Ocular Health Implications of the Loss of Dynamic Range of Focus Function in Presbyopia

Presbyopia Is a Widespread, Undertreated, and Misunderstood Disease

Presbyopia is defined as the eye’s loss of ability to focus on objects at near distances, and it is the most common cause of age-related vision impairment. Presbyopia is a significant global health issue that is underdiagnosed. It affects all people in their 40s and older: an estimated 90 million people in the United States and more than 1 billion people worldwide, are affected.1 Of these, half a billion have no or inadequate spectacles, and 410 million are unable to perform important near tasks.13 Thus, presbyopia is both widespread and undertreated.

This disease is further complicated by lack of understanding of its progression and development. It is widely believed to be an unavoidable age-related condition instead of a preventable disease; as such, treatment options are mostly compensatory and not restorative. Such treatments often focus on refractive error, however accommodation is, at a fundamental level, a function involving biomechanics, movement, and shape changes. The movement and shape changes of the lens and other ocular structures allow a shift in focus to and from distant and near objects, as well as every distance in between. Historical presbyopic solutions are all compensatory treatments focusing only on the near refraction end goal, including reading spectacles. In addition, these corneal and intraocular lens approaches are static and fail to address the progressive loss of the dynamic movement that makes dynamic range of focus (DRoF) possible.

DRoF is the normal, prepresbyopic condition of the eye. The term includes the elements of the eye that provide a continuous range of focus instead of discreet near and far foci. DRoF involves neuromuscular and optical-based responses to stimuli. DRoF has optical, biomechanical, and neural components, which is why “visual perception” is quite unique from one individual to another.4 Age-related changes in the connective tissues, muscles, and even reflexivity to light stimuli all impact the eye’s ability and efficiency for DRoF function. These biomechanical dysfunctions also progress with age. Therefore, presbyopia results in a progressive loss of DRoF, a dysfunction that cannot be addressed with compensatory lenses or exchange of power at the cornea or lens to achieve near vision. These solutions only offer symptomatic relief, along with a compromise in other visual focal points.

Biomechanics and Ocular Rigidity Play an Important Role in Presbyopia Development

Although the cause of presbyopia is not fully understood, age-related changes to ocular connective tissue biomechanics play a major role.5,6 Traditional teaching is that presbyopia is due to stiffening of the lens and lens capsule7: as the lens and lens capsule become stiffer with age, the ciliary muscle is unable to produce sufficient resultant forces to overcome this added resistance to move and shape the lens into an accommodated position to achieve DRoF for near vision tasks. However, more recent studies demonstrate the importance of extralenticular tissues to DRoF and how they may contribute to presbyopia.5,6

Ocular rigidity (OR) is the globe’s ability to resist pressure in response to volume increases, and it also undergoes changes associated with age.813 Due to the change in scleral biomechanical properties,8,14 overall OR increases with age, and it is correlated with a decline in DRoF and is therefore a likely culprit causing the loss of DRoF function. The sclera, for example, exerts pressure on the underlying ciliary muscle and influences the overall rigidity of the eye.8,14 Scleral movement is also apparently important during accommodation. For example, the sclera near the limbus in the nasal region notches inward during accommodation in young healthy eyes, but this movement is lacking or diminished in presbyopes.15 This loss of movement is likely associated with the natural increasing scleral stiffness observed with age.1620 It is possible that OR affects the pathogenesis and clinical course of various ocular conditions, including glaucoma, age-related macular degeneration (AMD), presbyopia, cataract formation, and corneal changes following refractive surgery.21

Remembering the importance of movement in accommodation, these tissues must maintain proper elasticity to achieve DRoF, but age is associated with loss of tissue elasticity. The Bruch’s membrane-choroid complex (BMCC) and retina also play important roles in DRoF and contribute to accommodative movements, including acting as an elastic spring to store energy and pull the lens backward during disaccommodation (near to far focus).2224 These accommodation biodynamics are controlled by the neuromuscular function of the accommodation apparatus. These connective tissues are also affected by age in predictable ways, like all other tissues. The structures of the BMCC undergo increased stiffening with age,25 which is associated with a loss of elastic “spring” force and contributes to the loss of DRoF that occurs with presbyopia.24

This increasingly problematic biomechanical dysfunction induces mechanical impingement on the structures that play key roles in the eye’s ability to control intraocular pressure (IOP), such as the scleral spur, Schlemm’s canal, and the trabecular meshwork.26 These structures all work together to modulate IOP and regulate the hydrodynamic functions of the eye. The integration of these biomechanical components impact overall ocular health and fitness and is especially susceptible to age-related change and dysfunction.

Figure 1. Negative effects of advanced glycation end products (AGEs). AGEs lead to impaired cell function, altered signaling pathways, and increased collagen crosslinking. These processes, particularly crosslinking, are responsible for stiffening of the sclera and other ocular structures with age. (Adapted from Roorda MM. Therapeutic interventions against accumulation of advanced glycation end products (AGEs). Glycative Stress Research 4(2): 132-143, 2017).

Figure 2. Anatomy of the anterior eye near the limbus. (Reprinted from Hughes MO, Luce CA. Depicting the Anterior Eye in Two and Three Dimensions. Part Two: Iris, Limbus and Sclera. Journal of Biocommunication: 2005;31:2).

Collagen Crosslinking Is the Molecular Underpinning of Scleral and Ocular Rigidity

The biomechanical properties of ocular tissue, and therefore lens stiffness, capsular stiffness, and ocular rigidity, are largely determined by collagen. Collagen is a ubiquitous extracellular matrix protein of connective tissue, and its structure lends elasticity properties to the tissue with which it is associated.27 For example, the stress-strain curves of the sclera, which have shallow “toe” and steep “heel” sections, are formed as collagen fibers uncrimp and begin to bear their load uniformly across fibers.27,28

An important structural element of collagen fibers is crosslinking, in which adjacent fibers become covalently linked to each other via lysine residues. While some collagen crosslinking is normal in young, healthy eyes, collagen crosslinking increases with age.16,29,30 This process occurs in all ocular connective tissues as the production of advanced glycation end products (AGEs) increases with age. This increased AGE-induced crosslinking is a major contributor to lens and scleral stiffness, which in turn cause cataracts and ocular rigidity.16 AGEs have been identified as a trigger for oxidative stress and inflammation affecting organ health and function in other parts of the body, including the heart and brain.31

Figure 3. Aqueous humor circulation and the important relationship between accommodation and hydrodynamics. (Adapted from Krey HF, Bräuer H. 1998. Chibret Augenatlas: Eine Repetition für Ärtze mit Zeigetafeln für Patienten. Munich: Chibret Med Serv).

Could Ocular Rigidity Underlie Multiple Diseases of the Aging Eye?

Presbyopia is not the only age-related eye disease: cataracts, AMD, primary open angle glaucoma, and diabetic retinopathy occur with increasing frequency with age and are correlated with the onset and progressive problem of AGEs.3234 Moreover, AGEs have been established as biomarkers for all ocular pathologies, including progressive lens stiffness and progressive ocular rigidity in presbyopia, as well as lens death, which produces cataracts.33,34 Presbyopia has been proposed to be an early symptom of cataract.35 Multiple diseases have been associated with increasing ocular rigidity, including presbyopia, glaucoma, and AMD.21

Moreover, the movements associated with DRoF might be critical to maintaining other parts of the eye in a healthy state. The crystalline lens, along with extralenticular structures of the accommodative apparatus, move in a fluid medium (aqueous humor) and via that medium cause transient pressure changes and hydrodynamic movements during accommodation. These neuromuscular and biomechanical structures within the accommodative complex also impose stretch forces upon important structures, such as the trabecular meshwork, during ciliary muscle contraction, during accommodation and disaccommodation.

Finally, accommodative movements that produce DRoF are also physiologically important for maintaining appropriate aqueous outflow, IOP hydrodynamics, and nutrient bathing of the lens in young, healthy eyes through the ciliaris, scleral spur, and trabecular meshwork. Therefore, the loss of efficient DRoF function is a gateway to multiple ocular pathologies when age-related biomechanical dysfunction occurs.36 This underlines the critical importance of restoring DRoF, which potentially provides an ocular health benefit, in addition to functional compensation, rather than simply providing refractory compensation. For this reason, attempting to restore DRoF might also have an added ocular health benefit, in addition to dynamic focusing ability. In consideration of the various physiological interactions in which the structures of the accommodation complex participate, restoring DRoF has the potential to delay the onset of other ocular diseases of advanced age. Restoring DRoF has clinical significance; therefore, it should be pursued. ■


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