Section 2 – Cataract
Chapter 35 – Pathophysiology and Epidemiology of Cataract
DEEPAK K. CHITKARA
ANTHONY B. HALL
A. RALPH ROSENTHAL
Lens abnormalities may be divided into two categories—abnormalities of lens size and shape, which are largely developmental, and abnormalities of lens clarity, or cataract. Cataract may be defined as any light scatter opacity in the lens, not necessarily with any demonstrable effect on vision. Cataract that is significant enough to impair vision is the leading cause of blindness worldwide. In this chapter, lens abnormalities related to abnormal growth and the epidemiology and causal factors in cataract formation are discussed.
NORMAL LENS GROWTH
The human lens, unlike the lens in other species, continues to grow throughout life. In addition, the growth rate is not linear but has distinct phases. Growth is most rapid in the embryonic and prenatal phases. The lens induction precedes development of the optic vesicle. It is thought that a large area of head ectoderm acquires a “lens bias” in response to signals from the anterior end neural plate ( Fig. 35-1 ). At the 2.6?mm stage the optic vesicle develops from the forebrain. Signals from the optic vesicle cause the lens-biased tissue to differentiate further into the lens placode (or plate). As the placode grows, it forms the lens pit below its center. This lens pit is lined by flattened lens epithelial cells. As the pit enlarges into a lens vesicle, the epithelial cells within it break down and disappear by the 16?mm stage. The enlarging pit forms a sac, which initially is open at the surface by the lens pore. This pore closes with further growth, which results in a spherical lens vesicle by the 8–9?mm stage. The vesicle is approximately 0.2?mm in diameter at this stage.
The cells of the posterior wall of the vesicle then elongate, which results in obliteration of the cavity of the vesicle. Meanwhile, the anterior cells become less crowded and assume a cuboidal shape—these cells will become the lens epithelium. Eventually, the cells of the posterior wall become separated from the epithelial cells anteriorly and the capsule posteriorly to form the embryonic nucleus. The lens capsule is secreted by the cells of the equator and those of the posterior wall by the 13?mm stage. At the 17?mm stage the lens diameter is about 350?µm in the anteroposterior plane and 300?µm in the equatorial diameter. Further growth takes place by the division of pre-equatorial epithelial cells, which become the germinative zone of the lens. New fibers are added here throughout life.
The lens at birth is almost spherical, with a slightly shorter sagittal than equatorial axis. After birth, lens growth slows down, but an important shape change occurs, such that most of the growth is equatorial in the first two decades.  The sagittal width may even decrease as a result of increased zonular tension and central compaction of lens fibers. As a result, the lens begins to take on the characteristic shape of the mature adult lens. Later, lens growth is in the sagittal axis with limited equatorial growth. This limitation leads to increased curvature of the lens, and the anterior chamber steadily shallows.
Figure 35-1 Embryonic development of the lens. The lens placode invaginates into the cavity of the secondary optic vesicle.
The suspensory ligaments of the lens develop as fibrils, which pass across the ciliary region of the neuroectoderm to the lens equator after the third month of intrauterine life at the 65?mm stage. Their arrangement is regular by the 110?mm stage.
ANOMALIES OF GROWTH
Aphakia may be primary or secondary. Primary aphakia is a rare condition associated with gross malformations such as microphthalmos, microcornea, and nystagmus. It is proposed that a primary defect in surface ectoderm or in the formation of the optic cup is responsible.
Secondary aphakia is distinguished from primary aphakia by the presence of some remnant of lens tissue or capsule. It may
be associated with developmental abnormalities, such as microcornea, or it may occur as a result of partial or complete absorption of the lens in congenital cataract from rubella.
Duplication of the Lens
A metaplastic change in surface ectoderm may prevent the invagination of lens placode and thereby the formation of a single vesicle, which may lead to a duplication of the lens. The condition is usually associated with corneal metaplasia and coloboma of the iris and choroid.
Microspherophakia is a bilateral condition in which a defect in the development of lens zonules leads to the formation of small, spherical lenses. The condition may be familial and occur as an isolated defect or it may be associated with other defects in the Weill-Marchesani syndrome and hyperlysinemia. The condition results in lenticular myopia and lens dislocation, which is usually downward. As a result, pupil block and glaucoma are common complications.
In lens coloboma a congenital indentation of the lens periphery occurs as a result of localized absence of the zonule. The condition is usually unilateral and may be associated with coloboma of the iris, ciliary body, and choroid.
Lenticonus and Lentiglobus
In both lenticonus and lentiglobus an abnormality of the central lens curvature occurs, associated with thinning of the lens capsule and deficiency of epithelial cells in the affected region. The resultant protrusion of the lens surface may be conical, as in lenticonus, or spherical, as in lentiglobus; the protrusion may be anterior or, more commonly, posterior. The abnormality may be inherited as an autosomal recessive trait or associated with other abnormalities, such as Alport syndrome (familial hemorrhagic nephritis) or oculocerebral syndrome of Lowe associated with posterior lenticonus.
Both lenticonus and lentiglobus may cause lenticular myopia with irregular astigmatism and an oil droplet reflex on retinoscopy. The conditions are commonly associated with opacification of the posterior pole fibers. The opacification occasionally extends into the nucleus. Spontaneous rupture of the capsule may occur occasionally.
In internal lenticonus the surface of the capsule has a normal contour, but the nucleus within forms a cone anteriorly, posteriorly, or in both directions. This condition is very rare and may be a developmental defect in childhood or acquired in adult life.
A subluxation of the lens is described as a partial displacement, whereas a complete displacement is termed dislocation of the lens.
The causes of ectopia lentis may be familial or secondary to eye disease and trauma. Traumatic ectopia is by far the most common cause of ectopia lentis and is usually associated with signs of trauma to other ocular structures, such as angle recession. A history of ocular trauma, however, does not preclude other causes of ectopia lentis.
Ectopia may be secondary to a weakening of the zonule by uveitis or to its degeneration associated with hypermature cataracts, pseudoexfoliation of the lens capsule, and ciliary body tumors. Familial causes include an autosomal dominant form, which is usually bilateral and symmetrical and may be congenital or develop in youth. A recessive form is also recognized, which is associated with other developmental abnormalities of
Figure 35-2 Marfan syndrome. A retroillumination slit-lamp photograph of ectopia lentis associated with Marfan syndrome.
the eyes such as iris coloboma, microspherophakia, aniridia, and ectopia pupillae congenita.
Deficient development of the zonule causes ectopia lentis in association with other systemic conditions such as Marfan syndrome, Weill-Marchesani syndrome, homocystinuria, sulfite oxidase deficiency, and hyperlysinemia.
A subluxated lens causes a tremulous iris (iridodonesis), a fluctuating anterior chamber depth, and/or unstable lens movements (phacodonesis). The lens is commonly displaced vertically upward in Marfan syndrome and downward in Weill-Marchesani syndrome and homocystinuria ( Fig. 35-2 ). Vitreous may herniate forward into the anterior chamber and pupil-block glaucoma may result from either vitreous or the lens, if it displaces anteriorly. Posterior displacement of the lens may cause lens-induced uveitis. The subluxated lens causes progressive-induced myopia and astigmatism, reduced amplitude of accommodation, and monocular diplopia.
INCIDENCE AND PREVALENCE OF CATARACT
The World Health Organization (WHO) estimated that in 1990 of the 38 million blind people in the world, cataract accounted for 41.8%, nearly 16 million people. Blindness is defined in this context as a best-corrected visual acuity of less than 10/200 (3/60) in the better eye.
Throughout the world the elderly population is increasing. For the period 1980–2020 the projected increase in the elderly population for the developed world is 186%, while in developing countries the projected increase is 356%. On this basis, the WHO estimated that there will be 54 million blind people aged 60 years or older by the year 2020. Consequently, cataract surgery will continue to consume an increasing proportion of health care budgets in the developed nations. In the United States, current cataract-related expenditure is estimated to be over $3.4 billion annually. In the developing world, the number of new cataract cases far outstrips the rate of surgical removal. In Africa alone, only about 10% of the 500,000 new cases of cataract blindness each year are likely to have their sight restored surgically.
It is estimated that if onset of cataract could be delayed by 10 years the annual number of cataract operations performed would be reduced by 45%.   This requires identifying risk factors for cataract. Age-related cataract is a multifactorial disease in which genetic, environmental, socioeconomic, and biochemical
factors may act synergistically. Epidemiological studies have identified a number of risk factors, which suggests that a substantial proportion of cataract blindness is avoidable.
The role of sunlight in the development of cataract is controversial.     Support for an association between cataract and ultraviolet B (UV-B) irradiation is provided by geographic correlation studies, which demonstrate an association between hours of sunshine or UV-B flux and the prevalence of cataract. The studies do show that areas with more hours of sunshine have a greater prevalence of cataract, which provides ecological evidence of an association between UV-B and cataract.
Also, experimental studies reveal that artificial sources of UV-B produce lens opacities in animals, both in vivo and in vitro.   Although these lens opacities may have a different morphology from those found in human cataract, they do support the hypothesis that solar UV-B exposure may cause lens opacities in humans. However, large-scale epidemiological studies in the United States do not show a consistent association with UV-B exposure.
In summary, the epidemiological evidence supports an association between cortical cataract and UV-B exposure, but it is not strong enough to show a causal link.
Severe dehydration from diarrhea causes acidosis and increased plasma urea concentration. Two case-control studies from India indicate a three- to fourfold risk of cataract following remembered episodes of life-threatening diarrhea.   In England a weaker association was found. Nevertheless, the frequency of dehydration in the developing world and the suggestion that up to 38% of cataract in India could be attributed to severe diarrhea warrant further study.  
Antioxidants, particularly the antioxidant vitamins A, C, and E, have the potential to protect the lens from oxidative damage. Evidence from case-control studies suggests a possible protective effect from a high intake of antioxidants and high serum antioxidant levels.    Population-based studies provide some support for this hypothesis. The Beaver Dam Eye Study found that high levels of serum ß-carotene are protective against nuclear sclerosis in younger men. However, high levels of some carotenoids and a-tocopherol are associated with nuclear sclerosis, particularly in women. Until the results of interventional trials are known, the recommendation of supplementation with vitamins to reduce the incidence of cataract cannot be justified.
A number of indicators of poor nutrition have been found to be associated with increased risk of cataract in India.  Patients with diarrhea are often malnourished. The confounding effect of these variables makes the risk attributable to each difficult to assess.
Many case-control studies demonstrate an association between diabetes and cataract. Two early prevalence studies confirmed an association between cortical cataract and diabetes in diabetics under the age of 65 years. The Beaver Dam Eye Study found that diabetics are significantly more likely than nondiabetics to have cortical lens opacities or require cataract surgery. Once again, the relationship is stronger in younger age groups. The apparent reduction in risk may arise because the effect of age on lens opacities becomes more important in both diabetics and nondiabetics. The difference may also be a result of higher mortality in older diabetics.
Smoking and Alcohol
Cross-sectional, longitudinal, and case-control studies show an increased risk of nuclear lens opacities in smokers.   Furthermore, the Beaver Dam study showed that previous heavy alcohol consumption is associated with an increased risk of all opacities.
Data from case-control investigations in a variety of populations show a consistent association between low education and all types of cataract.  This effect persists after adjustment for various factors, such as diet, smoking, and UV-B exposure. No obvious biological link exists, and further research is needed.
Aspirin may protect the lens because it lowers plasma tryptophan, reduces the formation of sorbitol, and acetylates lens proteins. Its protective role is supported by animal studies, but the epidemiological evidence is not consistent.  Some case-control studies show a protective effect for aspirin and aspirin-like analgesics.  However, a prospective study of aspirin use and cataract extraction in nurses failed to show a protective effect. Similarly, a randomized, double-blind, placebo-controlled trial by U.S. physicians did not produce a significant reduction in cataract risk in those taking aspirin versus those taking placebo.
The association between corticosteroid use and posterior subcapsular cataract has been noted consistently since 1960.  
Population-based and case-control studies suggest a small, increased risk of cortical cataract in women. Evidence from the Beaver Dam Eye Study suggests that estrogen may have a protective effect against cataract.
Glaucoma has long been regarded as a risk factor for cataract. However, medical or surgical treatment of glaucoma may increase the risk of cancer. Sophisticated measurement of lens transmission and fluorescence indicated that untreated, primary, open-angle glaucoma or ocular hypertension does not seem to increase significantly the risk of developing cataract.
In the Beaver Dam Eye Study, segregation analysis was used to show that there may be recessive genes that predispose the population to both cortical and nuclear cataract. Linkage analysis is required to identify these genes and locate them on the genome.
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