Ординатура / Офтальмология / Английские материалы / Handbook of Optical Coherence Tomography_Bouma, Tearney_2002

lenses. OCT may be readily integrated with laparoscopes to permit internal body OCT imaging with a simultaneous en face view of the scan registration [46,56]. Hand-held probes have also been demonstrated [56,57]. These devices resemble light pens and use piezoelectric or galvanometric beam scanning. Hand-held probes can be used in open field surgery to permit the clinician to view the subsurface structure of tissue by aiming the probe at the desired structure. These devices can also be integrated with conventional scalpels or laser surgical devices to permit realtime viewing as tissue is being resected.

Another class of imaging probes includes flexible miniature devices for internal body imaging. Because OCT beams are delivered using fiber optics, small-diameter scanning endoscopes and catheters can be developed. The first clinical studies of internal body imaging were performed using a novel forward-scanning flexible probe that could be used in conjunction with a standard endoscope or bronchoscope [46,57]. This device used a miniature galvanometric scanner to produce one-dimen- sional forward beam scanning in a 1.5–2 mm diameter probe. Transverse and linear scanning OCT catheter-endoscopes have also been developed [50,58,59]. Figure 13 shows an example of a transverse scanning OCT catheter-endoscope. The catheterendoscope consists of a single-mode optical fiber encased in a hollow rotating torque cable coupled to a distal lens and a microprism that direct the OCT beam perpendicular to the axis of the catheter. The cable and distal optics are encased in a transparent housing. The OCT beam is scanned by rotating the cable to permit transluminal imaging, in a radarlike pattern, cross-sectionally through vessels or hollow organisms. The catheter-endoscope has a diameter of 2.9 French or 1 mm, comparable to the size of a standard intravascular ultrasound catheter. The development of even smaller diameter OCT catheter-endoscopes is possible.

Figure 13 also shows an example of an OCT catheter-endoscope image of the gastrointestinal trace and arterial imaging in the New Zealand White rabbit [60,61]. A short-pulse Cr4þ : forsterite laser was used as the light source to achieve high resolution with real-time image acquisition rates [43]. The two-dimensional image data were displayed using a polar coordinate transformation in gray scale and were recorded in both Super VHS and digital formats. OCT images of the esophagus permitted differentiation of the mucosal and submucosal layers of the esophageal wall. OCT images of the artery were performed with saline flushing to reduce scattering from blood.

These types of OCT imaging probes are small enough to fit in the accessory port of a standard endoscope or bronchoscope and permit an en face view of the area being scanned simultaneously with the tomographic image. Alternatively, they can be used independently, for example in intra-arterial imaging, where access to small arteries or other luminal structures is required. A comprehensive discussion of OCT imaging probes is presented in Chapter 5.

Image processing and display are performed by a software module of the OCT system. One of the advantages of electronic image data is that they can be processed using a wide range of techniques. Electronic image data are also amenable to electronic transmission, storage, and retrieval. There are several general categories of image processing techniques that can be applied to OCT images. These include motion correction algorithms, noise or speckle reduction algorithms, resolution enhancement algorithms, segmentation algorithms, and display algorithms. Perhaps the most widely used algorithms to date are the motion correction algo-

Figure 13 Examples of a miniature OCT catheter and images. (A) This 2.9 F (1 mm) diameter catheter is designed for transverse intraluminal imaging. A single-mode fiber is contained in a rotating flexible cable with distal beam optics that emit at 90 from the catheter axis. (B) In vivo OCT endoscopic image of the esophagus in a New Zealand White rabbit showing an example of internal body imaging. The image has 10 m axial resolution and 512 circumferential pixels and was taken at 4 frames per second. (C) The mucosa, submucosa, inner muscularis, and outer muscularis are well differentiated. (D) OCT catheter image of arterial structure using saline flushing to reduce scattering from blood. The intima is less than 10 m and is not resolved; the medium is visible as highly scattering. Small OCT probes enable a wide range of internal body imaging applications. (From Refs. 50 and 61.)

rithms that are used in ophthalmic imaging [28]. Because the resolution of OCT is extremely high, it is essential to compensate for motion of the eye during image acquisition. The dominant motion that blurs the image occurs in the axial (longitudinal) direction, because retinal structure in this direction has dimensions on the micrometer scale. Changes in the longitudinal position of the eye can be corrected for because the optical ranging measurement itself determines the longitudinal position of the retina. The tomographic image is constructed by performing sequential axial scans at different transverse positions within the eye. The motion of the patient’s eye in the axial direction can be measured by correlating adjacent axial

data sets. Once the axial position of the patient’s eye is known, the scans in the optical tomographic image can be displayed in the axial direction to align the microstructural features. Changes in the transverse position are not eliminated when this type of image processing is used; however, small changes in transverse position do not produce significant degradation in image quality, because typical features are larger in the transverse dimension than in the axial (longitudinal) direction.

Numerous other algorithms for OCT have also been developed or are currently being investigated. Techniques for resolution enhancement based upon deconvolution and iterative estimation have been demonstrated that can improve image resolution [62–64]. Deionising and speckle reduction algorithms have been applied in ultrasound and are very promising for OCT. Segmentation techniques have been used extensively in ophthalmic OCT for detecting the thickness of the retina and retinal nerve fiber layer [65,66]. Segmentation and rendering techniques have been used for surgical guidance applications as well as for studying composite materials. A detailed discussion of surgical imaging is presented in Chapter 23, and imaging in composite materials is presented in Chapter 15. A more detailed discussion of image processing techniques in general is presented in Chapter 6.

1.11APPLICATIONS OF OPTICAL COHERENCE TOMOGRAPHY

The use of optical coherence tomography to perform two-dimensional measurements of optical backscattering or backreflection to image internal cross-sectional microstructure was demonstrated in 1991 [6]. OCT imaging was performed in vitro in the human retina and in atherosclerotic plaque as examples of imaging in transparent, weakly scattering media and highly scattering media. This study used a fiber-optic Michelson interferometer with reference arm scanning and a superluminescent diode low coherence light source at 800 nm with 10 m axial resolution. Since that time, numerous applications of OCT for both materials and medical applications have emerged. At the same time, the performance specifications and capabilities of OCT imaging technology have improved dramatically.

A number of features make OCT attractive for a broad range of applications. First, imaging can be performed in situ and nondestructively. High resolutions are possible with typical image resolutions of 10–15 m and ultrahigh resolutions of up to 1 m. High speed real-time imaging is possible with acquisition rates of several frames per second for 250–500 pixel images. OCT can be interfaced with a wide range of imaging delivery systems and imaging probes. OCT technology is based on fiber optics and uses components developed for the telecommunications industry. Image information is generated in electronic form, which is amenable to image processing and analysis as well as electronic transmission, storage, and retrieval. Finally, OCT systems can be engineered to be compact and low cost, suitable for applications in research, manufacturing, or the clinic.

Optical coherence tomography is a powerful imaging technology in medicine because it enables the real-time, in situ visualization of tissue microstructure without the need to excise and process a specimen as in conventional biopsy and histopathology. The concept of nonexcisional ‘‘optical biopsy’’ performed by OCT and the ability to visualize tissue morphology in real time under operator guidance can be used both for diagnostic imaging and to guide intervention. Coupled with catheter, endoscopic, or laparoscopic delivery, OCT promises to have a powerful impact on

many medical applications ranging from improving the screening and diagnosis of neoplasia to enabling new microsurgical and minimally invasive surgical procedures. The next sections describe the use of OCT in examples of various medical applications. These examples review previous research, describe the characteristics of OCT technology that are important for given applications, and present scenarios where OCT imaging may have a significant impact. OCT also has many nonmedical applications, ranging from materials imaging to optical recording. These applications are described in more detail in Chapters 14 and 15.

1.11.1 OCT Imaging in Ophthalmology

Optical coherence tomography was first applied for imaging in the eye, and to date it has had the greatest clinical impact in ophthalmology. The first in vivo tomograms of the human optic disc and macula were demonstrated in 1993 [28,67]. Numerous clinical studies have been performed in the last few years. OCT enables the noncontact, noninvasive imaging of the anterior eye and retina [25,68,69]. It is helpful to review ophthalmic OCT because it is the most clinically advanced application and is a model for other clinical applications.

Figure 7 shows an example of an OCT image of the normal retina of a human subject. OCT provides a cross-sectional view of the retina with unprecedented high resolution and allows detailed structures to be differentiated. Although the retina is almost transparent and has extremely low optical backscattering, the high sensitivity of OCT imaging allows extremely small backscattering features such as interretinal layers to be differentiated. The retinal pigment epithelium, which contains melanin, and the choroid, which is highly vascular, are visible as highly scattering structures in the OCT image.

Optical coherence tomography has been demonstrated for the detection and monitoring of a variety of macular diseases [69], including macular edema [70], macular holes [71], central serous chorioretinopathy [72], age-related macular degeneration and choroidal neovascularization [73], and epiretinal membranes. The retinal nerve fiber layer thickness, a predictor for early glaucoma, can be quantified in normal and glaucomatous eyes and correlated with conventional measurements of the optic nerve structure and function [65,66,74,75]. In addition, OCT has been applied for the evaluation of choroidal tumors [76], congenital optic disc pits [77,78], and argon laser lesions [79]. Retinal OCT images have been correlated with histology [80], and OCT has been used to investigate microanatomy and retinal degeneration in the chicken [81].

Because it can provide quantitative information on retinal pathology, which is a measure of disease progression, OCT is especially promising for the diagnosis and monitoring of diseases such as glaucoma or macular edema associated with diabetic retinopathy. Images can be analyzed quantitatively and processed using intelligent algorithms to extract features such as retinal or retinal nerve fiber layer thickness [65,66,74,75,82]. Mapping and display techniques have been developed to represent the tomographic data in alterative forms, such as thickness maps, to aid interpretation. Figure 14 (see color plate) shows an example of an OCT topographic map of retinal thickness. The thickness map is constructed by performing six standard OCT scans at varying angular orientations through the fovea. The images are then segmented to detect the retinal thickness along the OCT tomograms. The retinal thick-

Figure 14 Topographical mapping of retinal thickness as an example of image processing and display. The topographical representation is constructed by performing six OCT tomograms at different angles through the fovea. The tomograms are processed to extract retinal thickness, and the thickness values are interpolated over the macular region. The retinal thickness is displayed using a false color scale. Quantitative data of retinal thickness in nine different zones are also shown. These values are from a normative database and are displayed as mean and standard deviation. Quantitative data are more useful for screening purpose, whereas images are necessary for specific diagnosis or treatment planning. (See color plate.) (From Ref. 82.)

ness is linearly interpolated over the macular region and represented in false color. Retinal thickness values between 0 and 500 m are displayed by colors ranging from blue to red. The result is a color-coded topographic map of retinal thickness that displays the retinal thickness in an en face view corresponding to the macula. For quantitative interpretation, the macula was also divided into nine regions. Figure 14 shows the average retinal thickness measured from OCT imaging on 96 normal individuals with statistics including mean values and standard deviations (SDs) [82]. The SD provides a simple estimate of the measurement reproducibility.

The ability to reduce image information to quantitative form is important because it allows the construction of a normative database and calculation of statistics. The topographic thickness map demonstrates how OCT image information can be processed to yield different levels of detail. On the coarsest level, a single number, the foveal thickness, can provide a diagnostic indicator of macular edema in a patient. This type of information might be useful in a screening context, where high risk patient populations are screened in a primary care setting. On the next, more detailed level, the retinal thickness values in the nine regions can be used to more specifically localize the possible region where macular edema is present and improve the statistical accuracy of the measurement. The topographic false color map provides more graphic information that can be compared directly to the fundus image of the retina. Finally, the raw tomographic images contain the most detailed information and can be used to diagnose other retinal pathologies in addition to macular edema. This information would be useful for the ophthalmologist or specialist but would be excessively detailed for the primary care setting.

For the data to be used for screening or diagnosis, a normative database must be developed, requiring extensive cross-sectional studies. Diagnostic criteria must also be developed that will allow the OCT image or numerical information to be used to determine the presence or the stage of disease. The diagnostic criteria must have sufficient sensitivity and specificity. In many cases, screening or diagnosis is complicated by natural variations in the normal population. Ongoing clinical studies are investigating OCT for screening and diagnosis of diabetic macular edema and glaucoma, two leading causes of blindness.

Optical coherence tomgraphy has the potential to detect and diagnose early stages of disease before physical symptoms and irreversible loss of vision occur. Many thousands of patients have been examined to date, and numerous clinical studies are currently under way in many research groups and clinics internationally. OCT technology was transferred to industry and introduced commercially for ophthalmic diagnostics in 1996 (Humphrey Systems, Dublin, CA). With further development and clinical investigation, we expect that OCT will become a standard ophthalmic diagnostic tool within the next few years. For a more detailed discussion of OCT in ophthalmology, see Chapters 17 and 18.

1.11.2 Optical Coherence Tomography and Optical Biopsy

With recent research advances, OCT imaging of optically scattering, nontransparent tissues has become possible, enabling a wide variety of medical applications. One of the techniques that enables OCT imaging in nontransparent tissues has been the use of longer wavelengths, which reduces optical scattering [29–32]. By using 1:3 m wavelengths, image penetration depths of 2–3 mm can be achieved in most tissues. This imaging depth is not as great as that of ultrasound, but it is comparable to the depth over which many biopsies are performed. Many diagnostically important changes of tissue morphology occur at the epithelial surfaces of organ lumens. The capability to perform in situ, real-time imaging can be important in a variety of clinical scenarios, including (1) imaging tissue pathology in situations where conventional excisional biopsy would be hazardous or impossible, (2) guiding conventional biopsy to reduce false negative rates from sampling errors and the detection of early neoplastic changes, and (3) guiding surgical or microsurgical intervention.

Imaging Where Excisional Biopsy is Hazardous or Impossible

One class of applications where OCT could be especially powerful comprises those for which conventional excisional biopsy is hazardous or impossible. In ophthalmology, biopsy of the retina is not possible and OCT can provide high resolution images of retinal structure that cannot be obtained using any other technique. Another example of a scenario where biopsy is not possible is the imaging of atherosclerotic plaque morphology in the coronary arteries [32,83]. Recent research has demonstrated that most myocardial infarctions result from the rupture of small to moderately sized cholesterol-laden coronary artery plaques followed by thrombosis and vessel occlusion [84–87]. The plaques at highest risk for rupture are those that have a structurally weak fibrous cap [88]. These plaque morphologies are difficult to detect by conventional radiological techniques, and their microstructural features cannot be determined. Identifying high risk unstable plaques and patients at risk for myocardial infarction is important because of the high percentage of occlusions that result in sudden death [89]. OCT could be powerful for diagnostic intravascular imaging as well as for guidance of interventional procedures such as atherectomy and stenting.

Imaging studies of arterial lesions in vitro have been performed to investigate the correlation of OCT and histology [32,83]. Figure 15 shows an example of an unstable plaque morphology from a human abdominal aorta specimen with corresponding histology. Specimens were imaged by an OCT microscope prior to fixation. OCT imaging was performed at 1300 nm wavelength using a superluminescent diode light source with an axial resolution of 16 m. The OCT image and histology show a small intimal layer covering a large atherosclerotic plaque that is heavily calcified and has a relatively low lipid content. The optical scattering properties of lipid, adipose tissue, and calcified plaque are different and provide contrast between different structures and plaque morphologies. The thin intimal wall increases the likelihood of rupture. Currently, these lesions can be accurately diagnosed only by postmortem histology, and therefore interventional techniques cannot be used effectively to treat them. The ability to identify structural detail such as the presence and thickness of intimal caps using catheter-based OCT imaging techniques could lead to significant improvements in patient outcome.

Conventional angiography, ultrasound, or magnetic resonance imaging (MRI) do not have sufficient resolution to identify these lesions or to guide the removal of plaque by catheter-based atherectomy procedures. High frequency (20–30 MHz) intravascular ultrasound (IVUS) can be used to measure arterial stenosis as well as to guide intervention procedures such as stent deployment [90,91]. However, the resolution of IVUS is limited to approximately 100 m, and thus it is difficult to decisively identify high risk plaque morphologies [92]. Studies have been performed that compare IVUS and OCT imaging in vitro and demonstrate the ability of OCT to identify clinically relevant pathology [83]. In vivo OCT arterial imaging has also been performed in rabbits using a catheter-based delivery system [61]. Optical scattering from blood limits OCT imaging penetration depths, so saline flushing at low rates was required for imaging. These effects depend on vessel diameter as well as other factors, and additional investigation is required. A comprehensive discussion of OCT applications for cardiovascular imaging is presented in Chapter 26.

Figure 15 Optical coherence tomographic image showing atherosclerotic plaque in vitro and corresponding histology. This is an example of OCT imaging in tissues where standard excisional biopsy is not possible. The plaque is highly calcified with a low lipid content, and a thin intimal cap layer is observed. The high resolution of OCT can resolve small structures such as the thin intimal layer that are associated with unstable plaques. OCT could have important applications for diagnosis and interventional guidance in cardiovascular disease. (From Ref. 32.)

Detecting Early Neoplastic Changes

Another major class of OCT imaging applications applies in situations where conventional excisional biopsy has unacceptably high false negative rates due to sampling errors. This is the scenario in the detection of early neoplasia. OCT can resolve changes in architectural morphology that are associated with many early neoplasias. Studies have been performed in vitro to correlate OCT images with histology for pathologies of the gastrointestinal, female reproductive, pulmonary, and biliary tracts [60,93–101]. Preliminary studies in human subjects have also been performed using endoscopyand laparoscopy-based OCT imaging [46,57,102].

One of the key issues for the use of OCT imaging in the detection of early neoplastic changes is the ability to differentiate clinically relevant pathologies with a given image resolution. Many early neoplastic changes are manifested by disruption of the normal glandular organization or architectural morphology of tissues. These changes can be imaged using standard 10–15 m resolution OCT systems. Figure 16 shows an example of an in vitro OCT image of normal colon and ampullary carcinoma. The OCT image of the colon epithelium shows normal glandular organiza-

Figure 16 Imaging neoplastic changes. OCT images of gastrointestinal tissues in vitro showing normal colon and ampullary carcinoma. OCT can image differences in architectural morphology or glandular organization that are associated with neoplastic changes. The normal colon shows columnar epithelial morphology with crypt structures visible. The carcinoma, on the left of the image, is characterized by a loss of normal epithelial structure. Normal structure, visible on the right, has progressive disorganization of the crypts in the region nearing the cancer. Architectural morphology such as this can be imaged with standard OCT resolutions of 10–15 m. (From Ref. 60.)

tion associated with columnar epithelial structure [60]. The mucosa and muscularis mucosa can be differentiated due to the different backscattering characteristics within each layer. Architectural morphology such as crypts or glands within the mucosa can be seen. The OCT image of ampullary carcinoma shows disruption of architectural morphology or glandular organization. The area on the right of the image is normal, while the carcinoma is on the left of the image. The crypt structures have become dilated and distorted in the middle of the image, with complete loss of structure in the carcinoma.

The ability to delineate tissue architectural morphology could increase the diagnostic capabilities of conventional endoscopy, allowing a wide range of clinical disorders to be addressed. Endoscopic ultrasound has recently been introduced as a new technology for high resolution endoscopic imaging [103–108]. Using ultrasound frequencies in the range of 10–30 MHz, axial resolutions in the range of 100 m can be achieved [109–111]. Imaging of the esophagus or bowel requires filling the lumen with saline or using a liquid-filled balloon to couple the ultrasound into the tissue. Ultrasound can be used as an adjunct to endoscopy to diagnose and stage early esophageal and gastric neoplasms. Impressive results have been achieved using high

frequency endoscopic ultrasound, which demonstrates the differentiation of mucosal and submucosal structures.

Using standard OCT, image resolutions of 10–15 m are achieved, sufficient to enable the visualization of tissue architectural morphology. OCT can also be used to assess other features such as the integrity of the basement membrane. Ultrahigh resolution OCT with resolutions of 1–5 m enables cellular level imaging and could expand the range of neoplastic changes that can be imaged [22,43,44,112]. The imaging depth of OCT is 2–3 mm, less than that of ultrasound. However, many diseases originate from or involve epithelial structures, and imaging the microscopic structure of small lesions is within the range of OCT.

Conventional excisional biopsy often suffers from high false negative rates because the biopsy process relies on sampling tissue, and the diseased tissues can easily be missed. OCT could be used to identify suspect lesions and to guide excisional biopsy to reduce the false negative rates. This would reduce the number of costly biopsies, and at the same time clinical diagnoses could be made using excisional biopsy and histopathology, which is the established clinical standard. In the future, after detailed clinical studies and more extensive statistical data become available, it may be possible to use OCT directly for the diagnosis of certain types of neoplasias or for determining the grade of dysplasias.

The development of miniature, flexible OCT imaging probes and high speed OCT imaging systems enables the acquisition of OCT images of internal organ systems. Imaging of the pulmonary, gastrointestinal, and urinary tracts and arterial imaging have been demonstrated in animals [50,61,100]. Preliminary OCT internal body imaging studies in patients have been performed in many different organ systems, including the gastrointestinal, urinary, pulmonary, and female reproductive tracts [46,57,113]. These studies demonstrate the feasibility of performing internal body OCT imaging and suggest a broad range of future clinical applications. More systematic studies that compare OCT imaging with histological or other diagnostic endpoints are needed. At present, several research groups are performing numerous clinical OCT imaging studies, and more detailed data should be available shortly. Comprehensive discussions of OCT imaging applications in different organ systems are presented in Chapters 21, 24, 25, 27, and 28.

1.11.3 Guiding Surgical Intervention

In another important class of applications, OCT is used for guiding surgical intervention. The ability to see beneath the surface of tissue in real time can guide surgery near sensitive structures such as vessels or nerves as well as assisting in microsurgical procedures [52,54]. Optical instruments such as surgical microscopes are routinely used to magnify tissue to prevent iatrogenic injury and to guide delicate surgical techniques. OCT can be easily integrated with surgical microscopes. Hand-held OCT surgical probes and laparoscopes have also been demonstrated [56].

One example of a surgical application for OCT is the repair of small vessels and nerves following traumatic injury. A technique capable of real-time, subsurface, three-dimensional, micrometer-scale imaging would permit the intraoperative monitoring of microsurgical procedures, giving immediate feedback to the surgeon that could improve outcome and enable difficult procedures. Studies have been performed in vitro that demonstrate the use of OCT imaging for diagnos-