Ординатура / Офтальмология / Английские материалы / Ocular Disease Mechanisms and Management_Levin, Albert_2010

1.Fauci AS, Dale DC, Balow JE. Glucocorticoid therapy: mechanism of action and clinical considerations. Ann Intern Med 1976;84:304–315.

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28.Costagliola C, Cati-Giovannelli B, Piccirillo A, et al. Cataracts associated with long-term topical steroids. Br J Dermatol 1989;120:472–473.

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chaperones. Mol Cell Endocrinol 2007;275:2–12.

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Overview

Presbyopia (from the Greek presbys, elder or old, and, -ops, eye) is a progressive condition where the ability to focus on nearby objects is gradually lost as part of the natural aging process. Although the development of presbyopia appears to begin in the second decade of life, it does not become a significant problem for most people until they reach their 40s, when it becomes increasingly difficult to read, sew, or use a computer without visual assistance. It is sometimes confused with far-sightedness because far vision remains relatively unaffected. However, although the eye’s far point of focus is not significantly altered, the near point (the closest comfortable focus) is gradually receding toward the far point, reducing the range over which clear focus can be attained. Although presbyopia is not lifeor visionthreatening, it nevertheless “represents a significant economic cost to society,” as reported by the National Eye Institute (http://www.nei.nih.gov/resources/strategicplans/ neiplan/frm_cross.asp). It also reduces quality of life and is a universal harbinger of middle age.

Clinical background

Key symptoms and signs

The range over which one can focus – one’s accommodative amplitude – declines throughout life. A small child has an accommodative range of 15–20 D (from infinity to about 5 cm, or the tip of one’s nose), while a young adult’s range is about 10 D (infinity to about 10 cm), reducing to less than 1 D (infinity to about 1 meter) by about 60. Thus diminution of the ability to focus on near objects is the hallmark of presbyopia. This loss becomes particularly apparent to individuals, generally in their 40s, in the process of performing familiar tasks. It may become more difficult to focus on print at normal reading distances, particularly at low light levels, or it may take a perceptible amount of time to shift focus from one distance to another, or prolonged close work might lead to eyestrain or headache (Box 34.1). When people complain that the print is suddenly too small or their arms are too short, they are likely becoming presbyopic.

Presbyopia

Jane F Koretz

Historical development

Why does presbyopia occur? It could be argued that the impact of presbyopia was moot for prehistoric hominids, since it is unlikely that their life span in general reached into their 40s, let alone their 50s. However, as will be discussed in more detail later, the changes in the anterior segment associated with visual aging lead specifically to the preservation of far focus at the expense of near. In terms of evolutionary pressure, it is possible that maintenance of distance vision was a survival advantage in spotting and avoiding predators, as well as in locating prey. Indeed, even in modern times, average human refraction around the world is roughly 1 D hyperopic.

Epidemiology

Because presbyopia is an integral part of the human aging process, its impact is theoretically universal once middle age has been reached. There appears to be no significant difference in the progression of the condition between males and females or among different human ethnic groups. What will differ is the apparent age of onset. Some of this difference arises simply from a natural Gaussian distribution of traits across the human population, and some from an individual’s lifestyle (e.g., web page designer versus national park ranger). For an emmetropic (20/20 or 6/6 visual acuity) eye, apparent onset is generally in one’s 40s and progresses until total loss of objective visual range by about 60. A subjective range of about 1 D, due largely to the pinhole effect (a constricted pupil providing an increased depth of focus), remains, but will clearly be dependent on the illumination intensity of ambient light. The impact of presbyopia will be different from emmetropes for those with refractive errors, with far-sighted (hyperopic) individuals more severely affected and near-sighted (myopic) individuals less so. For hyperopes, the location of their far point is further away than for emmetropes, and their most comfortable near point will also be further away for a given age. As a result, their ability to focus on nearby objects will be diminished at an earlier age, and the apparent onset of presbyopia may be in their late 30s or even earlier. In contrast, myopes have a far point that tends to be nearby, so their receding near point does not lead to the functional visual loss experienced by their emmetropic and hyperopic friends. As a consequence, many

Box 34.1  Symptoms of presbyopia

•Age

•Decrease in ability to focus nearby

•Increase in comfortable reading distance

•Eyestrain

•Headaches after prolonged focus

•Trouble focusing when tired or stressed

•Slow response to change in focus distance

•Need for increased illumination

presbyopic myopes find themselves needing additional optical assistance only for distance viewing (e.g., driving); this “myopic advantage” is lost when invasive procedures like laser in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK) have previously been used for refractive correction.

Diagnostic workup

Diagnosing presbyopia is straightforward, especially since many patients diagnose themselves. A person’s age is of course a major consideration, since it is the primary risk factor. Symptoms will include the gradual onset of several of the following: decreased ability to focus on nearby objects; increase in comfortable reading distance (“arms too short”); eyestrain; headaches after prolonged visual tasks; trouble focusing when tired or stressed; slow visual response to a change in focus distance; and need for increased illumination. Further assessment can be incorporated into a standard eye exam, which may identify additional potential contributory factors. A simple reading test using well-illuminated text of graded sizes at a standard distance (e.g., 35 cm or 14 inches) can be helpful both in characterizing the degree of near-vision loss and in determining the appropriate refractive correction.

Differential diagnosis

Although presbyopia is generally an easily identified condition, there are nevertheless other potential factors affecting changes in visual range that must be considered and eliminated. These factors can include nuclear cataract development, untreated diabetes, central nervous system disorders, macular degeneration, and migraines. In general, a thorough refractive history combined with a standard ophthalmic examination that includes slit-lamp biomicroscopy and inspection of the retina should serve to eliminate most of these possibilities. Presbyopia can also be confused with hyperopia when a subject’s refractive history is unknown; however, hyperopia in an adult over 35 would be indistinguishable from presbyopia, and would be treated as such.

Treatment

Because of the universality of presbyopia in older individuals, there are many different options available for mitigating its effects. Historically, the very first contribution to the treatment of presbyopia was developed in 1784, when Benjamin Franklin combined two pairs of glasses – one for distance

Physiology and pathophysiology

vision and one for close work – into the first set of bifocals (bifocles). Reading glasses, bifocals, progressives, and even trifocals, remain the most common methods for providing one or more different comfortable refractive distances for eyes that can no longer focus on near objects, and are the most versatile option for a visual system that continues to change from the onset of presbyopia into the 60s. It is possible for presbyopes to test out and buy their own reading glasses from a pharmacy or supermarket; if both eyes have similar or identical refractions, this is a reasonable if limited strategy for the long term. However, if there are significant differences between the two eyes due to refractive or other differences, or if there are special visual requirements (e.g., sustained focus on a computer monitor) it becomes important to have glasses or other optical prostheses professionally prescribed.

A second set of options involves contact lenses. There are a growing number of different designs of contact lenses available for presbyopes, either bifocal (one refractive range within the circumference of a second) or multifocal (simultaneous images at two or more different refractive powers), which have received a mixed response from users. An additional alternative is monovision contact lenses, where the refractive correction for one eye is set for focus at a distance and the other for focus nearby; although the image received by each eye is clear, the concomitant loss of depth perception has a vertiginous effect which some people cannot overcome. A general drawback to the use of contact lenses for presbyopia is the decrease in tear production with increasing age in the target population, but, like glasses, an advantage is that a change in prescription is easy to do.

A third set of alternatives involves direct alteration of the visual system. These currently include monovision through LASIK, conductive keratoplasty, or other procedures altering corneal shape (and thus refractive power), and scleral relaxation and scleral expansion surgeries. The same problem as experienced in contact lens-mediated monovision – loss of depth perception – is a consequence of surgical monovision, so it is important to ensure that this can be tolerated before the procedure is performed. Modifying scleral shape has not been very successful up to this point in treating presbyopia, although it continues to have its fervent advocates and detractors. In development are methods for altering lens properties in situ using laser techniques or replacement of the natural lens with an intraocular lens implant that restores accommodation. These and other novel approaches for the treatment of presbyopia and restoration of accommodative range continue to be designed, developed, and tested, and it is likely that effective new options for treatment will be available within the next decade (Chapter 35).

Physiology and pathophysiology

Introduction

Image formation by the human eye involves refractive contributions from both the cornea and the crystalline lens, with the cornea a passive component and the lens and associated structures an active contributor. In order to understand presbyopia, which is a natural consequence of the aging process, it is first necessary to understand accommodation, the mech-

anism by which this focusing is effected, and the age-related changes in this mechanism that are associated with loss of accommodative amplitude.

Accommodation

The human focusing mechanism is the subject of qualitative, if not quantitative, agreement.1 Focus on points closer than infinity (for the human eye, about 6 meters or 20 feet) involves an increase in the sharpness of curvature of the crystalline lens surfaces, an increased thickening of the lens along the optical axis, a shallowing of the anterior chamber, and essentially no change in the distance from the cornea to the posterior lens surface along the axis (Box 34.2). This process was, in essence, first described in the 19th century by Helmholtz (Figure 34.1) in his Treatise on Physiological Optics, although Helmholtz was certainly not the first to develop hypotheses about the mechanism. It is the causative factors through which these alterations in lens shape, thickness, and position relative to the cornea occur that are the subject of intense debate,2–12 and that lead to presbyopia.

The crystalline lens is located in the anterior segment of the eye behind the iris, suspended in place by the zonules of Zinn (Figure 34.2), which connect the lens to the ciliary muscle through insertions into the collagenous lens capsule surrounding the lens fiber cells.13 Light enters the eye through the cornea, which provides the major refractive component of the system, due in part to its small radius of curvature and to the comparatively large increase in refractive index in going from air to the cornea. The light emerging from the posterior surface of the cornea, after passing through the circular slit of the iris, arrives at the lens, which provides a variable refractive contribution to the system (Figure 34.3). When focused at infinity, the lens is at its flattest and thinnest along the optical axis, while the ciliary muscle is relaxed; closer focus involves a carefully controlled relaxation of the forces acting upon the lens, coupled to ciliary muscle contraction, and allows the lens to “round up” and increase its refractive contribution (Figure 34.4).

Modern versions of the helmholtzian model of accommodation directly couple ciliary muscle contraction, and its shift of net muscle mass anteriorly and inward, with lens elastic recovery and net anterior movement of lens mass.12,14 In contrast, modern versions of the classic hydraulic theory, such as that proposed by D Jackson Coleman,3,15,16 suggest that ciliary muscle contraction exerts a force on the choroid, which in turn generates an increased pressure through the

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B

Figure 34.1  (A) Helmholtz drawing demonstrating his theory of accommodation. The left half of the image shows relaxed accommodation. The right half shows the increase in lens thickness and decrease in equatorial diameter after ciliary muscle contraction. (B) A composite of two magnetic resonance imaging (MRI) images. The left half is an image acquired with relaxed accommodation, while the subject, a young

adult, views a far target. The right half is an image acquired during accommodation, while the subject views a near target. It shows an increase in lens thickness and a decrease in equatorial diameter upon ciliary muscle contraction. (Reproduced with permission from Strenk SA, Strenk LM, Koretz JF. The mechanism of presbyopia. Prog Retin Eye Res 2005;24:379–393.)

Figure 34.2  Retroilluminated image/schematic representation of the crystalline lens in the anterior segment, viewed perpendicular to its axis of symmetry. The lens is suspended within the circle of the ciliary muscle by fibers of the zonular apparatus, which serves to connect the lens capsule and muscle. (Modified from Koretz JF, Handelman GH. How the human eye focuses. Sci Am 1988;256:92–99.)

vitreous that alters lens shape by deforming the anterior hyaloid membrane; the latter acts something like a diaphragm, separating anterior and posterior segments, cradling the posterior of the lens, and being forced in an anterior direction when the vitreous-chamber pressure is

Ciliary body

Zonules Retina Cornea

Lens

Vitreous body

Figure 34.3  Schematic of image formation by the human eye. Light at the air–cornea interface is refracted inward, passing through the biological aperture of the iris before being further refracted through the crystalline lens to focus on the fovea. (Modified from Koretz JF, Handelman GH.

How the human eye focuses. Sci Am 1988;256:92–99.)

B D

Figure 34.4  When a change of focus from far to near occurs, the lens exhibits very specific changes in shape. Its thickness increases, its equatorial diameter decreases, and its surface curvature, particularly on the anterior, becomes sharper. These changes are due to the contraction of the ciliary muscle ringing the lens equator; reduction of the diameter of the ciliary ring relaxes the zonular force acting on the lens, resulting in it “rounding up” and leading to a decrease in anterior-chamber depth. Change of focus from near to far reverses these changes, as ciliary muscle relaxation leads to increased force acting on the lens. (Modified from Koretz JF, Handelman GH. How the human eye focuses. Sci Am 1988;256:92–99.)

increased. Aside from this force application in the hydraulic theory, the other role that the ciliary muscle would play is to maintain lens position within the anterior segment. While a preponderance of data appears to support a helmholtzian representation of accommodation, it has also become evident that the support of the vitreous is a critical factor.17 A third model of accommodation18–20 suggests that ciliary

Physiology and pathophysiology

muscle contraction is coupled with increased equatorial zonular tension on the lens, and that presbyopia is the result of loss of the capacity to alter this tension. This model serves as the basis for the scleral expansion and scleral relaxation procedures mentioned earlier, but remains controversial because there is little or no independent verification for it.

The crystalline lens

The lens itself is not the ideally deformable material molded by changes in capsular shape, as originally suggested by Helmholtz and successors. In fact, the human lens is an intricate and highly organized structure (Figure 34.5) that grows throughout life.21–26 New lens fiber cells differentiate from the single layer of epithelial cells found on the anterior lens surface, gradually elongating to as much as 2 mm and becoming integrated with other lens fiber cells into a flattened hexagonal packing with interconnections between each fiber cell and its six nearest neighbors. These fiber cells gradually lose their nucleus, organelles, and other inclusions while maintaining cellular protein concentrations in excess of 300 mg/ml. Such high concentrations are required of any protein solution exhibiting a significant increase in refractive index over water. Proteins that are soluble in such high concentrations and exhibit transparency in the visible spectrum under these conditions and maintain these characteristics for decades are extremely rare. An additional property of these highly concentrated solutions is that they are quite viscous. Combining the tight packing of the lens fiber cells with their viscous contents and inability to slide past each other, it is no surprise that any model of accommodation at the cellular level must involve a redistribution of material within each cell, leading to an alteration in lens fiber curvature.

Recent work by Kuszak and colleagues27,28 has illustrated this process directly (Figure 34.6). They were able to show that the lens fiber cells are S-shaped in situ, and that they become “straighter” with accommodation, like a spring being released; this also results in the interleaved ends of the fiber cells separating from each other. This dynamic change in shape provides the ultrastructural basis for a rational explanation of lens elastic recovery, with potential energy stored in the nonaccommodated, flattened coils and released as the lens rounds up during accommodation. Thus, the lens fiber cells, individually and in combination, provide the conceptual link between the molecular (viscoelastic and optical) properties of the lens cytoplasm and its biomechanical and optical response at the whole-lens level to an accommodation stimulus.

Over the course of time, the lens undergoes specific changes which affect both its refractive capabilities and its viscoelastic (material) capacity for undergoing a change in overall shape (Figure 34.7). At the organ level, these changes have been most clearly delineated for the adult years (18–70 years). During this time the central region of the lens becomes more deeply embedded within the steadily growing lens, and the lens increases in volume and thickness with age.29–32 This increase in thickness is uneven between the anterior and posterior, due to differences in the shape of the lens fiber cells in each region, but linear with time. Because the lens equatorial diameter remains essentially constant during this period and the distance from the cornea to the

lens posterior remains constant, the additional lens mass appears along the sagittal axis and leads to a steady diminution of anterior-chamber depth.33,34

At the subcellular and supramolecular levels, there are equivalent age-dependent processes occurring, some of which have been characterized. The highly concentrated solutions of lens proteins, primarily the lens crystallins, functionally contribute to the lens’s heightened refractive index gradient. These proteins undergo a series of posttranslational modifications over time which may be associated with their longevity.35,36 In the aging of the prepresbyopic eye, there is a slow, linear reduction in lens transparency31

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due to lens discoloration and other chemical changes, and, more significantly, lens crystallin superaggregate formation; the latter process also contributes to an increased degree of glare, increasing night blindness, and decreasing contrast sensitivity. The rate at which these processes occur is very low, but they nevertheless affect the ability of the lens to act as a light refractor.

The increasing graininess of the lens fiber cell cytoplasm, combined with an increasing amount of superaggregated soluble and insoluble material, leads to a decreased refractive index related to the rate at which these processes occur.37–40 At the same time, the lens surfaces are becoming

more sharply curved due to the continuing addition of new lens fiber cells.32,41,42 Normally, one would expect that, with more sharply curved surfaces, the refractive power of the lens would increase, which would suggest that the ability to see far objects should be reduced with age, and not nearby ones. Indeed, the preservation of far vision at the expense of near despite the shape of the mature lens is the basis of Brown’s “lens paradox.”43 This paradox is resolved by the fact that the gradual reduction in lens refractive power due to molecular aging processes seems almost exactly to balance the increase in the sharpness of lens curvature. In reality the balance

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between these two opposing trends is slightly uneven,44,45 leading to a slight hyperopic increase of about 1 D, an additional aspect of the “myopic advantage.”

In the postpresbyopic lens, these degenerative processes at the molecular level show an increase in rate. This change has been modeled either as bimodal or exponentially increasing, but whichever is used to fit the data, the critical change in slope occurs in the same decade that presbyopia becomes a significant factor in visual function. It has been suggested that the increase in the rate of these processes is due to the inability of the lens to be reshaped through the

Box 34.3  Anterior segment and lens aging

•Increased sagittal lens thickness results from continued addition of lens fiber cells, thus, increased lens volume

•Constant equatorial diameter after 18–20 years old

•Constant anterior-segment length; thus, increased lens thickness balanced by decreased anterior-chamber depth

•Increased sharpness of lens curvature, especially the anterior surface

•Anterior shift of lens center of mass

•Anterior shift of uveal tract

•Decreasing lens transparency

•Increased resistance to lens deformation; factors include increased lens mass, decreased lens elasticity, and change in three-dimensional lens muscle orientation

accommodative mechanism, leading to a reduction in the efficiency of cytoplasmic “mixing” and the reliance solely on diffusion to establish and maintain chemical equilibrium throughout the lens. It is also likely that the increasing amounts of large soluble and large insoluble particles in the lens cytoplasm will affect the viscoelastic properties of the lens,46–48 making it harder for cytoplasm to flow within the lens fiber cells and thus for lens reshaping to occur; even if it is possible for flow to occur, however, the presence of larger particles will increase both the resistance to flow and the time-dependent response to an applied stress. Thus, events at the molecular and subcellular levels, along with the overall tissue changes that occur with age,49,50 can affect both the range of the accommodative process and the rate at which it takes place (Box 34.3).

The development of presbyopia

In order to understand the basis of presbyopia, a number of biometric studies looking for correlations between accommodative range and changes in the anterior of the eye with age have been performed. Table 34.1 provides two lists: factors that are independent of age and those that are agedependent. Many variables associated with the lens, such as thickness, anterior and posterior central radii of curvature, and center of mass, change significantly as a function of age. Other variables showing age dependence are less explicitly associated with the lens, such as the placement of the ciliary muscle and zonular apparatus within the anterior of the eye, but will nevertheless affect the overall geometry of the system. Of course, correlation does not prove causation, but combining many of these trends together leads to models that lay the blame for presbyopia primarily on the lens. One such is the geometric model of presbyopia, formulated by Koretz and Handelman1,12,51 on the basis of these and other biometric results combined with biomechanical modeling studies. Accommodation, according to this model, is helmholtzian, and is the result of changes in the magnitude and direction of forces applied by the ciliary muscle to the lens through the zonular fibers attached to the capsule enclosing the lens. Changes in lens shape are due to its inherent ultrastructure, since the discrete forces applied by the zonules to the capsule are evenly redistributed by its elastic properties into largely normal (perpendicular to the surface) forces. With increasing age, lens mass and thickness increase, but

Physiology and pathophysiology

Table 34.1  Testing the correlation between elements of the visual system and the development of presbyopia

The basic envelope – the globe and its divisions – remains essentially unchanged with age, but the geometry of the anterior segment and the properties of its components are altered

Age-independent factors

•Globe length

•Vitreous-chamber depth

•Anterior-segment length

•Corneal refractive power

•Lens equatorial diameter

Age-dependent factors

•Accommodative amplitude

•Anterior-chamber depth

•Lens thickness

•Lens refractive index gradient

•Lens shape

•Lens center of mass

•Lens transparency

•Lens elastic response

•Ciliary body/uveal tract geometry in anterior segment

•[Zonule and/or capsule material properties?]

Figure 34.8  Changes in the anterior segment with age illustrated with high-resolution in vivo magnetic resonance imaging of two

nonaccommodated lenses from subjects aged 26 (left) and 49 (right). Lens thickness, mass, and overall shape will change considerably, and the anterior chamber becomes shallower. Note that the ciliary muscle location relative to the cornea and lens is shifted with age as well, providing additional support for the geometric theory. (Reproduced with permission from Strenk SA, Strenk LM, Koretz JF. The mechanism of presbyopia. Prog Retin Eye Res 2005;24:379–393.)

the posterior lens surface along the optical axis remains about the same distance away from the cornea (vitreouschamber depth is constant), resulting in a net anterior movement of lens mass. At the same time, the zonular insertions into the capsule remain in the same location relative to the

Box 34.4  Aging of accommodation

•Increasing sharpness of curvature of all lens boundaries

•Changes in lens anterior, including thickness and curvature, greater than posterior

•Decreasing overall lens power

•Loss of accommodative range, as near point approaches far point

•Reduction in steepness of lens gradient refractive index compensating for increased lens sharpness of curvature nearly exactly (solution to “Brown’s lens paradox”)

•Change in lens geometry relative to ciliary body, uveal tract

•Changes in ciliary body geometry

optical axis, so that the geometric relationship between the muscle, the lens, and the zonules gradually changes, and the effective mechanical advantage of the system is gradually lost (Figure 34.8). That a change in the ciliary muscle location within the anterior segment also occurs may well be due to lens growth and the concomitant application of a distorting force on the muscle to relieve extra stress; interestingly, when the lens is removed, as in cataract surgery, the ciliary muscle bounces back to its original, youthful location. This model does not explicitly require increased lens stiffness to explain presbyopia, but it is clear that such a process would be consistent (Box 34.4). Other recent models of human accommodation and presbyopia are also primarily lens-based,12,52–54 which strongly implies that age-dependent changes in the lens and lens-associated structures directly affect loss of accommodative amplitude.

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2.Koretz JF, Handelman GH. Model of the accommodative mechanism in the human eye. Vision Res 1982;22:917– 927.

3.Coleman DJ. Unified model for accommodative mechanism. Am J Ophthalmol 1970;69:1063–1079.

4.Koretz JF, Handelman GH. A model for accommodation in the young human eye: the effects of lens elastic anisotropy on the mechanism. Vision Res 1983;23: 1679–1686.

12.Strenk SA, Strenk LM, Koretz JF. The mechanism of presbyopia. Prog Retin Eye Res 2005;24:379–393.

14.Fisher RF. The mechanics of accommodation in relation to presbyopia. Eye 1988;2:646–649.

25.Kuszak JR, Zoltoski RK. The mechanism of accommodation at the lens fiber level.

In: Ioseliani OR (ed.) Focus on Eye Research. Hauppage, NY: NovaScience, 2006:117–133.

29.Brown N. The change in lens curvature with age. Exp Eye Res 1974;19:175– 183.

32.Koretz JF, Cook CA, Kaufman PL. Aging of the human lens: changes in lens shape at zero-diopter accommodation. J Opt Soc Am A Opt Image Sci Vis 2001;18: 265–272.

33.Strenk SA, Semmlow JL, Strenk LM, et al. Age-related changes in human ciliary muscle and lens: a magnetic resonance imaging study. Invest Ophthalmol Vis Sci 1999;40:1162–1169.

34.Strenk SA, Strenk LM, Guo S. Magnetic resonance imaging of aging, accommodating, phakic, and pseudophakic ciliary muscle diameters. J Cataract Refract Surg 2006;32:1792– 1798.

38.Moffat BA, Atchison DA, Pope JM. Age-related changes in refractive index distribution and power of the human lens as measured by magnetic resonance micro-imaging in vitro. Vision Res 2002;42:1683–1693.

43.Koretz J, Handelman GH. The lens paradox and image formation in accommodating human eyes. In: Duncan G (ed.) The Lens: Transparency and Cataract. Rijswijk: EURAGE, 1986: 57–64.

45.Koretz JF, Cook CA. Aging of the optics of the human eye: lens refraction models and principal plane locations. Optom Vis Sci 2001;78:396–404.

53.Gerometta R, Zamudio AC, Escobar DP, et al.Volume change of the ocular lens during accommodation. Am J Physiol Cell Physiol 2007;293:C797–C804.