Ординатура / Офтальмология / Английские материалы / Shields Textbook of Glaucoma, 6th edition_Allingham, Damji, Freedman_2010

Figure 4.27 HRT-III. (Courtesy of Heidelberg Engineering.)

For the HRT to calculate these parameters, several preliminary steps are performed. First, a reference ring with an outer diameter of 94% and a width of 3% of the acquired image is placed on the image to define the retinal surface. The absolute height of that surface is then calculated, relative to the focal plane of the eye, and the mean height of that retinal reference ring is used to calculate the relative coordinate system, or reference plane. A correction for tilt is also made. Another surface, called the curved surface, is then defined after a contour line is drawn around the border of the optic disc. Topographic measurements are then calculated.

Because the magnitude of morphometric parameter values depends strongly on the chosen reference plane (479), defining the plane becomes a critical issue. Theoretical and practical problems have

complicated the choice of the reference plane. Various modifications of the position of the reference plane have been offered to compensate for possible thinning of the retina during the course of glaucoma (480, 481). The HRT software automatically defines a reference plane parallel to the peripapillary retinal surface and 50 µm posterior to the retinal surface at the papillomacular bundle (479, 482). The rationale for this definition is that, during development of glaucoma, the

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nerve fibers at the papillomacular bundle remain intact longest, and the nerve fiber layer thickness at that location is approximately 50 µm. All structure s located below the reference plane are considered to be the cup, and all structures located above the reference plane and within the contour line are considered to be the rim (Fig. 4.28). The cup of the optic nerve head is displayed in red, and the rim is displayed in blue and green. The distance between the reference plane and the retinal surface is used to measure the mean RNFL thickness.

Figure 4.28 A: Color photograph of a right optic nerve. B: Corresponding image from an HRT-II. The reference planes are the red lines.

Evaluation of Accuracy and Reproducibility of Confocal Scanning Laser Tomography

Numerous reproducibility studies have been reported for the HRT (483, 484, 485, 486, 487 and 488), revealing acceptably low variability. Tests that are reproducible will have a higher chance of detecting progression over time. Highly reproducible topographic data can be obtained with a nondilated pupil (485), although the accuracy and reproducibility declined when the pupil was very small or very dilated (489). It has been suggested that reproducibility can be improved in general by using a series of three examinations (483).

An accuracy study performed with the laser tomographic scanner by using a plastic model eye revealed low-average relative errors for diameter and depth (477). However, vertical disc diameter measurements with the HRT were significantly smaller than those obtained with planimetric methods (490). The reproducibility of the stereometric parameters was evaluated in different clinical studies in normal and glaucomatous eyes, and measurements were found to be highly reproducible (491), with typical coefficients of variation for area, volume, and depth measurements of about 5% (486, 487).

One lesson learned from the study of image analysis of the optic nerve head is that traditional parameters, such as cup-todisc ratio and neural rim area, are inadequate for interpreting the subtle findings in the disc and peripapillary retina in healthy and diseased states. To address this problem, the HRT provides a wide range of two-dimensional and three-dimensional information on the disc and peripapillary retina, which is displayed on a monitor and in hard copy. One of these parameters is referred to as cup shape measure, previously known as the third moment. This parameter relates to the frequency distribution of depth values relative to the curved surfaces inside the disc area and is a function of the overall shape of the optic nerve head. It was found to be the most useful indicator of the

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degree of glaucomatous optic nerve damage and early glaucomatous visual field loss (492, 493). In one study, the cup shape measure was the only parameter associated with changes in visual field (494). Other useful morphometric parameters include rim area, variation of height of contour line, and RNFL thickness (495). Less useful parameters include disc area, cup area, cup and rim volume, and mean and maximum cup depth. Optic nerve head parameters obtained by the HRT may be affected by age, refraction, or disc area (494, 496). Rim volume appears to be the only parameter unaffected by these factors (496).

The sensitivity and specificity of the various HRT topographic parameters vary significantly. In general, the sensitivities have been reported in the low-80s to -90s (%), with specificity ranging from the low-80s to the mid-90s (%) (497, 498, 499, 500, 501, 502 and 503). Except in eyes with advanced glaucomatous damage, classifying an individual eye as normal or glaucomatous is difficult to do with absolute certainty on the basis of single HRT parameters.

For better discrimination between normal and abnormal optic discs, the HRT software performs statistical analyses to allow a comparison between the examined optic disc and a database of normal eyes. Multivariate analysis methods that use combinations of individual parameters to classify an individual eye into a “normal” or a “glaucoma” grou p have been proposed (493, 495, 504, 505, 506 and 507). These studies have shown that, when the cup shape measure, rim volume, and retinal surface height variation are analyzed together, they appear to be the most important parameters to differentiate between normal and glaucomatous optic nerve heads. HRT-II was also

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reported to be able to classify the optic nerve head appearance as “normal,” “borderline,” or “outside normal limits” on the basis of the ratio of rim are a to disc area (Moorfields regression analysis) (508). However, in a prospective study, multivariate analysis and Moorfields regression analysis did not discriminate as well between patients with glaucoma and control participants (509).

Another method to detect glaucomatous change is the ranked-segment distribution curve analysis (510). To perform this analysis, the optic nerve head is divided into 36 sectors, each 10 degrees wide. The stereometric parameters are then calculated for each segment, sorted in descending order, and displayed as a graphic representation of the optic nerve head configuration. From a population of normal eyes, rankedsegment distribution curves for the 5th and 95th percentiles are calculated, and a patient's rankedsegment distribution curve is plotted against the normal curves.

In the Ocular Hypertension Treatment Study (OHTS) and the Early Manifest Glaucoma Trial (EMGT), conversion from ocular hypertension to glaucoma was by optic nerve criterion in 40% to 50% of cases (511, 512). In an ancillary study of OHTS involving use of confocal scanning laser ophthalmoscopy, large cup-disc area, mean cup depth, mean height contour, and cup volume had a positive predictive value between 14% and 40% for the development of COAG from ocular hypertension (513). Progression in glaucoma may be detected by calculating a change probability map (514), which uses three images acquired during the baseline and three images during the follow-up examination. The six images are aligned and normalized to each other. Each image cluster of 4 by 4 adjacent height measurements or pixels is then combined to create so-called superpixels, with 48 baseline height measurements and 48 follow-up height measurements. Then the variability of the baseline measurements is compared with the combined variability of the baseline and follow-up measurements at each superpixel. The resulting probability maps are displayed in color codes. White superpixels indicate no significant change; dark-brown superpixels indicate that the surface height has changed significantly, with an error probability of less than 5% (514).

As mentioned previously, HRT can distinguish discs with specific appearances that include focal ischemia, myopic glaucomatous changes, senile sclerotic changes, and generalized cup enlargement by comparing mean values for certain optic disc variables (515). However, the ability to detect glaucomatous damage varies considerably with the disc appearance. In studies of patients with ocular hypertension and patients with glaucoma, the HRT and visual field tests had fair to poor agreement in detecting glaucoma (516). Therefore, in the clinical setting, caution should be used when interpreting

HRT results on the basis of multivariate discriminant analysis or ranked-segment distribution curves. Clinical optic disc evaluation remains the most important method of detecting or following up patients with glaucoma, although information obtained with the HRT may have adjunctive value, and further refinement of the instrument may increase its value.

Other confocal laser scanners, including the Rodenstock 101 confocal scanning laser ophthalmoscope, are no longer commercially available. OCT can also be used to generate a topographic map. At the time of publication, the absence of a normative database for comparison limits the clinical utility of OCT for optic nerve topography.

Retinal Nerve Fiber Layer Imaging Confocal Scanning Laser Polarimetry

A confocal scanning laser polarimeter combines the concept of a confocal scanning laser and polarimetry to measure the RNFL thickness (517). Based on the assumption that the RNFL is birefringent, caused by the parallel microtubules in the nerve fibers (518, 519), a polarized diode laser light (780 nm) is changed when it penetrates the tissue. This change in the state of polarization is referred to as retardation and is linearly related to the thickness of the RNFL (518). The computer provides thickness data for concentric circles around the disc margin. The initial versions of this instrument—the Nerve Fiber Analyzer (NFA)-I and NFA -II—have since been upgraded several times. The current version, known as GDxPRO (Fig. 4.29), allows comparison of an individual's data against a large normative database.

In one study, the location of the peak retardation values was found to be in agreement with the values of RNFL thickness published for humans, but the retardation values around the disc were different from the anatomic data. The authors concluded that discrepancies between the retardation and anatomic data should be recognized in the clinical interpretation of polarimetric data (520). Differences of the corneal polarization axis naturally exist in healthy and glaucomatous eyes; therefore, influence of corneal birefringence should be properly compensated (521, 522). The variable corneal compensator individually corrects for polarization induced by the cornea and the lens (523, 524, 525, 526 and 527), improving the ability of GDx to discriminate between glaucomatous and healthy eyes. In general, the reported sensitivity and specificity of scanning laser polarimetry to detect glaucoma are above 80% (503, 528, 529).

Figure 4.29 GDxPRO, a portable scanning laser polarimeter. (Courtesy of Carl Zeiss Meditec, Inc.) P.77

Figure 4.30 Stratus OCT. (Courtesy of Carl Zeiss Meditec, Inc.) Optical Coherence Tomography

OCT was developed in the early 1990s and became available to ophthalmologists in 1996. A secondgeneration instrument was introduced in 2000, and a third-generation instrument, the Stratus OCT (Fig. 4.30), was introduced in 2002, achieving an increase in imaging speed and resolution. Later in the decade, several spectral-domain OCT machines (Fig. 4.31) became widely available. The first three generations of OCT are referred to as time-domain OCT.

The principle of OCT involves a low-coherence infrared (843-nm) diode light source, which is divided into reference and sample paths. Reflected sample light from the patient's eye creates an interference signal with the reference beam, which is detected in a fiber-optic interferometer. Cross-sectional images of the retina and disc are then constructed from a sequence of signals, similar to that of an ultrasound B- mode (530). Instead of sound waves, however, the OCT uses low-coherence light to quantify RNFL thickness, by measuring the difference in delay of backscattered light from the RNFL inside the imaged tissue. RNFL can be differentiated from other retinal layers with an algorithm that detects the anterior edge of retinal pigment epithelium and determines the photoreceptor layer position. Each resulting image consists of RNFL thickness measurements along a 360-degree circle around the optic disc (531). Multiple studies have demonstrated that RNFL thickness can be accurately measured with the OCT (532, 533, 534, 535, 536 and 537), however it was suggested that earlier versions of the OCT may have underestimated RNFL thickness (538). One study compared RNFL thickness measurements using the first generations of OCT, NFA, and HRT and achieved the most reliable results with the NFA, followed by HRT (539). However, other studies showed that the third generation of OCT was similar to scanning laser polarimetry and HRT in differentiating glaucomatous eyes from healthy eyes (540, 541). Unlike confocal scanning laser tomography, the OCT does not require a reference plane. Results of RNFL thickness measurements may vary with different instruments.

Figure 4.31 Two examples of spectral-domain OCT machines. A: Cirrus HD-OCT. (Courtesy of Carl Zeiss Meditec, Inc.) B: Spectralis OCT. (Courtesy of Heidelberg Engineering.)

The final resolution of OCT is determined by transverse and axial resolution; transverse resolution is determined by the spacing of the A-scan and is ultimately limited by the optics of ocular tissue. Axial resolution varies by wavelength and bandwidth of the light source. Current models of time-domain and spectral-domain OCT use the same diode light sources. Some ultrahigh-resolution ophthalmic OCT scanners are based on a commercially available titanium-sapphire laser. This system enables in vivo cross-sectional retinal imaging with axial resolution of approximately 1 to 3 µm, compared with approximately 10 µm for the OCT3 (542, 543). These OCT devices that use the titanium-sapphire laser sources are not commercially available because of prohibitive costs of the laser. Spectral-domain OCT does not rely on a beam splitter or moving reference mirror; instead, all of the reflected light returns to a spectrometer, and the wavelengths are converted by Fourier transformation to generate the images. This allows higher resolution than a timedomain OCT does, and faster acquisition time. Theoretically, the faster acquisition time should reduce the induced artifact from patients' eye movement, compared with OCT3.

OCT3 has a normative database and can differentiate glaucomatous and nonglaucomatous eyes with reported sensitivities and specificities generally ranging from the upper-60s to mid-80s (%) and the low80s to -90s (%), respectively (497, 498, 499 and 500). Thin OCT measurements are associated with the conversion of suspected glaucoma to glaucoma (544). The utility of OCT3 for determining progression in

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advance of functional testing is less clear. At the time of publication, comparison of spectral-domain OCT to OCT3 with regard to diagnosing glaucoma and progression of glaucoma has not yet been established.

Retinal Thickness Analyzer

The retinal thickness analyzer is another computerized system for measuring the retina thickness. It projects a laser beam onto the retina, and a fundus camera observes reflections from internal limiting membrane and in the retina until the light reaches the retinal pigment epithelium. The profile of light intensity contains peak reflections from the internal limiting membrane and the retinal pigment epithelium, and the thickness of the retina is calculated from the distance between the two peaks. The retinal thickness analyzer may be useful in glaucoma management to monitor retinal thickness (545,

546).

Clinical Value of Image Analyzers

In the few studies that have directly compared the different structural imaging technologies, OCT3 had better sensitivity and specificity, compared with the HRT-II and scanning laser polarimetry (528, 529). Early in the course of the disease process, these structural imaging technologies are very helpful in differentiating glaucomatous damage before achromatic (i.e., white-on-white) visual field change. Perhaps the most useful application is a negative result on a structural test in a patient with suspected glaucoma; it can be reassuring that no disease is detectable when visual field and structural testing find no abnormality. No single test has absolute sensitivity and specificity. When used alone, HRT, GDx, and OCT summary data reports may help differentiate between healthy eyes and glaucomatous eyes with mild to moderate visual field loss, although none of the instruments provided enough sensitivity and specificity to be used as a screening tool for early glaucoma (547). A combination of the best parameters from the three imaging methods significantly improves this capability (541) (Fig. 4.32). Information obtained with HRT, GDx, and OCT allows combining qualitative data with graphic visual information and quantitative data, and, with improved sensitivity and specificity of these instruments, the summary data reports may better assist the physician in the management of patients with glaucoma (531).

At this time, none of these structural technologies alone can be relied on to ascertain glaucomatous progression without corroborating evidence. However, these technologies continue to evolve and improve rapidly. At the time of publication, HRTIII and spectral domain are at the beginning of their use.

Techniques for Blood-Flow Measurement

Early studies on ocular blood flow are discussed earlier; they relate to the pathophysiology of glaucomatous optic neuropathy. This section considers new techniques for measuring ocular blood flow, which may one day have clinical application. Although studies have shown deficient blood flow in at least 50% of patients with normal-tension glaucoma, direct evidence that vascular factors contribute to the development of glaucoma optic neuropathy is lacking, because measurements of the optic nerve blood flow are limited by the small caliber of blood vessels and the volume of the optic nerve tissue being studied (548, 549 and 550).

In the past two decades, several methods have been developed to facilitate quantitative, comprehensive study of retinal, choroidal, and retrobulbar circulations. These techniques include vessel caliber assessment, pulsatile ocular blood-flow measurement, scanning laser fluorescein and indocyanine green (ICG) angiography of the peripapillary choroid and the retinal circulation, laser Doppler flowmetry, confocal scanning laser Doppler flowmetry, and color Doppler imaging (551). To fully assess optic nerve circulation, these techniques should be combined because no single technology can adequately describe the complex hemodynamics of the eye.

Angiography

New imaging technologies allow us to detect and follow very subtle changes of the structure and perfusion of the optic nerve head. These and other technologies may enhance the ability to diagnose and monitor glaucomatous disc damage (552).

Confocal scanning laser ophthalmoscopy can enhance angiographic examination of small vessels of the optic nerve head using fluorescein or ICG (553). The confocal scanning laser ophthalmoscopy allows acquisition of images of the retinal circulation and late leakage sites. Optical subtraction of the light contribution of the retinal circulation allows examination of the choroidal circulation and vice versa. At least three advantages of confocal scanning laser ophthalmoscopy over conventional instruments have been described as follows: (a) excellent visualization of the retinal circulation, (b) optical subtraction of retinal circulation, and (c) acquisition and processing of all data digitally with easy data exchange. This technology may potentially produce a three-dimensional map of the retinal and choroidal vasculature (554).

Heidelberg retina angiograph (HRA and HRA-II), which combines confocal scanning laser ophthalmoscopy technology with ICG and fluorescein angiography, is commercially available. With this instrument, several changes may be seen in peripapillary capillary vessels at the different glaucomatous

stages. Persons with early glaucomatous damage have an increase of the cup area, secondary to a reduction of the neuroretinal rim area, and ICG angiography shows an increase in prepapillary plexus visualization, which may be caused by increased blood flow while autoregulation is still functioning. Some patients with advanced glaucoma show significant capillary dropout on ICG angiography (555). The HRA can demonstrate the superficial and deep blood supply of the optic nerve, and simultaneous ICG and fluorescein angiography, and visualization of separate circulations in different planes. The technique allows overlaying ICG and fluorescein images or comparison of them side by side (556). One prospective study evaluated the correlation between the vascular supply of the optic nerve and visual fields. In eyes with a normal visual field, a diffuse microvascular filling pattern of the optic disc area was apparent with no filling defects, whereas angiography of glaucomatous eyes had good correlation with the visual field defect location (557).

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Figure 4.32 A:Color photograph of a glaucomatous optic nerve head showing advanced loss of the neuroretinal rim, especially inferotemporally. Peripapillary atrophy, arteriolar narrowing, and bayoneting of the retinal arterioles are also present. B: Corresponding OCT shows preservation of the nasal RNFL, but significant loss temporally. C: Topographic map by confocal scanning laser ophthalmoscopy of the same optic nerve. The red x denotes areas of neuroretinal rim thickness less than the normative database; the yellow! denotes areas of neuroretinal rim thickness in the border zone of normal in the same normative database. D: Corresponding automated achromatic visual field showing a near superior altitudinal defect and dense inferior arcuate and nasal step defect. E: Cross section of the optic nerve head by OCT. F: Topographic map by OCT of the same optic nerve.

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