Ординатура / Офтальмология / Английские материалы / Essentials in Ophthalmology Pediatric Ophthalmology Neuro-Ophthalmology Genetics_Lorenz, Borruat_2008

Core Messages

■Imaging of the optic nerve head and retinal nerve fiber layer (RNFL) can be a useful adjunct to the clinical evaluation of patients with neuroophthalmologic disease.

■Techniques for visualizing these structures have progressed over the last century and a half, from illustrations based on ophthalmoscopy to newer technologies whose resolution can provide a nearly cellular level of detail.

■Stereo photography is a widely used, albeit subjective, means of assessing optic nerve head topography.

■Optic nerve head analyzers were the first instruments to use computers to assess the optic nerve head, by analyzing either stereoscopic photographs or the deflection of parallel lines of light.

■Scanning laser ophthalmoscopy uses a diode laser to provide a three-dimen- sional image of the fundus. The confocal system helps remove stray light, increasing image quality.

■The Heidelberg Retinal Tomograph II is a scanning laser ophthalmoscope that scans along multiple planes of depth, creating a three-dimensional image. This scan can provide quantitative topographic detail of the optic nerve head, which calculates optic nerve head parameters that may be useful in the clinical assessment of glaucoma.

■The Scanning Laser Polarimeter (GDx) analyzes the “retardation” of polarized light to calculate the RNFL thickness, which makes it a useful test to assess nerve fiber layer defects in glaucoma.

■Optical coherence tomography (OCT) uses low-coherence reflectometry to produce high-resolution, two-dimen- sional, cross-sectional images of the optic disc, retinal nerve fiber layer and macula. RNFL thickness measured with OCT has been shown to have good correlation with visual field defects in glaucoma. OCT has been used to study RNFL thickness in many other conditions, but its clinical utility in these settings is not yet established.

■Enhancement of the optic nerve on MRI helps to identify inflammatory optic neuropathies. Ultra high resolution MRI may one day be available for extremely high resolution optic nerve images.

■New imaging technologies can provide objective measurements that aid in the detection and evaluation of neuroophthalmic disease, especially optic nerve cupping associated with glaucoma, but they should only be used in conjunction with the clinical exam.

■Ocular imaging technologies can be useful for the neuro-ophthalmologist, especially in identifying retinal pathology in cases of otherwise unexplained visual loss. Neuroimaging (i.e., MRI) of the optic nerve however, is an integral part of the evaluation of most patients with neurogenic visual loss.

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7.1 Introduction

The introduction of the ophthalmoscope by von Helmholtz in 1851 allowed physicians to view the fundus for the first time. Since then, drawings, photography and more recently computerized imagery have been used to document the appearance of the fundus. Advanced technology has provided reliable tools for recording anatomical details of the optic nerve and nerve fiber layer, which can assist in the management of patients with optic nerve disease, especially glaucoma.

Scanning laser polarimetry, confocal scanning laser tomography and optical coherence tomography are being used clinically in many centers, sometimes as part of routine evaluations of patients with glaucoma. This review will provide a brief historical perspective of the advantages and disadvantages of these and other methods used to record the appearance of the optic nerve head.

7.2Overview of Early Imaging Techniques

7.2.1 Optic Nerve Head Drawings

Drawings of the optic nerve head, especially with regard to the cup-to-disc ratio, remain the most routinely used clinical method for documenting the appearance of the optic nerve head. However, there can be disagreement even among skilled glaucoma specialists in the interpretation of the appearance of the optic disc [41]. Inconsistencies may exist even for a single observer [73], which is not surprising given that this method is entirely subjective.Thisvariabilitylimitsthevalueofdrawings in the management of patients. The need for more advanced techniques of documenting and analyzing the optic nerve head has resulted in the emergence of objective means to measure and display the topography of the optic nerve head.

7.2.2Direct Ophthalmoscopy of the Nerve Fiber Layer

A high-quality image of the retinal nerve fiber layer (RNFL) can be obtained simply by using the red-free (i.e., green) light source on a standard ophthalmoscope. The nerve fiber layer,

which is composed solely of axons of the retinal ganglion cells, appears as striations with a characteristic “rice grain” texture that are brightest at the superior and inferior poles, where the concentration of nerve fibers is the greatest. With this method, “slit” nerve fiber layer defects, which can be a subtle sign of optic nerve disease, can be detected [32]. Photographic images of the RNFL can be obtained by using a fundus camera with the appropriate filter. Disadvantages of ophthalmoscopy include: (1) the need for subjective interpretation; (2) potentially misleading appearances of the nerve fiber layer due to optical variations among individuals (especially related to the degree of fundus pigmentation); and (3) the difficulty in detecting subtle but diffuse (versus focal slit defects) optic nerve atrophy.

7.2.3Retinal Nerve Fiber Layer Photography

Photography can provide a high-resolution image of the RNFL as well. The RNFL substantially reflects bright, short-wavelength light (i.e., 490 nm blue light, produced with the excitation filter used for fluorescein angiography), while longer wavelengths pass through the retina and are absorbed by the retinal pigment epithelium. Media opacities such as cataracts decrease the penetration of blue light, and conditions associated with generalized fundus hypopigmentation (i.e., myopia) limit the visibility of the nerve fiber layer because of increased reflection by the sclera [34].

Photography can reveal localized or diffuse defects in the nerve fiber layer. Assessment of red-free RNFL photography has an average sensitivity and specificity of 80%–94% in differentiating between normal and glaucomatous eyes, with variation attributed to the observer, and to the patient’s age, ethnicity, and severity of field loss [67]. Sensitivity appears to vary especially with the severity of visual field loss, while ethnicity has been shown to have more of an influence on specificity. As a screening method for glaucoma in large populations, the sensitivity and specificity of red-free photography decrease to 64% and 84%, respectively [78]. A photographic grading system reflecting various nerve fiber layer appearances ranging from normal (i.e., broad, clearly striated nerve fiber bundles) to advanced diffuse atrophy

(i.e., no nerve fibers visible) has been proposed. This more detailed method of assessment provides improved interand intra-observer reliability, with intra-class correlation coefficients of 0.81–0.98 [47]. However, this method provides references only for grades of diffuse atrophy and thus excludes wedge-shaped defects, which are relatively common.

7.2.4Stereoscopic Optic Nerve Head Photography

With improved optics and methods of illumination, optic nerve head photography became the “gold standard” for documentation of the appearance of the optic nerve head. Typically, stereoscopic photographs are obtained from sequential exposures of the optic nerve head, one taken just nasal and another just temporal its central axis. The simultaneous method provides two stereoscopic images with a single exposure. This technique reduces the variability in stereoscopic quality often encountered with sequential photographs that require making alterations in the position of the patient’s head.

Fundus photography is widely used because it requires only relatively simple and inexpensive technology, and because of physicians’ experience and comfort in interpreting photographs. Photographs can be interpreted without contending with the vagaries and uncertainties of readings from devices that use newer and more unfamiliar technology. With this method, the sensitivity (94%) and specificity (87%) for experienced observers discriminating between normal and glaucomatous optic nerves [26] are fairly good,

but not at a level that is acceptable for patient management; hence the need for more objective and potentially more reliable means to assess the optic nerve head.

Newer technologies that have emerged have the additional notable advantage of being able to image specific structures, such as microtubules, or assess the thickness of the cellular, plexiform or nerve fiber layer of the retina, which might prove to be clinically valuable (Table 7.1). A review of the more widely used of these technologies is presented below.

Summary for the Clinician

■Optic nerve head drawings are common in clinical practice, but their value is limited because they are purely a subjective means of documentation.

■Direct ophthalmoscopy using the redfree filter is a useful means of observing the retinal nerve fiber layer (RNFL), but requires subjective interpretation, and is affected by optical variations among individuals.

■High-resolution images of the RNFL are possible with photography, but the quality of these images may be affected by media opacities and variable retinal pigmentation.

■Using two offset images, stereoscopic optic nerve head photography offers improved discrimination between normal and glaucomatous optic nerve heads.

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7.2.5 Optic Nerve Head Analyzers

A group of instruments, collectively referred to as optic nerve head analyzers, were the earliest methods that applied computerized technology to optic nerve head imaging. These instruments were the first to provide objective information about optic nerve head structure, specifically the neuro-retinal rim and the topography of the cup of the optic nerve head. The most significant “analyzers” are the Topcon IMAGEnet, the Humphrey Retinal Analyzer, the Rodenstock Optic Nerve Head Analyzer, and the Glaucoma-Scope. Though rarely used today, these devices formed the basis for the evolution of the more advanced technologies that are now routinely used.

7.2.5.1 The Topcon IMAGEnet

The first commercially available system was the Topcon IMAGEnet (Topcon Instruments, Paramus, N.J., USA). Standard fundus camera optics is used to produce stereoscopic images that are digitized. The user marks four points that are then taken to be the optic disc margin on each of the two photographs. Then 36 points 10º apart are automatically placed around the circumference of an ellipse created from the user-defined marks. The margin of the cup is defined at points 125 µm posterior to the four user-defined points on the disc margin. The angular relationship between two horizontally displaced points (i.e., the two photographic images) required to achieve focus on a point in space can be used to calculate depth. A three-dimensional map of the optic nerve head is then constructed.

7.2.5.2The Humphrey Retinal Analyzer

The Humphrey Retinal Analyzer (Humphrey, San Leandro, Calif., USA) obtains input from a redfree simultaneous stereoscopic camera, which produces two images that have slightly disparate levels of brightness in corresponding regions [17]. Three-dimensional images are generated from an algorithm that compares the brightness of corresponding points. The user stipulates eight

points on the margin of the optic nerve head (disc margin) that the analyzer uses as a reference plane, from which the depth of 400–650 points is computed. The edge of the cup corresponds to those points that are 120 µm beneath the user-defined disc margin. The use of subjective margins contributes to variability in results from this system [17].

7.2.5.3The Rodenstock Optic Nerve Head Analyzer

The Rodenstock Optic Nerve Head Analyzer

(Rodenstock Instruments, Danbury, Conn., USA) projects two sets of seven lines on the optic nerve head while a stereoscopic video camera obtains a digital image. The computer creates a contour map from the displacement of stripes as they cross the optic nerve head. The user must define the edge of the optic nerve head with four cardinal points. Depth values are calculated at 140 points along each of the 14 stripes. Points that meet or exceed a 150 µm drop in depth correspond to the area of the cup. Values for cup- to-disc ratio, disc rim area, cup volume, disc elevation, and total disc area are provided [5]. Reproducibility is better for cup-to-disc ratio and neural rim area than for cup volume, which becomes less reproducible with increasing cup size [65].

The Rodenstock Analyzer has shown promise in detecting changes that may predate clinical changes in optic nerve head anatomy. Significant differences were demonstrated in the neuroretinal rim area of affected and unaffected eyes of patients with unilateral glaucoma compared to eyes of normal subjects [9]. Also, the variability of topographic measurements obtained with the Rodenstock Analyzer is similar within normal and glaucomatous groups of patients [5], which simplifies attempts to use this device for comparative studies. There is a moderate degree of inter-image (i.e., different images on the same eye obtained at different times) variability with the Rodenstock Analyzer, which is believed to be secondary to variability inherent in the instrumentation and measurement. Compared to the Humphrey Analyzer, however, there is less intraobserver (i.e., same observer marks the same disc

margin repeatedly) variability with the Rodenstock device, which probably relates to the fact that only four (versus eight) user-defined points are required for the Rodenstock technique [17].

7.2.5.4 The Glaucoma-Scope

The Glaucoma-Scope (Ophthalmic Imaging Systems, Sacramento, Calif., USA) utilizes the technique of computed raster stereography, in which a series of parallel lines of light are projected onto the optic disc at an oblique angle. The GlaucomaScope requires a minimum pupil diameter of 4.5 mm, through which a series of 25 horizontal lines generated from a halogen lamp illumination system are projected across the optic nerve head at an angle of 9º using a near-infrared light (750 nm). The depth and volume of the cup are proportional to the amount of deflection of the lines. Shallow depths have small deflections while large deflections reflect deep excavations. A three-di- mensional anatomical image is reconstructed from the deviation of the projected lines and the image can be stored in digital form.

The operator identifies margins of the optic disc with at least eight points. Points on the nerve head 350 µm from the nasal and temporal margins are used as a reference plane to calculate the depth of the cup. A depression ≥140 µm below the reference plane is defined as the optic nerve head cup. Approximately 9100 real data points in an area containing 350 by 280 pixels are converted into depth values, providing a relatively high-resolution image.

At the time of the initial evaluation a reference point is selected, which is used to realign the nerve head on subsequent tests. Changes in depth values greater than or equal to 75 µm are reported as a change-from-baseline analysis. The Glaucoma-Scope provides reproducible depth measurements in both healthy and glaucomatous subjects. From a 25 cell “sample,” the mean standard deviation in a single pixel has been reported to be 15.42 µm for the population as a whole, 15.11 µm for healthy discs, and 15.57 µm for glaucomatous discs [30]. A report of interand intra-observer variability indicates that there is significant inter-observer agreement and moderate intra-observer agreement even under condi-

tions in which the contour line was drawn at each examination [16]. Although the Glaucoma-Scope is a relatively simple and reliable tool in some settings, it suffers from dependence on images that can be degraded by cataract, aphakia, pseudophakia, myopia and hyperpigmented fundi [16].

Summary for the Clinician

■Computer-based analytical imaging of the optic nerve head and RNFL began with the optic nerve head analyzers.

■The Topcon IMAGEnet and Humphrey Retinal Analyzer use digitized stereoscopic photography from which depth measurements are obtained and threedimensional images are constructed.

■The Rodenstock Optic Nerve Head Analyzer and the Glaucoma-Scope use the deflection of parallel lines of light to determine depth and create a three-dimen- sional image.

■These techniques require user-defined margins, and are subject to inter-observ- er variability and obscuration by media opacities.

7.3Modern Techniques

for Optic Nerve and Retinal Nerve Fiber Layer Imaging

7.3.1Scanning Laser Ophthalmoscopy and Tomography

The scanning laser ophthalmoscope illuminates a small spot to produce a high-contrast image. Reflected energy is detected and formed into an image. Scanning laser ophthalmoscopes are constructed as either a nonconfocal or confocal device, depending upon the optics used to detect the reflected light. In the nonconfocal system, two separate apertures are used – a central aperture for illumination of the eye, and a paracentral for light reflected from the eye. This optical arrangement suppresses corneal reflections that can substantially degrade image quality. The

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minimum spot size of illuminated retina (approximately 10–15 µm) is determined by the optical properties of the eye, specifically the clarity of the media and the focusing capabilities of the cornea and lens. The small-diameter laser beam can be delivered to a wide area of the retina by use of a rotating polygon, which provides horizontal scanning, and a galvanometer, which provides slower vertical scanning [51].

The confocal scanning laser ophthalmoscope employs a variation on the scanning device that more substantially removes out-of-focus, scattered light reflected from the retina. This improved optical quality is accomplished by permitting only the best -focused reflected light to reach the detector (Fig. 7.1). Elimination of the stray light (Fig. 7.2) yields a higher contrast image with a reduced depth of field relative to the

size of the aperture. The reduced depth of field permits high-resolution, layer-by-layer imaging of the retina [51, 56]. Five confocal scanning systems are available.

7.3.1.1 The Rodenstock System

The Rodenstock System uses a helium-neon or argon laser with a power of less than 0.1 mW to illuminate the retina. Approximately 10 J of energy is delivered during an interval of about 100 ns at a rate of 30 Hz. Analysis of differences in reflected wavelength is performed and a threedimensional image is constructed.

7.3.1.2The Heidelberg Laser Tomographic Scanner

The Heidelberg Laser Tomographic Scanner (LTS) (Heidelberg Instruments, Heidelberg, Germany) uses a Helium neon laser beam (632 nm). The user determines the range of depth over which images are detected. Most typically images are acquired from just in front of the blood vessels to a level posterior to the lamina [20]. Thirty-two consecutive focal planes beginning at the first reflections of the retina to the bottom of the excavation are automatically scanned. An algorithm is used to calculate the height at each of the pixels to produce a topographic map [20].

with strictly unilateral normal-tension glaucoma [84].

There is some evidence that HRT II may be a useful tool to screen high-risk populations for glaucoma. In one study that used HRT II to predict glaucoma, the negative predictive value was very high (0.84–0.99), although the positive predictive value was much lower. (0.31–0.68) [28]. It has not yet been shown that the use of HRT II to predict glaucoma is superior to the clinical exam alone.

The HRT II has been used to investigate the anatomical correlates of various pathological states of the optic nerve head and nerve fiber layer. One study found a reduction of the disc edge RNFL thickness, and the neuroretinal rim volume and an increase in the three-dimensional optic cup measurement in eyes with optic neuritis when compared to the fellow eye or eyes from normal controls [75]. In another study, HRT II assessments of the optic disc in nonarteritic ischemic optic neuropathy did not correlate with visual field defects, while RNFL measurements made with the GDx device did provide a reasonably good correlation [61]. The HRT II has also been used to demonstrate a decrease in optic disc size in women on short-term tamoxifen therapy [21].

Summary for the Clinician

■The HRT II uses confocal scanning laser ophthalmoscopy to scan the surface of the retina in up to 32 different planes, thereby creating a topographic map of the optic nerve head and surrounding retina.

■The HRT II can calculate optic nerve disc, cup and rim volumes and areas; cup-to-disc ratio; mean cup depth; cupshape measure; difference in height of the nerve fiber layer (height variation contour of the RNFL); and overall mean retinal nerve fiber layer thickness.

■Sources of variability with the HRT II include the computer-generated reference plane and the user-stipulated disc margins.

■HRT II may be a useful ancillary test in the assessment of glaucoma.

7.3.3Scanning Laser Polarimetry (“GDx”)

The Scanning Laser Polarimeter (GDx; Laser Diagnostic Technologies, San Diego, Calif., USA) is a confocal scanning laser ophthalmoscope with an integrated polarization modulator, corneal compensator, and polarization detector. The scanning polarimeter directs a polarizationmodulated laser beam (780 nm wavelength) onto the retina, which is partly reflected by subretinal tissue. Birefringence in the nerve fiber layer arises from the parallel arrangement of microtubules and other intermediate filament structures within the RNFL, so that light polarized in one plane travels faster than light polarized in a perpendicular direction. This difference in speed causes a phase shift (“retardation”) between the perpendicular light beams as they travel back to the detector. The amount of retardation can be used to calculate the thickness of the RNFL, although the value is more specifically a reflection of the density of microtubules in the measured tissue.

The cornea also demonstrates birefringence because of the parallel arrangement of stromal collagen fibers. The standard laser polarimeter accounts for this with a fixed corneal compensator (FCC) which subtracts the presumed birefringence of the cornea and lens from the calculated value [77]. The resulting number has been shown to correlate with the thickness of the RNFL [81]. The FCC uses a fixed axis (15° nasally downward) and a magnitude of retardation (60 nm) that is based on population norms [19, 83], but does not account for individual variations in corneal birefringence. A new modification uses a variable corneal compensator (VCC), which estimates an individual’s corneal birefringence by subtracting the macular retardation pattern from that of the peripapillary RNFL, using that difference to correct its readings [25, 79]. Discrimination between normal and glaucomatous eyes has been shown to be superior using VCC, especially when evaluating patients with early visual loss [70].

The scanning laser polarimeter performs retardation measurements at 65,536 locations in a 15º×15º field in approximately 0.7 s. This gives a 256×256 pixel image centered on the optic disc. Each pixel has a corresponding retardation value

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expressed in thickness units (TU). The software converts degrees of retardation into micrometers, where 1º of retardation equals 7.4 µm, based upon correlation of histological measurements in monkeys [81]. GDx analyzes subsets of the 65,536 pixels in each quadrant (superior, inferior, temporal, and nasal). The software contains ethnicityand age-specific normative databases of more than 1100 eyes from patients 18–80 years old.

With the GDx, there is good correlation between retardation and histopathological measurements in postmortem human eyes [80] and enucleated monkey eyes [83]. In normal subjects, scanning laser polarimetry reveals the expected high degree of inter-eye symmetry of nerve fiber layer thickness [22]. Therefore, it is reasonable to assume that any significant asymmetry in RNFL thickness is probably pathological. In normal eyes, the superior and inferior arcuate regions demonstrate the highest retardation measures [83], which is consistent with the higher density of nerve fibers in these areas. Retardation is lower over blood vessels where the overlying nerve fiber layer is thinner because the vessels are embedded in the nerve fiber layer [83]. These reproducible results increase the confidence that the GDx provides measurements that are clinically relevant.

The ability of the GDx to provide data that correlate with the anatomic status of the nerve fiber layer is perhaps best revealed by observing normal aging. The number of optic nerve axons decreases with age [10], with a loss of around 5000 optic nerve cells per year after the age of 40 years [2]. Linear regression analysis demonstrates decreased retardation measurements in the superior and inferior regions with increasing age in normal eyes [83]. The nerve fiber layer thickness determined by the nerve fiber layer analyzer decreases linearly with age by 0.2 µm per year [11]. Furthermore, the GDx has been shown to distinguish normal subjects from patients with glaucoma and suspected glaucoma (ocular hypertension and normal visual fields or large cup-to-disc ratio) [12].

In comparison to visual field testing, the GDx is a rapid and objective test. There is 96% sensitivity and 93% specificity between hemifield polarimetric RNFL measurements and the visual field mean deviation, which emphasizes the

potential clinical utility of this device [74]. The GDx has a sensitivity of 96% and specificity of 91% in identifying patterns of diffuse and localized nerve fiber layer loss [66].

Contact lenses and ablative corneal refractive surgery (i.e., photorefractive keratectomy) have no significant effect on GDx measurements [13]. However, other possible confounding variables must be taken into account when using the GDx. For example, the RNFL appears to show progressive thinning in relation to the severity of type II diabetic retinopathy [52]. Given the significant prevalence of diabetes in the glaucoma population, this one variable could lead to a “false-posi- tive” interpretation of glaucomatous optic nerve damage.

“False-negative” results have also been obtained with scanning laser polarimetry. In particular, the GDx failed to detect axonal loss in the temporal regions of the optic disc, in patients who had compression of the optic chiasm by a tumor, despite the fact that this area was clearly atrophic by funduscopy. The GDx was also poor at detecting nasal atrophy, which reveals the lack of utility for this technique in the evaluation of chiasmal or tract compression [46]. The same authors were able to identify nasal and temporal atrophy using optical coherence tomography, which is discussed below [45].

Summary for the Clinician

■The Scanning Laser Polarimeter (GDx) is a confocal scanning laser ophthalmoscope that includes a polarization detector that can detect the retardation of polarized light that occurs perpendicularly to the parallel fibers of the nerve fiber layer.

■The innate difference in polarization at right angles provides “birefringence,” which provides a useful optical means to define retinal anatomy.

■This retardation is used to calculate the thickness of the RNFL at various points, making the GDx an appropriate test for the detection of RNFL defects in glaucoma.