Ординатура / Офтальмология / Английские материалы / Mechanisms of the Glaucomas_Shields, Tombran-Tink, Barnstable_2008

Neurophysiology provides the basic knowledge regarding how RGCs respond to different kinds of stimulation. This literature is long and involved so it is impractical to cover it in any detail here. However, several excellent reviews exist (1,2). Pathophysiology provides information about how RGCs and other visual neurons respond to glaucomatous insult (3–7). Taken together, these areas of investigation allow directed choices to be made about methodology that can be employed to detect the functional and structural alterations caused by glaucoma. The determination of how structural change (RGC deficits) and visual field alterations (functional loss) are related has been a topic of interest to many investigators (8–31). The quantitative nature of the relationship between structural and functional loss in glaucoma, variations that occur for different stages of the disease process, responsiveness to treatment, and many other factors are encompassed by this topic of clinical inquiry. This chapter will provide a brief overview of the most common structural (form) and functional diagnostic test procedures that are used in the clinical management of glaucoma, and the relationship between structural and functional glaucomatous loss in glaucoma patients.

FORM (STRUCTURE)

There are many procedures that have been developed to evaluate the structural characteristics of the optic nerve head and retinal nerve fiber layer in glaucoma. Perhaps the most flexible and informative is through ophthalmoscopic examination. However, documentation of structural features is also an important part of the medical management of glaucoma. This section will provide a brief overview of photography of the optic nerve and several new imaging techniques known as scanning laser tomography (Heidelberg retinal tomography or HRT), scanning laser polarimetry (GDx), and optical coherence tomography (OCT), which provide information about the status of the optic nerve head and retinal nerve fiber layer.

Optic Disc Photography

Photography of the optic nerve head and retinal nerve fiber layer has been performed for many years (32).The photography can be performed with either a monocular or a stereoscopic view. Most practitioners prefer a stereoscopic view of the optic nerve head and retinal nerve fiber layer to be able to observe the three-dimensional topography of this region. A photograph of a glaucomatous optic nerve head is presented in Fig. 1. With this photograph, it is possible to observe the optic cup (the central pale region of the optic nerve head), the neuroretinal rim (the reddish-pink “doughnut” of tissue), the vascular supply, the retinal nerve fiber layer region, and other important features. Detection of features that are characteristic of glaucomatous optic neuropathy includes determination of vertical ovality of the optic cup, adherence of the neuroretinal rim tissue to the ISNT rule [a healthy optic nerve has the thickest neuroretinal rim area inferiorly, followed by superior, nasal, and temporal regions of the optic disc (83)], excavation notching and thinning of the neuroretinal rim (and their location), nerve fiber layer deficits, optic nerve pits, optic disc hemorrhages, alpha and beta peripapillary atrophy, and other relevant features of the region in and around the optic nerve head. Longitudinal progression of a glaucomatous optic neuropathy is determined by a deepening of certain regions of the optic cup, a mottled or moth-eaten appearance

Fig. 1. Optic disc photograph of the right eye of a patient with glaucomatous damage to both eyes. Not rim thinning a downward extension of the optic cup at the 6–7 o’clock location, which correlated well with a superior arcuate visual field defect.

of the underlying lamina cribrosa, displacement of vessels, widening of portions of the optic cup, and extension of earlier glaucomatous changes.

Scanning Laser Tomography (HRT)

Scanning laser tomography uses confocal imaging procedures to create a threedimensional representation of the optic nerve head and the surrounding retina (34). Confocal imaging allows light reflected from a specific optical plane (surface) at the retina to be captured, while significantly minimizing the influence of light reflected from other optical planes. In this manner, it is possible to perform an X–Y scan with a long wavelength laser to obtain an optical “slice” of the retina and optic nerve. Changes in the position of the laser source can provide multiple X–Y scans at different optical planes to create a series of images. These images can then be combined to produce a reflectance image and a topography image to create a three-dimensional reconstruction of the optic nerve head and surrounding retina. Several generations of confocal scanning laser tomographs have now been created, and the most popular version currently being used is the HRT. Measurements based on the HRT-imaging system have been reported to be helpful clinically in quantitatively characterizing glaucomatous damage to the optic nerve and in evaluating progression of the disease process. This imaging device has been available for the longest period of time and has

the most extensive research that has been devoted to it. The HRT has been incorporated into several multicenter clinical trials concerned with the treatment and management of glaucoma.

Figure 2 presents the HRT results for the right eye (OD) of a patient with glaucomatous damage in both eyes (as indicated by both structural optic disc characteristics and functional visual field loss). The baseline examination was performed in early 1999 and the results displayed are for late 2006. The analysis indicates that the optic disc findings are outside normal limits, particularly in the superior and inferior optic disc regions. Comparison with baseline results indicates that progression has occurred, particularly for the inferior portion of the optic disc. In this case, the patient also demonstrated superior and inferior arcuate nerve fiber bundle visual field defects that correlated well with the glaucomatous optic neuropathy.

Scanning Laser Polarimetry (GDx)

Scanning laser polarimetry uses a laser beam to illuminate the inner portion of the eye. The nerve fibers that travel from the retina to the optic nerve head contain a number of microtubule elements that produce birefringence of the incident laser beam. Birefringence results in a change in the polarization of the incident laser beam, which produces a retardation or delay for some components of the laser wavefront. The magnitude of retardation provides an indication of the thickness of the retinal nerve fiber layer. In this manner, it is possible to obtain a measure of retinal nerve fiber layer thickness in the region surrounding the optic nerve head to monitor the damage produced by glaucoma. Because other structures of the eye such as the cornea also have birefringent properties, it is necessary to compensate for these effects to restrict the birefringent effects to the retinal nerve fiber layer as closely as possible. Several modifications to the device have recently been made to achieve this goal (35).

The GDx instrument is a commercial device that performs retinal nerve fiber layer thickness measures in this manner as a tool for monitoring glaucoma. Studies by many investigators have shown that it is possible to measure retinal nerve fiber layer thinning produced by glaucoma through the use of this device (35). Currently, there is limited information about its ability to follow patients over extended time periods to monitor progression. Figure 3 presents the results for scanning laser polarimetry in the left eye of a patient with glaucomatous damage that is revealed by a thinning of the retinal nerve fiber layer in the superior portion of the retinal nerve fiber layer region, whereas other portions of the retinal nerve fiber layer appear to be within normal limits. This patient also has an inferior partial arcuate visual field defect that is consistent with the retinal nerve fiber layer loss.

Optical Coherence Tomography

OCT is an imaging technique that uses near-infrared low-coherence light (a superluminescent diode whose light is transmitted through fiber optics) to perform interferometry of the retinal nerve fiber layer for evaluation of glaucomatous damage. By using this procedure, OCT is able to perform high-resolution cross-sectional imaging of the retina and surrounding tissue using light in a manner similar to a B-scan obtained through ultrasound imaging. The reflection of light from different structures varies

thinning of the retinal nerve fiber layer in the inferior temporal portion of the scan, which corresponds well with a superior nasal step that was obtained with automated perimetric testing. Because new enhancements are being incorporated into more recent versions of OCT devices, this procedure appears to be an exciting and informative method of monitoring glaucomatous damage.

FUNCTION

In the following sections, the “stimulus” should be interpreted to mean the visual target characteristics (including its color, and its spatial and temporal parameters), the background that it is presented against (including its intensity, its color, and its spatial and temporal parameters), and the arrangement or pattern of testing throughout the visual field (e.g., 30-2 or 24-2 pattern of the Humphrey Visual Field Analyzer).

Standard Automated Perimetry (SAP)

The primary method of performing visual field testing today is automated static perimetry, where a small white target is projected onto a uniform white background. SAP has become the gold standard for clinical visual field evaluation for more than 15 years. The most recent advances for SAP include a new test strategy known as the Swedish Interactive Threshold Algorithm (SITA) that is available in two forms (Standard and Fast strategies) (37–40). SITA is based on Bayesian statistical principles and is able to perform testing with lower variability (within and between subjects) and markedly reduced test time, while retaining or slightly exceeding clinical performance. Other efficient test strategies known as Zippy Estimation of Sequential Thresholds (ZEST) (41,42) and Tendency Oriented Perimetry (TOP) (43,44) are also adaptive test procedures that have been recently introduced (46). Analysis of visual fields over time has also been facilitated by the introduction of the glaucoma progression analysis (GPA) procedure, which compares a single visual field to a baseline determination and evaluates whether the change in sensitivity for each test location is within or outside the expected variability of repeated measures on stable glaucoma patients (46). Additionally, it also evaluates whether three or more locations demonstrate a change that is outside expected values and whether this occurs for two successive tests (possible progression) or three successive tests (likely progression). Figure 5 presents a 24-2 SITA Standard visual field result for the right eye of a glaucoma patient, which shows mild superior visual field loss and an inferior arcuate nerve fiber bundle type of defect.

Short-Wavelength Automated Perimetry

For many years, the use of colored stimuli to perform visual field testing has been conducted. However, it was not until the pioneering two-color increment threshold technique by Stiles (47,48) that it was possible to isolate and measure the sensitivity of individual color vision mechanisms, including the short-wavelength-sensitive (blue) pathways. Recent evidence indicates that it is the “blue-on” color pathway transmitted by the small bistratified ganglion cells to the koniocellular layers of the lateral geniculate nucleus that is responsible for neural coding of the short-wavelength- sensitive (blue) color vision mechanisms (49–52). Several investigators were able to

adapt this technique to perimetry (53,54), which subsequently was converted into an automated procedure known as short-wavelength automated perimetry (SWAP) (55–60). Basically, SWAP is performed by superimposing a large short-wavelength (blue) stimulus onto a bright yellow background, which isolates the activity of shortwavelength sensitive mechanisms. Collaborative efforts among several laboratories permitted optimal test procedures to be identified, and these are now implemented on several commercially available automated perimeters (61). Although there are some difficulties associated with this test procedure, they have largely been overcome by refinement and further investigation of the procedure.

Longitudinal investigations performed by several laboratories have established that SWAP defects occur 3–5 years before standard automated perimetry (SAP) defects, are usually larger than SAP deficits, have a shape that is consistent with RGC nerve fiber bundle patterns consistent with glaucoma, are predictive of future SAP deficits, and many additional clinical advantages (55–60). SWAP has also been reported to be clinically useful for ocular and neurologic diseases other than glaucoma (33). An example of a superior arcuate glaucomatous visual field deficit for SWAP performed on the right eye of a glaucoma patient is presented in Fig. 6. In general, there are few functional test procedures that have undergone the level of evaluation and scrutiny of SWAP.

One of the disadvantages associated with SWAP is that the test procedures are quite time-consuming. However, recent work has been responsible for the development of an efficient forecasting procedure known as SITA SWAP (45,62,63). These implementations have expanded the dynamic range of SWAP testing, reduced the testing time to 3–4 min per eye, and maintained the clinical efficacy and value of the SWAP procedure.

Frequency-Doubling Technology Perimetry

A low spatial frequency sinusoidal grating (less than 1 cycle per degree) undergoing high temporal frequency counterphase flicker (>15 Hz) has the appearance of more light/dark bars than are physically present. By evaluating the amount of contrast needed to detect this stimulus at different visual field locations, a test known as frequencydoubling technology (FDT) perimetry is produced (64–66). FDT perimetry stimulates visual mechanisms that are especially sensitive to movement and rapid changes. Many studies have demonstrated that FDT perimetry provides clinically useful information for detecting and monitoring ocular and neurologic disorders (66), and appears to be more sensitive than traditional visual field test procedures. The FDT perimeter is easy to use, portable, resistant to blur and other confounding variables, and is well-liked by patients and examiners.

Recently, a second generation FDT device known as the Humphrey matrix has been developed (67). The matrix has a number of practical advantages as a clinical test instrument, including greater spatial representation of visual field information, more test procedures, and greater facility in monitoring patients. It has also been shown to have performance characteristics that are of high clinical importance. Foremost among its beneficial effects is the ZEST test strategy, which provides an efficient evaluation, provides consistent test times for all participants (41,42), and assures approximately equal reproducibility for all test locations throughout the entire operating range of the instrument (68). Figure 7 presents an example of Humphrey matrix test results for the