Ординатура / Офтальмология / Английские материалы / Hyperopia and Presbyopia_Tsubota, Boxer Wachler, Azar_2003

which are chemical and photochemical oxidation, glycation, and racemization. Antioxidant defense mechanisms may ameliorate some of these posttranslational changes. Also, with increasing age monomeric proteins associate in covalently bound aggregates to form high- molecular-weight aggregates whose hydrodynamic radii approach in size the wavelengths of visible light. As size increases, light scattering also increases to the point of lens opacification and frank cataract. Changes with age in protein conformation and phospholipid composition of fiber membranes increase nuclear rigidity and contribute to presbyopia. This chapter considers many of these changes in more detail.

In the past 15 years, epidemiological research on age-related cataracts (ARCs) has revealed risk factors that pertain to behavior (e.g., diet, smoking, lifestyle, drug use) and suggested that ARC may be a preventable disease (5,6). This is most encouraging, for each year increasing percentages of public and private health care budgets are used to provide surgical care for ARC.

A. AGING AND CHANGES IN LENS SIZE AND SHAPE

Several authors (7–12) have documented the growth of the lens throughout life. Koretz et al. analyzed (24) Scheimpflug photographs of the unaccommodated lens in 100 subjects from 18 to 70 years of age to determine the regions that changed with time. With Scheimpflug optics the lens image is in focus from the anterior to posterior pole. The geometric distortion of Scheimpflug images can be corrected (14), so that accuratemeasures of the lens can be obtained. Koretz et al. measured the lens with Hough transforms and other image analysis methods. The radii of the anterior and posterior surfaces of the whole lens decrease, but the volume increases with increasing age. In contrast, neither the shape nor the volume of the nucleus changes with age. The central clear zone and center of mass of the nucleus move anteriorly with age. The correlation between lens shape and location (relative to the cornea) is very high, confirming earlier results. Also, the anterior movement of the lens with age increases the likelihood of phakic IOL–lenticular touch and complications.

Another study (15) explored the relationship of accommodative convergence per unit of accommodative response (AC/A ratio), refractive error, and age to determine if the AC/A ratio was a risk factor for myopia. A high AC/A ratio was associated with—and a risk factor for—rapid onset of myopia. A higher AC/A ratio, associated with a flatter crystalline lens, increased the effort to accommodate, or “pseudocycloplegia.” Accommodative deficits in myopia may be the functional consequence of myopic enlargement of the eye. This enlargement was documented in a study (16) of changes in biometric measurements and refractive errors over a 3-year period in eyes of university students. After 3 years, the mean change in refractive error (in OD) was 0.52 / 0.45D (p 0.05). The mean lens thickness increased by 0.07 / 0.10 mm (p 0.05), and the mean elongation of the vitreous chamber was 0.27 / 0.30 mm (p 0.05). Regardless of the original refractive error, the change in refractive error over the 3-year period was toward myopia. There were no statistically significant changes in the curvature of the cornea or depth of the anterior chamber. The authors concluded that the myopic shift was due to an elongation of the vitreous chamber.

In a study of 1-year-old chickens (17), form deprivation vision such as is obtained through translucent glass or eyelids that have been sutured closed, even in fully grown birds, was associated with a myopic shift that was similar but not as large as that in neonatal chicks. The decreases in retinal dopamine seen in neonatal chicks were also seen

to a lesser degree in 1-year-old chickens. These studies suggest that form deprivation is one of the mechanisms controlling eye growth and causing myopia.

B. AGING AND CHANGES IN REFRACTIVE ERROR

The modulation transfer function (MTF) has been used (18) to estimate the overall optical performance of the eye with increasing age. In qualitative terms, the MTF is used to assess optical quality of lens combinations by measuring the degree to which a point source of light is dispersed to a spot, in this case on the retina. The average MTF was determined as a function of age and pupillary size. Not surprisingly, the MTF declined in an approximately linear fashion with age, but it did not vary with gender. The decline in MTF may account for the decline in contrast sensitivity function (CSF) with age.

C. PRESBYOPIA

In an important paper appearing in 1988 (19), Fisher recounted the classic argument that presbyopia was related to the force of contraction of the ciliary muscle and the resistance to deformation of the crystalline lens. He recounted the view of Donders (20), that presbyopia was caused by a decrease in the force of contraction of the ciliary muscle with age, and the opposing view of Helmholtz (21), that the lens became more difficult to deform with age due to lenticular sclerosis. Fisher found that, in fact, the ciliary muscle undergoes a compensatory hypertrophy as accommodative amplitude decreases with age. The force of contraction is about 50% greater at the onset of presbyopia than in youth. However, because of increased lenticular resistance, its effect on the amplitude of accommodation is small. Fisher claimed that the lens becomes more difficult to deform not because of lenticular sclerosis, since the lens substance does not lose water, but because the capsule loses its elastic force with age and the lens fibers, particularly in the nucleus, become more compacted with age. In fact, the nuclear fiber mass becomes more rigid with age, as was shown in subsequent studies.

Since Fisher’s work, considerable progress has been made in our understanding of the mechanisms of presbyopia. In 1991 (22), Pau and Kranz used a fine conical probe and a dynamometer to measure the resistance to penetration of various layers of the lens. The resistance to penetration increased with age, due primarily to a hardening of the nucleus. The cortex did not show this hardening. In an interesting study of the dynamic aspects of accommodation (23), Heron et al. showed that accommodation gain decreased and the phase lag increased with age. Reaction time, response time, and accommodative velocity did not change with age for a target oscillating sinusoidally in a predictable manner at modest amplitude. The main aging effect was a longer than predicted phase lag. In spite of decreasing amplitude of accommodation, other aspects of accommodative function were quite robust in the middle-aged eye.

In a very elegant study of accommodation in vivo using magnetic resonance imaging (MRI) in humans, Strenk et al. (24) showed that the muscle’s contraction decreased only slightly with increasing age. A decrease in the diameter of the unaccommodated ciliary muscle ring was highly correlated with advancing age. Unaccommodated lens thickness increased with age, but the thickness of the lens under accommodative effort was only slightly age-dependent. Their data shed light on what has been a lens paradox—namely, the decrease in the ciliary muscle’s diameter and an increase in lens thickness in the unaccommodated eye. These changes showed the greatest correlation with increasing age.

They concluded that presbyopia was actually due to the loss in ability to disaccommodate due to increases in lens thickness, the inward movement of the ciliary ring, or both.

The issue of whether the changes in the human lens are due to changes in the lens fiber mass or changes in the lens capsule were addressed directly in a recent study (25) of the biometric, optical, and physical properties of capsulated and decapsulated lenses. Lens focal lengths, thicknesses, surface curvatures, and spherical aberrations were measured for paired eye-bank lenses. Decapsulating the lens caused changes in focal length similar to those occurring in lenses stretched into an unaccommodated state. These phenomena were attributed to nonsystematic changes in lens curvatures. These data support the concepts that lens hardening is an important factor in presbyopia and that aging changes in the lens are not limited to the loss of accommodation and cataract. In addition there are substantial changes in the optical and physical properties of the lens with aging.

It is known that myopes have shallower accommodative stimulus/response functions (26), due possibly to reduced sensitivity to defocus. Jiang and White showed that a near task caused a small increase in the static accommodative response. In both emmetropes and late-onset myopes, near tasks also increased the interval for relaxing accommodation. These data suggest the existence of two subsystems that adapt differently to prolonged accommodative effort.

Heron et al. studied dynamic accommodation responses to small, abrupt changes in an accommodation stimulus (27). They concluded that for small stimuli within the amplitude of accommodation, the response dynamics (reaction and response times) over the adult age range (16 to 48 years) remained remarkably constant even though the amplitude of accommodation decreased progressively with age.

D.AGING, OXIDATIVE STRESS, LENS OPACIFICATION AND CATARACT

Considerable evidence has accumulated implicating oxidative stress as a major risk factor in age-related cataract (ARC) formation. Both chemical oxidation (H2O2) and photo-oxida- tion (secondary to UV irradiation) have been implicated. In addition to a cumulative increase with age in the oxidative damage to lens proteins and lipids, there is also a gradual reduction in the potency of the lens antioxidant defenses. In a recent study (28), the thiol and carbonyl contents of 62 cataractous (age-related idiopathic, diabetic, and myopic) lenses and ageand sex-matched clear lenses from patients undergoing vitrectomy or giant retinal tear surgery were compared. There was a statistically significant (p 0.01), ageassociated inverse relationship between the contents of P-SH and protein carbonyls. The changes were greater in cataractous than clear lenses and greater in diabetic and myopic cataracts than in age-related cataracts. The decrease in P-SH occurred earlier in diabetic and myopic cataracts than in ARCs. An increase in protein carbonyls 2 nmol/mg protein and a decrease in P-SH of 10 to 12 nmol/mg protein were always associated with lens opacification.

The tripeptide glutathione (GSH) is present at high concentrations (4 to 6 mM) (29) in the young lens and in the cortex of older lenses. It has been identified as one of the major antioxidant defenses in the lens. The GSH-redox cycle is very active in lens epithelium and cortex. Via this cycle, the lens detoxifies hydrogen peroxide, other active oxygen species, and dehydroascorbic acid. There appear to be separate mechanisms in LECs for the detoxification of hydrogen peroxide and hydroxyl radical. Recently, Truscott (30) and Moffat et al. (31) demonstrated a barrier to free diffusion of GSH within the lens that increases

with age. The low ratio of GSH/P-SH and the relatively inactive GSH-redox cycle in the nucleus make the nucleus more susceptible to oxidative stress than the cortex. That, indeed, this is the case has been demonstrated in animal models with hyperbaric oxygen (32), UVA irradiation (33,34), and the glutathione peroxidase knockout mouse (35–37). With increased oxidative stress in nuclei of lenses in these animal models, there is an increase in protein disulfides and light scattering. Also with reduced activity of the GSH-redox cycle, there is damage to Na , K -ATPase (an enzyme involved with many of the active transport mechanisms in LECs), to cytoskeletal proteins, and to membrane proteins involved in regulating membrane permeability. An excellent review of these topics has recently been published (38).

As oxidative stress increases and the size of the GSH pool decreases, some proteins thiols (P-SH) are converted to protein-thiol mixed disulfides (29), either protein-S-S- glutathione (PSSG) or protein-S-S-cysteine (PSSC). The formation of PSSG precedes the formation of PSSP (29) and increases insolubilization of lens proteins. Lou et al. (29) discovered that the early oxidative damage could be reversed if the oxidant was removed in time. This reversal is mediated by the enzyme thiol transferase (TTase), recently found in the lens. Lou et al. showed that recombinant TTase, although requiring GSH for activity, was much more efficient in dethiolating lens proteins than GSH alone. TTase favored PSSG over PSSC and gamma-crystallin-S-S-G over alpha-crystallin-S-S-G. TTase was also remarkably resistant to oxidation. The TTase dethiolase activity reactivates enzymes deactivated by S-thiolation. It is this ability to regulate and repair SH-dependent enzymes that suggests that TTase plays an important role in ARC formation.

In a study (39) of ascorbate oxidation and advanced glycation in the lens, the major advanced glycation end product (AGE), N(epsilon)-carboxymethyl-L-lysine (CML), was found to have an EDTA-like (chelator) structure that might bind copper. Ascorbylation led to increased CML formation, copper binding, and free radical formation in the lens. These results suggested that there is a vicious cycle in the lens between AGE formation, lipoxidation, metal binding, and oxidative damage. It is possible that chelators may play a role in the therapy of ARC.

In another interesting study of the possible value of antioxidants in the treatment of ARC (40), it was shown that chronic administration of vitamin E, but not of sodium ascorbate, restored the age-associated decrease in GSH content in rat lenses to levels comparable to those in younger rats. The age-associated decrease in lenticular glutathione peroxidase, glutathione reductase, and glucose-6-phosphate dehydrogenase was not reversed by chronic administration of either vitamin E or sodium ascorbate (40).

In addition to the age-associated change in lens proteins, there are age-associated changes in lens lipids. The percentage of sphingolipid nearly doubles with age, and there is also an increase in hydrocarbon chain saturation with age. These increases were much greater in the deeper layers of the lens (41). These data support the idea that the degree of lipid hydrocarbon order is determined by the amount of lipid saturation, and this, in turn, is regulated by the content of saturated sphingolipid. Hyperbaric oxygen treatment increases the lipid disorder in the nucleus and the levels of lipid hydroxyl, hydroperoxyl, and aldehydes. The transparency of the nucleus is also reduced as these lipid oxidation products accumulate in the lens.

The Roche European-American Cataract Trial (REACT) (42,43), the first prospective, randomized, placebo-controlled clinical trial of oral vitamins E and C, and betacarotene suggested that antioxidant treatment might slow the progression of ARC. A small but statistically significant deceleration of ARC was found after 3 years of treatment in

a cohort of American and British patients. In this study, the beneficial effect was seen in the entire cohort and in the subgroup of American patients but not in the subgroup of British patients. The basis for the different responses of American and British patients to the antioxidant treatment was not clear but may have been due to the fact that the British patients had slightly more advanced cataracts at entry.

E. AGING AND THE ZONULE

There has been very little research on the effects of aging on the zonule. Recently, however, a light and electron microscopic study of the human ciliary zonule has been published (44). The organization of the zonule as it inserts into the ciliary body was studied. Fibrillin is the major constituent of the zonule and also of microfibrils. Mutations in the fibrillin gene are thought to underlie the zonular abnormalities of Marfan’s syndrome. With aging, the zonular fiber becomes more fragile, increasing the risk of ocular pathology.

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lenses are relatively inexpensive, and though there are ongoing costs in terms of replacing the lenses, the lens care solutions, and having follow-up care, the expenditures are modest compared to the significant initial outlay for refractive surgery. Contact lenses can easily be exchanged as patient’s refractive error changes and so allows children and young adults to be fitted even before the refractive error has completely stabilized. In addition, older individuals have an option to change to presbyopic contact lenses as the need for additional correction for good near vision increases. Perhaps the key to the success of contact lenses is their flexibility: the ability to change lenses to meet patients’ changing visual needs and even give them the ability to return to spectacles or other vision correction method at any time. Most refractive surgery procedures are permanent and irreversible. If for any reason a patient is unhappy or dissatisfied with the surgical results, he or she “cannot go back again.”

B.REFRACTIVE SURGERY VERSUS CONTACT LENSES FOR THE CORRECTION OF REFRACTIVE ERRORS

1. The Contact Lens Candidate

As with any patient seeking correction of a refractive error, a complete eye exam is indicated. This would include obtaining a good history. It is important to determine how the patient will be using the refractive correction and whether it is to be used for a specific activity such as skiing, swimming, computer use, etc. Medical problems that might increase the risk of wearing contact lenses could include diabetes mellitus, immunosuppression, severe allergies, and possibly occupational hazards such as exposure to volatile gases. The eye examiner needs must be particularly attentive to lid function, since spreading of a tear film by blinking is central for the good fit of a contact lens. Evaluation for possible dry eyes is essential, since a poor tear film can interfere with the patient’s ocular health and/ or comfort with lenses.

Relative contraindications to contact lens wear are not different from those being considered when a patient is being evaluated a patient for refractive surgery: the inability to understand the risks and benefits of the correction modality, immunosuppressed patients, patients with only one functional eye, history of previous ocular problems including herpetic keratitis, previous ocular surgery such as glaucoma filtering procedures, chronic use of topical medications such as steroids, severe dry eyes, neovasclarization of the cornea, corneal dystrophies, and pregnancy. The key issues regarding more of contraindications that are specific to the fitting of contact lenses include patients who are unable or not willing to participate in appropriate lens care and follow-up care, patients who are unable to learn to insert and remove contact lenses or do not have a family member who can assist with this process, and patients who may have poor hygiene, which may put them at increased risk for infections associated with contact lens use.

C. SOFT CONTACT LENSES

Soft contact lenses are made of a plastic called hydrogel that can be shaped into lenses but maintains its flexibility and provides immediate quality vision and comfort for most patients.