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

Summary for the Clinician

■Results are more sensitive when the confounding effect caused by the normal birefringence of the cornea is removed with the more individually tuned variable corneal compensator (VCC).

7.3.4Optical Coherence Tomography

Optical coherence tomography (OCT) produces high-resolution, two-dimensional, cross-sec- tional images of posterior segment structures, including the optic disc, retinal nerve fiber layer, and macula. The OCT utilizes the principle of low-coherence reflectometry. The time required for light directed into the eye to be reflected back to a detector is related to the depth of the optical interface. For instance, light reflected from the internal limiting membrane returns to the detector more quickly than light reflected from a deeper structure such as the sclera. The time taken by light to travel to and from the eye is compared to the time of travel to and from a reference mirror by examining optical interference patterns. A larger number of optical interfaces produces a greater degree of variability in the timing of reflected signals and hence less coherence in the reflected light. The concept of optical coherence tomography is analogous to B-scan ultrasonography, except that optical, rather than acoustic, backscattering of light is used to create an image. Cross-sectional images are produced with a longitudinal/axial resolution and transverse resolution of 10–20 µm and 20 µm, respectively.

The Humphrey® OCT3-Optical Coherence Tomography Scanner projects an optical near-in- frared (diode, 820 nm), low-coherence light with a spot size of 20 µm onto the retina (Fig. 7.3). Low-coherence light passes through a beam splitter that produces two separate light paths. One path travels to a rapidly translating reference mirror and the other travels to the patient’s eye. A detector registers the light backscattered from the reference mirror and the patient’s eye. A comparison of the amplitude and timing of light from the two paths is made by a Michaelson in-

terferometer. An advantage of this technique is the fact that it does not require a user-defined reference plane.

Patterns of x-y scanning, which are determined by the operator, include arc, circle, composite circle, concentric rings, line, radial lines, and raster lines. The number of pixels between the anterior and posterior boundaries in which the reflectivities exceed software-determined thresholds defines the thickness of the RNFL [64]. OCT nerve fiber layer measurements can be obtained in the circle scan mode, in which a 3.4-mm-diameter circular scan of the retina centered on the optic nerve is made [64]. The system reports the overall RNFL thickness, the thickness in each of 12 sectors, and the thickness in each quadrant in microns. In addition, results are presented graphically in which retinal position (i.e., temporal, superior, nasal, and inferior) are plotted against RNFL thickness. Disc structure can be assessed by radial line scans. Optic disc structure measurements are expressed as disc area, cup area, rim area, cup-to-disc area ratio, horizontal cup-to-disc ratio and vertical cup-to-disc ratio. Cup-to-disc ratio and rim radius (mm) for each of 12 clock hours is expressed in table form. The OCT provides cross-sectional images of layers of the retina (Fig. 7.4), with a resolution of approximately 10 µm.

The OCT depends on the transparency of the optical media. Disease processes which affect the clarity of the optical media (i.e., cornea, lens, vitreous, retina) compromise the quality of the OCT images.

The reproducibility of the OCT is approximately 10–20 µm [64]. The overall reproducibility (root mean squared error) of the mean RNFL thickness measured with three scans was 7.0 µm in a sample of both normal and glaucomatous eyes [6]. These good performance values make the OCT well-fitted for clinical use. However, measurements obtained from glaucomatous eyes are more variable than from normal eyes [6]. This variability may be partially attributable to the relatively small number of sampled points acquired by OCT compared to the focal nature of some glaucomatous nerve fiber layer defects [6, 27].

Nonetheless, the OCT has been shown to demonstrate RNFL defects that agree with Humphrey 30-2 visual fields and abnormalities of the nerve

fiber layer visible in black-and-white fundus photographs [72]. OCT 2000 nerve fiber layer measurements demonstrate quantitative differences in nerve fiber layer between normal eyes and both glaucomatous and ocular hypertensive eyes [7].

7.3.4.1Using OCT for Glaucoma Evaluation

Retinal nerve fiber layer measurements with OCT correlate well with known anatomic variations in the RNFL [29]. In one study, good correlation between visual field loss and decreased RNFL thickness in the superior and inferior quadrants in glaucomatous eyes was demonstrated with the OCT [64]. The study also demonstrated a decrease in RNFL thickness in the inferior quadrant in glaucomatous eyes compared to normal eyes, and an overall decrease in thickness with increasing age in normal subjects and patients with glaucoma [64]. In one study, the presence of one or more quadrants with an area of RNFL thickness in the first percentile was used to predict a glaucomatous visual field on automated perimetry. Sensitivity and specificity for predicting field defects using this criterion were 89% and 92% respectively. [8] Average RNFL thinning has also been shown to correlate with the change in mean deviation (9.3 µm/5 dB) on Humphrey Field visual field testing [36]. Others have measured RNFL

internal reflectivity and correlated this with mean deviation obtained by automated perimetry [52].

7.3.4.2 Other Uses of OCT

OCT has been used to elucidate the pathological changes in, and enhance our understanding of, disease states of the optic nerve and RNFL. For example, OCT has recently been used to investigate changes in the nerve fiber layer in Leber’s hereditary optic neuropathy (LHON) patients and asymptomatic carriers of the disease mutations [3]. Eyes with LHON for more than 6 months had severely thinned RNFLs, partially sparing the nasal quadrant, while eyes in patients with early LHON had thicker RNFLs compared to controls in the superior, inferior, and nasal quadrants [3]. In cases where there was late-stage visual recovery, the RNFL was thicker when compared with cases without recovery, except temporally where the papillomacular bundle was equally affected. Interestingly, OCT also detected increased nerve fiber layer thickness in the temporal retina of asymptomatic male and female carriers of Leber’s hereditary optic atrophy mutation 11778, suggesting that OCT could be useful in following patients with pre-clinical LHON [62].

Even when it is not seen on clinical examination, submacular fluid secondary to chronic papilledema may be found with OCT [31] and the elevation of the optic nerve head itself

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can be visualized and measured (Fig. 7.5). In many of these cases, the OCT suggested that the submacular fluid tracked from the optic nerve, rather than leaking from the choroidal circulation.

OCT may be of value in characterizing pseudo versus true papilledema. The RNFL was observed to be thickened in superior and inferior quadrants of patients with either papilledema or congenitally crowded optic discs as compared with controls, but this test could not differentiate between the two groups [37]. By measuring the mean circumpapillary RNFL thickness, another group was able to differentiate papilledema from pseudopapilledema [49].

OCT has helped elucidate a variety of other retinal and optic nerve pathologies. Serous retinal detachments that were not observed with ophthalmoscopy, including those seen with Leber’s stellate neuroretinitis and branch retinal vein occlusion, can be easily identified by OCT [68]. Optic disc traction syndrome following ischemic central retinal vein occlusion was observed in three patients by OCT, while evidence for the syndrome was less evident on clinical examination or ultrasound [57]. OCT has also been used to show loss of RNFL thickness in patients with grades I–III optic nerve head drusen versus normal patients [55]. A different study showed that there was no loss in RNFL thickness in 23 patients with drusen over an 18month period [48]. The anatomical relationship between optic pits and associated macular pathology has also been investigated with OCT. In one study, it was shown that schisis-like cavities and areas of edematous retina communicated with the optic disc while associated retinal detachments did not [58]. Using OCT, it has been shown that patients with human immunodeficiency virus (HIV) but without cytomegalovirus retinitis and over 6 months of CD4 counts <100 cells/mm3 of blood were found to have thinner nerve fiber layers than healthy subjects or HIV patients with CD4 counts consistently over 100 cells/mm3 [40]. OCT has been used to confirm the characteristic bow-tie atrophy expected in the optic tract syndrome even when magnetic resonance imaging (MRI) was not able to detect the lesion [71].

The optic nerve atrophy seen after single episodes of optic neuritis has been shown with OCT to correlate with loss of RNFL thickness, confirming the presumption of axonal loss that is inferred by the clinical identification of optic nerve “pallor” [76]. Patients with multiple sclerosis have been observed to have reduced RNFL thickness using OCT, especially in those who have had optic neuritis [23]. Furthermore, the RNFL loss also correlated with a low-contrast measure of visual acuity and contrast sensitivity tests in patients with a history of optic neuritis [23]. Ethambutol-associated optic neuropathy has recently been studied with OCT [86], revealing an average loss of 79% of nerve fiber thickness in the temporal quadrant in patients with near-normal fundus examinations, supporting the notion of injury to the metabolically active fibers of the papillomacular bundle.

The application of OCT may further our knowledge of many rare conditions whose pathophysiology is unknown, once enough patients are studied. The cross-sectional depth of the white retinal lesion in the multiple evanescent white dot syndrome (MEWDS) has been shown to be at the level of the retinal pigment epithelium [1]. OCT has also been used to evaluate RNFL changes in methanol toxicity [24].

7.3.4.3Ultrahigh-Resolution OCT (UHR-OCT)

Recently, ultrahigh-resolution OCT has emerged as an experimental technology capable of visualizing tissue in vivo with an axial resolution of approximately 3 µm. This more advanced OCT method has mostly been used to study the retina in patients with age-related macular degeneration [50], macular hole, central serous chorioretinopathy, macular edema, RPE detachments, epiretinal membranes, vitreal macular traction, and retinitis pigmentosa [39]. Few studies have been done looking at the optic nerve head itself, but it is likely that this new technology will allow for much more detailed evaluation in the future. For example, one small study used UHR-OCT to demonstrate the persistence of Cloquet’s canal in 93% of normal healthy eyes [35].

er spatial resolution in its imaging of the optic nerve head and RNFL.

7.4Imaging of the Optic Nerve and Alzheimer Disease

Some histological and clinical studies have provided evidence that there is loss of retinal ganglion cells in patients with Alzheimer disease (AD) [59] although this is controversial [54]. Recent studies have now tried to confirm this association with objective, reproducible imaging techniques. In one study, the HRT scanning laser ophthalmoscope was used to assess optic disc parameters in 40 patients with AD and compare them with age-matched control patients [18]. Patients with the highest vertical cup-to-disc ratios measured by HRT were more likely to have AD than patients with the lowest values (odds ratio: 4.7). However, the risk of AD was sufficiently low in both groups so that the best sensitivity and specificity for AD, using 0.42 as a cut-off value

found no difference between them and control patients [38]. If there is degeneration of retinal ganglion cells on the basis of AD, the visual consequences of the degeneration must be relatively slight, especially in comparison to the sometimes prominent cortical visual symptoms experienced by approximately 43% of patients with AD [15, 42].

Summary for the Clinician

■Some studies using HRT and OCT have suggested that Alzheimer disease may be accompanied by RNFL degeneration, but other studies did not show this with GDx or electrophysiological testing.

7.5 Comparing Modalities

There are few studies that compare these different imaging techniques. Hence, it is not possible

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to provide firm guidelines about which testing method would be consistently the best to evaluate a given pathology. It should be appreciated that the various methods are readily interchangeable. One study in particular compared vertical disc diameter using HRT, OCT, and funduscopy and found poor agreement among the tests (kappa < 0.4) [4].

7.5.1 MRI

Conventional magnetic resonance imaging (MRI) is useful in grossly imaging the optic nerve and detecting compression, inflammation, and atrophy. The appearance of the optic nerve can in some cases be used to help differentiate disease processes that might clinically appear similar. In 32 patients with optic neuritis, for example, 31 demonstrated enhancement of the involved nerve, while only 2 out of 32 patients diagnosed with nonarteritic ischemic optic neuropathy (NAION) demon-

strated this finding [53]. MRI is therefore the best objective means to distinguish between these two forms of optic neuropathy that may otherwise be impossible to distinguish clinically [53].

While MRI clearly has a role in imaging the optic nerve as a whole, its resolution has not been sufficient to analyze the optic nerve head or nerve fiber layer. Extremely high-resolution MRI (µMRI) has been used to provide three-di- mensional in vitro images of the optic nerve with a resolution of less than 50 µm. Using this approach, Sadun et al. were able to image the lamina cribosa, the central retinal artery and vein, the interfascicular septae and the vascular circle of Zinn-Haller in cadaveric optic nerves [60] (Fig. 7.6). Of greater significance, they identified pathological structures in nerves of patients with LHON, such as atrophic fascicles, fluid-filled sacs, and thickened septae. Eventually, µMRI may emerge as a technology useful in the clinical evaluation of the microscopic properties of the optic nerve head and fiber layer, but at present it remains an experimental technology.

Summary for the Clinician

■Enhancement of the optic nerve on MRI is helpful in distinguishing optic neuritis or other inflammatory optic neuropathies from nonarteritic ischemic optic neuropathy.

■Extremely high-resolution MRI (µMRI) is an experimental technology that may one day offer extremely high-resolution three-dimensional images of the optic nerve in the clinical setting.

7.6 Conclusion

Since the introduction of the first ophthalmoscope, many advances have been made in nerve fiber layer and optic disc imaging. The initial group of nerve fiber layer analyzers formed the basis upon which confocal scanning devices, laser polarimetry, and optical coherence tomography were developed. New and improved commercial devices for imaging the optic nerve head and nerve fiber layer continue to emerge, enhancing our ability to study these structures in greater detail, and thereby understand more about their function in the living subject. These devices can provide objective measurements that aid in the detection and prospective evaluation of disease, especially optic nerve cupping associated with glaucoma. Finally, they may also provide us with information about differences in the response of the optic nerve head to various forms of injury, and eventually to treatments as well.

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