RETINA CLINICAL UPDATE Looking Deep Into the Eye: New Insights on the Choroid he choroid is regarded as some- thing of a black box, obscured Tas it is by the retinal pigment epithelium (RPE), under which it sits. With recent advances in imaging, how- ever, the lid has been lifted off the box. Most high-end optical coherence tomography (OCT) systems currently available allow ophthalmologists to see in vivo this highly vascular layer of the eye that lies between the retina and sclera. With these tools, ophthalmol- ogists can begin to understand how the vasculature changes and how that COMPARISON. This pair of images shows a healthy choroid (left) and a degenerat- affects disease states, said Gerard A. ed one with drusen (right). Lutty, PhD, at the Wilmer Eye Institute in Baltimore. OCT (the latter has yet to be approved Lutty said could lead to preventive Seeing the choroid not only makes it in the United States for visualizing the treatment. “In our work, we have seen more accessible to clinicians but is also choroid). Unlike EDI-OCT, which gives that the small vessels in the choroid die changing the management of certain a cross-sectional view, OCT-A is usually in AMD.”1 He added, “You can actual- diseases, said Glenn C. Yiu, MD, PhD, at viewed en face, as a bird’s-eye view. ly see when these small blood vessels the University of California, Davis. And It uses superfast scanning to visualize don’t have blood cells in them. If you in terms of research, more attention is blood flow, and it can focus at different knew the small blood vessels were not being paid to this tissue that supports levels to provide information on both functional [no blood cell movement], the photoreceptors with oxygen and retinal and choroidal vessels. “There is you could predict where choroidal neo- nutrients, said Robert F. Mullins, MS, tremendous excitement surrounding vascularization [CNV] might form, and PhD, at the University of Iowa (see OCT-A, especially because you do not it might allow you to treat the patient “Research Update”). need to inject dye, so it is much faster prophylactically.” [than fluorescein angiography],” Dr. EDI-OCT is a software application OCT-A and EDI-OCT Yiu said. Although OCT-A cannot show built into newer SD-OCT machines, This latest facet of the imaging revolu- dye leakage in the traditional way, ves- said Gregory Hoffmeyer, who is with tion is being driven primarily by OCT sel details also aren’t affected by leaking Carl Zeiss Meditec. It takes advantage angiography (OCT-A) and enhanced- dye, giving unprecedented details of of the greater depth and choroidal depth imaging OCT (EDI-OCT). small vessels, he added. details of the image that the machine OCT-A is an application for spectral- High-resolution OCT-A reveals generates, and the cross-sectional view domain (SD-OCT) and swept-source movement of blood cells, which Dr. exposes all the layers of the choroid, from the large vessels to the chorio- capillaris. Researchers using EDI-OCT BY MIRIAM KARMEL, CONTRIBUTING WRITER, INTERVIEWING GREG have found that some conditions co- HOFFMEYER, GERARD A. LUTTY, PHD, ROBERT F. MULLINS, MS, PHD, AND incide with either abnormal thickening Robert F. Mullins, MS, PhD F. Robert GLENN C. YIU, MD, PHD or thinning of the choroid. EYENET MAGAZINE • 33 Ophthalmologists who want to see roid involves polypoidal choroidal vas- determine if certain subtypes may be the choroid can ask the technician to culopathy, which is often treated with more responsive to anti-VEGF therapy. use the EDI feature, said Mr. Hoffmeyer. anti-VEGF agents and PDT. There is For example, Dr. Yiu said, a CNV with However, he cautioned, on some ma- evidence that the anti-VEGF agents can mature, large-caliber vessels may be chines, you may lose some resolution in reduce leakage, but PDT may be better more resistant to anti-VEGF therapy the retina when you click on EDI. at getting the polyps—which extend and may be a better candidate for peg- from the choroid into the subretinal pleranib (Fovista), an agent that blocks Potential Applications space—to regress, Dr. Yiu said. platelet-derived growth factor and is EDI-OCT for pachychoroid diseases. OCT-A for neovascular disease. “We currently undergoing clinical trials. These include a spectrum of conditions used to classify CNV based on leakage EDI-OCT for tumors. Most ocular with abnormal thickening of the large patterns on fluorescein angiography,” tumors, malignant or benign, originate choroidal vessels. A thickened choroid Dr. Yiu said. Then OCT came along in the choroid. In the past, tumors were may arouse suspicion of central serous and allowed ophthalmologists to quan- measured with B-scan ultrasound, but chorioretinopathy (CSC), Dr. Yiu said. tify the amount and location of leakage shallow tumors were hard to image. Increased choroidal thickness helps in AMD. “With the advent of OCT-A, EDI-OCT makes it possible to char- distinguish CSC from other conditions we can now visualize the structure of acterize small tumors in the choroid. and can help guide treatment. For the CNV more clearly, as details are not The technology also provides a way to example, after photodynamic therapy obscured by dye leakage. We can see if identify lesions arising from the sclera, (PDT) for CSC, resolution of subretinal a CNV complex is composed primarily such as sclerochoroidal calcifications, fluid may be associated with choroidal of finer capillary vessels or has a more which are benign, Dr. Yiu said. thinning over time. branched, arteriolized appearance.” EDI-OCT for uveitis. The use of Another benefit of seeing the cho- The ability to classify CNV may help EDI-OCT in uveitis is in early stages. protect the choroid in early disease from further degen- Research Update eration caused by an overactive complement system. In more advanced disease, where the loss of the choroid is Some areas under investigation include the following. more substantial, cell replacement therapy will be neces- Choriocapillaris in AMD. Dr. Mullins is trying to deter- sary. These advanced eyes may also have loss of RPE and mine which cells in the choriocapillaris are damaged early photoreceptor cells, he added. in the disease process and which survive. Using donor Antiangiogenesis. Dr. Lutty’s lab focuses on angiogen- eyes with early AMD and age-matched controls, his lab ic factors that stimulate new blood vessels as well as on has found that a larger number of drusen corresponds naturally occurring inhibitors of angiogenesis. Recent stud- to a greater loss of vasculature in the choriocapillaris. ies demonstrate that 3 antiangiogenic factors (thrombo- This suggests a link between blood vessel death and the spondin-1, endostatin, and pigment epithelium–derived earliest indication of AMD, he said. “We’re finding more factor) are reduced or missing, making the AMD choroid and more evidence that AMD is a disease that afflicts the susceptible to choroidal neovascularization.2 choroid and strikes it early.” Dry AMD. Dr. Lutty is working in animal models of dry The complement system. This system of proteins, AMD to see whether it is possible to replace cells lost to which is activated when it recognizes a foreign pathogen, the disease, including the cells that make up the choroi- can become overactive. Knowing that, Dr. Mullins ques- dal blood vessels. Because no drug can replace these tioned whether it might be overactive in a person with cells (the photoreceptors, RPE, and choriocapillaris), he AMD. The answer: The membrane attack complex was believes that we must rebuild this complex with several more abundant in patients with AMD. “And the location types of progenitors, including those for photoreceptors is right at the choriocapillaris,” he said. “We know the and RPE cells. “We know that choroidal vasculature is complement system is pushing AMD along.”1 affected in both wet and dry AMD. And there’s a group of This insight runs contrary to the theory that AMD is an retinal degenerations in which the choroid dies,” such as RPE disease, Dr. Mullins said. Yet in terms of the com- retinitis pigmentosa and Stargardt disease, Dr. Lutty said. plement system, it appears that the choroid is the site of “If there’s a drug for dry [AMD], it’s only going to stop the injury in many patients with AMD. “In these patients, the progression of atrophy, but it will still leave an atrophic RPE probably died because the choroid failed first.” Now region where you’ve lost the 3 cell types already,” he Dr. Mullins and his colleagues are exploring ways to repair added. The future, he said, holds the potential for gene a damaged choroid using choroidal endothelial cells gen- therapy to stop further degeneration and death of surviv- erated by induced pluripotent stem cells, which are taken ing photoreceptors. from any tissue in the patient and genetically modified to behave like embryonic stem cells. 1 Mullins RF et al. Am J Pathol. 2014;184(11):3142-3153. Some day, he said, researchers may find drugs to 2 Bhutto IA et al. Arch Ophthalmol. 2008;126(5):670-678. 34 • MAY 2016 For instance, in the case of Vogt-Koyan- agi-Harada syndrome, in which marked thickening of the choroid occurs, it is unclear how much of this thickening is due to inflammation or exudation, Dr. Yiu said. Treatment of this disorder may result in thinning of the choroid, although researchers don’t know wheth- er this is a treatment effect or natural Enhance progression of disease resolution. What’s Next? Care With Ophthalmologists are at that peculiar juncture where technology outpaces their ability to harness it.