Optical Coherence Tomography Findings in Uveitis

The development of optical coherence tomography (OCT) in the early 1990s was one of the most powerful and exciting advances for imaging the internal microstructure of biologic tissues.1 Optical coherence tomography is a particularly powerful ophthalmic imaging technique, as it provides real-time, noncontact, cross-sectional imaging of the anterior eye and retina, yielding images of tissue pathology without the need for invasive biopsy procedures and histopathologic staining. While OCT has far-reaching applications, it has been used increasingly to evaluate and manage a variety of posterior segment disorders, in particular, retinal pathologies. For example, it has been used to diagnose and guide treatment decisions in eyes with macular holes, vitreomacular traction, choroidal neovascularization, epiretinal membranes, and many more conditions. Moreover, it has been particularly useful for diagnosis and monitoring of retinal nerve head fiber thickness for glaucoma2 and macular edema associated with diabetic retinopathy or other macular conditions.3,4 This chapter reviews the basic principles of OCT and presents cases of chorioretinal inflammatory disease in which OCT was helpful in diagnosis or management.

Basic Principles of Optical Coherence

Tomography

The Medical Literature Analysis and Retrieval System (MEDLARS) defines OCT as “an imaging method using lasers that is used for mapping subsurface structure. When a reflective site in the sample is at the same optical path length (coherence) as the reference mirror, the detector observes interference fringes.” The basic principle of OCT imaging is analogous to conventional ultrasonic pulse echo imaging, except that OCT uses light while ultrasound uses acoustic waveforms. This difference gives OCT the advantage of not requiring direct contact with the tissue that is being investigated. Image resolution, which depends highly on waveform frequency, is another marked difference between ultrasound and OCT technology. Standard ultrasound uses high-frequency sound waves on the

order of 10 MHz, and is thus limited to a resolution of approximately 150 µm. Optical coherence tomography, on the other hand, uses low coherence length light (830 nm), resulting in optical resolutions on the order of 10 µm.5 Moreover, while high-frequency ultrasound technology is available, acoustic waveforms are strongly attenuated in tissue, leading to poorquality images beyond a tissue thickness of 5 mm.

The physical principles behind OCT are based on Michelson interferometry, which is similar to Sir Isaac Newton’s first description of white-light interference. Using fiber optic technology, low coherence light from a superluminescent diode is directed onto a beam splitter, which creates a measurement beam and a reference beam. The measurement beam of light is directed to the patient’s eye and is reflected from optical boundaries of differing indices of refraction. The indices of refraction at these boundaries are an optical property of the tissue being imaged and surrogate markers for histologic structure. The single reference beam is reflected off a reference mirror so that it returns and combines with the complex measurement echo. This combination is termed interference in optics. The distance between the beam splitter and the reference mirror is continuously varied and the interference pattern is monitored by a photoelectric detector that processes it into an electric signal. When there is maximal constructive interference between the light from the patient’s eyes and the reference paths, then the distance traveled by the light in both paths matches to within the coherence length of the light. Each of the multiple reflections will form a unique interference pattern with the reference beam, and this information will be translated into measurements of distance and thickness of the different ocular tissue structures.1,6

Two-dimensional cross-sectional images of ocular tissue microstructure are constructed by performing multiple axial measurements with the light source at different transverse positions. These data are then digitally filtered and analyzed and finally displayed as two-dimensional gray-scale or false-color representations. In the false-color representation, highly reflective structures are shown with bright colors, including red and white, while those with low reflectivity, such as vitreous, are

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shown with darker colors, including blue and black. Falsecolor representations have the advantage of improving one’s ability to differentiate tissue structures, but they have the disadvantage of producing artifacts in the image. With false-color representations, it is also important to understand that different colors represent different optical back-reflections and are not analogous to histologic staining. The most common OCT machine (OCT-3) that is being used in clinical practice currently consists of approximately 512 individual color-coded axial scans with high-resolution images (<8 µm).7 In comparison, the older OCT-2 machine created images composed of only 100 axial scans. The OCT-3 machine has the further advantage of being able to capture up to six images in 1 second (Table 17.1).8

The image resolution of OCT images is typically broken into two axes, corresponding to axial and transverse resolutions.5 Axial resolution increases inversely with respect to wavelength and proportionally with respect to the broadness of the spectral bandwidth. Shorter wavelength light has the advantage of not being absorbed by high water content structures such as the vitreous, and broader spectral bandwidth produces shorter coherence light beams. Axial resolution will not vary according to the scanning protocol selected. Transverse resolution is determined by the focused, diffraction-limited spot size on the retina9 and basically equates to the number of axial (A) scans performed during each sweep of the scanning beam. More A-scans require more time, which creates more difficulty in maintaining fixation for the patient and may therefore result in images with more “noise. ” A standard scan consists of 512 A-scans distributed over a 6-mm transverse sweep.

There are several different ways to scan OCT images. Scanning patterns include single lines of differing length and orientation; lines arranged radially, which are useful for mapping the optic disc; circumpapillary images, which are useful to assess the nerve fiber layer; and sequential parallel lines, which are useful to appreciate the three-dimensional structure of specific parts of the retina, particularly the fovea.10,11 The scans are always read from left to right, but the point at which the scan starts must be known. With older OCT software, the horizontal scan lines began in the temporal macula and passed toward the optic nerve in each eye. The right eye, therefore, would have 90-, 60-, 30-, 0-, 300-, and 330-degree scans performed clockwise, and the left eye 90-, 120-, 150-, 180-, 210-, and 240-degree scans performed counterclockwise. In newer

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OCT software, the scan lines of both right and left eyes pass from left to right as the patient is viewed by the doctor. Horizontal scans, therefore, now pass toward the optic nerve in the right eye and away from the optic nerve in the left eye. Vertical scans are always oriented from inferiorly to superiorly and are designated as 90-degree scans.

In an OCT image of normal retina, the nerve fiber and plexiform layers are highly reflective images, as illustrated by the bright colors in the false color image. The ganglion cell layer, inner and outer nuclear layers, photoreceptors, and choroid are weakly reflective as evidenced by their green-blue-black appearance. The boundary between the photoreceptor inner segments and outer segments is visible as a thin, highly reflective band due to the visual pigment rhodopsin. Immediately posterior to the photoreceptor band is the melanin-containing retinal pigment epithelium, which is similarly reflective. Finally, the choriocapillaris/choroid complex is similarly bright in color due to the vascular nature of this layer. It is difficult to distinguish the separation of the RPE/choriocapillaris/choroid using current OCT technology.

Because both the nerve fiber layer and the RPE/choriocapillaris layer are brightly reflective, the OCT is able to calculate retinal thickness, a useful parameter in the evaluation of macular disease. Retinal thickness is usually plotted as a central 1.0-mm foveal zone, four wedge-shaped zones between 1 and 3 mm from the center, and four larger wedge-shaped zones between 3 and 6 mm from the center. Thickness maps of the central macula are susceptible to inaccuracy related to poor fixation. Standard deviations of more than 10% in the central, foveal subfield suggests unreliable fixation and mapping. In addition, some maps contain artifact because they are off-center or there is inaccurate identification of the inner or outer retinal surface. This can occur with vitreous membranes, for example, or with large subretinal fluid collections. However, retinal maps can provide very graphic and useful images (Fig. 17.1).

Involuntary eye movement produces artifact that appears as undulations in the raw image. Processing refines the image by realigning the A-scans according to the anterior-posterior distance from the machine. Fixation loss is minimized by rapid scanning and use of a low-intensity fixation target that is visible to the patient, or by use of a fixation target for the fellow eye. The diode OCT beam itself is 830-nm wavelength, in the near infrared, and produces minimal patient discomfort, facilitating fixation.

17. Optical Coherence Tomography Findings in Uveitis

Highly reflective structures produce shadowing of underlying tissues, which can be mistaken for fluid collections. Cylindrical hyporeflective streaks oriented perpendicular to the retinal surface can arise from vitreous opacities or from large retinal vessels. In the case of retinal blood vessels they are helpful to confirm that the same portion of the retina is being scanned on sequential examinations. Media opacities degrade the resolution of the OCT scan, but usually do not completely obliterate it. Even in scans of very low resolution, important information can be gained by confirming that there is either no or little macular edema, based on a relatively nor- mal-appearing macular thickness. Small pupils have relatively little effect on OCT scanning. In the presence of clear media, OCT imaging through a small pupil will usually provide more usable information than fluorescein angiography.

The recent years have seen a significant advance in OCT technology, with new instruments of higher axial resolution currently only being used in research laboratories. In 2001, Drexler et al.9 described a new ultrahigh resolution, noninvasive in vivo method of ophthalmologic imaging of the retina and cornea in which short pulse laser light sources are capable of generating broadband light that provide axial image resolutions of 2 to 3 µm, enabling visualization of internal retinal architectural morphology. In fact, several of the 10 distinct layers of the retina can be visualized, and the comparison to a histologic micrograph is remarkable.7,9 Commercialization of the high-resolution technology will further increase information gained by OCT scanning.

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Applications of Optical Coherence

Tomography in Uveitis

Changes in Intraocular Fluid Content

Fluid accumulations, including macular edema, subretinal fluid, pigment epithelial detachments, and retinoschisis, result in lower amounts of backscattering on OCT imaging and appear hypolucent (Fig. 17.2).8 Hemorrhagic accumulations, or those with a significant exudative component, are usually

FIG. 17.1. Retinal map of a patient with healed, macular cytomegalovirus (CMV) retinitis. The patient presented with a history of CMV retinitis diagnosed elsewhere and a color photograph of a small white lesion possibly consistent with a cotton-wool spot. There was a question as to whether specific antiviral therapy needed to be continued. An optical coherence tomography (OCT) map clearly demonstrated retinal thinning depicted in blue and gray at the site of the previous white lesion, consistent with a prior necrotizing infection and not with a cotton-wool spot, which is characterized by inner retinal edema. The color scale corresponding to various thicknesses is shown below the map. Severe macular edema would appear yellow, red, or white on a map. The standard nine-ring array next to the map displays the average thicknesses in each of the areas. The central 1 mm thickness is normal. Vision was 20/20.

FIG. 17.2. Sudden vision loss in multifocal evanescent white dot syndrome with optic nerve edema. (A) Horizontal radial macular scan in a young woman with a sudden, unilateral reduction in vision and no vitreous inflammation. The hypolucent area under the foveal depression is fluid. The detached photoreceptors above it appear somewhat hyperreflective and may be involved in the inflammatory process. On either side of the foveal depression there is mild diffuse intraretinal edema indicated by the reduced density of the tissue, but the photoreceptors are attached. The aspect of the scan at right, closest to the optic nerve, shows another subretinal fluid collection. The hyperreflectivity of the inner retina on this aspect of the scan identifies this as a right eye. By convention the 0-degree (horizontal) scan in the right eye begins temporally and scans toward the nerve. Earlier versions of software had the horizontal scan of the left eye also directed toward optic nerve. More recently the 0-degree scan has been directed from the patient’s right to the patient’s left, as for the right eye. (B) Color photograph. There is optic nerve edema. The yellow color under the papillomacular bundle and the subfoveal yellow spot correspond to the fluid seen on the scan, and there is perifoveal edema. Indocyanine green (ICG) angiography showed hypofluorescent spots consistent with an atypical multifocal evanescent white dot syndrome.

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FIG. 17.3. In this patient with long-standing uveitis and 20/60 visual acuity, there is a thin membrane elevated over the retina that probably corresponds to the internal limiting membrane as a thin connection from the membrane to the outer retina and appears to be a Müller cell. The foveal region consists of a lamellar hole and attached photoreceptors. The long-standing edema is evidenced by the overall poor definition of retinal layers. A thin layer of subretinal fluid is visible on the left side of the frame, and the retinal thinning on the right side of the frame has led to hyperreflectivity of the retinal pigment epithelium (RPE)-choriocapillaris layer as more light reaches these layers when the overlying tissue is thin. There might be some benefit to reduction of the fluid seen on the left, but the chances of a significant improvement in vision in this eye are small.

hyperreflective, but in addition block any backscattering from the tissue underlying the fluid. There may be some minimal backscatter from the fluid cavity.

Macular Edema

Detection

Cystoid macular edema in uveitis provides an elegant demonstration of the retinal anatomy that influences the classic petaloid appearance or, when long-standing, produces more complicated patterns (Fig. 17.3). In uveitis, where thin-walled central cysts can be confused with macular holes, OCT can help distinguish between true cystoid edema, which would likely respond to medical treatment, and a macular hole, which would not.

FIG. 17.4. Optical coherence tomography (OCT) scan of a uveitis patient with long-standing cystoid macular edema and the clinical appearance of a large central cyst or macular hole. Vision was 20/50. The scan shows two items of interest. The first is that the inner retina is intact but extremely thin, and there is no macular hole. The second is that the foveal photoreceptors are intact and attached, accounting for the relatively good vision. Given the thin appearance of the retina, treatment with injectable corticosteroids might lead to flattening of the cyst but little visual improvement. Note that the same linear signals are seen connecting the inner and outer retinas as in Figure 17.3. These probably represent Müller cells.

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The appearance of macular edema on OCT has been described as three typical patterns: cystic retinal changes manifested as hyporeflective spaces within the retina, diffuse thickening of the macula, and subfoveal fluid detected by loss of normal signal from the subretinal space.12,13 Optical coherence tomography imaging has also led to the realization that patients with cystoid macular edema and good vision typically show maintained attachment of photoreceptors without subfoveal fluid (Fig. 17.4). Thus, morphologic information gained by OCT aids understanding of the anatomic features affecting vision.

Correlation with Visual Prognosis

Optical coherence tomography technology has recently been used to correlate the morphologic features of macular edema and macular thickness with visual acuity in patients with uveitis. Markomichelakis and colleagues14 studied 84 eyes of 60 patients with uveitis and macular edema. Optical coherence tomography was used to detect the three patterns of macular edema: diffuse macular edema, cystoid macular edema, and serous retinal detachment. Diffuse macular edema was the most common type, involving 54.8% of eyes, with cystoid edema in 25% of eyes. An additional 14.3% of eyes had both cystoid macular edema and serous retinal detachment, and 5.9% of eyes had both diffuse macular edema and serous retinal detachment. Epiretinal membrane was common. Maculas with cystoid edema were thicker than those with diffuse edema. Visual acuity was inversely related to macular thickness, presence of cystoid edema, and subretinal fluid. For examples of diffuse and cystoid edema, and subretinal fluid see Figures 17.2A, 17.4, and 17.5B.

Reinthal and colleagues15 also investigated OCT in the management of macular edema in uveitis. They reported no difficulty in obtaining scans in patients with mild to moderate media opacity. A wide range of macular thicknesses was detected in the uveitic group, with foveal heights from 168 to 810 nm. Various patterns of cystic change were detected, the most common being confluent cysts. Other patterns included several discrete cystic spaces, and a single large central cyst.

Monitoring Response to Treatment

Serial examination of macular edema is thought to allow for more accurate follow-up of response to treatment.16 Optical coherence tomography is now commonly used in long-term monitoring of macular edema, especially in patients undergoing treatment (Fig. 17.5). It is difficult to ensure perfect registration between serial images,17 but this does not seem to be strictly necessary for macular edema, in which the changes in the retina occur on a fairly gross scale. Macular thickness in the central subfield or total macular volume can be used as single measures that summarize the overall status of the macula.

Correlation with Change in Visual Acuity During Treatment

Reinthal and associates15 documented changes in visual acuity that correlated with changes in OCT appearance during follow-up. Documentation of an anatomic change with reduction in intraretinal fluid without visual improvement probably indicates outer retinal damage that will not respond to additional treatment with corticosteroids. Small residual collections of subfoveal fluid are an additional cause of the failure of vision to completely recover following treatment. These collections of fluid are probably also the source of the central yellow “spot” recognized as a minimal form of noncystic macular edema in uveitis (Figs. 17.2 and 17.5A,B). A perhaps

underappreciated aspect of OCT documentation of CME is the ability of the clinician to use the images to educate the patient as to the cause of reduced, distorted, or minimized vision. With very little teaching, the OCT images become very obvious and interpretable to most patients.

Subretinal and Intraretinal Exudations

Whereas the formation of cystoid or diffuse macular edema is generally a slow process that minimally disrupts tissue planes, preserves the architecture of the Müller cells, and probably results from capillary leakage combined with poor reuptake of fluid, the formation of large collections of subretinal or intraretinal fluid is likelier to be a more rapid process with a higher

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grade leak. This hypothesis is supported by fluorescein angiography in which staining of the macular cysts may not be seen until the late stages of the angiogram, but the pinpoint leaks causing serous retinal detachments appear in the earliest stages of the angiogram and are often markedly hyperfluorescent.

Vogt-Koyanagi-Harada Syndrome

Optical coherence tomography has provided insight into patterns of fluid leakage in some disorders. Maruyama and Kishi18 studied 42 eyes of 21 patients with acute Vogt-Koyanagi-Harada (VKH) syndrome with OCT. Retinal detachment with subretinal fluid

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was found in 69% of eyes, whereas 17 eyes (40%) had principally fluid accumulation in the outer retina. Four eyes had both patterns. Intraretinal fluid was associated with greater leakage of dye on fluorescein angiography. This pattern appears to be highly characteristic of VKH, but is not a formal aspect of the diagnostic criteria for VKH, which were formulated prior to the widespread use of OCT. The explanation for this distribution of exudative fluid is unclear. Either there is substantial leakage from the intraretinal vessels in the outer plexiform layer in addition to the presumed trans-retinal pigment epithelium (RPE) choroidal leaks, or the phenomenon relates to tissue compliance in the face of a large pressure gradient around the leak point.

17. Optical Coherence Tomography Findings in Uveitis

Figure 17.6 demonstrates the complex patterns of fluid leakage in VKH that produce overlapping fluid collections at various depths. Unlike central serous choroidopathy in which fluid leakage comes mainly from the choroidal layer, there are no serous retinal pigment epithelial detachments. The OCT findings are therefore somewhat different than predicted for a primarily choroidal inflammation. The discrepancy may arise because the leakage is so diffuse that it does not have time to collect in well-defined RPE detachments, but the OCT suggests that the exudative fluid may also arise from the retinal circulation.

Syphilitic Chorioretinitis and Sympathetic

Ophthalmia

Syphilitic chorioretinitis and sympathetic ophthalmia show similar patterns of intraretinal and subretinal fluid accumulation (Figs. 17.7 and 17.8). The pattern therefore seems to be one that indicates a common mechanism rather than a common etiology. None of the three disorders is typically considered to be a retinal vasculitis with obvious hyperfluorescence of large retinal vessels, although this is occasionally seen in some cases. Leakage from smaller caliber retinal vessels is compatible both with the fluorescein angiogram and the OCT appearance.

Changes in Intraocular Tissue Density

Disease-related alterations in tissue can produce changes in reflectivity as well as in thickness. Thickening with

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hypolucency indicates increased fluid content, but thickening with increased reflectivity probably indicates an infiltration. These hyperreflective infiltrations can be seen in both the retina and the choroid in inflammatory diseases. Scar tissue, inflammatory infiltrates, hard exudates, or hemorrhage also result in higher reflectivity. These are generalizations. Since the degree of reflectance is a property of contrast between the lesion and the surrounding tissue, some infiltrates or scars could result in low backscattering or might produce no change in reflectivity; however, an increase in reflectance is the general rule. Since these lesions are generally clearly visible, the usefulness of OCT compared to fluid accumulations is somewhat less; however, the assignment of the level of involvement is very helpful in inflammatory disease. Because the penetration of light is limited into the choroid, only the innermost lesions can be imaged.

Retinal Hyperreflective Lesions

Toxoplasmic chorioretinitis on OCT produces a distinctive inner retinal hyperreflectivity that can be helpful diagnostically (Fig. 17.9). Presumably this is due to both the proliferation of tachyzoites and the infiltration of inflammatory cells. This can occur at a stage when the lesion itself is not yet white.19 Cytoid bodies (cotton-wool patches) also display inner retinal hyperreflectivity, but would ordinarily be distinguishable from toxoplasmic chorioretinitis by other features, such as vitreous inflammation and a feathered appearance of the retinal whitening corresponding to the nerve fiber layer.

Choroidal Hyperreflective Lesions

Multifocal choroiditis produces very distinctive inner choroidal lesions that are hyperreflective (Fig. 17.10). A major clinical dilemma is determining whether secondary choroidal neovascularization is present in fresh, elevated lesions. Optical coherence tomography is useful in imaging subretinal extension of the lesions and fluid collections, both of which would be suggestive of neovascularization that might require laser photocoagulation.

Conclusion

Optical coherence tomography imaging of inflammatory lesions provides additional information that can be correlated with clinical examination and angiographic findings to improve diagnosis and treatment. Its exact role in the management of uveitic diseases remains to be defined. It is anticipated that more clinical studies of OCT will be done in specific uveitic entities in the future and that interpretive criteria will be further refined.

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