Accommodation and presbyopia: the ciliary neuromuscular view

Presbyopia (literally, "old eye"), the age-related loss of the ability to accommodate, is the most common ocular affliction in the world. Although the lens no doubt has a major role in presbyopia, altered lens function could be in part secondary to extralenticular age-related changes, such as loss of ciliary body forward movement. Centripetal ciliary muscle movement does not seem to decrease significantly with age. Loss of elasticity of the ciliary muscle posterior attachments may be an important factor contributing to presbyopia. Even if loss of ciliary muscle mobility is not causally related to presbyopia, it may limit the performance of putatively accommodating intraocular lenses now being developed by academic and industrial groups.     

Magnetic resonance imaging of aging, accommodating, phakic, and pseudophakic ciliary muscle diameters

PURPOSE: To quantify in vivo accommodative changes in the aging human ciliary muscle diameter in phakic and pseudophakic eyes. SETTING: Department of Surgery/Bioengineering, UMDNJ-Robert Wood Johnson Medical School, Piscataway, and the Institute of Ophthalmology and Visual Science UMDNJ-New Jersey Medical School, Newark, New Jersey, USA. METHODS: Images were acquired from 48 eyes of 40 people between the ages of 22 and 91 years, 1 eye of 32 phakic volunteers and both eyes of 8 patients who had monocular implantation of a single-piece AcrySof intraocular lens (IOL) (Alcon Laboratories). Images were acquired during physiological accommodation and with accommodation at rest, and the diameter of the ciliary muscle ring was measured. RESULTS: Results show the ciliary muscle remains active throughout life. The accommodative change in its diameter (mean 0.64 mm) (P<.00001) was undiminished by age or IOL implantation. Preliminary data showed that the accommodative decrease in muscle diameter in phakic and pseudophakic eyes was statistically identical. The phakic eyes had a marked decrease in ciliary muscle diameter with advancing age for both accommodative states (P<.000001 and P<.000001), which did not appear to be altered by IOL implantation. The lens equator was constant with age in the unaccommodated human eye, resulting in decreased circumlental space with advancing age in the phakic eyes. CONCLUSION: Although the undiminished ability of the ciliary muscle to decrease its diameter with accommodation can be relied on in strategies for presbyopia correction, even in advanced presbyopia, the decreasing circumlental space and its potential effects on zonular tension must also be considered.     

Accommodation and presbyopia : part 1: physiology of accommodation and development of presbyopia

Accommodation is a dynamic change in the dioptric power of the eye. According to the widely accepted and experimentally confirmed theory of Helmholtz, it is achieved by release of zonular tension with contraction of the ciliary muscle and consecutive modelling of the shape of the crystalline lens by the elastic lens capsule. The ability to accommodate is gradually lost with age (presbyopia). Because of difficulties in examining the accommodative apparatus in vivo, many theories, in part contradictory, about the mechanism of accommodation and the origin of presbyopia have been developed. In recent years experimental studies have greatly increased the knowledge about the acommodative apparatus and suggest a multifactorial aetiology of presbyopia. A better understanding of the physiology of accommodation and presbyopia can contribute to the development of effective treatments.     

Akkommodation und Presbyopie

Accommodation is a dynamic change in the dioptric power of the eye. According to the widely accepted and experimentally confirmed theory of Helmholtz, it is achieved by release of zonular tension with contraction of the ciliary muscle and consecutive modelling of the shape of the crystalline lens by the elastic lens capsule. The ability to accommodate is gradually lost with age (presbyopia). Because of difficulties in examining the accommodative apparatus in vivo, many theories, in part contradictory, about the mechanism of accommodation and the origin of presbyopia have been developed. In recent years experimental studies have greatly increased the knowledge about the acommodative apparatus and suggest a multifactorial aetiology of presbyopia. A better understanding of the physiology of accommodation and presbyopia can contribute to the development of effective treatments.     

Age-related changes in human ciliary muscle and lens: a magnetic resonance imaging study

PURPOSE: To use high-resolution magnetic resonance (MR) images of the eye to directly measure the relationship between ciliary muscle contraction and lens response with advancing age. METHODS: A General Electric, 1.5-Tesla MR imager and a custom-designed eye imaging coil were used to collect high-resolution MR images from 25 subjects, 22 through 83 years of age. A nonmagnetic binocular stimulus apparatus was used to induce both relaxed accommodation (0.1 diopter [D]) and strong accommodative effort (8.0 D). Measurements of the ciliary muscle ring diameter (based on the inner apex), lens equatorial diameter, and lens thickness were derived from the MR images. RESULTS: Muscle contraction is present in all subjects and reduces only slightly with advancing age. A decrease in the diameter of the unaccommodated ciliary muscle ring was highly correlated with advancing age. Lens equatorial diameter does not correlate with age for either accommodative state. Although unaccommodated lens thickness (i.e., lens minor axis length) increases with age, the thickness of the lens under accommodative effort is only modestly age-dependent. CONCLUSIONS: Ciliary muscle contractile activity remains active in all subjects. A decrease in the unaccommodated ciliary muscle diameter, along with the previously noted increase in lens thickness (the "lens paradox"), demonstrates the greatest correlation with advancing age. These results support the theory that presbyopia is actually the loss in ability to disaccommodate due to increases in lens thickness, the inward movement of the ciliary ring, or both.     

Deterioration of amplitude of the accommodation with age and its possible restoration in the intraocular lens implanted eye]

This study aimed to determine whether pseudophakia which have deteriorated amplitude of accommodation with age, i.e., presbyopia and which received implantation of refractively changeable intraocular lenses after cataract extraction are able to regain accommodative function. According surveys on aging in the literature, functional deterioration of the ciliary muscle and the zonular fiber is not so striking compared to the changes of crystalline lens material and capsule. Consequently the artificially pseudophakic eye can be expected to regain accommodative function when the crystalline lens material could be replaced by an appropriately visco-elastic material before 80 years of age when the crystalline lens capsule still retain its elasticity.     

Accommodation and presbyopia

The mechanism of accommodation has been studied for at least four hundred years. The most interesting aspect of accommodation is that its time course is well in advance of other physiological functions – it begins to decline by adolescence and is lost about two-thirds of the way through the normal line span. The state of presbyopia is reached when accommodation has declined sufficiently to interfere with close tasks requiring acute vision. Presbyopia is generally considered to originate with the 'plant' of the accommodative system, either within the lens and its capsule or within their support structures. One of the lenticular theories, the Hess–Gullstrand theory, is distinguished from other theories by its claim that as age increases there is an increasing excess amount of ciliary muscle contraction beyond the ability of the lens and capsule to respond to it. For all other theories, the maximum possible amount of ciliary muscle contraction is always necessary to produce maximum accommodation, at least beyond the age at which it reaches its peak. From my review of the present understanding of the mechanisms of accommodation and the theories of the development of presbyopia, I conclude that there is overwhelming evidence against the Hess–Gullstrand theory and that it is unlikely that changes in the ciliary muscle contractility contribute significantly to the development of presbyopia.     

Questioning our classical understanding of accommodation and presbyopia

The development of precise instrumentation, electron microscopy, and enhanced analytical capabilities have renewed interest in understanding the mechanisms of accommodation and presbyopia. The properties of the ciliary muscle, the zonule, the lens capsule, and the crystalline lens are being reevaluated, suggesting, for example, that these components' elasticities change significantly with age and that the biochemical properties of the crystalline lens may be altered as the lens ages. The recent findings, mainly during the past decade, are contrasted with or incorporated into our classical understanding of the accommodative mechanism and presbyopia as stated originally by Helmholtz and Fincham.     

Enhancing trabecular outflow by disrupting the actin cytoskeleton, increasing uveoscleral outflow with prostaglandins, and understanding the pathophysiology of presbyopia interrogating Mother Nature: asking why, asking how, recognizing the signs, following the trail

Several major areas of work by the author and his international collaborators are reviewed. (1) The ciliary muscle in the non-human primate eye was disinserted at the scleral spur. Pilocarpine was then ineffective in increasing outflow facility, indicating that ciliary muscle contraction mediated the IOP-lowering effect of muscarinic cholinergics. (2) Compounds such as cytochalasins, H-7 and latrunculin A/B, which alter the actin cytoskeleton, cellular contractility and cellular adhesions in cultured trabecular meshwork cells, relaxed trabecular pathway cells and consequently the meshwork itself so as to decrease IOP and enhance trabecular outflow facility in non-human primates. Gene transfer approaches utilizing C3 and caldesmon over-expression by viral vectors to target specific steps in the cellular contractility/cytoskeleton/cell adhesion cascades characteristically altered trabecular meshwork cell morphology and increased outflow facility in organ-cultured anterior segments. (3) Prostaglandin F(2alpha) analogues enhanced matrix metalloproteinase production by ciliary muscle cells and scleral fibroblasts, leading to remodeling of the extracellular matrix of the ciliary muscle and sclera and consequently to increased uveoscleral outflow and decreased IOP in primates. (4) The rhesus monkey was an excellent model for human presbyopia, losing the accommodative response to cholinergic stimulation in the same timeframe relative to lifespan. No changes were found in ciliary muscle enzymes involved in acetylcholine biosynthesis or degradation or in muscarinic receptor numbers or affinity. Contractility of isolated ciliary muscle did not diminish with age, but posterior ciliary muscle attachments stiffened, suggesting a possible role in restricting muscle and consequently lens movement during accommodation. A model to reproducibly stimulate accommodation through central stimulation of the Edinger-Westphal nucleus was developed. Goniovideography and ultrasound biomicroscopic techniques allowed real-time recording and analysis of the accommodation-relevant structures. Surgical ablation of the intraocular structures involved in the accommodation response has led to further understanding of their roles and changes with age related to presbyopia. (5) Global collaborations such as those involved in these studies will be essential in the future, as science becomes "bigger".     

激光老视术后调节的双因素理论

目的 :对于“激光老视治疗”的临床结果及基于弹性改变假说及晶状体前移及晶状体松弛模式的眼调节机制进行分析。方法 :根据光在模型眼中的传导原理 ,导出了总屈光力因晶状体与角膜屈光力、前房深度、眼轴长度及折射率而改变的函数。使用晶状体伸张及调节实验值导出与总屈光力变化相关的眼参数的实验方程。激光术后调节幅度使用林氏动态模型进行描述 ,此模型含晶状体的前移及松弛两个分量。同时提出林氏 卡达假说 ,认为术后调节改变及低回退率来自于巩膜 睫状肌弹性的增加。结果 :调节 (AA)幅度大约为晶状体屈光力改变的 73%～ 76 % ,并且与睫状体的收缩及晶状体厚度增加呈非线性变化。我们提出对于 2 .0D的调节可由晶状体松弛 (LR)或前移 (AS)或LR及AS两者组合而达到。对于硬化的老年晶状体 ,AS是主要因素。结论 :激光老视治疗 (LAPP)的临床结果可由光在眼球的传导方式计算及由弹性改变假说和包含晶状体前移和松弛的动态模型的调节机制来分析 ,其中动态模式包含晶状体前移及松弛两个因素。     

Change in the accommodative force on the lens of the human eye with age

The aim of the study was to determine the age-dependence of the accommodative force on the lens in order to make it clear whether the causes of presbyopia are due to lenticular or extralenticular changes. A finite element model of the lens of an 11-, 29- and 45-year-old human eye was constructed to represent the fully accommodated state. Subsequently, the force that was needed to mould the lens into its unaccommodated state was calculated. The force on the lens appeared to be preserved with age, with only a slight increase to a value of approximately 0.06N. In conclusion, the preservation of the net force delivered by the extralenticular ciliary body indicates that the causes of presbyopia must be ascribed to lenticular changes.     

Age-related changes in human ciliary muscle.

PURPOSE: To examine the role of the ciliary muscle in accommodation and presbyopia. METHODS: Sixteen pairs of eyes from donors aged 1 to 107 years were treated with atropine or pilocarpine and then processed for light microscopy. Seven pairs were analyzed for treatment effects, including morphometric measurements of muscle dimensions, muscle fiber group area, and the percentage of connective tissue. RESULTS: The ciliary muscle shortened in length in response to drug treatment at all ages. The ciliary muscle of older subjects contained greater amounts of connective tissue and was shorter, wider and the internal apical edge moved forward. CONCLUSIONS: This study confirms previous reports that the human ciliary muscle retains its ability to contract throughout the lifespan. However, the ciliary muscle also displayed age-related changes, which may be partly accounted for by the forces exerted from the aging lens and zonules.     

Involutional changes in the human eye accommodative apparatus as evidenced by ultrasound biometry and biomicroscopy

The paper presents the results of studying involutional changes in the accommodative apparatus of the eye in presbyopia by ultrasound biometry and biomicroscopy. Persons aged 40-70 years who had presbyopia and emmetropic refraction and without concomitant eye disease were examined. In addition to routine studies, all the examinees underwent ultrasound biomicroscopy and ultrasound biometry. The age-related lenticular enlargement was established to be accompanied by a considerable reduction in the orbicular space of the posterior chamber of the eye to the extent of its transformation to a slotted space. The presbyopic patients were found to have a significantly diminished tone in the middle and posterior portions of the lenticular ligamentous apparatus to the extent of its sag, with the altered direction of their passage between the crystalline lenticular equator and the ciliary body crown, i. e. from meridional to radial. The revealed significant age-related topographic and anatomic changes in the orbicular portion of the posterior chamber of eye and in ligamentous tone, which are associated with the involutional increase in the size of the crystalline lens point to the great importance of decreasing the working accommodation distance in the development of presbyopia.     

The optics of the eye-lens and lenticular senescence

Although the lens of the eye is structurally a biological tissue, it functions as an optical element providing one third of the refracting power of the human eye, and a variable focus in younger years. Throughout a life-time the optical properties of the eye-lens alter, resulting in changes in function: there is a gradual depletion of the focussing amplitude from infancy to middle age, and a loss of transmittance in the later decades of life. The optical properties of the lens depend on its power, which in turn is determined by its physical dimensions (curvatures and thickness) and its refractive index as well as transmissivity and the organization of its internal components. The power of the functional lens is, however, modifiable by virtue of the lens being attached via the zonule to the ciliary muscle. The contraction and relaxation of the latter respectively increases and decreases lens power in accordance with innervations determined by the physical distance of external objects to be imaged on the retina. This review will consider many of these features and how alterations in any of them may lead to changes in lenticular function. However, as we have recently devoted a detailed study to presbyopia [1] its mechanism will not be considered here.     

Accommodative ciliary body and lens function in rhesus monkeys, I: normal lens, zonule and ciliary process configuration in the iridectomized eye

PURPOSE: The underlying causes of presbyopia, and the functional relationship between the ciliary muscle and lens during aging are unclear. In the current study, these relationships were studied in rhesus monkeys, whose accommodative apparatus and age-related loss of accommodation are similar to those in humans. METHODS: Centripetal ciliary body and lens equator movements were measured during accommodation in 28 eyes of 21 rhesus monkeys (ages, 5.7-26 years) by goniovideography. Ultrasound biomicroscopy was performed in 21 eyes of 17 monkeys. Narrowing of the angle between the anterior aspect of the ciliary body and the inner aspect of the cornea was used as a surrogate indicator of forward ciliary body movement during accommodation. RESULTS: Average centripetal ciliary body movement in older eyes (age > or =17 years, n = 16) was approximately 20% (0.09 mm) less than in young eyes (age, 6-10 years, n = 6), but not enough to explain the 60% (0.21 mm) loss in centripetal lens movement nor the 76% (10.2 D) loss in accommodative amplitude. Average forward ciliary body movement was 67% (49 degrees ) less in older (n = 11) versus young (n = 6) eyes. Maximum accommodative amplitude correlated significantly with the amplitude of centripetal lens movement (0.02 +/- 0.003 mm/D; n = 28; P < 0.001) and with forward ciliary body movement (3.34 +/- 0.54 deg/D; n = 21; P = 0.01). CONCLUSIONS: Decreased lens movement with age could be in part secondary to extralenticular age-related changes, such as loss of ciliary body forward movement. Ciliary body centripetal movement may not be the limiting component in accommodation in the older eye.     

Polymer refilling of presbyopic human lenses in vitro restores the ability to undergo accommodative changes

PURPOSE: Because presbyopia is thought to be accompanied by increased lens sclerosis this study was conducted to investigate whether refilling the capsule of the presbyopic human lens with a soft polymer would restore the ability of the lens to undergo accommodative changes. METHODS: Accommodative forces were applied to natural and refilled lenses by circumferential stretching through the ciliary body and zonular complex. Nine natural lenses and 10 refilled lenses from donors ranging in age from 17 to 60 years were studied. Two refill polymers with a different Young's modulus were used. The lens power was measured by a scanning laser ray-tracing technique, and lens diameter and lens thickness were measured simultaneously while the tension on the zonules was increased stepwise by outward pull on the ciliary body. RESULTS: In the natural lenses the older lenses were not able to undergo power changes with stretching of the ciliary body, whereas in the refilled lenses, all lenses showed power changes comparable to young, natural lenses. The refilled human lenses had a higher lens power than the age-matched natural lenses. The Young's modulus of the polymers influenced the lens power change when measured with the ciliary body diameter increased by 4 mm. CONCLUSIONS: Refilling presbyopic lenses with a soft polymer enabled restoration of lens power changes with mechanical stretching. Because sclerosis of the lens is an important factor in human presbyopia, refilling the lens during lens surgery for cataract could enable restoration of clear vision and accommodation in human presbyopia.     

The effect of cataract extraction on the contractility of ciliary muscle

PURPOSE: To evaluate the changes in the pilocarpine-induced contractility of the ciliary muscle in eyes with presbyopia before and after cataract extraction using ultrasound biomicroscopy (UBM). DESIGN: Prospective interventional case series. METHODS: A clear corneal phacoemulsification and posterior chamber intraocular lens (AcrySof SA60AT; Alcon Laboratories, Fort Worth, Texas, USA) was implanted in 23 eyes in 15 subjects. UBM was performed with and without instilling 2% pilocarpine, as well as before and two months after cataract extraction. The mean (+/- standard deviation) age was 65.33 +/- 6.09 years (range, 56 to 75 years). The increase in the axial length of the ciliary body (CBAXL) was used as a surrogate indicator of the centripetal ciliary muscle contraction during accommodation. Images of the ciliary body were compared visually using Adobe Photoshop 7.0 (Adobe Systems Inc., San Jose, California, USA). RESULTS: The CBAXL value with and without pilocarpine before cataract extraction was 1.708 +/- 0.165 mm and 1.689 +/- 0.187 mm, respectively, which was not significantly different (P = .261). The CBAXL value with and without pilocarpine after cataract extraction was 1.998 +/- 0.375 mm and 1.675 +/- 0.279 mm, respectively, which was significantly different (P < .001). The visually compared configurations of the changes in the ciliary body were compatible with the analysis of the measured parameters. CONCLUSIONS: Pilocarpine induced only subtle movement of the ciliary body before cataract surgery. However, after cataract extraction, it induced significant centripetal movement of the ciliary body compared with that without pilocarpine. This shows that a lenticular sclerotic component may influence both lens movement and the contractility of the ciliary muscle, and is believed to be related to the presbyopia.     

The mechanism of accommodation in primates.

OBJECTIVE: To study the accommodative mechanism in primates using monkeys, in light of a recently proposed novel accommodative mechanism in primates and a concomitant controversial surgical procedure for the reversal of presbyopia, DESIGN: Experimental study. METHODS: Accommodation was induced by stimulation of an electrode surgically implanted in the midbrain and by topical ocular application of muscarinic agonists. Pharmacologic disaccommodation was achieved by topical application of a muscarinic antagonist. Movements of the lens equator and the ciliary body were imaged during accommodation and disaccommodation using ultrasound biomicroscopy and goniovideography, and the images were analyzed to determine the direction and the extent of the movements. RESULTS: Despite the systematic eye movements occurring with electrical stimulation and the nonsystematic eye movements occurring with pharmacologic stimulation, in all instances the ciliary body and the lens equator moved away from the sclera during accommodation. CONCLUSIONS: Movement of the accommodative structures is consistent with the classic mechanism of accommodation described by Helmholtz, and contrary to that recently proposed by Schachar.     

Comparison of the behavior of natural and refilled porcine lenses in a robotic lens stretcher

The mechanism by which the eye dynamically changes focal distance (accommodation), and the mechanism by which this ability is lost with age (presbyopia), are still contested. Due to inherent confounding factors in vivo, in vitro measurements have been undertaken using a robotic lens stretcher to examine these mechanisms as well as the efficacy of lens refilling - a proposed treatment for presbyopia. Dynamic forces, anterior and posterior curvatures, and lens thickness are all correlated for young natural and refilled porcine lenses. Comparisons are made to lenses refilled with a homogeneous polymer system. The amplitude of accommodation of the young porcine lens is very small such that it may be a suitable model for presbyopia. The behavior of refilled lenses was highly dependent on the refill volume. The volume could be tuned to maximize accommodative amplitude in the refilled lens.     

Edinger-Westphal and pharmacologically stimulated accommodative refractive changes and lens and ciliary process movements in rhesus monkeys

During accommodation, the refractive changes occur when the ciliary muscle contracts, releasing resting zonular tension and allowing the lens capsule to mold the lens into an accommodated form. This results in centripetal movement of the ciliary processes and lens edge. The goal of this study was to understand the relationship between accommodative refractive changes, ciliary process movements and lens edge movements during Edinger-Westphal (EW) and pharmacologically stimulated accommodation in adolescent rhesus monkeys. Experiments were performed on one eye each of three rhesus monkeys with permanent indwelling electrodes in the EW nucleus of the midbrain. EW stimulated accommodative refractive changes were measured with infrared photorefraction, and ciliary process and lens edge movements were measured with slit-lamp goniovideography on the temporal aspect of the eye. Images were recorded on the nasal aspect for one eye during EW stimulation. Image analysis was performed off-line at 30 Hz to determine refractive changes and ciliary body and lens edge movements during EW stimulated accommodation and after carbachol iontophoresis to determine drug induced accommodative movements. Maximum EW stimulated accommodation was 7.36+/-0.49 D and pharmacologically stimulated accommodation was 14.44+/-1.21 D. During EW stimulated accommodation, the ciliary processes and lens edge moved centripetally linearly by 0.030+/-0.001 mm/D and 0.027+/-0.001 mm/D, with a total movement of 0.219+/-0.034 mm and 0.189+/-0.023 mm, respectively. There was no significant nasal/temporal difference in ciliary process or lens edge movements. 30-40 min after pharmacologically stimulated accommodation, the ciliary processes moved centripetally a total of 0.411+/-0.048 mm, or 0.030+/-0.005 mm/D, and the lens edge moved centripetally 0.258+/-0.014 mm, or 0.019+/-0.003 mm/D. The peaks and valleys of the ciliary processes moved by similar amounts during both supramaximal EW and pharmacologically stimulated accommodation. In conclusion, this study shows, for the first time, that the ciliary processes and lens edge move centripetally, linearly with refraction during EW stimulated accommodation. During pharmacological stimulation, the ciliary processes move to a greater extent than the lens edge, confirming that in adolescent monkeys, lens movement limits the accommodative optical change in the eye.