AGE-RELATED CATARACT: MANAGEMENT AND PREVENTION
3. OXIDATION OF LENS MATERIAL AND CATARACT FORMATION
AGE-RELATED CATARACT: MANAGEMENT AND PREVENTION 163 1997) descent. Although gender as a risk factor is clearly not subject to alteration, some studies suggests that post-menopausal use of estrogen may be associated with reduced risk of nuclear cataract (Cumming and Mitchell,1997). However, other studies have been unable to confirm this finding (McCarty et al.,1999).
Risk factors of importance in certain subpopulations include ocular conditions, such as uveitis and retinitis pigmentosa, both thought to be associated with PSC opacities, perhaps because of breakdown of the blood-ocular barrier and subsequent entry of cataractogenic factors into the eye. Ocular surgery is also an important risk factor, especially trabeculectomy (Klein et al., 1995; Collaborative Normal- Tension Glaucoma Study Group,1998) and retinal surgery (Wong et al.,2002). It has been suggested that surgically created alternative pathways for the drainage of aqueous from the eye may deprive the lens of aqueous-borne nutrients necessary to preserve normal clarity. A dose dependent association (measured both in terms of concentration and length application) between age-related cataract and mitomycin C, an anti-metabolite used regularly in glaucoma surgery, has also been established in a trial setting (Ramkrishnan et al.,1993). Ocular trauma can clearly be associated with lens opacity in certain individuals, although studies suggest that the impact on the prevalence in the population of lens opacity is probably minimal (Wong et al., 2002). Finally, periocular irradiation with gamma rays (Chen et al., 2001) and proton beams (Brovkina and Zarubei, 1986) can be associated with various forms of lens opacity. These smaller, well-defined subpopulations with a relatively high risk of rapid-onset cataract could ultimately serve as ideal subjects for trials of anti-cataract medications, although the relevance of the findings of such studies to age-related cataract would be unknown.
Finally, there are number of other risk factors for lens opacity which are either poorly understood, or, although they may be of importance for certain groups, do not represent a significant risk for the population as a whole. Several studies (Wong et al.,2001;Lim et al.,1999) have suggested that refractive errors, typically myopia, are associated with age-related cataract, particularly nuclear cataract and PSC (Lim et al.,1999; Wu et al.,1999;Vasavada et al., 2004). It is well known that increased refractive index of the lens in advanced nuclear cataract may cause a secondary myopia; pre-existing myopia may also serve as an independent risk factor (Lim et al.,1999). The mechanism for such as association, if indeed it exists, is not understood.
3. OXIDATION OF LENS MATERIAL AND CATARACT
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protein-poor phases causing local changes in refractive index and thus increased light scattering (Benedek, 1997). Protein aggregation increases with age. The crystallins, which constitute approximately 90% of the total protein content of the lens, accumulate and show many age-related oxidative changes. These include formation of disulfide and other inter- and intramolecular cross-links and methionine oxidation, all of which result in the aggregation of high molecular weight molecules.
Therefore, the protein redox status seems to be fundamental to maintain the lens function and transparency. It may be possible that local or systemic conditions affecting the protein redox status, such as myopia and diabetes, influence this process (Altomare et al.,1997).
Recently, it was hypothesized that a threshold of lipid oxidation might exist above which the opacification takes place and that this could be surpassed earlier in some subjects predisposed to cataract formation (Borchman and Yappert,1998).
The assessment of carbonyl and sulfhydril proteins has been suggested as being a valuable index of the protein redox status in the lens (Altomare et al., 1997).
In fact, the level of carbonyl proteins, derived from amino acids during metal- catalyzed oxidation of proteins in vitro and in vivo, represents a direct measure of the oxidative injury to these molecules (Stadtman,1992). The sulfhydryl proteins, known to have structural and functional role in the crystalline lens, contain an elevated number of thiol groups and, therefore are reduced as a result of oxidation.
A linear relationship between subject age and the amount of protein carbonyl groups has been found in the human eye lens cortex. It has been already shown that during senile cataract development a progressive decrease in SH content of the crystallins occurs.
It is estimated that the oxygen tension in the vicinity of the lens is low, yet this is sufficient to support some aerobic lens metabolism and is sufficient to act as a source of reactive oxygen species (ROS). A significant proportion of lenses and aqueous humor taken from cataract patients have elevated H2O2 levels. Because H2O2, at concentrations found in cataract, can cause lens opacification and produces a pattern of oxidation similar to that found in cataract, it is concluded that H2O2 is the major oxidant involved in cataract formation (Ramachandran et al., 1991).
This viewpoint is further supported by experiments showing that cataract formation in organ culture caused by photochemically generated superoxide radical, H2O2, and hydroxyl radical is completely prevented by the addition of a GSH peroxidase mimic. The damage caused by oxidative stress does not appear to be reversible and there is an inverse relationship between the stress period and the time required for loss of transparency and degeneration of biochemical parameters such as ATP, GPD, nonprotein thiol, and hydration. After exposure to oxidative stress, the redox set point of the single layer of the lens epithelial cells (but not the remainder of the lens) quickly changes, going from a strongly reducing to an oxidizing environment (Ito et al., 1993). Almost concurrent with this change is extensive damage to DNA and membrane pump systems, followed by loss of epithelial cell viability and death by necrotic and apoptotic mechanisms (Kleiman et al., 1990). There are evidences suggesting that the epithelial cell layer is the initial site of attack
AGE-RELATED CATARACT: MANAGEMENT AND PREVENTION 165 by oxidative stress and that involvement of the lens fibers follows, leading to cortical cataract (Worgul et al.,1989).
Lately it has been shown that Sex Steroid hormones regulate ocular tissues in addition to their conventional target tissues (Gupta et al.,2005). The female gender has been found to display an increased incidence of cataracts, as compared with age-matched men. This increased risk is seen in woman population after menopause only (Gupta et al., 2005; Leske et al., 2004). Protective effect of Sex Steroid Hormones in the perspective of cataractogenesis in females has been substantiated by epidemiological information. The Beaver Dam Eye Study suggests a modest protective effect of estrogen exposure on the lenses of women in the context of age related opacities (Klein et al.,1994). The results indicated that the current use of post-menopausal estrogens is associated with decreased risk of severe nuclear sclerosis. The study also showed that from menarche to menopause the life span of woman is associated with protective effect and decreased risk of nuclear sclerosis and cortical opacities. Recently it is shown that lenses from female rats are more resistant to transforming growth factor (TGF) induce cataract then those from males. In young age estrogen provides protection against cataract by counteracting the damaging effects of TGF(Chen et al.,2004;Hales et al.,1997). Proper ionic milieu and hydration of lens cells are essential to maintain transparency of crystalline lens. Estrogen maintains proper ionic composition by its non-genomic action (Singh and Gupta,1997a). Further, estrogens are known for increasing water imbibitions and retention of hydration in the target tissues (Singh and Gupta,1997b).
The lens possesses repair mechanism, both at a cellular and at a molecular level and it has an ability to isolate damaged fibers and the histology of this has been shown. At the molecular level, a number of scavenger molecules are present that protects against oxidative stress. Lens membranes contain Vitamin E, which protect against lipid peroxidation. GSH, a patient free redial scavenger, is synthesized in the lens from amino acid precursors. (L-glutamic acid, L-cysteine, and L-glycine).
It is present in high concentration in the cortex and in the epithelium, and at a lower concentration in the nucleus (Pau et al.,1990). It is probably important in maintaining lens proton thiols in the reduced state, such as that of Na+K+ATPase or of the lens crystalline thiols. It maintains ascorbate in the reduced state and scavenges peroxides and radiation induced free radicals Vitamin C, always in high concentration in the aqueous is actively transported into the lens, where it is at a higher concentration. Like GSH, it is an effective reducing agent. Other compounds, carotenoids, choline, taurine, and thioredoxin-T have been ascribed similar roles.
3.1 Management of Age-related cataract
Cataract surgery is the only remedy of the age related cataract today. Unless the patient presents with an eye threatening condition e.g. hypermautre cataract, where advising immediate surgery is inevitable, this decision to operate should be on patients discretion. If the individual is comfortable in his day to day activities e.g. reading, moving about at home, etc. he can be advised to wait until such
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time when his present routine activities are curtailed owing to cataract. Glare is another debilitating symptom of cataract for which an active individual needs to be operated. This happens particularly in context of night driving or even in bright sunlight.
The ultimate goal of a cataract surgery is to restore and maintain the precataract vision and to alleviate the other cataract-related symptoms. In the quest for perfection, the techniques and approaches followed by cataract surgeons have constantly evolved over the years from Intra Capsular Cataract Extraction (ICCE) to Aqualase (water jet technique). The phacoemulsification technique, which allows an exquisite intraoperative control and a consistent closed-chamber removal of cataract, undoubtedly reigns supreme in the developed countries. This technique has brought cataract surgery results as close to anatomical perfection as possible with the current technology and skills. In order to increase safety and to achieve faster visual rehabilitation for their patients, many surgeons are now adopting topical anesthesia with an adjunctive intracameral 1% lidocaine (Shah et al.,2004) instead of the peribulbar variety, which is till popular with most surgeons around the world.
Incisions have progressed to sub-3 mm size on the temporal clear corneal region, which affords easier access to the cataract under topical anesthesia. Understanding the distinctive uses of the newer dispersive and cohesive viscoelastics has helped ensure better corneal endothelial protection during phacoemulsification. Of the wide range of phaco techniques developed to suit different cataracts and their related conditions, recommendations are for those that ensure endocapsular (posterior plane) phacoemulsification, which ensurse far superior long-term outcome. (Vasavada AR, Raj SM, Nehalani BR, MR Praveen, P @ P=3P. Video film presented at the symposium of American Society Of Cataract & Refractive Surgeons, 2005, Washington DC, USA).
In the actual phacoemulsification technique, a sub 3 mm clear corneal tunnel is fashioned followed by injection of viscoelastic to form the anterior chamber.
Anterior capsular opening (capsulorhexis) is created with the help of a bent needle (cystotome). Hydrodisection procedure is then performed to free the nucleus from the capsule. After ensuring a freely rotating nucleus, a wide trench or crater is created which is confined within the area of the capsulorhexis. After achieving sufficient thinning of the nuclear plate (atleast 90% of the total central depth), the phaco tip is buried at 6 o’clock, using controlled U/S power, to produce a vacuum seal. This results in an effective hold on the nucleus; the “step by step chop in situ and lateral separation” maneuver (Vasavada and Singh, 1998) is then performed by placing the chopper adjacent to the phacotip (Figure 1). The entire nucleus is chopped thus in a step-by-step fashion by rotating the chopped fragment clockwise and repeating the same chop technique. Finally the chopped wedges are consumed in the central space using the “stop, chop and stuff technique” (Vasavada and Desai, 1996) ensuring a completely endocapsular phacoemulsification (Figure2).
After emptying the capsular bag off the nucleus, the cortical matter is aspirated using bimanual irrigation and aspiration system. This is followed by foldable intraocular lens implantation in the capsular bag.
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Figure 1. “Step by step chop in situ and lateral separation” maneuver to divide the nucleus of cataract into small wedges
Cataract surgeons today, in their relentless pursuit of perfection and excel- lence, are still looking into the probable advantages of other available options like ultrasound assisted by a secondary energy source such as PhocoTimesis, and fluid-assisted cataract removal like Aqualase™, pulsed hot water technology and the LASER-assisted cataract removal. Although some of these alter- native futuristic techniques are available today, they have not been extensively adopted.
Posterior capsule opacification (PCO) is the prime deleterious consequence of cataract surgery. This aphoristic concern over the clarity of the posterior capsule shall undoubtedly dominate the future arenas of research and innovation. Presently, improving the IOL design and material appears to be a more practical means of reducing the incidence of PCO. The use of accommodative material also has a bright future if the absence of capsular opacification can be ensured. The current experimentation and innovation to perfect the chemoemulsification technique may turn out to be and easier alternative. The concept of implanting an intraocular drug delivery device at the end of cataract surgery is in its infancy. Its routine use in future may definitely bring significant relief to a surgeon from the worries of patient compliance and ensure an excellent round the clock postoperative medical control.
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Figure 2. Consumption of wedges in the central space by “stop, chop and stuff technique”
4. PREVENTION STRATEGIES: PRESENT LIMITATIONS