Ординатура / Офтальмология / Английские материалы / The Retina and its Disorders_Besharse, Bok_2011

beyond the accommodative ability of the eye will reduce visual acuity by a similar amount to an equivalent degree of myopia. Astigmatism, particularly where the meridia of astigmatism are oblique, will also reduce uncorrected vision significantly.

Other aberrations of the eye beyond defocus and astigmatism further limit visual acuity. Retinal image quality can be improved by viewing monochromatic stimuli (to reduce chromatic aberration) and by using a deformable mirror to correct coma, trefoil, and other higher-order aberrations of the eye. Under these ideal conditions, Williams and colleagues have shown that subjects are able to resolve gratings of up to 55 cycles per degree, equivalent to a visual acuity of approximately –0.30 logMAR (6/3; 20/10).

Assuming that an image is perfectly focused on the retina, the next limit on visual resolution is the spacing of the retinal photoreceptors. In order to detect a grating, alternate black and white bars must fall on adjacent photoreceptors. This theoretical limit of vision, known as the Nyquist limit, is equivalent to a grating with light to dark separation of 1/√D, where D is the center-to-center separation of two photoreceptors. In the fovea, D is approximately 3 mm, equivalent to a visual angle of approximately 55 cycles per degree – almost identical to the value found by Williams. This confirms that in people with good vision, all of the limits on visual acuity are precortical. Amblyopia, where vision is reduced despite the absence of any eye disease, is dealt with elsewhere in the encyclopedia.

Visual Acuity across the Retina

Nonfoveal vision is limited by many elements. First, the eye’s optics are not optimized for viewing off the visual axis, and peripheral vision is subject to greater aberration than central vision. Second, the size of photoreceptors increases and their density falls with increasing eccentricity. The number of photoreceptors per retinal ganglion cell also increases, from less than one photoreceptor per ganglion cell in the fovea to more than 20 photoreceptors per ganglion cell in the far periphery. The volume of visual cortex devoted to noncentral retina is also proportionally lower. It is unsurprising, therefore, that visual acuity falls quickly with increasing distance from the fovea (Figure 4). This is one reason for the severely reduced visual acuity of people with central vision loss from diseases such as age-related macular disease.

Visual Acuity over Life

Over the first year of life, visual acuity assessed by a preferential looking test appears to be reasonably stable

Figure 4 Letter visual acuity measured in peripheral vision as a function of degrees of eccentricity. Data from Anstis, S. M. (1974). Letter: A chart demonstrating variations in acuity with retinal position. Vision Research 14(7): 589–592.

at around 6 min of arc. Between a child’s first and third birthday, visual acuity improves exponentially to reach 1 min of arc. A further small improvement in resolution ability to approximately 0.75 min of arc is achieved by age 5 years. In the absence of eye disease, this value remains relatively constant until the sixth decade. In a populationbased study of nearly 5000 older adults, Klein found a decrease in visual acuity to a mean value of approximately 2 min of arc in those aged over 75 years. Of course, this reflects the age-related nature of many diseases which affect visual acuity, such as cataract, glaucoma, diabetic retinopathy, and age-related macular degeneration. Figure 5 plots data from the studies of Mayer and Klein.

Visual Standards

In most countries, there is a visual-acuity requirement for car drivers. While the level and measurement technique varies between countries, the acuity limit is usually approximately 0.3 logMAR. Commercial airline pilots are required to have a binocular visual acuity of 0.0 logMAR.

Best corrected binocular visual acuity of 1.0 logMAR or poorer is used as a definition of low vision or partial sight in many countries, with acuity of worse than 1.3 logMAR being described as severe sight impairment.

Hyperacuity

Some visual tasks can be performed with a far greater degree of precision than would be suggested by the MAR. Alignment tasks such as Vernier discrimination (where the offset of one line with respect to another is detected, Figure 6(a)) can be performed with misalignment of less

Age (years)

Figure 5 Variation in visual acuity over life. From Mayer, D. L. and Dobson, V. (1982). Visual acuity development in infants and young children, as assessed by operant preferential looking.

Data from Vision Research 22(9): 1141–1151 and Klein, R., Klein, B. E., Linton, K. L., and De Mets, D. L. (1991). The beaver dam eye study: Visual acuity. Ophthalmology 98(8): 1310–1315.

must be for it to be seen. If a target moves with velocity of 40 s 1, the MAR is increased to about 2 min of arc, while at 80 s 1, acuity is about 3 min of arc.

In peripheral vision, slow image motion (less than 10 s 1) slightly improves visual acuity for peripherally presented targets, perhaps because it breaks the phenomenon of Troxler fading.

Target motion at the retina can be induced by target movement, by eye motion, or by head motion. Many eye diseases, particularly those of the macula, are associated with poor fixation stability of the eye. This poor eye stability increases retinal image motion, and is significantly associated with poorer visual function. Small degrees of head motion do not significantly decrease visual acuity under normal conditions, but have a marked deleterious effect for subjects viewing through telescopic spectacles. Therefore, subjects with macular disease who have poor fixation stability and who view through telescopic low-vision aids have a marked impairment in their dynamic visual acuity.

See also: Chromatic Function of the Cones; Contrast Sensitivity; Photopic, Mesopic and Scotopic Vision and Changes in Visual Performance.

(b)

(a)

Figure 6 Examples of hyperacuity tasks. Misalignment of the lower element is easily visible. (a) Vernier alignment; (b) dot alignment: the offset of the middle dot with respect to the upper and lower dot is easily discerned.

than 5 s of arc – considerably less than the center-to- center spacing of a foveal photoreceptor. This is thought to be due to interpolation of the inputs of two or more adjacent neural elements.

Dynamic Visual Acuity

Throughout this article, visual acuity has been discussed for static targets. If the target is moved, central visual acuity decreases: the faster the target moves, the larger it

Further Reading

Anstis, S. M. (1974). Letter: A chart demonstrating variations in acuity with retinal position. Vision Research 14(7): 589–592.

Bailey, I. L. and Lovie, J. E. (1976). New design principles for visual acuity letter charts. American Journal of Optometry and Physiological Optics 53: 740–745.

Bennett, A. G. and Rabbetts, R. B. (eds.) (1989). Visual acuity and contrast sensitivity. In: Clinical Visual Optics, pp. 23–72. Oxford: Butterworth-Heinemann.

Brown, B. (1972). Resolution thresholds for moving targets at the fovea and in the peripheral retina. Vision Research 12(2): 293–304.

Committee on vision. (1980). Recommended standard procedures for the clinical measurement and specification of visual acuity. Report of working group 39. Advances in Ophthalmology ¼ Fortschritte der Augenheilkunde ¼ Progres en Ophtalmologie

41: 103–148. Assembly of Behavioral and Social Sciences, National Research Council, National Academy of Sciences, Washington, DC

Crossland, M. D., Culham, L. E., and Rubin, G. S. (2004). Fixation stability and reading speed in patients with newly

developed macular disease. Ophthalmic and Physiological Optics

24: 327–333.

Demer, J. L. and Amjadi, F. (1993). Dynamic visual acuity of normal subjects during vertical optotype and head motion. Investigative Ophthalmology and Visual Science 34(6): 1894–1906.

Klein, R., Klein, B. E., Linton, K. L., and De Mets, D. L. (1991). The beaver dam eye study: Visual acuity. Ophthalmology 98(8): 1310–1315.

Liang, J., Williams, D. R., and Miller, D. T. (1997). Supernormal vision and high-resolution retinal imaging through adaptive optics. Journal of the Optical Society of America. A, Optics, Image Science, and Vision 14: 2884–2892.

Mayer, D. L. and Dobson, V. (1982). Visual acuity development in infants and young children, as assessed by operant preferential looking. Vision Research 22(9): 1141–1151.

Plainis, S., Tzatzala, P., Orphanos, Y., and Tsilimbaris, M. K. (2007). A modified ETDRS visual acuity chart for European-wide use.

Optometry and Vision Science 84(7): 647–653.

Rosser, D. A., Cousens, S. N., Murdoch, I. E., Fitzke, F. W., and Laidlaw, D. A. (2003). How sensitive to clinical change are ETDRS logMAR visual acuity measurements? Investigative Ophthalmology and Visual Science 44: 3278–3281.

Thibos, L. N., Cheney, F. E., and Walsh, D. J. (1987). Retinal limits to the detection and resolution of gratings. Journal of the Optical Society of America. A, Optics, Image Science, and Vision

4: 1524–1529.

Westheimer, G. (1987). Visual acuity. In: Moses, R. A. and Hart, W. M. (eds.) Adler’s Physiology of the Eye: Clinical Application,

pp. 415–428. St Louis, MO: Mosby.

Glossary

Deformable mirror – A mirror equipped with an array of actuators on the back surface that can warp the mirror surface by small amounts into arbitrary shapes, allowing the correction of the eye’s aberrations.

Diffraction-limited resolution – The resolution of an optical system that has no aberrations, the image quality of which is reduced only by the diffraction of the light in the pupil of the system.

Lipofuscin autofluorescence – Lipofuscin is composed of many molecules that are by-products of the visual or retinoid cycle. These accumulate in the retinal pigment epithelium with aging and can be visualized in the living eye because they fluoresce when exposed to short wavelength light.

Point-spread function (PSF) – The light distribution in the image plane of an optical system such as the eye, formed from light from a point source outside the eye, such as a very distant star.

Retinal densitometry – A method to measure the density of photopigment in the living eye.

Shack–Hartmann wavefront sensor – A device capable of measuring the optical defects of an optical system such as the human eye. The output of a wavefront sensor can be used to control the shape of a deformable mirror in an adaptive optics system.

Stiles and Crawford effect – The fact that the eye is far more sensitive to light entering through a point near the center of the pupil than the pupil margin even though the irradiance at the retina is very little dependent on entry point in the pupil. This effect is caused by the waveguide properties of cone photoreceptors, which are more sensitive to light falling on their optical axes (which point near the center of pupil) than obliquely incident light.

The Benefit of Adaptive Optics in Vision

Science

The history of ophthalmoscopy after its invention by Helmholtz until today is marked by efforts to extract the most information possible from the light reflected from the retina. Over the last two decades, there has been a

concerted effort to improve the resolution of the imaging process in all three spatial dimensions. The development of optical coherence tomography (OCT) improved the resolution in the axial dimension, and has allowed the routine imaging of individual layers of cells in the retina. More recently, the introduction of adaptive optics (AO) has improved the resolution of fundus cameras in both transverse dimensions. The transverse resolution of the conventional fundus camera is limited not by the camera itself but by the optics of the human eye. The sources of image blur in the eye’s optics include diffraction, aberrations, and scatter. Diffraction is the image blur that results from the wave nature of light as it passes through the eye’s pupil. Blurring by diffraction is not inevitable; there are exciting techniques on the horizon that may eventually overcome the fundamental resolution limit set by diffraction, but no one has yet demonstrated this in the eye. A hypothetical eye that suffered only from diffraction would allow a resolution no smaller than about 1.4 mm when imaging wavelengths of light in the middle of the visible spectrum (550 nm). This is smaller than the smallest cells in the retina, so that if one could make the natural human eye limited only by diffraction, cellular and even subcellular features that are invisible in conventional fundus imaging could be seen. As shown in Figure 1 (upper panels), in a diffraction-limited eye, the larger the pupil, the smaller the image of a single point of light and therefore the better the resolution.

The monochromatic and chromatic aberrations of all eyes further blur the retinal image. The monochromatic aberrations of the human eye alone are greater than those of even a mediocre man-made optical system. As shown in Figure 1 (lower panels), increasing the pupil reduces the effect of diffraction, but exacerbates the effect of aberrations, with the best trade-off between the two occurring for pupil sizes around 3 mm. Light scatter, the third cause of loss in retinal image quality, is relatively unimportant in young eyes but it can greatly reduce retinal image contrast in older eyes, especially those with cataract. Not only is the retinal image blurred by the optical factors mentioned above, it is also exceedingly dim. The amount of light that can be delivered to the retina is limited for safety reasons and the retinal reflectance is low: 10–3–10–5 across the spectrum. This would be less of a problem if it were easy to integrate light over long exposures, but the eye is always moving; even an eye with excellent fixation moves about20 mm root mean square (rms) velocity. Eye motion artifacts are all the more troublesome in instruments with high magnification that are designed to look at cellular

Figure 1 The point-spread function (PSF) for a diffraction-limited eye and a normal eye at two different pupil diameters. The PSF corresponds to the light distribution on the retina produced by a point source of light infinitely distant from the eye. For the hypothetical diffraction-limited eye, the PSF diameter decreases in inverse proportion to the pupil diameter such that large pupils produce the best image quality. However, in the typical human eye, aberrations increase with increasing pupil size, eliminating the benefit of escaping diffraction at the largest pupils. The goal of AO is to correct the aberrations to produce the PSF of a diffraction-limited eye with a large pupil. Adapted from Roorda, A. Garcia, C. A., Martin, J. A., et al. (2006). What can adaptive optics do for a scanning laser ophthalmoscope? Bulletin de la Socie´te´ Belge d’Ophthalmologie

302: 231–244, Figure 1, with permission from Bulletin of the Belgian Societies of Ophthalmology (Copyright 2006).

structures that are often far smaller than 20 mm. Despite all these formidable limitations, it is possible to design fundus cameras that address all of them with varying degrees of success, making microscopic resolution of the living retina possible as described below.

Correcting the Eye’s Monochromatic

Aberration

It is possible to overcome the eye’s monochromatic aberrations with AO, a two-step process in which the eye’s wave aberration is measured and corrected, usually in real time. Figure 2 describes the principle of AO for imaging the eye. The monochromatic aberration of the eye is measured with a wavefront sensor. The measured aberration data are used to control a wavefront compensation device, usually a deformable mirror that corrects the wave aberration. Ideally, it would completely remove all the monochromatic aberrations, leaving diffraction and scatter as the only remaining sources of image blur. It usually takes several iterations of the measurement and correction loop to achieve the best correction, at which point it is possible to obtain a retinal image that is almost

Light from retina

Aberrated wavefront

Beamsplitter

Corrected Adaptive wavefront

mirror

Control system

Figure 2 Principle of adaptive optics. The system contains two key parts: the wavefront sensor and wavefront corrector. The wavefront sensor, usually of the Shack–Hartmann type, measures the monochromatic aberration of the eye. It uses a 2-D array of lenslets conjugate with the eye’s pupil to break the light from an infrared point source imaged on the retina into several hundred individual beams. Each beam is imaged on a CCD array. Its displacement on the CCD from where it would have landed had the eye been aberration-free indicates the slope of the wave aberration at that lenslet’s location in the pupil. Information from all the lenslets is combined to compute the overall wave aberrations of the eye. These data are used to control a wavefront compensation device that corrects the wave aberration. The most commonly used device is a continuous surface deformable mirror. This mirror has a flexible surface overlying an array of actuators that can push or pull on the mirror surface locally. If the mirror surface is shaped so as to mimic the shape of the wave aberration but with half the amplitude of the wave aberration, the wavefront reflecting from the surface will be perfectly flat, and the monochromatic aberrations of the eye will have been corrected. Adapted from Carroll, J. Gray, D. C., Roorda, A., Williams, D. R. (2005). Recent advances in retinal imaging with adaptive optics. Optics and Photonics News 16: 36–42, Figure 1, with permission from Optical Society of America (Copyright 2005).

completely aberration free in eyes with normal amounts of aberrations. The rate of measurement and correction required to keep up with the temporal variations in the eye’s wave aberration is relatively slow, at least compared with applications of AO in astronomy. Heidi Hofer has shown that measuring and correcting the wave aberration at 30 Hz or so is adequate to track the most important changes in the wave aberration, which are caused by microfluctuations in accommodation that have a temporal bandwidth of only a few Hertz. With complete wavefront correction, the point-spread function (PSF) is very

compact, approaching the light distribution produced by diffraction alone. Typically, one can achieve as much as an order of magnitude reduction in the rms wavefront error of a normal eye with this method. This provides a substantial improvement in image quality as shown in Figure 3.

Vision Correction with AO

One of the convenient features of AO correction is that the correction required to focus light onto the retina is the same as the correction required to image the retina at high resolution outside the eye. Many investigators have capitalized on the advantages of AO for vision correction as well as for retinal imaging. Correcting the higher order monochromatic aberrations (i.e., those other than defocus and astigmatism corrected by spectacles) produces a modest improvement in visual acuity and contrast sensitivity in the normal eye. The improvements can be dramatic in eyes with large amounts of higher-order aberrations such as those that suffer from keratoconus. The demonstration of these improvements in spatial vision with a deformable mirror has stimulated improvements in the control of laser ablation in refractive surgery as well as the fabrication of customized contact lenses that can correct higher-order aberrations. AO continues to be a valuable tool not only for correcting aberrations but also for generating specific patterns of aberrations so that their effects on vision can be studied conveniently. For example, it is possible to explore the design of contact lenses for presbyopes that increase the depth of field of the eye without the need to fabricate optical elements for each pattern one wishes to evaluate.

Retinal Imaging with AO

In retinal imaging, AO can be combined with almost any other imaging technology. David Williams’ laboratory at

the University of Rochester first demonstrated the value of a closed-loop AO system for retinal imaging, incorporating AO into a flood-illuminated system that acquired single snapshots of the retina with a resolution adequate to resolve cone photoreceptors near the fovea. Austin Roorda, then at the University of Houston, demonstrated that AO could also improve the resolution of the scanning laser ophthalmoscope (SLO). SLOs are potentially confocal devices and AO offers improvements in both axial and transverse resolutions. Moreover, AO improves the focus of the light on the confocal pinhole in front of detector, which increases the available signal. The AOSLO has a high lateral resolution of less than about 2 mm. The axial resolution of better than 60 mm, though poor by OCT standards, is nonetheless adequate for some optical sectioning of the retina. AO has also improved the transverse resolution of OCT, allowing a resolution of less than 3 mm in all three spatial dimensions in the retina. AO systems can also be combined with other imaging modalities such as phase contrast microscopy, polarization imaging, or fluorescence microscopy.

Compensating for Eye Motion

In many cases, the signals acquired in a single video frame of an AOSLO are weak enough to warrant frame averaging to increase the signal-to-noise ratio (SNR) of the image (Figure 4(a)). Eye motion between frames, which is substantial in the high-magnification images of AO systems, must be corrected before frame averaging can be achieved. One correction method is to register successive frames with normalized cross-correlation, the benefit of which is shown in Figure 3(c). However, it is not uncommon for single frames, such as the one shown in Figure 4(a), to have inadequate SNR for this method. In the case, illustrated here of autofluorescence imaging by Jessica Morgan at the University of Rochester, there was typically less than

one photon for every 5 pixels in each frame. As shown in Figure 4(b), this problem can be solved by simultaneously recording infrared reflectance images of the cone mosaic at the same retinal location. Eye motion between frames can be reliably recovered from reflectance images of cone mosaic with an accuracy of one-fifth of the diameter of a foveal cone, and this information can be used to register the low SNR images as shown in Figure 4(b).

Eye movements can also produce warping artifacts within each frame. Austin Roorda and Scott Stevenson have developed methods in which the relative locations of local retinal features are compared across frames to compute and correct the eye movement warping within each frame as well as translation between frames. Figure 5 shows

an AOSLO image motion before and after removing distortions from eye movements. Image motion after correction is reduced to a standard deviation of only 7 arcsec. David Arathorn at Montana State University, working in collaboration with Austin Roorda, has a fast software algorithm that can stabilize the retinal image in real time. This has very exciting applications for delivering light stimuli to single photoreceptors in both psychophysical and electrophysiological studies. Software registration approaches alone cannot address all the problems created by eye movements, particularly in AO instruments designed for routine clinical use where eye movements are much larger than the size of a single frame. In that case, successive frames do not share common features and cross-correlation cannot be

Movement (arcmin)

Time (s)

used. Dan Ferguson and Dan Hammer at Physical Sciences Incorporated have developed a hardware eye tracking system specifically for AO retinal imaging that complements the software approaches described above.

Imaging Cones

The ability to image cones at high resolution with AO opened a crucial window to examine both normal and abnormal processes in the retina. AO has made possible the first measurements of the antenna properties of single cones in the living human eye. Cone photoreceptors concentrate the image-forming light that passes through the pupil in the photopigment of the outer segment while simultaneously excluding stray light from sources that do not contribute to a sharp retinal image. This beneficial effect of the waveguide nature of cones gives rise to the psychophysical effect known as the Stiles and Crawford effect, in which the sensitivity of the eye declines dramatically for light beams that enter the margin instead of the center of the pupil. Austin Roorda and David Williams at the University of Rochester showed that nearby cones are remarkably well aligned with each other optically so that the angular tuning of a large group of cones is similar to the tuning function for a single cone.

Single cones imaged with AO in the living human eye show a striking variability in reflectance on a time scale of hours or days. The cause of this variability is unknown but could be related to the process of disc shedding in the cone outer segments. Don Miller at Indiana University has shown that, especially when the incoming light is highly coherent, there can be dramatic changes on very short time scales of 5–10 ms. These changes depend on the history of the cone’s light exposure and provide an optical method to monitor to the response of cones to light. Kate Grieve and Austin Roorda have also reported increases in infrared reflectance following exposure to light that may provide an alternative method to monitor functional activity in single cones in the retina.

The Cone Mosaic and Color Vision

The first major scientific application of AO in the eye, undertaken at the University of Rochester, was to determine the organization of the human trichromatic cone mosaic. By combining AO retinal imaging with retinal densitometry, individual cones can be characterized by their sensitivity to long (L), middle (M), or short (S) wavelength light, according to the cone opsin it contains, as the example shown in Figure 6. Experiments using this method have shown that mosaic of L and M cones in the human are essentially randomly organized. It has been known for some time from indirect methods that the relative numbers of L and M cones varies greatly from eye to eye. AO revealed just how large this variation can be even across normal subjects where a variation in the order of 40-fold in L to M cone

1.25

Figure 6 Cone mosaic of a human subject at a retinal eccentricity of 1.25 degree with normal color vision. Individual cones in each mosaic were categorized as L, M, or S cone types, using retinal densitometry, and false colored, respectively in red, green, and blue. Courtesy of O. Masuda.

ratio has been observed. The human S cones are arranged randomly near the fovea but with slight tendency toward regular distribution, a tendency that is more pronounced in the macaque monkey.

The development of AO for the eye has also made it possible to study color vision in living human eyes in novel ways because it is now possible to deliver tiny flashes of light that are smaller than single cones. Heidi Hofer showed that near-threshold AO-delivered flashes of monochromatic light at a single wavelength produce a rich variety of color percepts. Indeed, for every subject she studied, the range of color experiences was too large to be explained by a simple model in which all cones of the same class produced the same color experience upon stimulation. David Brainard at the University of Pennsylvania has successfully described the range of color experiences in Heidi Hofer’s data with a Bayesian model in which each cone feeds a specific circuit that provides the best estimate of the external stimulus given the local distribution of photon catches in the stimulated cone and its surrounding neighbors.

One of the most powerful applications of AO to date involves its use to characterize the topography of the cone mosaic in eyes in which the genotype is known. Until recently, it has been difficult to perform these studies with standard histological methods because of the difficulty in obtaining post-mortem tissue from eyes with specific and often rare genetic anomalies. Joe Carroll has shown that the cone mosaics of single gene dichromats appear completely normal despite the fact that they have two instead of the usual three cone photopigments (Figure 7(b)). On the contrary, dichromats with a specific polymorphism in one of the genes coding for a particular cone photopigment have a cone mosaic with numerous gaps corresponding to a spatially random loss of one class of cones (Figure 7(c); also see Figure 8 for another example).

Imaging Retinal Pigment Epithelium

The retinal pigment epithelium (RPE) lies immediately behind the photoreceptors and plays several critical roles in maintaining their function. RPE cell damage is implicated in many retinal degenerative diseases such as agerelated macular degeneration, retinitis pigmentosa, and Stargardt’s disease. The ability to image these cells in the living retina and to track changes in them over time may prove valuable for understanding both normal RPE function and retinal disease. In AOSLO reflectance imaging, the more reflective photoreceptor mosaic normally obscures RPE cells. Occasionally, RPE cells can be seen in patients

with retinal degenerative diseases, such as cone–rod dystrophy, where the overlying photoreceptors are absent. However, it has recently become possible to image the RPE mosaic in living human eyes in which the photoreceptor layer is intact, by taking advantage of the autofluorescence properties of lipofuscin in the RPE as shown in Figure 4(c). Statistical characterization of the RPE mosaic, for example, packaging arrangement and cell density across eccentricity, in both normal subject and patients may eventually prove to be valuable for the clinical diagnosis of earlier stages of retinal degenerative disease. It may ultimately prove possible to use AO to image subcellular structures in RPE cells