Optical Coherence Tomography Imaging for Glaucoma Today and Tomorrow. Christopher Kai-Shun Leung

REVIEW ARTICLE Optical Coherence Tomography Imaging for Glaucoma Today and Tomorrow Christopher Kai-Shun Leung Abstract: Digital imaging technologies for glaucoma diagnostics have evolved rapidly over the recent years. From time-domain optical coherence tomography (OCT) to spectral-domain and swept-source OCTs, the application of OCT for analysis of the anterior chamber angle and the optic nerve head (ONH) is expanding. The second-generation anterior segment swept-source OCT is able to image the configuration of the anterior chamber angle in 3 dimensions in less than 1 second and perform 360-degree analysis of the anterior chamber angle width for detection of angle closure. The morphology, density, and dimensions of the crystalline lens in relation to the anterior chamber can now be examined from the anterior corneal surface to the posterior lens surface, facilitating the investigation of the involvement of the crystalline lens in primary angle closure. Spectral-domain and swept-source OCTs have improved the measurement reliability of the lamina cribrosa and the neuroretinal rim configurations. Studying the deformation of the lamina cribrosa and ONH surfaces is relevant to decipher the mechanisms of ONH damage in the development and progression of glaucoma. Software and algorithms for automatic analysis of the anterior chamber angle dimensions and deformation of the ONH and lamina cribrosa surfaces are required to process large volumetric data sets, and they are under active development. It is expected that new imaging technologies will improve the detection and risk assessment of angle-closure and open-angle glaucomas. Key Words: glaucoma diagnostics, optical coherence tomography, optic nerve head, lamina cribrosa (Asia Pac J Ophthalmol 2016;5: 11 16) Digital imaging technologies have augmented the diagnostic precision of glaucoma. From visualization of the anterior chamber angle for detection of primary angle closure to measurements of the optic nerve head (ONH), neuroretinal rim, and retinal nerve fiber layer (RNFL) for diagnosis and monitoring of glaucomatous optic neuropathy, the scope of digital imaging for application in glaucoma diagnostics is expanding. In clinical practice, optical coherence tomography (OCT) is the prevailing technology for noncontact assessment of the anterior and posterior segments. The advancement from time-domain to spectraldomain and swept-source OCTs has significantly improved the scan speed (from 400 A-scans per second to up to 100,000 A-scans per second) and image resolution (from 10 20 μm to <3 5 μm in axial resolution). Two swept-source OCTs, the CASIA2 OCT (Tomey, Nagoya, Japan) and the Triton sweptsource OCT (Topcon, Tokyo, Japan), have been recently introduced for imaging the anterior and posterior segments, respectively. The second-generation anterior segment swept-source OCT has From the Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China. Received for publication October 19, 2015; accepted December 18, 2015. C.K.-S.L. received speaker honorarium from Carl Zeiss Meditec, Heidelberg Engineering, Tomey, and research support from Carl Zeiss Meditec, Optovue, Topcon, Tomey. Reprints: Christopher Leung, MD, 147K Argyle Street, 4/F Hong Kong Eye Hospital, Hong Kong. E-mail: tlims00@hotmail.com. Copyright 2016 by Asia Pacific Academy of Ophthalmology ISSN: 2162-0989 DOI: 10.1097/APO.0000000000000179 a scan speed of 50,000 A-scans per second and facilitates imaging of the entire anterior segment, from the anterior corneal surface to the posterior lens surface (Fig. 1). The Triton swept-source OCT has a scan speed of 100,000 A-scans per second. With a wavelength of 1050 nm, structures behind the retina and the ONH such as the choroid and the lamina cribrosa can be visualized in high resolution (Fig. 2). The principles of spectral-domain and sweptsource OCTs have been previously discussed. 1,2 This review summarizes some of the advances in OCT imaging technologies for examination and analysis of the anterior chamber angle, ONH, and neuroretinal rim parameters. ANTERIOR CHAMBER ANGLE IMAGING Although the diagnosis of angle closure has been essentially based on the assessment of the visibility of posterior trabecular meshwork with dark room gonioscopy, OCT at present is the only noncontact approach for reliable measurement of the anterior chamber angle width in the light and in the dark. 3 7 Beingadynamic structure, the iris directly governs the configuration of the anterior chamber angle, which varies substantively with the light intensity falling onto the pupil during the examination. Given the fact that the anterior chamber angle width is inversely proportional to the pupil size, angle closure can be missed by gonioscopy if light or indentation inadvertently widens the angle. 5 This is supported by a clinic-based study in Singapore demonstrating that angle closure was detected more often with anterior segment OCT compared with gonioscopy (59% and 33% of eyes had angle closure observed in at least 1 quadrant by OCT and gonioscopy, respectively). 8 However, it is worth noting that OCT may not substitute for gonioscopy because gonioscopy remains useful for evaluation of pigment and neovascularization of the angle, along with assessment of peripheral anterior synechiae (PAS) with indentation. The time-domain anterior segment OCT is limited in scan speed (2000 A-scans per second) and axial resolution (18 μm) and has largely been replaced by spectral-domain and sweptsource OCTs. Although existing spectral-domain OCT instruments are built for imaging the retina and ONH, some are equipped with external or internal add-on lenses for anterior chamber angle imaging. Notably, the visibility of the scleral spur, an important landmark for measurement of the angle width, can be compromised because the wavelength of the superluminescent diode laser in the spectral-domain OCT instruments is shorter than what is required for an adequate visualization of the anterior chamber angle. The advent of swept-source anterior segment OCT has considerably improved the visualization of the angle structures and facilitated comprehensive assessment of the angle for 360 degrees. The first generation of anteriorsegment swept-source OCT (Casia SS-1000 OCT) was introduced by Tomey (Nagoya, Japan) in 2008. The Casia SS-1000 OCT has a scan speed of 30,000 A-scans per second and an axial resolution of approximately 10 μm. With a scan protocol comprising 64 evenly spaced radial scans, each with 512 A-scans spanning a distance of 16 mm, anterior chamber angle configuration can be visualized for 360 degrees in less than 2 seconds. The test-retest variabilities of anterior chamber angle Asia-Pacific Journal of Ophthalmology Volume 5, Number 1, January/February 2016 www.apjo.org 11

Leung Asia-Pacific Journal of Ophthalmology Volume 5, Number 1, January/February 2016 FIGURE 1. Horizontal (0 180 degrees) B-scan (upper panel) and 3-dimensional reconstruction (lower panel) of an open-angle eye (A) and an angle-closure eye (B) imaged by the CASIA2 OCT. Notice the new swept-source OCT can capture the entire anterior segment from the anterior corneal surface to the posterior lens surface. width measurements including angle opening distance, trabecular iris space area, and trabecular iris angle are low. 4 Parameters that cannot be measured with time-domain and spectral-domain OCT instruments such as the iris volume and the area of PAS can be reliably measured with swept-source OCT. 9 12 Synechial angle closure can be differentiated from appositional angle closure by studying the differences in the angle configuration in the light and in the dark. Although angles with appositional closure would be widened with pupil constriction, the configuration of angle closure does not change with pupil size in synechial closure. 12 These new measures have improved our understanding of the pathophysiology and development of angle closure. For example, using 64 radial scans to segment and measure the iris volume, we showed that although the eyes with angle closure had a smaller anterior chamber volume compared with the eyes with open angle, the iris volume is similar between angleclosure and open-angle eyes. In other words, the relative contribution of the iris in crowding the angle when the pupil is dilated is more substantial in the eyes with angle closure. Thedevelopment of primary angle-closure glaucoma from primary angle closure is closely related to the formation of PAS. In fact, the degree of PAS (in terms of clock hours) evaluated with indentation gonioscopy is associated with the severity of optic disc damage in primary angle-closure glaucoma. 13,14 The swept-source OCT would be able to provide a more precise measurement of PAS for risk assessment of primary angle-closure glaucoma. The second-generation swept-source anterior segment OCT is currently under clinical testing and validation. The new generation has a faster scan speed (50,000 A-scans per FIGURE 2. A B-scan imaged by the Triton OCT (Topcon) showing that the anterior lamina cribrosa surface and the choroidal layer in high resolution. 12 www.apjo.org 2016 Asia Pacific Academy of Ophthalmology

Asia-Pacific Journal of Ophthalmology Volume 5, Number 1, January/February 2016 Optical Coherence Tomography Imaging for Glaucoma second), deeper scan depth (14 mm), and a higher scan resolution (8 μm). Imaging of the entire anterior segment can be completed in less than 1 second. This is an important improvement because saccadic eye movement and variation in pupil size during the scan, even for a few seconds, will introduce motion artifacts, degrading the image quality for 3-dimensional analysis. Further, the cornea and the crystalline lens can be captured in a single B-scan (Fig. 1A). The crystalline lens plays a critical role in determining the anterior chamber angle configuration, and lens/cataract extraction has been shown to be an effective treatment strategy for primary angle-closure glaucoma. 15 17 Lens vault (defined as the perpendicular distance between the anterior pole of the lens and the line joining the scleral spurs) and lens thickness are greater in eyes with angle closure. 18 Examination of the lens morphology in association with configuration of the anterior chamber angle is highly relevant in understanding the development and risk assessment of primary angle closure. The new generation swept-source OCT will also include an algorithm for automated/semiautomated detection of the scleral spur for measurement of anterior chamber angle parameters. The extent of angle closure will be computed and displayed for 360 degrees in the new software. Introduced in early 2015, the Triton OCT (Topcon) is another swept-source OCT instrument capable of anterior chamber angle imaging. Although the Triton OCT is built for posterior segment imaging, the anterior chamber angle can be imaged with an external add-on lens. With an axial resolution of approximately 3 μm, visualization of the Schlemm canal and the trabecular meshwork is feasible (Fig. 3). The cross-sectional area of the Schlemm canal has been reported to decrease with elevation of intraocular pressure (IOP) 19 and in eyes with primary open-angle glaucoma 20 and increase after topical IOP-lowering treatment 21 and trabeculectomy. 22 Evaluating the patency of the Schlemm canal and the collecting channels may provide prognostic information for medical and surgical management of glaucoma. However, the Triton OCT is limited by a shallow scan depth (3 mm), and the total number of scan lines in the anterior segment imaging protocol is currently limited to 12 radial scans, which may be not sufficient for 3-dimensional reconstruction of the entire anterior segment. Software for anterior chamber angle analysis has not yet been developed. It is notable that time-domain, spectral-domain, and sweptsource OCTs are all inadequate for imaging of the ciliary body. Any structures posterior to the iris are obscured in OCT images, and the ciliary body can only be partially revealed. Ultrasound biomicroscopy remains the only tool to visualize the ciliary body for investigation of the causes of secondary angle closure (eg, ciliary body tumor/cyst, plateau iris configuration). OPTIC NERVE HEAD IMAGING Measurement of ONH and Lamina Cribrosa Deformation Glaucomatous optic disc damage comprises ONH excavation, loss of neuroretinal rim, and thinning of the RNFL. Recent experimental and clinical studies have indicated that morphological changes of the ONH are complex in the development and progression of glaucoma. 23 25 Although it is not feasible to reliably quantify ONH excavation or deformation in clinical examination with slit-lamp biomicroscopy, spectral-domain OCT has afforded an objective and reproducible means to measure the loss of prelaminar tissue and displacement of the lamina cribrosa and ONH surfaces (Fig. 4). Yet, there is a lack of consensus and validated algorithms for measurement of deformation of the ONH and lamina cribrosa surfaces. For example, different scan protocols (raster scans vs radial scans) and scan density (ranging from 1 B-scan to 48 radial scans) have been reported in the literature for measurement of ONH and lamina cribrosa displacement, and there is no universally accepted protocol for ONH and lamina cribrosa imaging. Analysis of lamina cribrosa deformation is often limited by an incomplete segmentation of the anterior and posterior lamina cribrosa surfaces. Anterior and posterior lamina cribrosa surfaces are frequently undetectable in areas obscured by retinal blood vessels. The posterior lamina cribrosa surface is typically not visible even with adaptive compensation and enhanced depth imaging in spectral-domain and sweptsource OCTs. 26 Complicating the matter further, there are at least 7 commercially available spectral-domain and sweptsource OCT instruments, and they differ in scan speed, resolution, and image registration algorithm for ONH imaging. The optimal instrument, scan protocol, and analysis strategy for measurement of deformation of ONH and lamina cribrosa surfaces have yet to be determined. In a recent study, we analyzed the longitudinal changes of the ONH surface depth [ie, the perpendicular distances from a FIGURE 3. A horizontal (0 180 degrees) B-scan obtained from the Triton OCT with an external add-on lens for anterior chamber angle imaging. The trabecular meshwork and the Schlemm canal are highlighted. 2016 Asia Pacific Academy of Ophthalmology www.apjo.org 13

Leung Asia-Pacific Journal of Ophthalmology Volume 5, Number 1, January/February 2016 FIGURE 4. An example demonstrating posterior displacement of the ONH and anterior lamina cribrosa surfaces in a glaucomatous eye followed from January 10, 2010, to March 21, 2014. The scanning laser ophthalmoscopy image and OCT images of the vertical meridian [with and without tracing of the reference line (pink), ONH (green), and anterior lamina cribrosa (orange) surfaces] at the baseline (A) and latest (B) follow-up visits are shown. The ONH and the anterior lamina cribrosa surfaces displaced posteriorly by 38.3 and 53.2 μm, respectively. The prelaminar tissue thickness decreased by 31.9 μm. Figure is adapted from Wu et al. 25 reference line a line joining the Bruch membrane opening (BMO) to the ONH surface] and anterior lamina cribrosa depth (ie, the perpendicular distances from the reference line to the detectable anterior lamina cribrosa surface) in 138 eyes of 88 glaucoma patients followed for a mean (range) of 5.3 (4.0 6.4) years. 25 Applying the respective repeatability coefficients to detect significant changes of the ONH surface depth and the anterior lamina cribrosa depth (ie, the difference between final and baseline measurements), we observed not only posterior, but also anterior displacement of the ONH and anterior lamina cribrosa surfaces in glaucoma patients. Older patients and eyes with a smaller mean IOP during follow-up generally had less posterior deformation of the ONH and anterior lamina cribrosa surfaces. The sclera and lamina cribrosa stiffen with age. 27 29 Our finding underscores the complex interaction between IOP and the biomechanical properties of the lamina cribrosa and the sclera in determining the ONH morphology in glaucoma. Although the implication of posterior and anterior deformation of the lamina cribrosa in relation to glaucoma management remains largely uncertain, posterior ONH surface deformation has been shown to precede RNFL thinning and functional loss in experimental models of glaucoma 30 32 and in glaucoma patients. 33 Optic nerve head changes have been associated with an increased risk of progressive visual field loss. 34,35 Investigating ONH and lamina cribrosa deformation in relation to RNFL and visual field loss can provide insights into the time window for therapeutic intervention to prevent glaucoma progression. Measurement of Neuroretinal Rim Although neuroretinal rim loss is a cardinal feature of glaucomatous optic neuropathy, defining the boundary of the neuroretinal rim at the ONH is not straightforward. In the confocal scanning laser ophthalmoscope (CSLO), the neuroretinal rim is defined with reference to the clinically visible optic disc margin and an arbitrary reference plane positioned at 50 μm posterior to the temporal disc margin. Areas above and below the reference plane in a cross-sectional image are considered as the neuroretinal rim and optic cup, respectively. Although neuroretinal rim area measured by the CSLO has been widely adopted for detection and monitoring of glaucoma, neuroretinal rim measurement has been recently redefined, taking reference from the BMO. 36 38 The scientific basis of this conceptual change is rooted in the observation that clinically identified optic disc margin does not correspond to a single anatomic structure or an identifiable junction. 36 The new definition of neuroretinal rim is termed BMO minimum width (BMO-MRW), representing the minimum distance between the BMO and the internal limiting membrane (Fig. 5). In a study comparing the performance of BMO-MRW measured by spectral-domain OCT (Spectralis OCT, Heidelberg Engineering, Heidelberg, Germany) and Moorfield Regression Analysis of rim width measured by CSLO (Heidelberg Retina Tomograph, Heidelberg Engineering), the sensitivity of BMO- MRW (54% 79%) for discriminating glaucomatous from normal eyes was higher than Moorfield Regression Analysis of rim width (35% 64%) at 95% specificity. 37 The structure-function relationship in glaucoma was also stronger for BMO-MRW compared with CSLO neuroretinal rim measurements. 39 These studies highlight the importance of measuring the neuroretinal rim with reference to geometrically accurate properties. The BMO-MRW measurement, however, is not without limitations. Although the Spectralis OCTautomatically detects the BMO, manual confirmation for each of the 24 scan meridians is required to ensure that the detection is accurate. The location of BMO can be indistinct, most often at the temporal disc margin in eyes with peripapillary atrophy. The application of BMO-MRW for detection of progressive neuroretinal changes in glaucoma progression has not been investigated. Optical Coherence Tomography Angiography The application of OCT has also been extended to angiography and blood flow measurement. Reduced retinal perfusion in the peripapillary retina has been observed in glaucomatous eyes. 14 www.apjo.org 2016 Asia Pacific Academy of Ophthalmology

Asia-Pacific Journal of Ophthalmology Volume 5, Number 1, January/February 2016 Optical Coherence Tomography Imaging for Glaucoma FIGURE 5. Measurement of minimum rim width using the Spectralis OCT (Heidelberg Engineering). The minimum rim width represents the minimum distance between BMO and the internal limiting membrane. The left panel presents a normal eye, and the minimum rim width measurements are all within the normal 95% confidence limits. The right panel shows a glaucomatous eye with abnormal minimum rim width measurements over the superior and inferior sectors of the optic disc. The minimum rim width measurements are illustrated in 12 angle meridiansineacheye. Using swept-source OCT, Jia et al 40,41 computed and compared 3-dimensional optic disc angiography in 24 normal subjects and 11 glaucoma patients and showed that the visibility of the microvascular network was attenuated in glaucoma patients and that the disc flow index, a dimensionless value between 0 and 1 measured with the split-spectrum amplitude-decorrelation angiography algorithm (an algorithm to improve the signal-to-noise ratio of flow detection), was decreased by 25% in the glaucoma group. Using spectral-domain OCT, Liu et al 42 reported that the peripapillary flow index and peripapillary vessel density were highly correlated with visual field pattern SD in 12 glaucomatous eyes. The temporal relationship between perfusion insufficiency and visual field damage has not been established, and the role of OCT angiography in glaucoma management remains to be determined. SUMMARY Optical coherence tomography 3-dimensional analysis of the anterior chamber angle and the ONH has provided new information regarding the anatomy and pathophysiology of primary angle-closure glaucoma and the development of optic nerve degeneration in glaucoma. Challenges remain, however, in handling and interpreting big data generated from high-density volumetric scans. Automatic segmentation support for 3-dimensional analysis of the anterior chamber angle width and the ONH and lamina cribrosa parameters are under development and validation. REFERENCES 1. Fujimoto JG, Drexler W. Introduction to optical coherence tomography. Fujimoto JG, Drexler W, eds. Optical Coherence Tomography Technology and Application. Springer: Heidelberg; 2009:1 45. 2. Adhi M, Duker JS. Optical coherence tomography current and future applications. Curr Opin Ophthalmol. 2013;24:213 221. 3. Smith SD, Singh K, Lin SC, et al. 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