Optical coherence tomography (OCT) is a relatively new noninvasive. The Use of Optical Coherence Tomography in Neurology DIAGNOSTIC UPDATE

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1 DIAGNOSTIC UPDATE The Use of Optical Coherence Tomography in Neurology Cédric Lamirel, MD,* Nancy Newman, MD,* Valérie Biousse, MD* Departments of *Ophthalmology, Neurology, and Neurological Surgery, Emory University School of Medicine, Atlanta, GA Optical coherence tomography (OCT) is a noninvasive imaging technique routinely used in ophthalmology to visualize and quantify the layers of the retina. OCT allows direct visualization and measurement of the topography of the optic nerve head and retinal nerve fiber layer thickness in the peripapillary and macular regions with micron-scale resolution. These measurements are of particular interest in optic neuropathies and in numerous neurologic disorders in which there is axonal loss, such as multiple sclerosis. This article provides a detailed overview of OCT and its potential applications in neurology. [Rev Neurol Dis. 2009;6(4):E105-E120 doi: /rind0243] 2009 MedReviews, LLC Key words: Multiple sclerosis Optic neuropathy Optical coherence tomography Retinal nerve fiber layer Optical coherence tomography (OCT) is a relatively new noninvasive imaging technique routinely used in ophthalmology to visualize and quantify the layers of the retina with highly refined resolution, accuracy, and reproducibility. 1-5 Originally developed for retinal diseases and glaucoma, OCT allows direct visualization and measurement of the topography of the optic nerve head and retinal nerve fiber layer (RNFL) thickness in the peripapillary (the region around the optic disc) and macular regions with micronscale resolution. The RNFL thickness and macular volume are of particular interest in optic neuropathies and in numerous neurologic disorders in which there is axonal loss, such as multiple sclerosis (MS). This imaging technique was first reported in and in vivo retinal imaging was first demonstrated in the human eye in ; since then, 4 generations of OCT machines have been developed, and the third generation of commercially available OCT machines VOL. 6 NO REVIEWS IN NEUROLOGICAL DISEASES E105

2 Optical Coherence Tomography in Neurology continued Table 1 Third-Generation (Time Domain) and Spectral Domain Optical Coherence Tomography Commercially Available in the United States Name Manufacturer Generation Stratus OCT TM Carl Zeiss Meditec Inc. Time domain (Pleasanton, CA) Cirrus TM HD-OCT Carl Zeiss Meditec Inc. Spectral domain OCT Spectralis TM Heidelberg Engineering, Inc. Spectral domain (Heidelberg, Germany) RTVue-100 Optovue Corp. (Fremont, CA) Spectral domain 3D OCT-1000 Topcon Medical Systems (Paramus, NJ) Spectral domain Spectral OCT/SLO Opko Instruments (Miami, FL) Spectral domain 3D SD-OCT Bioptigen (Durham, NC) Spectral domain Prices vary from $65,000-$140,000 based on machine characteristics and options. 3D, three-dimensional; HD, high-definition; OCT, optical coherence topography; SD, spectral domain; SLO, scanning laser ophthalmoscope. (also called time domain OCT) is currently widely used in ophthalmology. Recently, several companies have developed newer versions of OCT, which use spectral domain technology (Table 1). Within 15 years, more than 6000 scientific articles have been published on the use of OCT in ophthalmology, and structural assessment of the optic nerve and the retina with OCT are now routinely used as efficacy endpoints in ophthalmic clinical trials In addition, it has been suggested that quantification of the RNFL thickness and macular volume by OCT may be used by neurologists to noninvasively quantify axonal and neuronal loss in the anterior visual pathways, thereby providing an objective marker and potential endpoint for future trials of neuroprotective agents in neurologic disease. 5 Other imaging technologies, including confocal scanning laser ophthalmoscopy (Heidelberg retina tomograph [HRT]; Heidelberg Engineering, Inc., Heidelberg, Germany), and scanning laser polarimetry (GDx; Carl Zeiss Meditec, Inc., Pleasanton, CA), also allow assessment of the optic nerve and peripapillary RNFL, and are still being used by many ophthalmologists, particularly for glaucoma. This article provides a detailed overview of OCT and its potential applications in neurology. What Is OCT and How Does It Work? OCT is often described as an ultrasonic scan that uses light instead of sound to map tissue microstructure. 6 It uses light to create high-resolution, quantitative, crosssectional images of biologic tissues (Figures 1, 2, and 3). OCT has numerous applications in medicine; it is now routinely used to produce cross-sections of all intraocular structures; it is also used to image layers of the mucosa during endoscopic procedures thereby allowing OCT-guided biopsies of the gastrointestinal tract. 11 Because OCT can visualize blood vessels and brain white matter when placed at the end of a probe, it may also be helpful in guiding the implantation of deep brain electrodes. 12 The resolution of OCT depends on the wavelength and the coherence length of the light beam and is better than ultrasound. The routinely used commercial third-generation OCT machines have a resolution of approximately 10 m, whereas the new spectral domain OCT has increased the spatial resolution to between 3 and 4 m, with imaging speeds of 25,000 to 40,000 axial scans per second approximately 50 times faster than the previous generation of OCT machines. Use of OCT in Ophthalmology In ophthalmology, OCT is routinely performed using a machine that usually requires pharmacologic dilation of the pupils and good patient cooperation (Figure 3). The eye is an easy organ to explore with this technique because of transparency of the media. To obtain good quality images, it is essential that the patient maintain fixation to avoid eye movements. It is also important that the media (intraocular structures) be clear to perform a reliable OCT; hence, OCT cannot be reliably performed in noncooperative patients or in patients with corneal opacities, dense cataracts, or vitreous hemorrhage. The OCT device was first adapted to a slit-lamp in 1993 to provide in vivo imaging of the retina. 7 The initial axial resolution was only 14 m and the number of scans was limited to 100 acquired in 2.5 seconds. In 1995, the technique was improved to perform multiple scans of the area of interest. 13 A circle scan was placed around the optic disc to measure the peripapillary RNFL thickness. Programs were designed to correct eye movement artifacts, and to automatically recognize the retina and measure the thickness and topography of the retinal layers. This new E106 VOL. 6 NO REVIEWS IN NEUROLOGICAL DISEASES

3 Optical Coherence Tomography in Neurology Figure 1. Cross-sectional images of the retina (macula) obtained by optical coherence tomography (OCT). (A) Fundus photograph of a right eye showing the position of the horizontal scan at the level of the macula, across the fovea. The scan begins on the temporal side of the macula and ends on the nasal side of the macula (blue arrow). (B) Cross-sectional image of the macula obtained with a third-generation OCT (time domain OCT). (C) Cross-sectional image of the macula obtained with a spectral domain OCT (Courtesy of Heidelberg Engineering, Inc., Heidelberg, Germany). (B) and (C) show the physiologic foveal depression in the center of the macula where the retinal layers are thinner. The box represents the location of the magnified views of the retinal layers with the third-generation OCT (D) and the spectral domain OCT (E) (Courtesy of Heidelberg Engineering, Inc.). The retinal layers are easily identified on these cross-sectional images. The retinal nerve fiber layer has high reflectivity and is represented in red on the image obtained with the third-generation OCT (D). Although spectral domain OCT provides black and white images (E), the resolution is better than with third-generation OCT (D) and nearly replicates a histologic cross-section of the retina. technique allowed recognition of numerous retinal disorders such as macular hole, epiretinal membrane, macular edema, central serous chorioretinopathy, and detachments of the pigment epithelium and neurosensory retina, with a good correlation with fundus examination and retinal fluorescein angiography. 14 Retinal thickness measurements by OCT became useful to serially follow patients with various retinal disorders such as diabetic macular edema Retinal thickness measurements by OCT became useful to serially follow patients with various retinal disorders such as diabetic macular edema and macular degeneration. and macular degeneration. The first commercial machine became available in 1996, and had an axial resolution of 10 to 15 m and acquired 100 axial scans in 1 second. The third generation of OCT, developed in 2002, provided much better quality images of both the macula and optic disc, with an axial resolution between 8 and 10 m and an acquisition speed of 400 scans per second. This third generation of OCT allows the technician to choose scan length, scan position, and scan type and to obtain fast-speed scans (allowing multiple scan acquisitions of the same area within 2.5 sec) to VOL. 6 NO REVIEWS IN NEUROLOGICAL DISEASES E107

4 Optical Coherence Tomography in Neurology continued Reference mirror Semi-transparent mirror Low coherence laser beam Computer Eye Figure 2. Schematic representation of time domain optical coherence tomography. A low-coherence infrared light (laser beam) is emitted from a superluminescent diode into the patient s eye through the pupil to scan the retina. The light beam is split in half by a semitransparent mirror so that half is sent into the patient s eye, and half is sent to a reference mirror. Light entering the eye is back-scattered, with different time delays resulting from differences in tissue-refractive indices. The light back-scattered from the eye and the light back-scattered from the mirror are then compared using a detector, which reconstructs differences in time delay and amplitude of reflection and forms an image. Multiple scans of the same retinal area are used to generate a 2-dimensional image. An algorithm mathematically uses this information to construct a grayscale or false-color image representing the anatomy of the retina. reduce eye movement artifacts (fast scan protocols). More recently, a new generation of OCT has emerged called spectral domain OCT, which uses Fourier transformation of the signal and decreases the acquisition time by a factor of The change of the laser beam also increased the axial resolution to between 3 and 4 m. 16 Spectral OCT has made it possible to represent volume and not just a 2-dimensional image as in the third-generation OCT (Figure 4). OCT can also be used to image the anterior segment of the eye, which is particularly helpful in refractive surgery. 17 Indeed, OCT has the ability to provide biometric measures to design refractive intraocular lenses, and to choose the most accurate lens for a specific patient. It can also image the iris and the iridocorneal angle. OCT can also be used to image the anterior segment of the eye, which is particularly helpful in refractive surgery. Figure 3. Example of a third-generation optical coherence tomography machine and patient s positioning. The patient sits with his chin on the chin rest. The test lasts between 5 and 10 minutes, during which the patient needs to be able to sit up with his head still and fixate a light target with the studied eye. One eye is tested at a time, preferably after pharmacologic pupillary dilation. Good patient cooperation is important to limit eye-movement artifacts, particularly to maintain fixation, especially with the new spectral domain machine. Some of the new machines have an eye tracker to avoid eye-movement artifacts. When the eye studied cannot fixate (because of poor vision), then proper fixation may be achieved by asking the patient to fixate an external target with the fellow eye. The images obtained can be immediately reviewed on the monitor. OCT in Macular Diseases The best application of OCT in ophthalmology is for macular diseases; indeed, many macular disorders are not easily seen on funduscopic examination. Whereas retinal fluorescein angiography allows good evaluation of the retina, it is time consuming and moderately invasive, and it does not allow visualization of the vitreoretinal interface. OCT has helped ophthalmologists understand the physiopathology of various macular disorders, such as macular holes, that are related to traction of the vitreous on the macula (Figure 5). 1 OCT is currently routinely used not only for diagnosis, but also to evaluate the effects of treatments on numerous retinal disorders such as macular holes, epiretinal membranes, macular edema, age-related macular degeneration, central serous retinopathy, and serous retinal detachment. All recent clinical trials in ophthalmology, including those evaluating treatments for common conditions such as diabetic retinopathy or age-related macular degeneration, have incorporated OCT as a major outcome measure along with measurements of visual function. 9,10 Ophthalmologists are now using OCT to individually adapt treatments of retinal diseases for their patients and an OCT machine can be found in every single ophthalmologist s office with an expertise in retinal disorders. OCT in Optic Neuropathies Because OCT provides imaging of the optic nerve topography (and precise measurement of the cup size and its depth), and also measures the peripapillary RNFL thickness, which reflects axonal loss, it is now E108 VOL. 6 NO REVIEWS IN NEUROLOGICAL DISEASES

5 Optical Coherence Tomography in Neurology Figure 4. Examples of images obtained with a spectral domain optical coherence tomography (OCT). The new spectral domain OCT has a better resolution and a faster acquisition time than third-generation OCT. This allows scanning a volume of a predefined region of interest. (A) Fundus photograph of a normal left eye showing the position of 2 scans (macula in red, disc in blue). For each scan the orientation is indicated by superior (S), nasal (N), inferior (I), and temporal (T). (B) 3-dimentional reconstruction of an abnormal macular scan with serous detachment of the retina. The black space shown as (*) represents the detachment. The edge of the optic nerve head is seen on the nasal side of this macular scan. (C) 3-dimensional reconstruction of an optic nerve head with mild cupping and some temporal peripapillary atrophy. (B and C, Courtesy of Heidelberg Engineering, Inc., Heidelberg, Germany.) Figure 5. Third-generation optical coherence tomography (OCT) findings in macular hole. (A) Fundus photograph of a right eye with a macular hole showing the location of the OCT scan through the center part of the macula (fovea). (B) Early stage of macular hole with vitreo-retinal traction (arrow) leading to a macular cyst (arrowhead). (C) Complete macular hole (arrow) with disruption of the inner layers of the retina. routinely used to image optic nerves, particularly in patients with glaucoma (Figures 6, 7, and 8). The RNFL contains the retinal ganglion axons that form the optic nerve. These retinal ganglion cells have no myelin and can be easily visualized. Axons of retinal ganglion cells of the same area are packed together in bundles that can be observed on fundus examination as striations of the RNFL. Lesions of these axons result in localized loss of theses bundles that can be detected on fundus examination or on fundus photographs, and eventually produce optic nerve pallor and corresponding visual field defects. 18 However, the detection of RNFL defects by funduscopic examination or on fundus photographs can be difficult and is often delayed because visible detection of RNFL atrophy requires loss of 50% of neural tissue and optic disc pallor typically takes 4 to 6 weeks to appear after optic nerve injury. 19 RNFL thickness, measured by OCT, is decreased in patients with chronic optic neuropathies and optic atrophy, and can be detected earlier than funduscopic changes. Because RNFL defects are caused by degeneration of axons within the anterior visual pathways, which may result from all causes of optic neuropathies (compression, inflammation, ischemia, degeneration), OCT has been proposed as a structural biomarker for axonal integrity in the anterior visual pathway. Measurement and monitoring of the peripapillary RNFL thickness in patients with neurologic disorders (with or without optic neuropathies) has become a hot topic, generating hundreds of publications and a great deal of enthusiasm among neurologists and ophthalmologists. 4,5 Because RNFL fibers are perpendicular to the direction of the OCT light beam and the most anterior layer of the retina, the RNFL is one of the retinal layers with the greatest reflectance on OCT. This allows the RNFL to be automatically segmented and measured accurately by computer algorithms. RNFL thickness measurements are obtained using circular scans around the optic nerve in the peripapillary region (Figures 7 and 8). The diameter of this circle was first chosen arbitrarily to avoid the disc margin, even in the case of large discs, and to allow sampling of the thick peripapillary RNFL close to the optic nerve head. The latest fast RNFL thickness protocol performs 3.4-mm diameter circular scans around the optic nerve head in VOL. 6 NO REVIEWS IN NEUROLOGICAL DISEASES E109

6 Optical Coherence Tomography in Neurology continued Figure 6. Optic nerve head analysis with third-generation optical coherence tomography (OCT). (A) Fundus photograph of the right eye showing the location of the OCT scan through the optic disc. (B) Results of the optic disc scan as typically shown by a third-generation OCT. 1) Cross-section image of the vertical scan (radial scan analysis) showing the anatomy of the optic disc and its cup. The software recognizes the edge of the retinal pigment epithelium/basal membrane complex (arrowheads), which corresponds to the margins of the optic nerve head in this vertical meridian. The green-blue line connecting both edges is the reference plane. The software then recognizes the rim, which is indicated in red and corresponds to the area located 150 m above the reference plane; the cup is the area located under the reference plane and is colored in green-blue. The disc diameter (1.76 mm) and the cup diameter (1.32 mm) are indicated below the cross-section image. 2) The scan is repeated along 6 different axes and the software provides a reconstruction called optic nerve analysis results. The red circle represents the disc margin obtained from the 6 scans; the green-blue central area represents the edge of the cup. The disc area (2.296 mm 2 ) and the cup area (1.685 mm 2 ) are indicated below this image. Figure 7. Peripapillary retinal nerve fiber layer (RNFL) thickness measurement with a third-generation optical coherence tomography (OCT). The white circle placed over the optic disc indicates the location of the scan which begins in the temporal (T) part of the optic disc, then moves to the superior (S), the nasal (N), the inferior (I) parts, and back to the temporal part of the optic disc. The software produces a cross-sectional image of the peripapillary retina which is color-coded and shows the temporal, superior, nasal, and inferior areas. The RNFL is the most superficial layer, and is thicker in the superior and inferior parts of the optic disc seconds (Figures 7 and 8). The algorithm measures only the thickness of the first hyper-reflective layer, which is the RNFL (shown between the 2 thin white lines in Figure 7). The thickness of the RNFL is higher in the superior and inferior part of the optic disc than in the nasal and temporal part. Comparison with a normative database can aid in identifying overall thinning of the layer, as well as focal defects. Measurements of the peripapillary RNFL thickness can also be repeated over Measurements of the peripapillary RNFL thickness can also be repeated over time in the same patient to document changes. time in the same patient to document changes. OCT also allows measurement of the macular RNFL thickness, which can be used to calculate macular volume. It has been suggested that measurement of peripapillary RNFL thickness reflects axons (and therefore allows quantification of axonal loss), whereas measurement of macular thickness and volume reflects neurons (and therefore allows quantification of neuronal loss). This is because the macular region contains mostly ganglion cell bodies, as the nerve fibers are around the macula to avoid obscuring the most sensitive area for vision. Therefore, the assessment of macular volume may be a noninvasive way to determine whether neuronal degeneration is occurring in addition to axonal loss. 1,4 Comparison of RNFL thickness measurements with a third-generation OCT versus spectral domain OCT has shown better sensitivity and specificity for the new spectral domain OCT. 1,15 However, the results obtained with these 2 machines are different and cannot be directly compared for the same patient. E110 VOL. 6 NO REVIEWS IN NEUROLOGICAL DISEASES

7 Optical Coherence Tomography in Neurology RNFL THICKNESS AVERAGE ANALYSIS Microns S OD T I 105 N 104 Signal Strength (Max 10) TEMP SUP NAS INF TEMP Microns TEMP SUP NAS INF TEMP Microns TEMP SUP NAS INF TEMP OD OS OS Imax/Smax Smax/Imax Smax/Tavg Imax/Tavg Smax/Navg Max-Min Smax Imax Savg Iavg Avg. Thickness WE MEL OD (N = 3) OS (N = 3) Patient/Scan Information DOB: 3/6/1972, ID: , Female Scan Type Fast RNFL Thickness (3.4) Scan Date 11/25/2008 Scan Length mm N 130 S I T 64 OD OS Signal Strength (Max 10) 8 Normal Distribution Percentiles 3 100% 95% 5% 1% 0% Figure 8. Results of peripapillary retinal nerve fiber layer (RNFL) analysis performed with a third-generation optical coherence tomography (OCT). Four important steps are necessary to correctly interpret this scan: 1) check the name, sex, and age of the patient; 2) check the signal strength to make sure the scan is reliable (7 and 8 here); 3) look at the average RNFL thickness in each eye (86.36 m in the right eye and m in the left eye in this case); 4) look at where the thinning is worse for each eye (mostly superior and temporal in the right eye in this case). The graphs shown on the left represent the RNFL thickness in each quadrant studied (right eye above and left eye below), beginning with the temporal part of the optic disc, then followed by the superior, the nasal, the inferior, and back to the temporal part. The patient s results are indicated as a thin black line. The green, yellow, and red areas indicate the distribution of findings in a large number of patients matched for sex and age. The graph at the bottom shows the results obtained in each eye allowing better comparison of each eye. OCT in Glaucoma. Chronic openangle glaucoma is the most common chronic optic neuropathy and a major cause of visual disability worldwide. It typically manifests as optic nerve cupping and progressive axonal loss, visual field defects, and elevated intraocular pressure. OCT has become an extremely useful tool in the diagnosis and follow-up of patients with glaucoma because of its ability to measure the topography of the optic nerve head (and to precisely quantify the size of the cup), and to measure the RNFL thickness (which reflects axonal loss). OCT is now routinely included as a major outcome measure in glaucoma clinical trials. 1,8 Interestingly, a recent study showed that imaging of the optic nerve head shape and cup by third-generation OCT is not better than stereoscopic photography interpreted by a glaucoma expert; however, OCT is superior to fundus photography when stereoscopic photography interpretation is done by a general ophthalmologist. 20 Measurement of the RNFL thickness with OCT has been found to be useful in early glaucoma when automated perimetry is still normal, but not when other clues such as elevated intraocular pressure, disc appearance, or family history suggests glaucoma. 21 Optic Disc Atrophy. All neurologic disorders affecting the anterior visual pathways and all optic neuropathies eventually produce some degree of optic nerve atrophy. Numerous VOL. 6 NO REVIEWS IN NEUROLOGICAL DISEASES E111

8 Optical Coherence Tomography in Neurology continued studies have shown thinning of the RNFL in various optic neuropathies, including optic neuritis, compressive optic neuropathies, ischemic optic neuropathies, and hereditary and toxic optic neuropathies (Figure 9) Additionally, recent studies have suggested that reduced RNFL thickness correlates with visual function after an optic neuropathy. 24,27,30,31 As for glaucomatous optic neuropathies, OCT may allow earlier detection of axonal loss than funduscopic examination or visual field testing, and may be used to monitor patients with optic neuropathies as well as neurologic disorders affecting the anterior visual pathways. It has also been suggested that OCT may be used to predict visual recovery from compressive optic neuropathy. 32,33 However, despite the obvious application of OCT in neuro-ophthalmic disorders, its routine use remains limited at this point, mostly because of lack of studies showing its superiority to neuro-ophthalmic examination, including fundus photography and automated perimetry. OCT for the diagnosis of optic neuropathy. The diagnosis of optic neuropathy is usually straightforward, based on clinical examination, visual field testing, and sometimes electrophysiology. Rarely, in presumed subtle unilateral or bilateral chronic optic neuropathies, or in patients with incidentally found optic nerve pallor, the diagnosis of optic neuropathy can be challenging. In these cases, measurement of the peripapillary RNFL is helpful when it shows decreased RNFL in the eye with decreased vision, or decreased RNFL in cases with incidentally found optic Recent studies have suggested that reduced RNFL thickness correlates with visual function after an optic neuropathy. nerve pallor and otherwise normal visual function. In patients with unexplained central visual loss, in whom the physician hesitates between a maculopathy and an optic neuropathy, an OCT of the macula is often helpful. However, with the exception of selected cases of optic neuritis or compressive optic neuropathy (see below), there are no studies showing that obtaining an OCT to measure the peripapillary RNFL contributes to the diagnosis or enhances the clinical care of patients with known optic neuropathies. OCT to predict visual recovery. Visible loss of RNFL is delayed by a few weeks in all acute optic neuropathies, explaining why optic nerve pallor takes between 4 and 6 weeks to develop. Many patients with optic nerve damage have a good visual prognosis despite abnormal visual fields and obvious optic nerve pallor. Being able to predict which patients may recover spontaneously or with a specific intervention would greatly enhance the management of patients with nonglaucomatous optic neuropathies. 24,31-34 To date, the main use of OCT as a predictive tool is for patients with compressive optic neuropathies from sellar and suprasellar tumors. 24,32,33 Two recent studies 32,33 have shown that reduction of the average peripapillary RNFL below 70 to 80 m is associated with poor visual outcome despite surgical decompression of these tumors, independent of the patient s age and duration of compression. Interestingly, a previous study of patients with optic neuritis had suggested the same threshold of 75 m for the peripapillary RNFL thickness as an indicator of poor visual recovery after optic neuritis. 34 These studies remain limited, but suggest that visual recovery may not be good despite therapeutic interventions in patients with chronic optic neuropathies and visual loss when the average peripapillary RNFL is below 75 m. It is also important to emphasize that many optic neuropathies are associated with disc edema or disc elevation acutely, which increases the peripapillary RNFL thickness (Figure 10). Furthermore, it takes weeks for retrograde axonal degeneration to occur, especially in retrobulbar optic nerve injury. This is why RNFL measurement with OCT is not helpful in most acute optic neuropathies, and why most studies have included patients with chronic optic neuropathies and long standing visual loss. Optic Disc Edema. As emphasized above, most studies have evaluated thinning of the RNFL in patients with chronic optic neuropathies and optic atrophy. However, OCT can also measure increased peripapillary RNFL when there is optic nerve edema. This has been demonstrated OCT can also measure increased peripapillary RNFL when there is optic nerve edema. in a few studies that also emphasized that RNFL thickness measurement was not as reliable with optic nerve edema because of the difficulty to define the center of the disc and the ideal position of the circle in which scans are obtained (Figure 10). 25,35 In addition, OCT does not seem to E112 VOL. 6 NO REVIEWS IN NEUROLOGICAL DISEASES

9 Optical Coherence Tomography in Neurology A B RNFL THICKNESS AVERAGE ANALYSIS Microns OD T 57 S N I 64 Signal Strength (Max 10) TEMP SUP NAS INF TEMP S Microns OS N I 69 T 26 Signal Strength (Max 10) TEMP SUP NAS INF TEMP Microns Imax/Smax Smax/Imax Smax/Tavg Imax/Tavg Smax/Navg Max-Min Smax Imax Savg Iavg Avg. Thickness OD (N = 3) OS (N = 3) OD OS Normal Distribution Percentiles 100% 95% 5% 1% 0% Patient/Scan Information TEMP SUP NAS INF TEMP OD OS Scan Type Fast RNFL Thickness (3.4) Scan Date Scan Length mm Figure 9. Severe retinal nerve fiber layer (RNFL) thinning in compressive optic neuropathy as obtained on a third-generation optical coherence tomography (OCT). (A) Fundus photographs of both optic nerves showing bilateral severe optic atrophy. (B) Peripapillary RNFL obtained on a third-generation OCT. The quality of the test is good as shown by signal strength of 9 in each eye. There is severely decreased average RNFL thickness (47.85 m in the right eye and m in the left eye) with diffuse thinning of the RNFL in all quadrants. The red color indicates that this patient s results fall within the lowest percentile of the normal distribution in the normative database used as controls. VOL. 6 NO REVIEWS IN NEUROLOGICAL DISEASES E113

10 Optical Coherence Tomography in Neurology continued A B D Microns TEMP SUP NAS INF TEMP 0 C m Figure 10. Third-generation optical coherence tomography (OCT) results in disc edema. (A) Fundus photograph of the right eye showing disc edema. The red line (B) shows the location of the cross-sectional image of the retina shown in B; the white line (D) shows the location of the cross-sectional image shown in D; the yellow circle (D) shows the position of the scan used for retinal nerve fiber layer (RNFL) thickness measurement shown in (E). (B) Cross-section image of the macula showing increased thickness nasal to the macula (adjacent to the optic disc) related to peripapillary retinal edema (*). (C) Map of the macular thickness obtained from 6 different scans of the macula. In the center, the normal foveal depression is preserved with the depression represented in blue. On the right side of the map (corresponding to the nasal part of the macula adjacent to the swollen optic nerve head), increased thickness from retinal edema is indicated by the white color (*). (D) Vertical scan along the optic nerve head showing the optic disc edema in red, and the absence of cupping. The adjacent retinal edema artificially enlarges the optic disc margins. (E) Result of the peripapillary RNFL thickness that is above the 95th normal percentile for almost all parts of the disc. The black line is interrupted because the patient s RNFL thickness is greater than 300 m (which is the maximum shown on the graph, although the software can calculate greater values). E reliably allow differentiation among true optic nerve head edema, congenitally crowded optic nerves, and optic nerve head drusen. 25,35,36 Only 1 study, which included 20 patients with disc edema and 20 patients with optic nerve head drusen, suggested that the thickness of the RNFL in the nasal part of the optic disc combined with the shape of the optic disc elevation on OCT might be helpful in discriminating optic disc edema from optic nerve drusen acutely. 37 Sequential peripapillary RNFL thickness measurements with OCT are an objective way to document improvement of optic nerve head edema in anterior optic neuropathies as well as in papilledema from raised intracranial pressure. However, no study has shown that OCT is more effective than clinical examination and fundus photography to follow these patients. One study suggested that RNFL thickness at baseline correlated with ultimate visual field deficit in a group of 22 patients (44 eyes) with idiopathic intracranial hypertension followed for 12 months. The authors suggested that for every increase of 10 m of RNFL thickness, the mean deviation of the visual field at the last follow-up visit was decreased by 0.6 db. 31 However, it is important to emphasize that resolution of disc edema is the rule with all optic neuropathies, whether they improve functionally or not. Severe optic atrophy with devastating visual loss is associated with complete resolution of disc edema (hence the saying, dead axons don t swell ), confirming that in patients with disc edema or papilledema, documentation of visual function and old-fashioned formal visual field testing is much more important than sophisticated imaging of the RNFL by OCT. 25 Optic Neuritis. Optic neuritis is similar to other optic neuropathies E114 VOL. 6 NO REVIEWS IN NEUROLOGICAL DISEASES

11 Optical Coherence Tomography in Neurology in terms of OCT findings. The first OCT study in optic neuritis was published in 1999 by Parisi and colleagues, 22 and compared average peripapillary RNFL thickness in 14 MS-related optic neuritis patients and 14 control subjects. Not surprisingly, they found a significant thinning of the RNFL average thickness and RNFL temporal thickness in the optic neuritis group compared with control subjects (by an average of 46%; P.01), and to the nonaffected fellow eye of these MS patients (by an average of 28%; P.01). A subsequent study in 2005 by Trip and coworkers 38 used a newer OCT machine to correlate RNFL measures with visual function among 25 patients with optic neuritis who had incomplete visual recovery (11 with MS and 14 with a clinically isolated syndrome), and 15 control patients. This study confirmed an average 33% reduction in RNFL thickness in the affected eyes of patients with previous optic neuritis compared with the eyes of matched control subjects, and an average 27% reduction when the affected and unaffected eyes of the same patient were compared (P.001). They also showed that reduced RNFL correlated with impaired visual function. A subsequent study of the same cohort of patients with optic neuritis published in 2006 showed a correlation among optic nerve atrophy, abnormal visual function, decreased visual evoked potentials amplitude, and RNFL thinning and macular volume loss. 39 This study suggested that axonal loss contributes to optic nerve atrophy following a single attack of optic neuritis. 39 The same year, Fisher and coauthors, 40 using a third-generation OCT, reported the results of OCT performed in 90 MS patients (some without a history of acute optic neuritis) and 36 control patients. The average RNFL thickness was reduced in all eyes of MS patients (92 m) compared with control eyes (105 m), with the lowest RNFL values noted in MS patients with a prior clinical history of optic neuritis (85 m). They also correlated the RNFL thickness to visual acuity tested with a low-contrast chart and with contrast sensitivity, functional measurement shown to best capture MSrelated visual impairment. For every one-line decrease in low-contrast letter acuity or contrast sensitivity score, the mean RNFL thickness decreased by 4 m. Another series of 12 optic neuritis patients suggested a good correlation between RNFL thinning and visual acuity, 3 months after an episode of optic neuritis. 41 In this small study, for every 1-line decrease in Snellen visual acuity, the mean RNFL thickness decreased by 5.4 m. In 2006, Costello and associates 34 reported on the peripapillary RNFL as measured by OCT in 54 patients with acute unilateral optic neuritis and showed a threshold of 75 m, below which there was a linear relationship between mean RNFL thickness and mean deviation on automated perimetry. This study suggested that RNFL thickness may predict visual recovery after optic neuritis. The same group subsequently compared RNFL thickness between the 2 eyes of 78 patients who had 1 episode of unilateral optic neuritis. 42 They showed that the earliest significant intereye differences were seen in the temporal region 2 months after the episode of optic neuritis; they also showed that RNFL thinning progressed for up to 6 months, and then stabilized from 7 to 12 months after acute optic neuritis. Two other studies have suggested a correlation between structural and functional measures of optic nerve integrity in patients with optic neuritis. 43,44 Correlation between the topography of RNFL thinning and the location of the visual field defect on Swedish Threshold Interactive Algorithm (SITA) automated perimetry was shown in 28 eyes with optic neuritis, 43 whereas a similar correlation was found between the amplitude of multifocal visual evoked potentials and RNFL thickness in 50 patients with MSrelated optic neuritis. 44 OCT in MS Numerous studies are using OCT to evaluate patients with MS. This is mostly based on the fact that a large majority of MS patients develop optic neuritis and optic atrophy. In addition, it has been suggested that RNFL thickness is a marker of axonal loss, and that retinal axonal loss reflects central nervous system (CNS) axonal loss in MS, 2-5 beyond the RNFL loss expected from optic neuritis. RNFL Thickness as a Marker of Axonal Loss Recent studies have shown that thinning of the peripapillary RNFL is observed not only in MS patients who have episodes of optic neuritis, 22,34,38,40 but also in the presumably asymptomatic fellow eyes of these patients, 45 as well as in MS patients who never had clinical acute optic neuritis. 45,46 These findings are consistent with previous reports of ongoing subclinical structural damage with axonal loss observed on brain magnetic resonance images (MRIs) of MS patients, 47,48 reinforcing the belief that early treatment of MS may prevent severe axonal loss. 49 Evidence that MS is associated with axonal loss in the afferent visual system has been available for several decades. This was shown on red-free retinal photography as early as The anterior visual system is such a frequent target of MS that, on VOL. 6 NO REVIEWS IN NEUROLOGICAL DISEASES E115

12 Optical Coherence Tomography in Neurology continued postmortem analysis, almost all patients with MS are found to have changes in the optic nerve and RNFL, regardless of whether they have previously experienced optic neuritis. 51,52 Based on these data, it has been suggested that examination of the visual system could be used effectively to illustrate the histopathology of the disease process in MS, 3,4 even in patients without clinical evidence of optic neuritis. Hence, measurements of the peripapillary RNFL thickness and macular volume by OCT may be a reliable way to estimate axonal loss in MS patients. Some authors have suggested that measurement of RNFL thickness by OCT may be a better way than brain MRI to detect and monitor axonal loss in MS based on the following: (1) OCT is easy, fast, noninvasive, and much cheaper than MRI; (2) the resolution of OCT is far better than that of brain MRI when measuring early axonal loss; (3) there is no myelin in the retina, RNFL measurements are independent of myelin disorders, and may only reflect the axonal thinning or loss; (4) it is relatively easy to correlate OCT findings with visual function using wellvalidated functional instruments such as visual acuity, low-contrast visual acuity, contrast sensitivity, color vision, visual fields, and visual evoked potentials; and (5) there is a good correlation between RNFL thinning observed with OCT and alteration of visual function. The possibility that RNFL thickness measured by OCT can reflect anterior visual pathway integrity, thereby serving as a measure of more global axonal degeneration in the CNS, is supported by recent studies demonstrating correlations of RNFL thickness with MRI-measured brain atrophy and MS disease subtype. 46,53-56 These data reinforce the hypothesis that the eye can be used to model mechanisms of axonal degeneration. Indeed, ongoing clinical trials of neuroprotective agents have already begun to include OCT measures as outcomes, particularly in MS, Alzheimer disease, and Friedreich ataxia. 2-4 It has been suggested that examination of the visual system could be used effectively to illustrate the histopathology of the disease process in MS. RNFL Axonal Loss Reflects CNS Axonal Loss in MS Since 2006, it has been suggested that RNFL thickness measurement by OCT may be used as a surrogate marker for assessment of brain atrophy in MS. 40 RNFL thinning was correlated to optic nerve atrophy measured on both conventional MRI, 39 and magnetization transfer ratio (MTR). 57 A study of 61 patients with MS showed a moderate correlation between the RNFL thickness and the brain white and gray matter volumes measured on conventional MRI, but not with the volume of T1, T2, or gadolinium-enhanced lesions. 50 A similar study on 18 patients with MS confirmed this relationship between RNFL thickness and normalized brain and white matter volume. 55 This study also found that a larger number of T2 lesions correlated with a thinner RNFL. A study of 51 MS patients suggested that the correlation between RNFL thickness and brain MRI measures of cerebral atrophy was better in the subgroup of patients without a clinical history of optic neuritis than in patients with previous episodes of optic neuritis. 58 In another study of 40 patients with MS, RNFL thickness independently correlated with the brain parenchymal fraction (BPF) derived from high-resolution anatomic MRI. In this study, BPF also correlated with the Expanded Disability Status Scale (EDSS) score. 59 More recently, 60 a similar correlation was found between RNFL thickness and T1 or T2 lesion volume, gray matter atrophy, MTR, and diffusion tensor imaging measures in MS patients with or without a history of optic neuropathy. These MRI parameters also correlated with low-contrast visual acuity, suggesting that retinal axonal loss reflects CNS axonal loss in MS. Retinal Axonal Loss May Reflect MS Severity More disabled MS patients may have a thinner RNFL on OCT. A 2-year longitudinal study of a cohort of 61 MS patients 45 found an inverse correlation at baseline between RNFL thickness and disability measured by the EDSS score (thicker RNFL correlated with worse disability). During follow-up, the subgroup of patients with more active disease developed a thinner temporal quadrant RNFL when compared with neurologically stable patients. Another study of 52 MS patients 60 showed thinner RNFL in the temporal quadrant of patients who had progression of their neurologic disability in the prior 2 years compared with patients who had remained neurologically stable. The EDSS score correlated with both average and temporal thickness of the RNFL. A larger cohort study of 163 patients confirmed a thinner RNFL in patients with progressive disease (primary or secondary) compared with patients with relapsing remitting disease, even when adjusting for age and duration of the disease. 54 Decreased macular volume measured by OCT was found only in the group of patients with secondary progressive disease. Another study measured the RNFL in 23 patients with primary E116 VOL. 6 NO REVIEWS IN NEUROLOGICAL DISEASES

13 Optical Coherence Tomography in Neurology progressive MS and in 27 patients with secondary progressive MS without any history of optic neuritis in the studied eye 46 and found thinning of the RNFL only in the temporal quadrant of patients with primary progressive MS, whereas the group with secondary progressive MS had significant RNFL thinning in overall mean, superior, and temporal quadrants. In a prospective study of patients with a single episode of optic neuritis, Costello and colleagues 61 attempted to predict which patients would convert to clinically definite MS over a mean follow-up of 34 months. They compared the RNFL thickness 1 year and 2 years after the onset of optic neuritis of 21 patients who did not develop MS and in 29 patients who developed MS, but failed to show that RNFL thickness was a strong predictive marker of developing MS in patients with isolated optic neuritis. However, other studies have shown thinner RNFL after optic neuritis in patients with neuromyelitis optica compared with MS patients RNFL Thickness As a Marker of Axonal Loss in Other Neurologic Disorders Several studies have demonstrated evidence of RNFL thinning in various neurologic diseases in which there is brain atrophy, such as Alzheimer disease and Parkinson disease, suggesting that this technology might also prove useful in other neurodegenerative disorders. Four studies have shown decreased average RNFL in patients with Alzheimer disease compared with age-matched controls, but there was no correlation between RNFL and cognitive impairment. Similarly, 3 studies suggested decreased average RNFL in patients with Parkinson disease compared with agematched controls, but its correlation with disease duration or disability remains debated. Such results are not surprising and confirm the possible use of OCT to measure the RNFL thickness and macular volume as surrogate markers for axonal loss in neurologic diseases other than MS; however, more studies will be needed before recommending the use of OCT in individual patients with degenerative neurologic disorders or as an outcome measure in clinical trials. How To Interpret a Third-Generation OCT As with all ancillary tests, the OCT needs to be interpreted by an experienced reader and correlated to the clinical indication. The results vary based on the machine used, the quality of the test, as well as the technique used. Most ophthalmology offices use a time domain OCT (third-generation OCT); some also have a spectral domain OCT, the results of which cannot be directly compared with a third-generation OCT (Table 1). Once the OCT is performed, a few basic steps need to be followed before interpreting the OCT (Figure 8): 1. Check the name and the date of birth entered by the technician performing the test. Because the RNFL decreases with age, 72 the patient s data are compared with an age-matched group control. If the entered age is wrong, the patient s results will be compared with the wrong normative database. 2. Check the reliability of the test by looking at the signal strength indicated in the right upper corner (Figure 8). The signal strength varies from 1 to 10, with 1 being very poorly reliable and 10 being excellent. The RNFL thickness varies with the strength of the signal. 73 If the strength is low, the RNFL thickness will be underesti- mated with possible false results of RNFL atrophy. If the signal strength is under 7, the results cannot be trusted, and the test should be repeated or discarded. Causes of low-strength signals include small pupil (this is why most patients pupils are pharmacologically dilated), media opacities (corneal opacity, cataract, vitreous hemorrhage, intraocular inflammation), and dirt or fingerprints on the lens placed on the OCT machine. 3. Ensure that the circle scan of the OCT was correctly placed around the optic disc. A misplacement of the circle scan can lead to false results 74 and it is essential to position the circle exactly the same way when a follow-up OCT is performed (Figures 7 and 8). This step is dependent upon the technician performing the test. The fundus photograph on the printout showing the placement of the OCT scan is helpful but not totally reliable because the photography is taken after the OCT scan is completed. 4. Check the accuracy of the algorithm that determines the RNFL. The patient s results are indicated as a thin white line on the crosssection image (Figure 7). In cases of low-strength signal or in cases of optic disc swelling, the lines may be incorrectly placed, in which cases the tests cannot be interpreted. If all parameters checked are correct, then the OCT can be interpreted and the RNFL thickness analyzed (Figure 8): 1. The table in the center of the page provides many numbers corresponding to various disc areas, but the most important is the bottom line, which indicates the average RNFL thickness for the right and the left eyes, respectively, and the difference between the 2 eyes. VOL. 6 NO REVIEWS IN NEUROLOGICAL DISEASES E117