Themechanismofpresbyopia ARTICLEINPRESS

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Progress in Retinal and Eye Research 24 (2005) 379–393

The mechanism of presbyopia

Susan A. Strenk

^a

, Lawrence M. Strenk

^b

, Jane F. Koretz

^c,

aDepartment of Surgery, Robert Wood Johnson Medical School—University of Medicine and Dentistry of New Jersey, Piscataway, NJ 08855, USA

bMRI Research, Inc., Cleveland, OH 44130, USA

cBiochemistry and Biophysics Program, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY 12180-3590, USA

Abstract

Accommodation in humans refers to the ability of the lens to change shape in order to bring near objects into focus.

Accommodative loss begins during childhood, with symptomatic presbyopia, or presbyopia that affects one’s day to day activities, striking during midlife. While symptomatic presbyopia has traditionally been treated with reading glasses or contact lenses, a number of surgical interventions and devices are being actively developed in an attempt to restore at least some level of accommodation. This is occurring at a time when the underlying cause of presbyopia remains unknown, and even the mechanism of accommodation is occasionally debated. While Helmholtz’ theory regarding the mechanism of accommodation is generally accepted with regard to broad issues, additional details continue to emerge. Age-related changes in anterior segment structures associated with accommodation have been documented, often through in vitro and/or rhesus monkey studies. A review of these ﬁndings suggests that presbyopia develops very differently in humans compared to non-human primates. Focusing on non-invasive in vivo human imaging technologies, including Scheimpﬂug photography and high-resolution magnetic resonance imaging (MRI), the data suggest that the human uveal tract acts as a unit in response to age-related increasing lens thickness and strongly implicates lifelong lens growth as the causal factor in the development of presbyopia.

Contents

1. Introduction . . . 380

2. Aging and the uveal tract . . . 382

3. Aging and the lens . . . 384

3.1. Lens growth . . . 384

3.2. Lens mechanics . . . 388

4. Lens growth and the uveal tract . . . 389

5. The Modiﬁed Geometric Theory of presbyopia development . . . 390

6. Conclusion . . . 391

Acknowledgement . . . 391

References . . . 391 www.elsevier.com/locate/prer

doi:10.1016/j.preteyeres.2004.11.001

Corresponding author. Tel.: +1 518 276 6492; fax: +1 518 276 2344.

E-mail address: koretj@rpi.edu (J.F. Koretz).

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1. Introduction

Theories regarding the mechanisms of accommodation and presbyopia date back to the 17th century and earlier, and have been extensively reviewed in several articles and chapters (Cramer, 1853; Helmholtz, 1855, 1924; Fincham, 1937; Weale, 1992; Atchison, 1995;

Schneider et al., 2001). Rather than an exhaustive discussion, an overview is presented here to show how ideas about these processes evolved. Descartes (1677) correctly attributed accommodation to changes in lens shape, with lens curvature increasing in order to permit viewing of near objects. He lacked experimental evidence to support his hypothesis and believed that the change in lens shape was caused by the ﬁbers that suspend the lens. Experimental evidence was provided by Cramer (1853); by observing Purkinje images, he qualitatively described an increase in anterior lens curvature in response to accommodation. He imagined ciliary muscle and iris contraction to bring about this increase in anterior lens curvature; the ciliary muscle by acting on the choroid which in turn acts upon the vitreous and thus the lens and iris by directly acting upon the anterior lens surface (Fincham, 1937).

Helmholtz, also utilized Purkinje images, but recognized that the zonules play a key role in accommodation.

Helmholtz described ciliary muscle contraction as causing a reduction in zonular tension that allows the crystalline lens to increase its curvature, decreasing its equatorial diameter while increasing its thickness; he supported his theory with evidence and provided a mathematical treatment (Helmholtz, 1855, 1924).

Tscherning (1895) vigorously challenged Helmholtz’

theory, suggesting essentially the complete opposite:

that ciliary muscle contraction causes an increase zonular tension and thus during accommodation the zonules push the plastic lens cortex around the rigid nucleus to change lens shape – no change in lens thickness occurs (Tscherning, 1895; Fincham, 1937;

Schneider et al., 2001). In 1909, Tscherning was forced to concede that lens thickness increases with accommodation and introduced a second theory that nonetheless relied on increasing zonular tension in response to ciliary muscle contraction (Tscherning, 1909). This same year, Gullstrand expanded Helmholtz’ mechanism of accommodation to include the elastic force of the choroid as the restoring force to ciliary muscle contraction (Gullstrand in Helmholtz, 1924). In 1932, Pflugk modified Tscherning’s theory, finding it necessary to envision a role for the vitreous and the iris as well as anterior chamber pressure in order to explain how increasing zonular tension might account for accommodative increase lens curvature (Pflugk, 1932;

Fincham, 1937; Schneider et al., 2001). In 1937, Fincham described the role of the elastic lens capsule in accommodation. Coleman’s hydraulic suspension

theory, introduced in 1970, describes the vitreous as applying a force producing a change in catenary shape for the posterior lens surface leading to changes in anterior lens curvature (Coleman, 1970).

While studying the accommodative mechanism in humans has been hampered by difﬁculty visualizing the ciliary muscle and lens periphery in-vivo, the over- whelming weight of scientiﬁc evidence has long favored a Helmholtzian explanation of accommodation with regard to broad issues (although there still remain proponents of a Tscherning-type mechanism in which it is supposed that both the lens equator and zonular tension increase upon accommodation (Schachar, 1992);

this theory was later modiﬁed to specify equatorial zonular tension (Schachar et al., 1996)). As early as 1909 Gullstrand, citing anatomical and physiological studies, wrote, ‘‘it is doubtful if there is a more complete chain of proof in all of medical science. Modern investigators have established that the theory of the mechanism of accommodation remains unchanged, in all essential features, just as Helmholtz, by a real inspiration of genius, considering the state of knowledge at the time, conceived it’’ and of Tscherning, ‘‘Tscherning says the

‘hypothesis’ of Helmholtz appears no longer tenable;

yThe only conclusion that can really be drawn from this statement is, that the cause of this lack of comprehension must be sought either in the ‘hypothesis’

of Helmholtz or in Tscherning himself’’ (Gullstrand in Helmholtz, 1924). Gathering of direct, in-vivo evidence from human subjects has been hampered by the presence of the iris; nonetheless a handful of unique cases have provided support for the Helmholtz theory of accommodation. In 1937, Fincham published ﬁndings obtained from a slit-lamp study of accommodation in a 22 year old man, who had lost his iris through trauma. This case of aniridia provided a unique opportunity to record accommodative changes in the lens periphery and ciliary processes, which are otherwise shielded from view by the iris and Fincham was able to show that accommodation produced a decrease in the diameter of both the ciliary processes and lens equator and an increase in lens thickness. In 1997, retro-illumination infrared video photography of a young albino subject indicated that the lens equator is reduced upon accommodation (Wilson, 1997). More recently, the case of a 19 year old albino provided a similar opportunity to utilize optical coherence tomography (OCT) to observe potions of the anterior segment during accommodation; this would not have been possible in a normal eye as the pigment epithelium of the iris blocks the light source’s wavelength. While the lens equator could not be visualized, observations of lens thickness, curvature and ciliary body diameter supported the Helmholtz theory of accommodation (Baikoff et al., 2004). Direct, statistically signiﬁcant, support for the Helmholtz theory of accommodation, obtained from in-vivo studies

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of accommodating subjects with intact, normal eyes, has been recently provided by Strenk and colleagues using high-resolution MRI (Strenk et al., 1999, 2004a). This method is unique in providing direct and simultaneous visualization of the ciliary body, ciliary muscle and the entire lens in the intact human eye and conclusively demonstrates what Helmholtz stated 150 years ago:

‘‘yif the pull of the zonule is relaxed in accommodation for near vision, the equatorial diameter of the lens will diminish, and the lens will get thicker in the middle, both surfaces becoming more curved’’. Fig. 1 includes both Helmholtz’ drawing illustrating his theory of accommodation, and a corresponding MR image.

While Helmholtz’ theory regarding the basic mechanism of accommodation has attained near universal support, the same cannot be said about his theory regarding the cause of presbyopia. Certainly Helmholtz’

suggestion that lens sclerosis (or more broadly, lens mechanical changes) causes presbyopia has received some attention (Helmholtz, 1855); nonetheless, a number of age related changes occur in both the lenticular and extra-lenticular accommodative structures and the causal factors of age-related accommodative loss leading to presbyopia remain undeﬁned. Donders (1864) suggested that presbyopia occurs because the ciliary muscle is unable to shorten. The Tcherning-Pluugk theory, put forth in 1909, attributes accommodative loss to reduced movement and ﬂuidization of the vitreous (Schneider et al., 2001; Fincham 1937). Fincham (1937) believed reduced capsular elasticity to be responsible for accom-

modative loss. In time two mutually exclusive theories evolved to explain the onset of presbyopia: the Duane- Fincham or lenticular theory and the Hess-Gullstrand theory or extra-lenticular theory. These two theories, have been discussed in detail and are only concerned with the relationship between ciliary muscle contraction and lens response (Stark, 1988; Atchison, 1995);

consequently, each may well represent an oversimpliﬁ- cation of the mechanisms involved in the etiology of presbyopia. Noting that most of the accommodative structures show age-related changes, Weale (1989) suggested that the cause of presbyopia is multifactorial.

Koretz and Handelman (1988) similarly envisioned a more complex mechanism involving age related changes in the geometric relationship between the lens and surrounding accommodative structures, resulting from lens growth. They proposed lens growth as the causal factor in the development of presbyopia, with mechanical changes in the lens material described as an effect rather than a cause of presbyopia. In 1992, Bito and Miranda proposed that a loss of choroidal elasticity prevents the ciliary muscle from returning to its rest state; essentially presbyopia is then a loss of disaccom- modative ability.

Much of the controversy and confusion regarding the mechanisms of both accommodation and presbyopia has resulted from the difficulty of fully visualizing the accommodative structures in vivo in the intact human eye. Specifically, the iris prevents direct visualization of the ciliary muscle and the lens periphery by screening this region from optical methods of visualization; these methods are further complicated by the refractive power of the cornea, which distorts imaging of the remainder of the lens. Nonetheless, Koretz and colleagues have employed Scheimpflug slit-lamp photography, a non- invasive optical imaging technique, in conjunction with appropriate optical correction algorithms, to provide a wealth of information on lens development and aging in accommodating human subjects (Cook and Koretz, 1998;Cook et al., 1994;Koretz et al., 1984, 2001, 1994).

Ideally, accommodative changes in the intraocular structures of the anterior segment need to be simulta- neously visualized within the same eye, preferably in the absence of pharmacological agents; this was not possible until recently, when Strenk and colleagues (1999) developed high-resolution MRI techniques and instrumentation for in-vivo imaging of the anterior segment.

While this method is limited in both spatial and temporal resolution, it offers unsurpassed soft tissue contrast, greatly exceeds the spatial resolution of traditional MRI, is free of optical distortions, and thus permits visualization of the entire undistorted human lens and its relationship to the iris, ciliary body and ciliary muscle in any desired imaging plane and without the need to disturbthe uveal tract either by iridectomy or by the use of pharmacological agents. Scheimpﬂug

Fig. 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 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.

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imaging offers even higher spatial resolution images, differentiates the lens capsule from the lens material, and yields detailed information on lens internal anatomy and its response to both age and accommodation.

Scheimpﬂug and MRI are thus two powerful and complementary imaging technologies that have been cross-validated, as measurements obtainable with both modalities are statistically equivalent (Koretz et al., 2004). The capability of combining these two non- invasive in vivo imaging techniques to bring further scrutiny to bear on the aging human lens and its relationship to the surrounding accommodative structures offers the promise of ultimately establishing the mechanisms of both presbyopia and accommodation, as well as providing needed information regarding the outcome of surgical interventions designed to restore accommodation. A comparison of an MRI image and a Scheimpﬂug image is provided inFigs. 2 and 3.

2. Aging and the uveal tract

The middle layer of the eye, or uveal tract, consists of the choroid, the ciliary body, the iris, and its central opening, the pupil. These structures are continuous and act as a unit in response to forces applied by both age- related lens growth and accommodative lens thickening in humans, with the pupillary margin serving to link lenticular changes to anterior and inward uveal tract displacement (Strenk et al., in preparation). At one time it was believed that age-related changes in ciliary muscle

contraction could be the cause of presbyopia. Indirect evidence for this theory was obtained by examining accommodative amplitude in response to pharmacological stimulation of the ciliary muscle (Duane, 1909, 1925;Fincham and Walton, 1957;Eskridge, 1984). Such studies are problematic as drugs affect the iris and the ciliary muscle, thus depth of focus as well as the direct effect of iris contraction on the amplitude of accommodation will complicate the results. More recent microscopy studies of ﬁxed samples, demonstrate that the human ciliary muscle develops more connective tissue with age and in different regions (Tamm et al., 1992b; Pardue and Sivak, 2000) as compared to the rhesus ciliary muscle (Lutjen–Drecoll et al., 1988). These studies also suggested that human ciliary muscle atrophy may occur in post-presbyopic subjects; however, this is likely an effect of presbyopia, rather than a cause, since signiﬁcant increases in connective tissue do not appear to occur in subjects still capable of accommodation.

Additionally, accommodative amplitude begins to decline during childhood, long before muscle atrophy would be expected (Borish, 1975). Studies using impedance cyclography, an in vivo albeit indirect method, suggest that ciliary muscle function does not decrease with age in humans (Swegmark, 1969;Saladin and Stark, 1975).

The high-resolution MRI technique (Strenk et al., 1999) is the only modality that allows distinct and simultaneous visualization both of the ciliary muscle and the surrounding ciliary processes in the intact human eye; the ciliary processes are responsible for

Fig. 2. The Scheimpﬂug image of a 42 year old subject. (FromKoretz et al., 2004, reprinted courtesy of the Optical Society of America.)

Fig. 3. The MRI image of a 42 year old. (FromKoretz et al., 2004, reprinted courtesy of the Optical Society of America.)

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secreting aqueous humor and appear more intense than the ciliary muscle in the MR image (Fig. 3). The accommodative and age-related behavior of the ciliary processes does not track that of the muscle. The accommodative change in the diameter of the rather amorphous ciliary processes is far less than that of the muscle and, unlike the ciliary muscle, the diameter of the ciliary processes does not appear to decease with advancing age (Strenk et al., 2000). Consequently, caution must be used when interpreting data from ultrasound based techniques that visualize primarily the ciliary processes and attempt to extrapolate these ﬁndings to the muscle. MRI studies of subjects ranging in age from 22 to 83 show no statistically signiﬁcant age- related change in ciliary muscle contraction (as indicated by a decrease in ciliary muscle diameter with accommodation), although the existence of a possible trend toward a minimal age-related decrease in ciliary muscle contraction might be argued (Strenk et al., 1999).

Nonetheless, the collection of additional data, with an expansion of the age range to 91, provides clariﬁcation:

no age-dependent change in ciliary muscle contraction occurs (Strenk et al., in preparation). In stark contrast, in vitro microscopy studies of rhesus monkeys ciliary muscle reveal decreased contractile response to pharmacological stimulation with advancing age (Lutjen-Dre- coll et al., 1988). Subsequent studies reveal that this decline in ciliary muscle response is likely due to decreasing choriodal compliance rather than an inability of the muscle to contract (Tamm et al., 1991, 1992a) as muscle mobility is restored if its posterior (choriodal) attachment is disrupted. The researchers speculate,

‘‘decreased compliance of the posterior insertion of the ciliary muscle could be an essential factor for presbyopia in rhesus monkeys’’ (Tamm et al., 1991) and it is

‘‘sufﬁcient to explain presbyopia in this species, without invoking any other age-related alterations in the ciliary neuromuscular function or lenticular elasticity’’ (Tamm et al., 1992a).

Although loss of ciliary muscle mobility due to choroidal changes appears to play a signiﬁcant role in the development of presbyopia in monkeys, this does not appear to be a factor in human presbyopia. MRI studies provide deﬁnitive evidence that the human ciliary muscle maintains its mobility throughout life (Strenk et al., 1999, 2004a), thus indicating that the choroid remains capable of restoring the muscle to its resting state. Additional evidence of a functional human choroid is suggested in reports of pseudoaccommodation in pseudophakic subjects (Findl et al., 2003;

Nakaizumi et al., 1992; Altan-Yaycioglu et al., 2002):

anterior IOL movement presumably occurs in response to ciliary muscle contraction—although a conclusive demonstration of this mechanism has not been published. Since the choroid acts as the restoring force to ciliary muscle contraction, anterior IOL movement in

response to accommodative stimuli indicates that the choroid retains at least some elasticity. Finally, MRI imaging of cataract patients reveals that IOL implantation returns the iris and ciliary muscle to a position of relative youth (Strenk et al., in preparation). Lifelong lens growth in these advanced presbyopes results in an anterior shift of the lens center of mass, a marked decrease in anterior chamber depth and an anterior displacement of the uveal tract; however enucleation and implantation of the much smaller IOL allows the iris and ciliary muscle to return to a more posterior location. This indicates that the human choroid retains its elasticity, as it is able to bring the ciliary muscle and iris back to their more youthful location when the age- enlarged lens is removed. Moreover, in these patients the ciliary muscle remains capable of contraction, as indicated by its changing diameter seen with MR imaging, further indicating a functional choroid. In other words, it appears that after removal of the age- enlarged crystalline lens, the uveal tract returns to both its youthful position and function. Thus the only signiﬁcant effect of aging on the human uveal tract appears to be its mechanical displacement as a result of lens growth.

Both histological (Tamm et al., 1992b; Pardue and Sivak, 2000) and in-vivo MRI (Strenk et al., 1999, 2004a) studies reveal that the ciliary muscle apex is displaced both inward and anteriorly with age in humans; this displacement likely occurs as a result of increasing lens thickness (Strenk et al., in preparation) since, after enucleation, the human uveal tract returns to its youthful position and function. Tamm, Tamm and Rohenreport: ‘‘These findings are in marked contrast to findings in the ciliary muscle of rhesus monkeys. In these animals, the ciliary muscle becomes fixed in a position far posteriorly with increasing age, as seen in young eyes after relaxation of the muscle’’ further indicating a very different aging process of the monkey’s uveal tract. The anteroposterior location of the uveal tract also shows species differences in response to accommodation. In vivo MR imaging of the human eye demonstrates no measurable anteroposterior change in ciliary muscle position with physiological accommodation (Strenk et al., 2004a). This finding is confirmed by in vivo OCT imaging of a 19 year-old albino subject; the lack of pigment in the iris allowed the infrared beam to penetrate through and thus permitted visualization of the otherwise obscured ciliary body (Baikoff et al., 2004). Conversely, in vitro studies of the rhesus ciliary muscle have indicated that with pharmacologically induced contraction, the ciliary muscle moves anteriorly as well as inward (Lutjen-Drecoll et al., 1988). These interspecies differences demonstrate that while the accommodative systems of monkeys and humans are similar and both develop presbyopia at approximately the same (normalized) rate (Kaufman et al, 1982; Bito

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et al., 1982), aging has very different effects on the uveal tract of each species.

In addition to intrinsic species differences, experimental methods that rely either upon pharmacologically induced ciliary muscle, and thus iris, contraction or that require iridectomy may also contribute to these differing findings. Helmholtz speculated that the contraction of the iris, which occurs concomitantly with ciliary muscle contraction, may contribute somewhat to the accommodative increase in anterior lens curvature (Helmholtz, 1924). Weale (1992) caculated that the contribution of the iris may be as much as 20–25% of accommodative amplitude. Additionally, the findings of Strenk and colleagues suggest that the iris plays a role in the development of presbyopia (Strenk et al., in preparation). Crawford et al. (1990) found that iridectomy results in a reduction in maximum accommodative amplitude with drug-induced accommodation in rhesus monkeys; they speculate that drug induced contraction of the iris may displace the ciliary muscle more than would occur with physiological accommodation. In pseudophakic human subjects, Findl (2003) finds that pilocarpine (which causes both iris and ciliary muscle contraction) induces supra-accommodation and thus greater anterior IOL displacement than that which occurs in response to physiological accommodation alone. Similarly, Strenk and colleagues find that unlike physiological accommodation in phakic subjects which does not cause anterior ciliary muscle displacement (Strenk et al., 2004a), pharmacologically induced accommodation in pseudophakic subjects causes anterior displacement of both the iris root and the ciliary muscle (unpublished data). These findings have implica- tions beyond understanding the mechanism of accommodation. They also have a bearing on the evaluation of accommodating IOLs, since data obtained with pharmacologically induced accommodation clearly over- estimate the amount of pseudoaccommodation that will occur with physiological accommodative effort.

3. Aging and the lens 3.1. Lens growth

The crystalline lens is a complex structure. Lifelong growth is a deﬁning feature of the crystalline lens, which is formed embryonically from an inverted epidermal layer that constantly generates new cells (Davson, 1990).

Unlike skin, where the oldest cells are eventually shed, lens growth involves addition of the newest differentiated cells to the lens surface; this is analogous to the trunk of a tree, where increasing distance from the surface is correlated with increasing cell age. The lens ﬁbers arise continuously from the differentiation of epithelial cells located on the anterior lens surface, with

morphological changes initially appearing near the lens equator. The cells elongate, becoming increasingly ribbon-like, and lose all of their organelles and the metabolic apparatus associated with cell growth and division, eventually becoming little more than sacks of highly concentrated proteins. Thus, new lens ﬁber cells are continuously laid down over older ones which in turn are displaced inward, producing specialized, differentiated epithelial cells that exhibit a ﬂattened hexagonal cross-section with interconnections between cells to preserve relative orientation.

Within the lens, the fiber cells are laid down into concentric shells that provide an additional level of internal organization (Koretz et al., 1994; Kuszak, 1995). In order for the differentiated fiber cells to assemble into a closed surface with minimal diminution of optical quality, the ends of the fiber cells assemble to form tight connections that define a line, or suture. For the fetal lens, there are three sutures each radiating from the symmetry axis on the anterior and posterior of the lens; the anterior ‘‘Y’’ defined by these sutures is matched by a posterior ‘‘Y’’ rotated 60ô to minimize aberration. As the size of the lens increases, a new shell is initiated with three-six sutures each on the lens anterior and posterior, again rotated relative both to each other and to the ‘‘Y’’ sutures of the inner shell. A third shell, with six-nine sutures per surface, is initiated when the second shell is complete and follows the same general pattern to minimize aberration due to the sutures. Generally the fourth shell, with nine-fifteen sutures on each surface, is also the last (Koretz et al., 1994; Kuszak, 1995; Kuszak et al., 2004; Taylor et al., 1996). These morphologically characterized shells appear to be correlated with the zones of discontinuity, discontinuous concentric regions observed in slit-lamp images (Koretz et al., 1994; Brown, 1974), and this correlation directly links lens ultrastructure with lens optical organization.

In order for the crystalline lens to provide a refractive contribution to the visual system, it must exhibit a refractive index higher than the surrounding media (aqueous and vitreous humors). This is accomplished through internal fiber cell protein concentrations in excess of 300 mg/ml, while its transparency in the visible spectrum is the result in part of the fiber cells shedding their nuclei, organelles, and indeed any internal cytoplasmic structure large enough to scatter light. Although these internal protein concentrations are extremely high, they are organized in a non- crystalline fashion that can be compared to a liquid crystal, with a well-defined nearest neighbor distance and a random second-nearest neighbor (Benedek, 1983).

This mechanism ensures that transparency is maintained independent of lens size, shape, and curvature (Koretz et al., 1994; Yaroslavsky et al., 1994; Zhao and Bettelheim, 1995).

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Both Scheimpﬂug and MRI in vivo human imaging studies reveal that human lens thickness increases throughout life (Brown, 1974; Koretz et al., 1989, 2001, 2004;Cook et al., 1994;Strenk et al., 1999). The human anterior segment length (the distance from the cornea to the posterior lens surface) is constant with age, thus increasing lens thickness causes a decrease in anterior chamber depth (distance from the cornea to the front of the lens) and with increasing age an anterior displacement of the lens center of mass occurs. This increase is due primarily to an increase in the thickness of the anterior portion of the lens (Strenk et al., 2004b;

Cook et al., 1994; Koretz et al., 2001); there is an increase in posterior lens thickness as well, but it is smaller than for the anterior. Because of blockage by the iris, in vivo information on the human lens equatorial diameter, circumlental space, and cross-sectional area was not available until recently when high-resolution ocular MRI techniques and instrumentation were developed (Strenk et al., 1999). Since MR allows visualization of the lens equator, the total lens cross- sectional area as well as that of the anterior and posterior portions of the lens can be obtained individually, by using the equator as the dividing line. These studies revealed that both lens thickness and lens cross- sectional area increase with age throughout adult life and that the increase in lens cross-sectional area with age is due almost entirely to an increase in the anterior portion of the lens (Strenk et al., 1999, 2004b). Thus, looking at the lens grossly, lens growth appears to primarily involve the anterior portion of the human lens.

These studies also reveal that the length of the unaccommodated lens equator is constant with age and has a mean value of approximately 9 mm (Strenk et al., 1999). Thus while reduced circumlental space is seen with advancing age, it does not result from an increase in the lens equator, rather it results from the ciliary muscle moving closer to the lens with advancing age (Strenk et al., 1999). The accommodated lens equator is smaller than the disaccommodated equator, and this difference decreases with advancing age. During accommodation, zonular tension is reduced, so a decrease in the lens equator is expected. An age-dependent increase in the equator of the accommodated lens is similarly expected as lens accommodative response (which includes a decrease in lens equator length coupled with an increase in lens thickness) is diminished with advancing age. It should be noted that the while the accommodated lens equatorial length increases with advancing age, it never exceeds that of the unaccommodated lens equator. Capsular dimensions and mechanics may simply limit the maximum possible size of the human lens equator regardless of the effects of lens growth or zonular tension. Information is unavailable on the effect of age on the rhesus monkey lens equator.

Characterizing human crystalline lens shape as a function of age or accommodation is critical for understanding the optics of physiological image formation, and more importantly, for modeling the accommodative process and the development of presbyopia.

However, the lens must be studied in situ, and ideally in vivo, to preserve the three-dimensional relationship between it and other elements of the anterior segment, as well as the pattern of forces acting upon it; the shape of an isolated human lens depends critically on the support methods used, and its optical properties may also be a function of the preservation method. In general, the same central region of the lens that participates in image formation, a ‘‘cylinder’’ of about 3 mm diameter, can be visualized in situ using a number of different optical methods. Classically, central lens curvatures were estimated using Purkinje images, while more recently, lens thickness and other internal globe dimensions along the optical axis can be determined using A-scan ultrasonography.

In the early 1970s, Nicholas A. Phelps Brown resurrected the Scheimpﬂug method for examining the central anterior segment (Brown, 1972, 1972, 1973a–c, 1974). The anterior segment along the optical axis is illuminated with a slit beam, and this region is photographed at an angle and with a tilted image plane such that image compression is partially neutralized.

The entire lens cannot be observed with this method, since the iris screens the equatorial region of the lens, but a good portion of the central region of the anterior segment can be captured. Although the resultant images are both distorted and variably compressed, the effect of these factors can be defined and compensated for so that the corrected images can provide information about central lens shape and thickness, as well as anterior chamber depth and anterior segment length. Lens curvatures from these images have been fitted to a variety of mathematical functions, including hyperbo- loids, spherical sections, and ellipsoids, but the simplest fit that minimizes assumptions and encompasses a variety of conical sections, is a second order polynomial.

Brown’s initial attempt at curve fitting clearly showed that the central region of the lens surfaces was much more highly curved than the regions surrounding it, whether looking at changes in lens shape with age or accommodation. Later re-analysis of some of these images confirmed his observations (Koretz et al., 1984) and led to further studies of both human and rhesus lenses in vivo with Scheimpflug or Scheimpflug-type cameras.

High-resolution MRI allows the complete shape of the human lens proﬁle to be deﬁned and demonstrates that fourth order polynomials are required to describe both the anterior and posterior lens surfaces in their entirety, however, these reduce to second order polynomials when the lens periphery is ignored (Koretz

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et al., 2004). With resting accommodation, both Scheimpflug and MRI data from subjects ranging in age from 18 to 50 years reveal that the anterior curvature of the human lens is less than the posterior curvature and that the anterior curvature increases with age, while the posterior curvature remains constant (Koretz et al., 2004); although if the entire human lifespan is considered, the posterior surface curvature does increase slightly with age (Brown, 1974;Koretz et al., 1984). Thus with advancing age the anterior surface curvature of the human lens approaches that of the posterior. This is consistent with the finding that lens growth primarily affects the anterior portion of the human lens (Strenk et al., 2004b). Conversely, in the rhesus monkey, lens growth appears to be symmetric in the anterior and posterior portions. In the rhesus, the lens posterior curvature exceeds the anterior, and both curvatures increase with age, although not as rapidly human lens curvatures (Koretz et al., 1988). Moreover, the growth pattern of the rhesus monkey lens is quite different from that of the human lens: the posterior curvature of the rhesus monkey lens increases more rapidly with age than the anterior (Koretz et al., 1987a, b). Thus with age, the anterior and posterior surface curvatures of the human lens converge, while those of the rhesus monkey diverge. Consequently, the posterior curvature of the rhesus monkey lens always exceeds that of the anterior; this species difference in lens growth patterns may be related to the observation that unlike the human ciliary muscle, that of the rhesus becomes fixed posteriorly with age (Tamm et al., 1992b).

Scheimpﬂug slit-lamp studies have provided a wealth of information regarding lens internal structures and how they change with development, aging, and accom-

modation (Fig. 4). In the developing human eye, the region usually called the lens nucleus is not well delineated, but can be close in size to the lens itself.

This large central region appears to be gradually compacted at a rate approximately comparable to the addition of lens ﬁber cells on the anterior and posterior lens surfaces, so that youthful crystalline lenses appear to exhibit a constant sagittal thickness up to adulthood.

The rate of cortical lens ﬁber addition during this time is much greater than that observed in the adult human lens, gradually slowing down to the adult rate by around age 20 yr. At the same time, the central region of the lens ceases further thickness and volumetric changes and the unaccommodated lens equator, observed by high- resolution MRI, reaches its maximum adult breadth.

Beyond this point in time, increase in the size of the adult lens is due entirely to addition of cortical ﬁber cells, resulting in a linear increase in overall thickness with increasing age (Koretz et al., 1994). As noted previously, the increase in cortical thickness with age in the adult human lens is strongly asymmetric, with the anterior of the lens exhibiting the majority of this increase relative to the posterior; this asymmetry is most likely a function of the very different surface area sizes of the anterior and posterior, which affect the dimensions of the ﬁber cells. The growth pattern in the adult rhesus lens is, in contrast, close to symmetric for the anterior and posterior. As a result, the fetal nucleus is likely centered anteroposteriorly in the monkey lens, while the majority of the fetal nucleus is located in the posterior portion of the human lens (Taylor et al., 1996;

Moffat et al., 1999).

Controlled changes in lens shape lead to changes in the overall focal length of the eye, the accommodative

Fig. 4. Scheimpﬂug slit-lamp photographs of human subjects’ lenses aged (L to R) 19, 33, 45, and 69 yr. Top row—not accommodated. Bottom row—fully accommodated; focus (L to R) of 9, 4.5, 1 and 0.25 diopters. (FromKoretz and Handelman, 1988, reprinted courtesy of Scientiﬁc American.)

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process (Fig. 1). When the eye is focused on infinity, the crystalline lens is at its flattest and thinnest, and is under maximum tension. The contraction of the ciliary muscle leads to a reduction in the magnitude of the forces acting upon the lens, allowing it to ‘‘round up’’, with changes in lens shape and curvatures linearly related to accommodation. In the human eye, as studied by both Scheimpflug photography and high-resolution MRI, the distance from the corneal apex to the posterior lens pole is essentially constant; thus the relaxation of lens stresses leads to a more sharply curved anterior surface, a more sharply curved posterior surface (although the actual change in central radius of curvature is much smaller for the posterior than the anterior), and a movement of the lens center of mass anteriorly. This brings the anterior lens surface closer to the cornea while preserving the distance from the lens posterior to the retina; high pair- wise correlations between these processes suggest that the anterior segment acts essentially as a single optical unit (Koretz et al., 1995).

A major advantage of Scheimpﬂug imaging is the capability of observing changes in regions within the lens—the lens nucleus and the zones of discontinuity—

and correlating them with changes in overall lens shape.

The lens nucleus itself (defined for these studies as the boundary of the first zone of discontinuity) changes with accommodation in the same way as the lens overall; the nucleus is flattest when the eye is focused on infinity and

‘‘rounds up’’ during accommodation, with its change in shape linearly related to accommodation. The change in lens thickness along the visual axis during accommodation is due entirely to the change in shape of the lens nucleus, with axial cortical thickness remaining unchanged (Koretz et al., 1984). The zones of discontinuity are also visible in these images, and their curvatures can be measured and analyzed using the same methods applied to the lens surfaces. As the lens changes shape during an accommodative change, the curves deﬁning the boundaries of adjacent zones change their curvature in the same linear manner, and can thus be used as internal references. It is especially interesting to note that the curves from each half of a human lens, when graphed as inverse radius of curvature vs. distance from the lens surface, deﬁnes a straight lines for each accommodative state. This indicates that lens deformation during a change in focus is an integrated process involving coupled alterations in curvature throughout the lens body.

Differences are again observed between the human and rhesus eye and lens. Not only does the rhesus monkey lens grow differently than the human lens, it also exhibits a different pattern of deformation upon accommodation. During accommodation, the anterior and posterior portions of the rhesus lens ‘‘round up’’

equally, so that the lens center of mass is not changed;

the distance from the cornea to the center of mass is

maintained, but the distance from the cornea to the posterior lens surface increases with increasing accommodation. Conversely, when the human lens ‘‘rounds up’’ the distance from the cornea to the posterior lens surface is essentially maintained and it is the center of mass that is displaced anteriorly.

With increasing age, non-accommodated lenses of both humans and rhesus become more sharply curved, albeit with different patterns of change on the anterior and posterior surfaces. In general, it would be expected that surfaces with smaller radii of curvature would provide a greater refractive contribution, and thus that the eye’s distance vision would be lost while near vision was preserved; that humans (and monkeys!) instead experience a gradual loss of near vision while far vision is preserved is known as ‘‘Brown’s lens paradox’’.

Resolving this paradox in humans requires a compensatory reduction in the refractive index or indices of the aging lens, so that the refractive power of the unaccommodated lens remains essentially unchanged.

A variety of refractive index gradients (GRINs) have been proposed, ranging from a simple Gullstrand-type model where the lens nucleus and lens cortex are assigned values, to a power function with a strongly age-dependent level of complexity. Indirect (Siebinga et al., 1992) and direct (Moffat et al., 2002) experimental data suggest that the actual refractive index proﬁle of the lens is intermediate between these two extremes; a model GRIN based in part on the data of Siebinga and colleagues has been effectively utilized in conjunction with the Scheimpﬂug and biometric data to characterize paraxial image formation as a function of accommodation and of age (Koretz and Cook, 2001).

In general, any GRIN for the human crystalline lens must be both age-dependent, leading to a gradual reduction in overall lens refractive power to compensate for the increased lens curvature, and physiologically plausible, such that an underlying biochemical mechanism at the sub-cellular level can explain the age dependence of the GRIN. It is interesting to note that the age-related changes in unaccommodated lens shape with age are almost entirely compensated for by an age-related reduction in the GRIN; the two processes are not, however, exactly balanced, and overall lens power tends to decrease by about 1 diopter with aging.

Thus with age, a compensatory decrease in the gradient index of refraction (GRIN) of the human lens is required. Koretz et al. (1988) speculated that this may not hold true for the rhesus, ‘‘It is possible that lens growth, which increases the distance between the intralenticular refracting interfaces and thus reduces refractive power, is itself sufﬁcient in the rhesus to compensate for small increases observed in sharpness of lens curvature. If so, the rhesus, unlike the human, would not need to modify its lenticular refractive indices with age.’’

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3.2. Lens mechanics

While Helmholtz accurately described the general accommodative mechanism, he did not distinguish between the capsule and the lens material, and supposed the elastic lens material to exist in its more rounded form in the absence of zonular tension. However, Fincham (1937) observed that upon removal of the capsule, the lens assumed its unaccommodated shape and he hypothesized that an elastic capsule molds a plastic lens material. It is now understood that both the lens material and capsule have elastic properties (Weale, 1963) and that the capsule acts as a force distributor during accommodation (Koretz and Handelman, 1982), thus age-related changes in the mechanical properties of either could hypothetically contribute to the development of presbyopia. Fisher measured the age dependence of Young’s modulus of the human lens capsule and found that it decreased with age (Fisher, 1969).

More recent experiments by Krag and Andreassen (2003) reveal that while the capsular thickness increases with age, the Young’s modulus of the lens capsule increases until age 35 years, and then remains constant;

the authors attribute the difference in these ﬁndings compared with those of Fisher to their observation that Fisher’s work was not done using physiological forces.

Nonetheless, the claim that age-related changes in capsular elasticity are sufﬁcient to account for the onset of presbyopia is not substantiated by either the data of Fisher or Krag and Andreassen.

Helmholtz (1855) proposed that ‘‘lens sclerosis’’

caused presbyopia. If sclerosis is understood to mean decreasing water content, research in this area has produced mixed ﬁndings.Fisher and Pettet (1973), using vacuum dehydration, report that lens water content is constant with age.Lahm et al. (1985)also used vacuum dehydration to determine that the total water content for the nucleus decreases while that of the cortex is essentially constant. However, more recent work using Raman microspectroscopy, in-vitro MRI, and a freeze drying method indicates nuclear water content increases with age (Siebinga et al., 1991; Bettelheim et al., 2002;

Deussen and Pau, 1989), and water content is not evenly distributed across the lens (Siebinga et al., 1991;

Bettelheim et al., 2002). Further Deussen and Pau (1989)determined that regional differences in the water content of postmortem human lenses decrease signiﬁ- cantly within 24–48 h of death. In any case, the in-vivo behavior of water in the lens is likely governed in large part by pressure (both intraocular and accommodative);

in vitro MRI studies of the isolated lens indicate increasing pressure causes a conversion of free to bound water (Bettelheim et al., 2002, 2003;Bettelheim, 1999).

Helmholtz’s view on ‘‘lens sclerosis’’ can be more broadly framed as a supposition that changes in lens mechanical properties are the causal factor in the

development of presbyopia. Over the last forty years, there have been a number of attempts to test the possible age dependence of mechanical properties of the human lens in vitro. Fisher (1971) by spinning isolated lenses, calculated the equatorial and polar Young’s modulus with age and demonstrated very little, if any increase in Young’s modulus before age 50, even though accommodative loss occurs throughout life and over ﬁfty percent is lost by this age (Weale, 1999). Glasser and Campbell (1999) applied a compressive force to the isolated human lens (18 and 185 h post-mortem; average 63 h post mortem) and measured the resistance to deformation. Once again, between the ages of 20 and 50, there is little change in the resistance to deformation.

Glasser and Campbell also measured the radius of curvature of the anterior half of the isolated lens and showed that it increased with age, directly contradicting numerous in-vivo studies of the accommodating human lens. This discrepancy is likely the result of limitations inherent in in-vitro study of the isolated lens ((i.e.

postmortem tissue handling including lenticular changes that have been reported to occur within 24–48 h post mortem (Deussen and Pau, 1989), and the non- physiological pattern of applied forces)) coupled with undersampling of the lens surface. Inexplicably only forty percent of the lens surface was used and this undersampling likely manifests as an artiﬁcial increase in the radius of curvature.

Van Alphen and Graebel (1991) performed uniaxial stretching of the intact lens and found a signiﬁcant correlation between the measured equatorial and polar spring constants and age, although regression lines were not reported. Pierscionek (1993, 1995) measured the anterior and posterior curvatures of lenses with radial stretching and found that over the age of 50, very little change in curvature occurs. Glasser and Campbell (1998) performed radial stretching of isolated human lenses (between 9 and 120 h postmortem, average 48 h) and measured their focal lengths. After considerable debate surrounding the statistical interpretation of the data (Weale, 1999; Glasser and Campbell, 1999), and subsequent data replotting (Glasser and Campbell, 1999), the data indicate that the lens focal length is constant with age until age 70. In general, the value of in-vitro stretching experiments is limited, as the geometric relationship between the ciliary muscle and lens was not known at the time these experiments were conducted. High-resolution in vivo MRI images of the accommodative structures (Strenk et al., 1999, 2004a, b) clearly show that the ciliary muscle is anterior to the lens equator in the human eye. Unfortunately, during these stretching experiments the ciliary muscle and lens equator were positioned in the same plane, thus an artiﬁcial anterior-posterior force was produced on the lens, limiting the change in lens thickness in older lenses.

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As noted above, in-vitro study of the mechanical properties of the isolated lens has serious limitations including post-mortem tissue handling, artifactual deformation of the lens (Weale, 1999), and the application of non-physiological forces. Significantly,Deussen and Pau (1989) report that regional differences in water content of postmortem human eye lenses decrease significantly within 24–48 h of death. Thus care must be taken in interpreting findings from such studies. Even so, taken together, these in-vitro experiments cannot be said to support the theory that presbyopia results from changes in lens mechanical properties since accommodative loss begins during childhood and significant mechanical changes in the lens are not seen until after the age at which accommodation is almost entirely lost.

If anything, these studies suggest the opposite; that mechanical changes in the lens occur as a result of accommodative loss.

Helmholtz viewed the lens material as incompressible, but today this is generally regarded as a vast over- simplification. The theoretical calculations of Koretz and Handelman (1982, 1983) indicate the lens can be compressed, and describe zonular stresses being con- verted by the capsule into a uniform compressive force on the lens material. Koretz and Handelman (1982) further present a mathematical model of lens mechanics, valid over a range of Poisson ratios less than 0.46, thus, necessitating a compressible material. While the lens contains a large amount of water, which is incompressible, lens mechanics should not be modeled as a simple fluid filled sack (Weale, 1989). Rather, the lens is a complex structure of interconnected lens fiber cells, proteins and intracellular space. Lens fiber cells stack and interlock in an interdigitized manner preventing them from moving past each other. This suggests that the range of possible lens material deformation is determined by the intricate ultrastructure of the lens and that shape changes likely result from a redistribu- tion of cytoplasm within each lens fiber cell (Koretz and Handelman, 1982). This observation as well as the wealth of information on lens anatomy and ultrastructure point to the value of examining the entire intact lens, ideally in-vivo, when attempting to study lens mechanical changes. As previously mentioned, study of the intact isolated lens is complicated by a number of limitations. Even more problematic are studies that attempt to determine mechanical properties of the lens by utilizing methods that mechanically compromise its integrity (i.e., by slicing or chopping it); this disrupts the intricate ultrastructure of the crystalline lens and thus provides information of limited value in understanding the mechanisms of accommodation and presbyopia. A discussion of such studies is beyond the scope of this review.

Compressibility of the lens, i.e., Poisson’s ratio, has never been measured. However, recent in-vivo MRI

studies of Strenk and colleagues (Strenk et al., 2004b) suggest that the lens material is compressed with relaxed accommodation when zonular tension is maximized.

The amount of compression decreases with age, as would be expected, since circumlental space and hence zonular tension decrease with age (Strenk et al., 1999).

In-vitro MRI studies (Bettelheim et al., 2002, 2003;

Bettelheim, 1999) of the isolated human lens have described a reversible, age dependent, syneretic response in which an increase in pressure leads to a conversion of a portion of the free water in the lens to bound water, implying a tighter packing of lens proteins; a tighter packing of lens proteins would result in lens compression during resting accommodation when the lens is under greater pressure. The lens compression found with in-vivo MRI is limited to the smaller anterior portion of the lens. The smaller surface area of the anterior portion and the distinct anatomy of the anterior lens capsule likely result in greater compressive forces being applied to the anterior lens material with resting accommodation. Vibratome sections (Taylor et al., 1996) as well as in vitro MR images (Moffat et al., 1999) of the human lens indicate that the fetal nucleus is primarily located in the posterior portion of the lens. As the fetal and embryonic nuclei are harder than the surrounding adult nucleus, juvenile nucleus, and cortex and since differences in cell morphology exist between these regions (Taylor et al., 1996) the posterior portion of the lens might remain unresponsive to any pressure from the lens capsule. The anterior lens capsule, which is attached to the thickest zonular ﬁbers, is signiﬁcantly thicker than the posterior capsule (Bron et al., 1997) and acts as a force distributor (Koretz and Handelman, 1982) for the lens material, yetFincham (1937)describes the posterior capsule as ‘‘lax and cockled’’ when the lens material is removed. Moreover, unlike the posterior capsule, the anterior is the thickest basement membrane in the body.

This anterior compression decreases with age, possibly reﬂecting age-related changes in the anterior lens material. Conversely, this reduction in compression could simply result from an age-related decrease in zonular tension as the ciliary muscle moves closer to the lens with advancing age.

4. Lens growth and the uveal tract

Reported mechanical changes in the human lens capsule and lens material cannot account for the early onset of accommodative loss; indeed signiﬁcant mechanical changes appear not to occur until after accommodation is almost completely lost. Moreover, in stark contrast to the age-related changes in the rhesus uveal tract (which may be sufﬁcient to explain the development of presbyopia in this species), human ciliary muscle contraction is undiminished throughout life

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and the human choroid maintains its elasticity. While theories on the development of presbyopia have often focused on age-related changes in either lenticular or extra-lenticular components individually, the continuous increase in the size of the human lens throughout life affects its geometric relationship to the other accommodative structures, demanding that a more complex view of the development of presbyopia be taken (Koretz and Handelman, 1988). The MRI technique developed by Strenk and colleagues is unique in providing important information about the relationship of the lens to the other accommodative structures in the intact human eye. Currently, no method exists that can provide similar information about the intact rhesus monkey eye. Ultrasound studies have contrast and ﬁeld- of-view limitations. Similarly, gonioscopic or video- graphic studies of iridectomized monkey eyes remove the iris (an important accommodative structure) and do not provide information on the anteroposterior posi- tions of the remaining accommodative structures. Thus the geometric relationship between the iris, ciliary muscle and lens of the aging rhesus monkey is not known. Human lens growth occurs primarily in its anterior portion, while a balanced pattern of growth of the anterior and posterior has been shown for the rhesus monkey lens. How this different lens growth pattern affects the geometric relationship between the lens, ciliary muscle and iris in the rhesus monkey is unknown, although it may be related to choroidal changes in the rhesus which ﬁx the rhesus ciliary muscle posteriorly with age. In contrast, the human ciliary muscle displaces anteriorly with age.

Koretz and Handelman (1988)hypothesize that lens growth is the causal factor in the development of presbyopia in humans, with mechanical changes in lens material secondary to accommodative loss and likely resulting from an increased rate of biochemical degra- dative processes (Koretz and Handelman, 1982, 1983, 1988). According to this Geometric Theory, lens growth acts on the muscle directly through the zonules: as the geometric relationship between the muscle and lens changes with age, zonular tension increases, yet a diminished component of zonular force is available in the radial direction, ultimately rendering ciliary muscle contraction ineffective. It is also noted that as lens curvature increases with advancing age, the ability to effect an additional accommodative increase in curvature decreases as there is an intrinsic limit—a sphere—to how far the lens can ‘‘round up’’.

5. The Modiﬁed Geometric Theory of presbyopia development

More recent ﬁndings reveal that the human uveal tract acts as a unit in response to both lens growth and

accommodation (Fig. 5), suggesting an alternate avenue by which lens growth may act upon the ciliary muscle and result in accommodative loss (Strenk et al., 2004b;

Strenk et al., in preparation). The iris root and ciliary muscle are displaced anteriorly at the same rate as the age-related increase in lens thickness. This preserves the anteroposterior relationship between the ciliary muscle and the zonular insertion band on the lens, which has been calculated to remain a fixed distance from the anterior pole of the lens with advancing age (Farns- worth and Shyne, 1979;Weale, 2000). Nonetheless, the ciliary muscle is moving inward with age while the lens equatorial length is constant, so the circumlental space decreases significantly with age (Strenk et al., 1999), and thus zonular tension likely decreases with advancing age. The iris root and pupillary margin also move inward at the same rate as the inward movement of the ciliary muscle. The Modified Geometric Theory (Strenk et al., in preparation) describes the effect of lens growth on accommodative loss as follows: The pupillary margin of the iris rests on the anterior surface of the lens, and upward forces applied by the lens to the iris are translated to the iris root and the ciliary muscle. Scleral curvature produces a tangential force, causing an inward as well as anterior displacement of ciliary muscle and the iris root, thus reducing pupil diameter. This reduced pupil diameter brings the pupillary margin closer to the thickest part of the anterior lens surface, thus amplifying the effect of lens thickness on iris root and ciliary muscle anterior/inward displacement and the cycle continues as the lens continues to grow. As the ciliary muscle moves upward and inward with age, circumlental space is reduced, resulting in decreased zonular tension. A reduction in zonular tension during resting accommodation, necessarily leads to both increased lens curvature and a reduction in lens accommodative response. Thus, like the Geometric Theory, this Modified Geometric Theory also provides that lens growth ultimately leads to the inability of the lens to change shape. Secondarily, the Modified

Fig. 5. A composite of MRI images of the unaccommodated eye (a 26 year old subject on left and 49 year old subject on the right). Note the age related anterior displacement of the uveal tract.

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Geometric Theory provides a possible mechanism for the development of senile miosis, the reduced pupil diameter seen with advancing age. The Modiﬁed Geometric Theory takes into account what was previously known about the human accommodative system as well the new information that has emerged from the recent in-vivo MRI studies. Speciﬁcally, this new theory is consistent with the following observed age-related changes: reduction of circumlental space, anterior/

inward displacement of the ciliary muscle, anterior/

inward displacement of the iris, lack of lens equatorial growth coupled with a signiﬁcant increase in lens thickness, increase in lens cross-sectional area and curvature, decrease in lens compression, and undiminished ciliary muscle contraction.

6. Conclusion

Much of the controversy and confusion regarding the underlying mechanisms of accommodation and presbyopia results from a lack of in-vivo information on the accommodative structures as they relate to each other in the intact human eye. The high-resolution MRI instrumentation and technique developed by Strenk and colleagues is the only method that allows in-vivo visualization of the ciliary muscle and the entire lens in the intact, accommodating human eye and its application to the study of presbyopia continues to yield significant new findings. Lenticular changes alone appear responsible for the development of presbyopia in humans, while decreased choroidal compliance and the consequent loss of ciliary muscle motility appear sufficient to explain the development of presbyopia in the rhesus monkey. While human ciliary muscle contraction is undiminished throughout life, lifelong lens growth displaces the human uveal tract anteriorly and inward, ultimately rendering ciliary muscle contraction ineffective. Enucleation of the age-enlarged crystalline lens appears to restore both the youthful position and function to the human uveal tract. In vivo high-resolution MRI is limited in both spatial and temporal resolution, thus it provides only limited information regarding internal lens structures and cannot provide information on accommodative dynamics. While the Scheimpflug imaging technique developed by Koretz and colleagues does not permit visualization of the entire lens, its superior resolution produces exquisitely detailed images of the lens capsule and internal lens structures in-vivo in the human eye. It is anticipated that combining data obtained from these two powerful, non-invasive, imaging modalities will further elucidate human accommodative mechanics and provide useful feedback on surgical interventions designed to restore accommodation.

Acknowledgement

JFK would like to thank George H. Handelman for his continuing interest in and contributions to studies on the mechanisms of accommodation and presbyopia.

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