New imaging technologies promise earlier diagnosis and detection and allow real-time evaluation of a patient’s response to treatment. The timing of their emergence couldn’t be better.
New retinal imaging technologies are giving clinicians and researchers the ability to quantitatively measure the retina in micrometers, irrespective of visual acuity findings. Moreover, that measurement is happening in situ and in real time.
As a result, optical coherence tomography (OCT) scanning and, to a lesser extent, the retinal thickness analyzer (RTA), are expanding the potential for early diagnosis and paving the way for evaluation of both standard and emerging treatments for a number of retinal diseases.
“Previously, ophthalmologists were limited to the clinical examination of the retina through slit-lamp biomicroscopy of the macula in conjunction with fluorescein angiography,” noted Paul Sternberg Jr., MD. “Yet with the advent of OCT, we now have a noninvasive method to measure macular thickness or swelling, for instance, bringing an entirely new dimension to the search for better diagnostic and evaluative modalities for patients.”
OCT is “a wonderful adjunct to an ophthalmic practice and it teaches you an enormous amount about vitreoretinal and vitreomacular relationships,” said Sharon Fekrat, MD. Overall, she said, “OCT offers detail that we have not had previously. Although we have not studied in the context of a clinical trial how it impacts clinical care, I would suspect that the majority of retina specialists will state that the detail provided by OCT does improve the ophthalmic care that we provide.” (See “Machine vs. Machine” for more on the RTA.)
OCT in Clinical Practice
Retina specialists are using OCT in myriad ways, including the detection and measurement of retinal detachments, assessment of macular holes, evaluation of eyes undergoing photodynamic therapy and assessment of response to new treatments such as intravitreal corticosteroid injections (see “OCT Meets Kenalog”).
Within the context of one substantial clinical challenge—detection and treatment of macular edema—retinal experts offered the following observations:
Early diagnosis. Dr. Sternberg emphasized that OCT aids in early diagnosis. “Studies have shown that you want to treat and catch macular edema early,” he said. “You can be more effective in reducing vision loss down the road if you start treatment in the initial stages—especially with diabetic macular edema, which has more treatment options. OCT goes a long way in making early detection possible.” Dr. Fekrat concurred, noting that “OCT is useful in detecting subtle macular edema that may be difficult to detect on contact lens biomicroscopy.”
Monitoring treatment. Dr. Fekrat uses OCT often for eyes with retinal vein occlusion to measure the amount of cystoid macular edema before and after a variety of treatment interventions. Other researchers have noted that OCT measures the response of CME more accurately and less invasively than fluorescein angiography.
Patient education. An additional benefit of OCT is its usefulness as a patient education tool. “The images provide a wonderful graphic to educate patients about their eye conditions,” Dr. Fekrat said.
“It is very helpful to show patients the need for treatment and the value of it,” agreed Ingrid U. Scott, MD, MPH. “With OCT, it is easy to show patients the macular edema present before treatment and the improvement of edema following treatment. And if the edema recurs, it can help patients understand why repeated treatments are necessary.”
Caveats to consider. As with any technology, there are drawbacks to take into account: OCT can produce artifacts, said Jennifer I. Lim, MD. In addition, there is a learning curve when using the device. “In a busy retina practice, it is important that someone—either the technician or ophthalmologist—have hands-on experience working with this machine,” Dr. Lim said. “We witnessed in our own practice that it took some time to accurately read and interpret OCT scans.”
Cost also is a factor; a single OCT unit costs just under $62,000.
Machine vs. Machine
How OCT works. This noninvasive, noncontact, transpupillary imaging technology can image retinal structures in vivo with a resolution of 10 to 17 µm.
OCT is analogous to ultrasound, using advanced photonics and fiber optics instead of sound to obtain images. Whereas ultrasound produces images from backscattered sound “echoes,” OCT uses infrared light waves that reflect off the internal microstructure within the biological tissues. Cross-sectional images of the retina are produced using this optical backscattering of light.
The frequencies and bandwidths of infrared light are orders of magnitude higher than medical ultrasound signals—resulting in image resolution eight to 25 times greater than any sonic modality. Consequently, the anatomic layers within the retina can be differentiated and retinal thickness can be measured.
The technique itself was invented at the Massachusetts Institute of Technology in 1991, and Carl Zeiss Meditec purchased exclusive rights from MIT to develop the technique for ophthalmic diagnostic use. It introduced the original technology commercially in 1995 and its OCT3 machine received FDA clearance in February 2002.
How RTA works. Like the OCT, the RTA provides a noninvasive method to measure macular thickness or macular swelling. However, it has not caught on in the clinical arena as quickly as has OCT. At this point, noted Barbara A. Blodi, MD, RTA is used more for research purposes.
This technology uses a computerized laser slit lamp to measure retinal thickness at the central 20 degrees of the macula and overlays a map of measurements on the patient’s retinal image. This instrument can detect and document as little as 34 µm of macular edema. Serial RTA studies can be used to monitor progression of macular thickening as diabetic macular edema increases or resolves in response to local and systemic therapy.
Talia Technology Inc. launched the research RTA (RRTA) in 1995 for the purposes of investigational studies, and in 1999 introduced its first commercial version of the RTA.
The company recently released the RTA 4.2 version, which includes a nonmydriatic disc topography option, high-resolution digital fundus imaging and 3-D disc topography.
OCT or RTA? Dr. Blodi noted that the OCT seems to provide better quality and quantitative data than the RTA. “The RTA may give you a topographical map of the retina, specifically in the macula, but that is often what we can see on clinical examination. The OCT provides slices through the tissue and that gives you a dimension that you cannot see through biomicroscopy or RTA.”
Dr. Lim added that there is “great potential for the RTA, but it has not been validated in clinical studies.”
OCT2 or OCT3? Last September, the NEI and the University of Wisconsin launched a study comparing measurements obtained using older and newer models of the OCT scanner. The rationale for the study: Multicenter trials of diseases such as macular edema are taking place at sites across the country —some of which use the older OCT2 model and some the OCT3. Thus, it is necessary to determine whether the two models give comparable results.
Whatever the outcome of this particular study, there’s no question that OCT has become invaluable in retinal research. As the NEI states in the study description, there is a “broad clinical consensus that OCT is superior to stereoscopic color fundus photography, fluorescein angiography and clinical biomicroscopic examination in measuring retinal thickness and is capable of documenting fairly small changes in thickness.”
For retinal specialists, this appears to be one of those times of confluence, when new technology meets new treatments.
For instance, within the context of treating macular edema, several treatment options are emerging. But “only one technology—laser—has gone through the rigors of a controlled, clinical trial,” said William F. Mieler, MD. “We need to move cautiously until the other technologies can be tested.”
Fortunately, OCT and RTA can advance this goal by providing groundbreaking views of the retina, helping researchers judge which treatment modalities are effective. The unprecedented view of the retina has the potential to unlock clues that previously could only be viewed ophthalmoscopically—giving researchers an edge in their search for better treatments.
OCT Meets Kenalog
The use of triamcinolone acetonide (Kenalog) has increased exponentially over the past three years, with the drug being evaluated in patients with diabetic macular edema, postoperative CME, branch retinal vein occlusion (BRVO) and central retinal vein occlusion (CRVO).
One macular edema treatment study currently being coordinated is the SCORE study,1 sponsored by the NEI. This multicenter, randomized Phase 3 trial is designed to assess the efficacy and safety of standard care vs. Kenalog injections for the treatment of macular edema associated with CRVO and BRVO.
Study rationale. Dr. Scott and her colleague, Michael S. Ip, MD, from the University of Wisconsin, submitted the initial grant proposal that led to the trial. “Preliminary short-term results concerning the use of intravitreal triamcinolone acetonide injections to treat macular edema associated with a variety of etiologies are promising,” Dr. Scott said.
However, she noted, improvements observed both anatomically (on clinical examination and by OCT testing) and functionally (in terms of visual acuity) are often transient. “Thus, the question becomes, what is the cost/benefit ratio of repeated injections of a steroid into the eye?”
Dr. Scott pointed out that intravitreal steroid injections may be associated with a number of side effects, including cataract formation and elevated IOP. In addition, there are potential adverse events associated with the injection procedure itself, such as endophthalmitis (infectious or noninfectious), retinal detachment, vitreous hemorrhage and lens injury. “We don’t have long-term results of this approach,” she said, “and what we do have are just case reports and case series. The SCORE study will permit evaluation, in a standardized fashion, of efficacy and safety.”
The study will include three treatment arms: standard care (observation for patients with CRVO; grid laser photocoagulation for patients with BRVO without dense macular hemorrhage; observation with grid laser photocoagulation if and when the hemorrhage clears for patients with BRVO with dense macular hemorrhage) and two different doses of intravitreal steroids (1 milligram vs. 4 mg).
“Currently, the most commonly employed dose for intravitreal triamcinolone acetonide injections is 4 mg, although there are no scientific data to inform us that this is the optimum dose,” Dr. Scott said. “We want to see if we can achieve the same beneficial outcomes with a lower dose. This may permit us to achieve the same efficacy outcome while lowering the rate and severity of associated adverse events.”
OCT’s role. “OCT is helpful in quantifying the response to treatment,” said Dr. Scott, “and while it certainly does not replace the clinical examination, it provides a degree of precision on a quantitative level that clinicians previously have not had available.”
OCT was useful in the preliminary study, conducted at the Universities of Wisconsin and Miami, of Kenalog for CRVO. In a retrospective review of 13 patients with macular edema with CRVO who were treated with an intravitreal injection of the drug, OCT demonstrated significant anatomic improvement in a majority of the patients.2
The timing is right for the SCORE study. While Kenalog appears promising, “Right now, we know that steroid injections are not permanent, and the benefit lasts for only a few months,” said Dr. Mieler. “And the downsides are often daunting. Researchers are looking at sustained-release devices in the eye that may provide a more sustained response, but these too must undergo rigorous testing.”
1 Stands for “Standard Care vs. Corticosteroid for Retinal Vein Occlusion.”
2 In press, Arch Ophthalmol.
Meet the Experts
Barbara A. Blodi, MD Associate professor of ophthalmology and visual science at the University of Wisconsin. Financial interests: None.
Sharon Fekrat, MD Associate professor of ophthalmology and faculty director of the Duke Eye Imaging Services at Duke University. Financial interests: None.
Jennifer I. Lim, MD Associate professor of ophthalmology at the University of Southern California and medical director of clinical trials at the Doheny Retina Institute, Doheny Eye Institute. Financial interests: None.
William F. Mieler, MD Professor and chairman of ophthalmology at the University of Chicago. Financial interests: None.
Ingrid U. Scott, MD, MPH Associate professor of ophthalmology at the University of Miami. Financial interests: None.
Paul Sternberg Jr., MD Professor and chairman of ophthalmology and visual sciences at Vanderbilt University. Financial interests: None.