Optical Coherence Tomography in Retinal Diseases Sandeep Saxena, Travis A Meredith
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Optical Coherence TomographyCHAPTER 1

Sandeep Saxena,
Travis A Meredith
2
 
INTRODUCTION
A retina specialist uses a variety of imaging techniques to evaluate retinal pathology. Fundus photography, fluorescein and indocyanine green angiography, and ultrasonography, are among the frequently used methods. However, these techniques do not give detailed information regarding cross-sectional retinal anatomy, and do not provide quantitative retinal thickness measurements.
New emerging medical imaging technologies can improve not only the diagnosis and clinical management but also the understanding of pathogenesis of disease. Therefore, they promise to have a significant impact in clinical practice and research. Imaging instruments, including optical coherence tomography (OCT; Carl Zeiss Meditec Inc., Dublin, California, USA), the Retinal Thickness Analyzer (RTA; Talia Technology Inc., Tampa, Florida, USA), and the Heidelberg Retinal Tomograph (HRT; Heidelberg Engineering, Heidelberg, Germany) have been used to produce cross-sectional and surface topographic retinal images, and quantitative retinal thickness data.
A need has existed in medicine for a technology capable of ‘optical biopsy,’ imaging at or near the resolution of histopathology without excisional biopsy.1 Advances in optics, fiberoptics, and laser technology have led to the development of a noncontact, high-resolution optical biomedical imaging technology, called optical coherence tomography (OCT).2-5 In 1990, OCT was invented at the Massachusetts Institute of Technology in Boston. In 1993, the first in vivo human retina images were obtained. In 1995, the first clinical retinal images were obtained.
Optical coherence tomography is a new technique for high-resolution cross-sectional visualisation of retinal structure.6 Optical coherence tomography achieves 2- or 3-dimensional cross-sectional imaging of retina by measuring the echo delay and intensity of back-reflected infrared light from internal tissue structures. Using a classic optical measurement technique known as low-coherence interferometry7-13 in combination with special broad-bandwidth light, OCT achieves high-resolution, cross-sectional visualisation of tissue morphologic characteristics at depths significantly greater than the penetration depth offered by conventional bright-field and confocal microscopy.
A- and B-scan ultrasonography require physical contact with the eye and are routinely used in ophthalmic diagnosis, with a typical longitudinal resolution of 150 µm.14,15 Imaging with OCT is analogous to ultrasound B-scan in that distance information is extracted from the time delays of reflected signals. However, the use of optical rather than acoustic waves in OCT provides a much higher (≤ 10 micron) longitudinal resolution in the retina versus the 100-micron scale for ultrasound. This is due to the fact that that the speed of light is nearly a million times faster than the speed of sound. Use of optical waves also allows a non-contact and noninvasive measurement. This technique is presently being used increasingly to evaluate and manage a variety of retinal diseases. Optical coherence tomography has been used to identify epiretinal membranes and macular holes, to differentiate macular holes from simulating lesions, to identify lamellar macular holes, macular cysts, vitreomacular traction, subretinal fluid, pigment epithelial detachment, and choroidal neovascularisation. It can be used to identify and quantify macular edema, and to measure retinal thickness changes in response to therapy.16 The ability to non-excisionally evaluate tissue can have a significant impact on the diagnosis and management of a wide range of diseases.173
 
BASIC PRINCIPLE
Optical coherence tomography is based on the principle of Michelson interferometry.7-13 Low-coherence infrared light coupled to a fiber-optic travels to a beam-splitter and is directed through the ocular media to the retina and to a reference mirror, respectively. Light passing through the eye is reflected by structures in different retinal tissue layers. The distance between the beam-splitter and reference mirror is continuously varied. When the distance between the light source and retinal tissue is equal to the distance between the light source and reference mirror, the reflected light from the retinal tissue and reference mirror interacts to produce an interference pattern. The interference pattern is detected and then processed into a signal. The signal is analogous to that obtained by A-scan ultrasonography using light as a source rather than sound. A two-dimensional image is built as the light source is moved across the retina. The image is in the form of a series of stacked and aligned A-scans, which produces a two-dimensional cross-sectional retinal image that resembles that of a histology section. This imaging method thus can be considered as a form of in vivo histology. Digital processing aligns the A-scans to correct for eye motion. Digital smoothing techniques are used to further improve the signal-to-noise ratio.18
 
Image Display
Stratus OCT (OCT-3; Carl Zeiss Meditec Inc., Dublin, California, USA) is an advanced imaging device. It can be used in the absence of dilation in many individuals, and usually requires a 3-mm pupil for adequate visualisation. The imaging lens is positioned 1 cm from the eye to be examined and adjusted independently until the retina is in focus. An infrared-sensitive charge-coupled device video camera documents the position of the scanning beam on the retina.
The OCT image can be displayed on a gray scale where more highly reflected light is brighter than less highly reflected light. Alternatively, it can be displayed in color whereby different colors correspond to different degrees of reflectivity. On the currently commercially available OCT scanners, highly reflective structures are shown with bright colors (red and white), whereas those with low reflectivity are represented by darker colors (black and blue). Those with intermediate reflectivity appear green.
 
Image Resolution
Optical coherence tomographic image resolution depends on several factors. Resolution can be considered in the axial (z axis) or transverse (x-y) planes.
Axial resolution depends on the wavelength and bandwidth of the incident light. Shorter wavelength light, in the 800 nm range, is not absorbed as much as longer wavelength light by high water content structures such as the cornea and vitreous. This property allows adequate light penetration to the retina, and excellent axial resolution. Hence, light with a broader spectral bandwidth enhances axial resolution by producing a shorter coherence light beam. Current commercial scanners employ a low coherence super-luminescent diode source (820 nm). The presently available model Stratus OCT (OCT-3) has a theoretical axial resolution ≤ 10 micron.
Transverse resolution is essentially wavelength-independent. It is limited to a theoretical maximum of approximately 10 microns. Depending on the scan mode, OCT-3 can produce 512 scan points in the x-axis. Furthermore, the reference mirror in the OCT, scans four times more rapidly than that of the older generation 4OCTs. The light detector has been improved too. Together, these modifications produce images with significantly greater transverse resolution at a higher scan speed.
 
VOLUMETRIC OPTICAL COHERENCE TOMOGRAPHY
Jaffe and Caprioli18 have coined the term “volumetric optical coherence tomography (VOCT)” to quantify retinal thickness throughout the macula. To obtain such tomogram using commercially available software on the Stratus OCT, the retinal thickness map (RTM) scan mode and analysis function, or the fast retinal thickness map (FRTM) scan mode and analysis function, is used. With these scan modes, six radial scans are obtained.
In the RTM mode, each of the six individual scans is manually acquired sequentially by the operator; while, in the FRTM mode, each of the sequential scans is obtained automatically by the OCT software. Each of the six scans is oriented radially, 30 degrees from one another, and intersect at the foveal center. Each radial scan (typically obtained at a scan length of approximately 6 mm) produces a cross-sectional image. 19 The OCT software locates the inner retina at the vitreoretinal interface and the outer retina at the retinal pigment epithelial-photoreceptor outer segment interface, based on differences in the image reflectance patterns. The software then places a line on the inner retina and another on the retinal pigment epithelium. A retinal thickness measurement is determined as the distance between these lines at each measurement point along the scan's x-axis. From these scans, a surface map reconstruction is created. The surface map is displayed as a false color image whereby retinal thickness at each point is represented by a different color. Bright colors (for example, red and white) represent thick regions, and dark colors (for example, blue and black) represent thin areas. Intermediate thickness regions are displayed as green and yellow. Because the data point density is greater centrally than peripherally, interpolated thickness measurements of regions further from the fovea are determined from fewer measurements, and may be less accurate, than those in central regions.18
Typical RTM or FRTM scan and analysis OCT printout yields a lot of data. These include:
  1. Cross-sectional images for each of the six radial scans,
  2. Measurement of central foveal thickness (calculated as the mean and standard deviation of the retinal thickness at the intersection of the six radial scans),
  3. Measurement of retinal thickness in nine separate regions in the macula,
  4. Surface map reconstruction display,
  5. Measurement of retinal volume contained under the area represented by the surface reconstruction.
The central foveal thickness measurement is particularly useful, as it includes the thickness measurement variability among the six radial scans. Typically, this variability is less than 5%. Volumetric scanning is especially useful to quantify changes in retinal thickness. Thickness measurements determined by this technique are reproducible.19
 
STRATUS OPTICAL COHERENCE TOMOGRAPHY
 
Instrument
Stratus OCT is an interferometer that resolves retinal structures by measuring the echo delay time of light (broad bandwidth near-infrared light beam; 820 nm) that is reflected and backscattered from different 5microstructural features in the retina. The instrument electronically detects, collects, processes and stores the echo delay patterns from the retina. With each scan pass, the instrument captures from 128 to 768 longitudinal (axial) range samples, i.e. A-scans. Each A-scan consists of 1,024 data points over 2 mm of depth. Thus, the instrument integrates from 131,072 to 786,432 data points to construct a cross-sectional image (tomogram) of retinal anatomy. It displays the tomograms in real time using a false color scale that represents the degree of light backscattering from tissues at different depths in the retina. The system stores the scans, which can be selected for later analysis.
The instrument delineates intraretinal, cross-sectional anatomy with axial resolution of ≤10 microns and transverse resolution of 20 microns. Its software package includes 19 scan acquisition protocols and 18 analysis protocols. The video camera enables to view the patient's fundus and to store video and scan images together. The data management system enables storage of patient histories, for monitoring patients over time. Images and data can be archived on rewritable DVD-RAM discs. The inkjet printer generates color hard copy.
 
Patient's Experience
The patient's experience with the Stratus OCT is normally brief and comfortable. An experienced operator can acquire several scans from each eye in the space of 5–7 minutes. An exam usually requires the patient to look inside the ocular lens of the Patient Module for 1–3 minutes at a time for each eye, depending on the number of scans desired. The instrument acquires most scans in about 1 second. The additional time is required to position the ‘Patient Module’ before scanning and to optimize scan quality. The patient need not remain in the head mount throughout an examination, since the operator can reposition the ‘Patient Module’ as needed. Internal or external fixation may be selected. During positioning, what the patient sees with the study eye is a rectangular field of red punctuated with a green target light. Normally, the patient can look at this field for several minutes at a time without discomfort or tiredness. During scan alignment, the patient sees the scan pattern in motion on the red field. It is traced rapidly at first, while in scan alignment mode, then more slowly in scan acquisition mode. Finally, during scan acquisition, the patient sees a bright greenish-white flash, like a camera flash. This is the video camera acquiring a red-free fundus image for storage with the scan image. The operator has the option of acquiring scans without the flash and, therefore, without a high contrast image.
 
ADVANTAGES OF OPTICAL COHERENCE TOMOGRAPHY
There are several advantages of OCT as a diagnostic imaging technique:
  1. It is noncontact unlike ultrasound and noninvasive, unlike fluorescein angiography.
  2. Patients, especially children, easily tolerate it.
  3. It is extremely helpful in providing quantitative information regarding macular thickness changes over time.
  4. It is a valuable teaching tool for the physicians as well as patients.
 
DISADVANTAGES OF OPTICAL COHERENCE TOMOGRAPHY
Although OCT is an extremely valuable technique, there are limitations and potential pitfalls to its use:6
  1. Optical coherence tomographic images are degraded in the presence of media opacity, for example dense cataract.
  2. Scan quality is dependent on the skill of OCT operator.
  3. Optical coherence tomographic scanning may not be possible with uncooperative patients.
  4. Measurements of foveal thickness may be inaccurate if the scan is not centered over the fovea.
 
COMPARISON OF OPTICAL COHERENCE TOMOGRAPHY WITH STANDARD TECHNIQUES
Stereo-fundus photographs and fluorescein angiography are the other methods of evaluating macular thickness. Retinal thickening determined by stereo-fundus photography correlates well with that measured by OCT. Macular hyperfluorescence seen on fluorescein angiography correlates well with increased retinal thickness measured by OCT. However, occasionally, eyes with macular hyperfluorescence do not appear thickened by OCT, and, conversely, some eyes without macular hyperfluorescence look thickened by OCT. Fundus photography, fluorescein angiography, and OCT, together, provide complementary information regarding macular disorders.
Fundus photography, unlike OCT, does not yield objective quantitative measurements of retinal thickening, and neither fundus photography nor fluorescein angiography gives information about cross-sectional retinal morphology or high-magnification surface topographic images. However, fluorescein angiography can provide information about the origin of macular fluid leakage, and retinal vascular abnormalities, while fundus photography may demonstrate subtle macular lesions not seen by OCT or clinical examination.18
 
COMPARISON OF OPTICAL COHERENCE TOMOGRAPHY WITH COMMERCIALLY AVAILABLE INSTRUMENTS
HRT and RTA are the other commercially available instruments, in addition to OCT, to measure retinal thickness and to evaluate retinal morphology. All can effectively measure retinal thickness in normal eyes, and in eyes with macular edema. There is a high degree of correlation between retinal thickness determined by OCT and that measured by RTA.20-23 For patients with very early diabetic retinopathy without clinically significant macular edema, RTA may be more sensitive than OCT to detect macular thickening. However, RTA may produce a larger number of falsely elevated retinal thickness measurements, and produces retinal images less effectively than OCT in eyes with media opacity.21,22,24 The HRT may be more effective than OCT and RTA to image the outer retina in the presence of retinal hemorrhage and hard exudates.25 The HRT can also demonstrate surface topology. However, images are acquired relatively slowly.
 
ULTRAHIGH RESOLUTION OPTICAL COHERENCE TOMOGRAPHY
Standard ophthalmic OCT provides more detailed structural information than any other ophthalmic diagnostic technique. Despite the promising and clinically valuable results of these OCT studies, the axial resolution and performance of standard clinical ophthalmic OCT technology can be significantly improved. Many of the early pathologic changes associated with disease are still below the resolution limit of standard OCT. Intraretinal structures, such as the ganglion cell layer, the photoreceptor layer, and the retinal pigment 7epithelium, are often involved in early stages of ocular diseases but cannot be resolved with standard OCT. One of the most powerful approaches for obtaining ultrahigh resolution is the use of femtosecond laser light sources for OCT imaging.
Drexler and Fujimoto developed a clinically viable ultrahigh-resolution ophthalmic OCT system based on a commercially available titanium-sapphire laser. This system can be used in a clinical setting, enabling in vivo cross-sectional imaging of macular pathologies with unprecedented axial resolution of approximately 3 µm. Ultrahigh-resolution imaging studies were performed which demonstrated that ultrahigh-resolution OCT permits visualisation of all principal intraretinal layers, including the ganglion cell layer, inner and outer plexiform and nuclear layers, external limiting membrane, and the inner and outer segments of the photoreceptor layer in selected macular pathologies. Ultrahigh-resolution OCT imaging using a laboratory prototype femtosecond titanium-sapphire laser light source has recently been demonstrated to achieve an axial resolution of 1 to 3 µm in nontransparent and transparent tissue, enabling unprecedented in vivo subcellular26 as well as intraretinal 27,28 visualisation. Ultrahigh-resolution OCT enables all of the major intraretinal layers to be visualised noninvasively in vivo, and images have excellent correlation with known retinal morphologic features.29
Comparison of Zeiss Meditec OCT-3 and Ultrahigh-resolution OCT is shown in Table 1.1.
Table 1.1   Comparison of Zeiss Meditec OCT-3 and Ultrahigh Resolution-OCT
Zeiss Meditec OCT-3
Ultrahigh Resolution-OCT
Prototype superluminescent diode
Low-cost Ti: Sapphire laser
~ 30 nm bandwidth
~ 12.5 nm bandwidth
~ 10 micron axial resolution
~ 3 micron axial resolution
512 cross section A-scans
600 cross section A-scans
1,024 points per line
3,000 points per line
 
OPTICAL COHERENCE TOMOGRAPHY AND SCANNING LASER OPHTHALMOSCOPE TECHNOLOGY
Optical coherence tomography imaging requires a series of image processing programs. Two specific limitations are recognised with the current device:
  1. Errors in A-scan image correlation and interpolation: Cross-correlation and interpolation errors of A-scan increase as the scan lengths increase from 3 to 10 mm, making image quality less reliable.
  2. Precise anatomic localisation of the OCT image from the red-free image: The anatomic localisation is compromised because the red-free image depicting the position of the OCT trace is not pixel linked. The red-free images are derived from live video images by a frame grabber during the examination and serve as a rough estimate of the OCT B-scan anatomic position.
A new device is being developed to create OCT B-scan images (without the use of A-scans) and use simultaneous red-free Scanning Laser Ophthalmoscope (SLO) pixel-linked images for precise OCT image localisation. The OCT B-scan images are created by horizontal scanning (x-y) in the ophthalmoscopic plane, at increasing depths. This technology also permits accumulation of information from entire planes of tissue at varying depths, creating a new image format called C-scan. Numerous C-scan images can be computer processed into 3-D OCT images that permit volumetric and linear measurements. The new technology utilises a beam splitter at the light source to create two channels. One channel uses conventional SLO to 8create red-free images, while the other channel is used to create simultaneous OCT images. Since the images are pixel linked, precise anatomic localisation of OCT image is possible.
 
FUSION TECHNOLOGY OF OPTICAL COHERENCE TOMOGRAPHY AND ULTRASONOGRAPHY
Fusion technology of optical coherence tomography and ultrasonography is being developed that produces pixel-wise combination of images of differing modalities to obtain added diagnostic value. It produces a single image from a set of input images. The fused image provides more complete information for interpretation of ocular tissues and layers. This produces improved anatomic delineation. Imaging and identification of tissue boundaries is possible. High resolution of layers increases the accuracy of measuring the thickness of nevi and small melanomas. Accurate choroidal thickness measurement is also possible.
Optical coherence tomography will be used increasingly to diagnose and manage retinal diseases. Improvements in scanning hardware and software will facilitate its use in the future. It is likely that commercial scanners will incorporate ultra-broad spectral bandwidth light sources as they become less costly, a modification that will greatly enhance axial resolution. In addition, more studies are needed to identify the range of retinal diseases for which OCT is useful, and to determine the relative usefulness of OCT to diagnose and follow patients compared with alternative imaging techniques. In many cases, OCT provides information complementary to that available by alternative methods. However, more information is needed to determine when OCT testing alone would suffice. In addition, care is needed to avoid artifacts and image misinterpretation.18
Optical coherence tomography has become an established method for imaging retinal diseases. It is now an accepted method for making quantitative measurements in studies on the cause and course of macular holes, vitreoretinal traction, pigment epithelial detachment, macular edema, and diabetic retinopathy. Its potential benefit in the evaluation of age-related macular degeneration and a variety of other diseases is currently under investigation. In clinical practice, optical coherence tomography images add information to the biomicroscopic findings and results of other imaging techniques or functional testing and can significantly help in making critical decisions. Its future role in routine clinical practice will depend on further technical development and the results of long-term studies.30 This sequential imaging technique will aid in our understanding of the rapid evolution of retinal pathology and response to treatment in the research and clinical setting.31
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