RETINAL IMAGING Imaging for Diabetic An overview of the module of the Heidelberg Retina Tomograph 3.

BY KEMENI E. TENKU, BS; MALIK Y. KAHOOK, MD; CULLEN BARNETT COT, CRA; NARESH MANDAVA, MD; AND SCOTT C. N. OLIVER, MD

maging techniques used in assessing retinal anatomy Light that is deeper or shallower than this focal plane is sup- have evolved from photography to stereophotography pressed to provide an optical section of the retina corre- to fluorescein angiography, and now include several sponding to a specific focal plane or depth. Therefore, the Ilaser-based imaging devices. Various retinal diseases, 2-D image acquired at a focal plane carries only information such as diabetic macular edema (DME), age-related macular of the object layer located at that focal plane. By automati- degeneration (AMD), and vascular occlusive disease, lead to cally shifting the confocal aperture, optical sections of up to swelling within the retina and subsequent vision loss. 64 at focal planes (depths) can be obtained to create a 3-D Quantifying these changes is important for diagnosis and image (Figure 2). follow-up. In addition, accurate and reproducible measure- ments are essential to determine whether therapeutic inter- THE RETINA MODULE TECHNOLOGY ventions are causing anatomical improvement. The The field of view over the macula scan is 15o x 15o, Heidelberg Retina Tomograph (HRT; Heidelberg approximately 4.5 x 4.5 mm, and the tissue around the Engineering, Vista, CA) is a confocal scanning laser ophthal- fovea is scanned to a depth between 1 and 4 mm, which moscope (SLO) platform that obtains topographic images is automatically adjusted based on the thickness of the of ocular anatomy. DME is a principal application under tissue. The image produced has a transverse optical reso- investigation using the retina module of the HRT. This article lution of 10 um/pixel. The 2-D digital image obtained per summarizes the basics of the HRT retina module and report optical section has a resolution of up to 384 x 384 pixels. pertinent applications for diabetic retinal disease. Z-axis penetration may achieve depth resolution up to 64 pixels, and analysis of Z-profile signal width reliably RETINA IMAGING TECHNOLOGY quantifies macular thickening.1 Three series acquisitions The Heidelberg Retina Tomograph 3 (HRT 3) utilizes con- are obtained for each study, with typical intermeasure- focal scanning laser technology to capture images of the ment variability of less than 30 µm. The data is analyzed , , and retina. Images of the retina are and presented to the clinician for interpretation. obtained with a rapid scanning class I 670-nm diode laser to acquire and analyze 3-D images of the posterior segment. The laser beam is emitted and travels through a confocal pinhole before being focused on a single point on the retina. The emitted beam is redirected in the x-axis and y-axis along a plane of focus perpendicular to the optical axis (z-axis), using two oscillating mirrors to obtain a 15o x 15o image. The reflected light is separated from the incident beam, deflected by a beam splitter and passed through a confocal imaging aperture (diaphragm) to reach a lumi- nance detector. Point images are combined digitally to pro- duce a 2-D image (Figure 1). The confocal aperture allows only light reflected from a Figure 1. Graphic representation of the confocal scanning certain focal plane (depth) to reach the luminance detector. laser ophthalmoscopy.

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to obtain the value of the retinal thickness for each of the nine zones (Figure 4). Retinal thickness values in microns are shown for each of the nine zones. Simulated color topography allows for quali- tative assessment. The retinal thickness map also calculates retinal volume in cubic millimeters for each of the 9 zones (Figure 5). In addition to the 2-D thickness map shown above, an interactive 3-D retinal thickness map can be produced. This interactive 3-D image provides a 3-D view of the retina allowing physicians to easily see where thickening has occurred. Reflectance Image. The reflectance image or map is a false color image that resembles a retinal photograph. It captures the differences in the surface appearance of the retina. It enables the interpretation of both the retina index and reti- Figure 2. Acquisition of 3-D image by compiling multiple na thickness in light of visible anatomical fundus abnormali- 2-D sections. ties. It also allows estimation of study quality based on clari- ty and brightness of the image obtained (Figure 6). RESULTS Three algorithms are used to analyze data obtained with COMPARISON WITH OTHER RETINAL the HRT3 retina module: the Retinal Edema Index, the SCANNING TECHNIQUES Retina Thickness Map, and the Reflectance Image. The importance of the edema index in the evaluation of The Retinal Edema Index. The edema index map (retinal DME has already been established, as changes in the edema edema index) is a grayscale image that reveals areas of rela- index have been shown to correlate with changes in visual tive macular thickening. Distortion of normal reflectivity function.2 In the same study, the edema index values were due to topographic surface abnormalities results in a shown to have high reproducibility between measurements. “stretched” signal that can be converted to retinal edema Intraobservation variability has been reduced to less than index values. Detection of macular surface irregularity using 15% for macular volume mapping.3 Further validation of HRT3 prior to clinical detection of macular edema is a valu- HRT volumetric measurements were performed by able potential application (Figure 3). Zambarakji and coworkers,4 who demonstrated a high cor- The edema map is divided into a nine-zone grid using relation between three examinations for both intraobserver three concentric circles with radii of 500 µm, 1000 µm, and (P<.001) and interobserver variability (P<.001).4 1500 µm, divided into quadrants. Each zone is analyzed sep- Due to high specificity and good sensitivity of HRT topo- arately and an edema index for that zone is determined graphic assessment, the HRT retina module has been used (Figure 3). The position of the nine-zone grid can be manu- as a screening modality for the detection of diabetic macu- ally adjusted, and the new position is used automatically for lopathy. Early studies of volumetric mapping using HRT all additional analyses of the same patient in order to minimize variability. Normal edema index values are 1.10 ± 0.30 arbitrary units (au). Values between 1.50 au and 1.80 au are consid- ered borderline and greater than 1.80 au is out- side normal limits. The Retinal Thickness Map. The retinal thick- ness map gives absolute micrometer measure- ments of the thickness of the nine zones around the fovea. Unlike the edema index, which uses just the vitreoretinal interface, the retinal thick- ness function localizes both the internal limiting membrane (vitreoretinal interface) and the reti- Figure 3. Edema index map (left) and edema index (right) of a normal nal pigment epithelium, and produces two signal macula. Measured values are compared against standardized values to peaks. The difference between the peaks is used determine edema index value.

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thy in another report on the same study.10 In both studies, FA complemented clinical examination by revealing subtle changes and identifying perfusion and leakage abnormali- ties. In a small series, HRT demonstrated agreement with FA, and was slightly more sensitive than early-generation optical coherence tomography (OCT), for the detection of DME.11 In another series using FA as the standard for diagnosing DME, HRT was noted to have higher sensitivity but lower specificity than OCT.12 DME may be treated with laser, intravitreal steroid injec- tion, intravitreal anti-VEGF injection, and surgery. In one study, injection of triamcinolone acetonide 8 mg resulted in an improvement in vision of 0.43 logMAR units, which cor- Figure 4. The major signal peaks detected by the light scans responded to a 36% reduction in the MEM values on HRT at the internal limiting membrane and the retinal pigmented at 6 months (P<.001).13 In a study of a single injection of epithelium.The distance between these peaks determines bevacizumab 2.5 mg, logMAR visual acuity improved by macular thickness. 0.32 units, while the HRT MEM values significantly decreased by 33.3% (P<.001).14 This demonstrates that the found a sensitivity of 79% and a specificity of 85% compared HRT can also be used to accurately track anatomic improve- to clinical examination.5 A new scoring system for macular ments from treatment. edema by Hudson and colleagues6 had a specificity of 99% OCT has been extensively used to evaluate DME.15,16 OCT and sensitivity of 67% in hospitalized diabetic patients. measures the echo time delay and intensity of reflected In another study, the macula edema maps (MEMs) of 820 nm light beams on the posterior chamber of the eye. HRT II were compared with fundus biomicroscopy.7 Good Using OCT, high resolution 2-D cross-sectional images of agreement in identifying areas with DME was observed, the internal microstructure of the posterior ocular struc- with a Kendall coefficient of concordance of 0.80 (P<.01).7 tures are generated, including the retinal nerve fiber layer The Retinal Thickness Analyzer (RTA; Thalia/Marco, (RNFL), , and macula. Jacksonville, FL) is different technique used for the objective The use of OCT in the evaluation of DME focuses on the assessment of DME. It works on the principal of slit-lamp computation of the retinal thickness/volume of the macula. fundus biomicroscopy (FB), where vertical slits are scanned It has been demonstrated that macular thickness can be sequentially across the area of the retina to generate a topo- quantified with OCT.17 Hee and coworkers18 demonstrated graphic map of the retinal thickness. Guan and coworkers8 that the central macular thickness measured by OCT corre- recently demonstrated that the retina module of HRT 2 lates with visual acuity with a sensitivity greater than that of offered an improved sensitivity (92%) and a comparable slit-lamp biomicroscopy. In addition, they commented that specificity (68%) in the detection of DME compared to the even in the absence of fluorescein leakage, there could be RTA, which had a sensitivity of 57% and a specificity of 71%. increases in retinal thickness and loss of visual acuity. Fluorescein angiogra- phy (FA) is a long-estab- lished standard for evalua- tion of DME. In the Early Treatment Diabetic Study,9 FA was used as key investiga- tive technique for the classification of . Diffuse capil- lary leakage was one of the risk factors that was closely associated with the severity or progres- Figure 5. Retinal thickness map of a normal patient. Retinal thickness and volume is calculated sion of diabetic retinopa- for each macular zone.

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be able to detect early DME, so that it can be used as a screening tool. ■

Malik Y. Kahook, MD, is an Assistant Professor in the Department of Ophthalmology at the University of Colorado Denver, and Director of Clinical Research at the Rocky Mountain Lions Eye Institute. Naresh Mandava, MD, is Professor and Chair of the Department of Ophthalmology at the University of Colorado Denver. Scott C. N. Oliver, MD, is an Assistant Professor in the departments of Ophthalmology and Medicine, Division of Medical Oncology, and serves as Director of the Ophthalmic Oncology Center at the University of Colorado, Denver.

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