle fluorescein angiography.”
CRVO. Dr. Suner has also used ultra-wide-angle fluorescein angiography to visualize conditions such as central retinal vein occlusion and branch retinal vein occlusion. “We’ve been surprised to find that although CRVOs have edema in the center of the retina, they also have areas of nonperfusion in the periphery. And this peripheral nonperfusion, which then leads to macular edema, can be treated with laser therapy.”
Mr. Kelly notes that some SD-OCT units are multifunctional—able to simultaneously capture retinal fundus photos, autofluorescence, infrared, high-speed indocyanine green angiography (ICG) or fluorescein angiography, along with SD-OCT. High-speed ICG allows visualization through fluid and blood to identify underlying neovascularization secondary to AMD when it would be ill-defined on fluorescein angiography.
Multimodality machines improve efficiency by eliminating the need to move patients from machine to machine and also enable point-to-point comparison of 2-D images, such as fluorescein angiography, with those from SD-OCT, Mr. Kelly said. “When we use SD-OCT in combination with fluorescein angiography and/or ICG, we can see a cross-sectional view of clinical features, such as abnormal blood vessel growth and its surrounding disrupted tissue architecture. These capabilities aid in determining etiology and, in turn, assist clinicians in choosing from the appropriate available treatments.”