Ординатура / Офтальмология / Английские материалы / Ocular Disease Mechanisms and Management_Levin, Albert_2010

entirely known, but may in some patients be related to a phenomenon called primary vasospastic syndrome.25 There is a longstanding discussion whether reduced blood flow in glaucoma is a primary phenomenon playing a causal role in the disease process or secondary due to optic nerve atrophy and loss of retinal ganglion cells. Since it has widespread systemic manifestations, vascular dysregulation is, however, unlikely to be a direct consequence of the ocular morphological changes associated with the disease.

Pressure autoregulation

A variety of experiments indicate that pressure autoregulation is to some extent altered in patients with POAG. A study performing 24-hour ambulatory blood pressure monitoring and diurnal measurement of the IOP revealed significant blood pressure drops during the night, which were more pronounced in patients with NTG than in patients with anterior optic neuropathy.26 In patients with arterial hypertension receiving oral hypotensive therapy a significant association between progressive visual field loss and nocturnal hypotension was seen. This observation played a key role in the formulation of the hypothesis that nocturnal systemic hypotension may be associated with episodes of nocturnal ischemia at the level of the optic nerve head contributing to glaucomatous damage (Figure 29.5).27

Only recently this concept was expanded by introducing the idea that increased fluctuations of OPP may generally

Pathophysiology

represent a risk factor for glaucoma. A study by Plange and coworkers28 confirmed increased blood pressure dipping during the night in NTG, but also showed a generally increased variability of blood pressure over 24 hours. This was confirmed and extended in larger study populations,29,30 where fluctuations in OPP were consistently associated with parameters of visual field damage and optic nerve head remodeling.

Using single-point laser Doppler flowmetry it was observed that glaucoma patients with systemic hypertension have higher blood flow values than glaucoma patients without systemic hypertension.31 Although such data must be interpreted with caution, because laser Doppler flowmetry does not provide absolute blood flow measurements, they indicate an abnormal association between blood pressure and blood flow, suggesting a breakdown of autoregulation in glaucoma. In addition, it has been argued that systemic antihypertensive treatment may even further decrease optic nerve head blood flow in glaucoma, thereby increasing the risk of progression.31 These data were confirmed in a much larger study population using scanning laser Doppler flowmetry (Figure 29.6).32 This abnormal relation between ocular hemodynamic parameters and systemic blood pressure appears to be directly related to the disease process. In a study using color Doppler imaging a negative association between resistance index in the ophthalmic artery and central retinal artery was only observed in patients with progressive

Rim blood flow (a.u.)

MAP versus RimBF, healthy control subjects correlation: R = 0.01, P = 0.94

1000

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Rim blood flow (a.u.)

Map versus RimBF, POAG and OHT patients correlation: R = 0.30, P <0.001

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visual field damage, but not in patients with stable visual fields.33

Finally, a number of studies investigated the response of ocular blood flow parameters in response to experimentally induced changes in perfusion pressure. Both an increase and a decrease in blood pressure have been induced, leading to vasoconstriction or vasodilatation as part of the auto­ regulatory response, respectively. The first study indicating impaired retinal blood flow autoregulation in glaucoma used the blue-field entoptic technique during an experimental increase in IOP.34 The maximum increase in IOP at which retinal white blood cell flux remained constant was higher in healthy controls than in glaucoma patients. Evidence for reduced retinal autoregulation in glaucoma was also seen in a study employing the retinal vessel analyzer.35 During a step increase in IOP the reaction of retinal vessel diameters was less pronounced in glaucoma patients than in healthy controls.

A variety of studies used changes in posture to induce changes in OPP, because they can easily be implemented with minimal discomfort for the participating subjects. In a color Doppler imaging study an abnormal velocity response to posture was observed in the central retinal artery, but not in the ophthalmic artery.36 An abnormal response to changes in posture was also seen in patients with OAG using combined measurements of retinal blood velocities and retinal vessel diameters.37 Only a few studies tried to investigate optic nerve head blood flow in glaucoma patients during artificial changes in perfusion pressure. Indication of abnormal autoregulation at the level of the optic nerve head was observed in a study using scanning laser Doppler flowmetry after a therapeutic IOP reduction.19,38

Endothelial dysfunction

The mechanism behind abnormal autoregulation in patients with glaucoma is largely unknown. In recent years, however,

228

it has been hypothesized that it may be related to endothelial dysfunction. This concept has recently been reviewed in some detail.39 Endothelial dysfunction refers to a number of complex biochemical alterations resulting in the inability of endothelial cells to perform their normal physiological function. These alterations are initiated by increased oxidative stress leading to pathological alterations in the cellular balance of mediators produced by endothelial cells. Diseases of chronic endothelial dysfunction such as atherosclerosis, systemic hypertension, or diabetes are characterized by a decrease in the biosynthesis and/or bioavailability of nitric oxide (NO), and increased superoxide and endothelin production.

In the eye the vascular endothelium plays a key role in the regulation of blood flow both under physiological conditions and in response to changes in perfusion pressure and agonists.40 In glaucoma endothelial dysfunction can involve various tissues and is not limited to vascular functions. It has for instance been shown that endothelial leukocyte adhesion molecule-1 (ELAM-1), the earliest marker for the atherosclerotic plaque in the vasculature, is consistently present on trabecular meshwork cells in the outflow pathways of eyes with glaucoma, providing an interesting link between increased IOP and vascular diseases.41 In the present chapter, however, the focus will be directed towards the vascular aspects of endothelial dysfunction in glaucoma. A variety of studies indicate alterations of the l-arginine/NO system in glaucoma. In POAG patients, decreased aqueous humor total nitrite levels were found to be indicative of reduced NO production.42 An in vitro study, however, reported increased levels of the three isoforms of NO synthase in the optic nerve head of patients with glaucoma.43 One needs, however, to consider that in this experiment the most pronounced changes were reported for NO synthase-1 (neuronal NO synthase) and NO synthase-2 (inducible NO synthase).

In vivo studies also revealed that glaucoma patients show signs of an abnormal l-arginine/NO system, mainly based

Figure 29.7  Abnormal response of ocular blood flow parameters to systemic nitric oxide synthase inhibition in patients with primary open-angle glaucoma (POAG) as compared to healthy control subjects indicating endothelial dysfunction. (Reproduced with permission from Polak K, Luksch A, Berisha F, et al. Altered nitric oxide system in patients with open-angle glaucoma. Arch Ophthalmol 2007;125:494–498.)

on an abnormal vascular response to either agonists that induce NO-dependent vasodilatation or NO synthase inhibitors. In patients with NTG a number of studies indicate generalized endothelial dysfunction as evidenced from experiments assessing forearm blood flow. Reduced vasodilator responses in the forearm of patients with NTG were observed after intra-arterial administration of acetylcholine44 and after hyperemia.45 In patients with POAG an altered response of ocular blood flow to a systemically administered NO synthase inhibitor was shown (Figure 29.7).46 Whereas in this study the systemic hypertensive response to NO synthase inhibition was comparable between POAG patients and age-matched healthy controls, the glaucomatous group showed reduced response in terms of ocular hemodynamic parameters. This is well compatible with the hypothesis of reduced endothelial NO production in the ocular vasculature.

The hypothesis that the L-arginine/NO system is involved in the pathogenesis of glaucoma has been supported by a number of genetic case-control studies. In an early study sequence analysis demonstrated a C/T substitution at the 5′ sequence position nucleotide -690 from the transcription start site, which lies between the cAMP regulatory element and an activator protein-1 binding domain in the NO syn- thase-3 gene.47 This polymorphism was significantly associated with POAG. Logan et al48 found that the distribution of

Pathophysiology

Box 29.6  Native molecules that alter ocular

blood flow

•  Nitric oxide* •  Endothelin-1*

*Evidence exists that this molecule may be involved in the pathogenesis of glaucoma.

NO synthase-3 alleles was significantly different in subjects who had glaucoma with migraine when compared with control subjects without glaucoma.

Endothelin-1 has been hypothesized to act as a contributor to glaucoma pathophysiology.49 The possible involvement of the endothelin system is not limited to the vascular effects of the peptides, but may also comprise interaction with neurotrophic support, astrocyte activation, tissue remodeling, and cell death. A complete discussion of this topic is, however, beyond the scope of the present chapter. Hence, the focus is directed towards the vascular aspects of the endothelins. Early studies revealed that patients with NTG show elevated basal plasma ET-1 concentrations.50,51 Increased plasma ET-1 levels were also found in progressive POAG patients, but not in stable patients.52 Increased plasma levels of ET-1 are, however, found in a variety of cardiovascular and neurological diseases and are far from being specific for glaucoma. Hence, increased ET-1 plasma levels in glaucoma more likely reflect sites of locally increased ET-1 production rather than directly contributing to the disease process. This is compatible with ET-1 primarily being a paracrine factor and the observation that glaucoma patients show increased ET-1 aqueous humor levels.53,54

More importantly there is evidence for altered regulation of the endothelin system and abnormal vascular responses to the peptide. In healthy subjects a change from the supine to the upright position is associated with an increase in ET-1 plasma levels, which is absent in patients with NTG.55 In response to cooling POAG patients showed an increase in ET-1 plasma levels, which was absent in healthy control subjects.56 In addition, POAG patients with acral vasospasm showed more visual field deterioration after cooling than patients without acral vasospasm. Altered vasoreactivity to endothelins or their receptor antagonists was reported in different studies. In vitro, arteries dissected from gluteal fat biopsies of patients with NTG showed an enhanced reactivity to ET-1.57 In vivo reduced vasodilator responses to a specific ETA receptor antagonist were observed in the forearm of NTG patients, whereas the response to ETB receptor antagonists was preserved.58 In addition, glaucoma patients with lower systemic blood pressures were more sensitive to the vasoconstrictor effects of ET-1 in the forearm than patients

with higher blood pressures.59 Such an association between systemic blood pressure and ET-1 reactivity was absent in the healthy control group.

Additional evidence for the involvement of the endothelin system in glaucoma pathophysiology arises from genetic studies. In patients with NTG the GG genotype of the ETA receptor (c+70G) was associated with more pronounced visual field loss, indicating that it is related to progression of the disease.60 In another South-east Asian population another polymorphism (c+1222T) of the ETA receptor gene was significantly associated with NTG.61 Other studies, however, failed to detect an association between genetic variants in the ET-1 gene and glaucoma47,48 (Box 29.6).

Conclusion

Numerous studies now indicate vascular dysregulation in glaucoma, which is unlikely to be a consequence of the disease process. A direct link between vascular dysregulation and progression of the disease has not been provided, but a number of indirect observations point in this direction. Investigating ocular blood flow regulation in clinical practice in glaucoma patients is not easy, because it is dependent on significant instrumental requirements, but it has rewarded us with numerous insights into the mechanisms underlying the disease.

9.Jonas JB. Clinical implications of peripapillary atrophy in glaucoma. Curr Opin Ophthalmol 2005;16:84–88.

10.Broadway DC, Nicolela MT, Drance SM. Optic disk appearances in primary open-angle glaucoma. Surv Ophthalmol 1999;43(Suppl. 1):S223–S243.

11.Tielsch JM, Katz J, Sommer A, et al. Hypertension, perfusion pressure, and primary open-angle glaucoma. A population-based assessment. Arch Ophthalmol 1995;113:216–221.

15.Leske MC, Heijl A, Hyman L, et al. Predictors of long-term progression in the early manifest glaucoma trial. Ophthalmology 2007;114:1965–1972.

16.Flammer J, Pache M, Resink T. Vasospasm, its role in the pathogenesis of diseases with particular reference to the eye. Prog Retin Eye Res 2001;20:319– 349.

17.Drance S, Anderson DR, Schulzer M, et al. Risk factors for progression of

visual field abnormalities in normaltension glaucoma. Am J Ophthalmol 2001;131:699–708.

21.Galassi F, Sodi A, Ucci F, et al. Ocular hemodynamics and glaucoma prognosis: a color Doppler imaging study. Arch Ophthalmol 2003;121:1711–1715.

27.Graham SL, Drance SM. Nocturnal hypotension: role in glaucoma progression. Surv Ophthalmol 1999;43(Suppl. 1):S10–S16.

30.Choi J, Kim KH, Jeong J, et al. Circadian fluctuation of mean ocular perfusion pressure is a consistent risk factor for normal-tension glaucoma. Invest Ophthalmol Vis Sci 2007;48:104–111.

32.Fuchsjäger-Mayrl G, Wally B, Georgopoulos M, et al. Ocular blood flow and systemic blood pressure in patients with primary open-angle glaucoma and ocular hypertension. Invest Ophthalmol Vis Sci 2004;45:834– 839.

38.Hafez AS, Bizzarro RL, Rivard M, et al. Changes in optic nerve head blood flow after therapeutic intraocular pressure reduction in glaucoma patients and ocular hypertensives. Ophthalmology 2003;110:201–210.

39.Resch H, Garhofer G, Fuchsjäger-Mayrl G, et al. Endothelial dysfunction in glaucoma. Acta Ophthalmol 2009;87: 4–12.

44.Henry E, Newby DE, Webb DJ, et al. Peripheral endothelial dysfunction in normal pressure glaucoma. Invest Ophthalmol Vis Sci 1999;40:1710–1714.

46.Polak K, Luksch A, Berisha F, et al. Altered nitric oxide system in patients with open-angle glaucoma. Arch Ophthalmol 2007;125:494–498.

49.Yorio T, Krishnamoorthy R, Prasanna G. Endothelin: is it a contributor to glaucoma pathophysiology? J Glaucoma 2002;11:259–270.

S E C T I O N 4

Lens

C H A P T E R 30

Clinical background

A cataract is any opacification of the lens. Visually significant cataracts may be present at birth or may occur at any time thereafter, but incidence increases exponentially after 50 years of age.1 Age-related cataracts are responsible for nearly half of all blindness worldwide.2,3 As longevity increases, the impact of cataracts on society is expected to increase. At present, surgical removal of the lens opacity with implantation of an intraocular lens (IOL) is the standard of care throughout most of the world where cataract surgery is available. Although this is usually a safe and effective treatment, intraocular surgery is an expensive and technically challenging solution for such a widespread problem. Rare but serious surgical complications include intraocular infection and inflammation and swelling of the retina (cystoid macular edema). Secondary opacification of the lens tissue remaining after surgery may occur (secondary cataract or posterior capsular opacification), the frequency of which depends on the age of the patient, the experience of the surgeon, and the type of IOL. Secondary cataract is treated by laser-mediated disruption of the posterior capsule of the lens, a procedure that requires expensive equipment and may incite further complications. There is no recognized medical treatment for age-related cataracts. For these reasons, identifying interventions to prevent or delay lens opacities represents an exceptional opportunity to reduce morbidity, increase productivity, and reduce health care costs.

The lens comprises an anterior layer of epithelial cells covering a mass of elongated fiber cells (Figure 30.1). Fiber cells are responsible for the transparency and refractive properties of the lens. The entire lens is surrounded by a thick, acellular capsule that provides structural support to the lens cells and a site of attachment for the zonular fibers that anchor the lens to the ciliary body. The lens grows linearly throughout life by the proliferation of epithelial cells near the equator and the differentiation of their progeny into fiber cells.4,5 Fiber cells are laid down in concentric shells over pre-existing layers of fiber cells (Figure 30.1). As part of their differentiation, fiber cells degrade their nuclei, mitochondria, and other membrane-bound organelles, preventing the synthesis of new proteins.6 Enzyme systems in mature fiber cells soon become nonfunctional. To maintain homeostasis (and transparency), most fiber cells depend on the

metabolic activities of the epithelium and a thin layer of metabolically competent superficial fiber cells.

This chapter outlines the major risk factors for age-related cataract, identifies areas where more knowledge is needed, and highlights promising opportunities for prevention. The information provided is not meant as a complete review of the biochemical mechanisms that may contribute to cataract formation, which would be a much larger undertaking. Instead, it explores the results of epidemiologic studies, biochemical and biophysical analyses of human lenses, and selected animal studies, to suggest the likely causes and potential treatment of clinically significant cataracts in humans.

Pathology

“Age-related cataract” encompasses at least three distinct diseases (Box 30.1). Although each involves opacification of lens fiber cells, these opacities occur in different regions of the lens, have different risk factors, and involve different pathologic mechanisms. Interventions to delay or prevent age-related cataracts must take into account these different pathologies. The three types are nuclear, cortical, and posterior subcapsular cataracts.

In most western populations, nuclear cataracts are the commonest reason for cataract surgery. Opacities occur in the central region of the lens, the lens nucleus, in fiber cells that were produced before birth (Figure 30.2). Opacification of the nucleus is associated with increased light scattering, caused by the aggregation or condensation of lens proteins, and increased coloration. Nuclear cataracts are associated with relatively minor effects on cell structure.7,8 In some populations, nuclear color may be responsible for most of the opacity, resulting in “brunescent” nuclear cataracts.

Cortical cataracts are the commonest reason for cataract surgery in many Asian populations and are frequently seen in western countries. They begin in the outer third of the lens, in cells that were generated postnatally. Cortical opacities are associated with gross disruption of the structure of fiber cells, local proteolysis, and protein precipitation.9–11 Opacities usually begin in small foci near the lens equator, then spread along the length of the fiber cells toward the optic axis and circumferentially to adjacent fiber cells (Figures 30.1 and 30.2). Cortical cataracts may progress for years

Bow region

Posterior cortex

Figure 30.1  Diagram showing the major structural features of the human lens. The diagram is not to scale; the epithelium and superficial, nucleated fiber cells comprise a smaller proportion of the adult lens than in the illustration.

Box 30.1  Age-related cataract is at least three

diseases

The three types of age-related cataract (cortical, nuclear, posterior subcapsular) occur in different regions of the lens, cause opacity by different mechanisms, and have different environmental, societal, and genetic risk factors. Studies that consider “cataract” as a single entity are likely to miss important relationships

before they impinge on the optic axis and become visually significant.

Posterior subcapsular cataracts typically account for less than 10% of age-related cataracts. They arise from epithelial cells that fail to differentiate properly into fiber cells.12,13 These cells migrate or are carried by their neighbors to the posterior pole of the lens, where they swell and form a plaque that scatters light (Figure 30.2). Because these plaques are in the optic axis, they significantly degrade vision, even when quite small.

Etiology

Other than age, lower socioeconomic status and poorer nutrition are often associated with increased risk of all types of age-related cataract.3 However, the specific components of these societal risks have been difficult to identify. Attempts to prevent or slow the progression of age-related cataracts by dietary supplementation have had modest success, at best.14–19

Many studies have shown that women are at greater risk of age-related cataracts, although this has not been a universal finding. Protective effects of hormone replacement therapy have been small or inconclusive.20–22 Given the natural, long-term exposure of women to estrogenic steroids, it is difficult to argue that these hormones offer significant protection against age-related cataract. It seems more likely that, if there is a role of female sex steroids in cataract, the decline in estrogen levels at menopause may increase risk.

The possibility that male sex hormones protect against cataract seems plausible, but has been little explored.23

Beyond these more general risks, each type of age-related cataract is associated with a distinct spectrum of environmental risk factors. The most consistent positive association with lifestyle and nuclear cataracts is smoking. Since smoking is preventable, it represent an important, though challenging, opportunity for intervention. Nuclear cataracts are more prevalent in warmer climates.24 Whether this is due to ambient temperature or to other nutritional or societal risks has not been established. Cortical cataracts are associated with greater sunlight exposure and diabetes. Although a contribution of sunlight exposure to cortical cataracts is well established, greater sunlight exposure accounts for only a small increase in the risk of cortical cataracts in a typical population.25–28 Numerous studies have shown that even the highest level of sunlight exposure represents no detectable increased risk for the development of nuclear or posterior subcapsular opacities.29 Posterior subcapsular cataracts are most often associated with diabetes and therapeutic treatment with steroids or ionizing radiation. When diabetes is reasonably well controlled, it presents only a modest increase in the risk of age-related cataracts.30 Most of the increase in cataract surgery in diabetics is due to posterior subcapsular opacities. Steroid-induced posterior subcapsular cataracts have typically been associated with long-term systemic administration, but are becoming more prevalent due to the increasing popularity of high-dose intraocular steroids to treat retinal inflammation and neovascularization.31,32 Because the biology of these cataracts is less well understood than other types, studying cataracts induced by steroids during retina therapy or in animal models33 may offer an opportunity for understanding better the pathobiology of this disease.

Environmental risk factors provide clues to the etiology of age-related cataracts (Box 30.2). Unfortunately, we know little about the biochemical mechanisms by which smoking contributes to nuclear cataracts or sunlight promotes cortical cataracts. Therefore, these risk factors have, so far, told us little about the pathogenic mechanisms underlying these diseases. Equally important, environmental factors that do not increase the risk of cataracts tend to rule out certain pathways in the cause of that type of cataracts. For example, the biochemical effects of sunlight exposure do not contribute significantly to the risk of nuclear or posterior subcapsular opacities. Therefore, it is reasonable to conclude that light-generated free radicals, for example, are not central to the etiology of these diseases.

As important as they may eventually be for understanding cataract etiology, environmental factors appear to account for a relatively small percentage of age-related cataracts. Other variables, many of which are less easily modified, are more significant contributors to the burden of disease. Among the most significant is genetic variation (Box 30.3).

Studies that measured the incidence of specific types of cataract in families, or between monozygotic (identical) and dizygotic (fraternal) twins, showed that approximately half of the risk of cortical and at least one-third of the risk of nuclear cataracts can be attributed to heredity.34–38 Increased risk of nuclear or cortical cataract was genetically separable in these populations, underscoring the distinct nature of these diseases. Although the subject of ongoing

Box 30.2  The contributions of environmental and

societal risk factors

Epidemiologic studies in populations around the world have identified recurring risk factors for the different types of agerelated cataracts. Nuclear cataracts are often associated with smoking, poorer nutrition, and living in a warmer climate.

Common risk factors for cortical cataracts include higher sunlight exposure and diabetes. Posterior subcapsular cataracts are associated with diabetes, use of immunosuppressive and intraocular steroids, and therapeutic radiation to the head. Anatomic factors, like lens thickness and the stability of the vitreous gel, also seem to contribute to the risk of nuclear and cortical cataracts. Surprisingly, the biochemical links that connect these risk factors to age-related cataracts are generally not known

Box 30.3  The potential importance of genetics

Studies of the prevalence of age-related cataracts in families and cohorts of twins demonstrated the importance of hereditary factors. Identifying the underlying genes may be valuable for preventing all types of age-related cataracts. Gene products usually function in metabolic pathways. Knowing these pathways may permit the suppression or augmentation of the biochemical reactions that make the lens more susceptible to or protect it from cataracts, respectively

studies, the genes associated with the increased risk of agerelated cataracts have not been identified in published studies.

Genetic risk factors may seem to present intractable barriers to treatment, especially for a common disease. However, understanding the genetics of age-related cataract may hold significant promise for therapeutic intervention or prevention. It is not always necessary to correct a genetic alteration at the DNA level to treat a gene-based disease. It may be sufficient to understand the pathway in which the defective gene acts, then design therapies that compensate for that defect to restore the function of the pathway. Genetic studies can also identify genes and pathways that protect against age-related cataracts. Enhancing the function of the pathways that, when impaired, increase the risk of cataracts, or augmenting pathways that normally protect against cataract could provide effective means to delay cataract formation in all individuals. For these reasons, identifying the genes responsible for promoting cataract or protecting the lens from cataract represents one of the most promising areas for future advances.

Epidemiologic studies have also identified anatomic risks for cataract. In a cross-sectional analysis of participants in the Beaver Dam Eye Study, individuals with thinner lenses were at much increased risk of cortical cataract, while those with thicker lenses had significantly more nuclear cataracts.39 Five-year follow-up of this population showed that individuals were more likely to develop cortical cataracts if their lenses were initially smaller.40 Those with larger lenses were more likely to develop nuclear cataracts. Similar associations between lens size and cataract have been identified in cross-

sectional and prospective studies in Japan and Singapore41 (K Nagai, K Sasaki, H Sasaki, personal communication). The reasons underlying the association between smaller (or thinner) lenses and cortical cataract have not been explored. Possible connections between larger lens size and nuclear cataract may involve the lens “diffusion barrier,” discussed below in the section on the natural history of nuclear opacification.

Like lens fiber cells and the proteins within them, the vitreous gel that lies between the lens and the retina is made early in life and is never regenerated or replenished. Gradual collapse (also called syneresis) of the vitreous body occurs to a greater extent in older individuals, presenting increased risk of retinal detachment, macular hole, and other retinal complications.42,43 The extent of vitreous liquefaction varies greatly in older individuals.42,44 Those with a more liquefied vitreous are at increased risk of nuclear cataracts.44,45 The increase in the length of the eye that occurs in high myopia (severe near-sightedness) is associated with early degeneration of the vitreous body and increased risk of nuclear cataract.41,46–48 The possible physiologic relationship between the structure of the vitreous body and nuclear cataract is discussed below in the section on oxygen and cataracts.

Pathophysiology of age-related cataract

Oxidative damage

All cataracts involve damage of lens cells and/or lens proteins, leading to increased light scattering and opacification. Much of this damage can be traced, directly or indirectly, to oxidative or free radical-mediated effects. However, it has been difficult to show that oxidative damage initiates human cataract formation, rather than being the final “executioner” of transparency. In fact, the lens appears to be remarkably well protected from oxidative stress. It is essential to discover how these protective mechanisms are broken down or overcome to understand cataract etiology. We discuss some of the likely causes for different types of age-related cataracts, linking them to oxidative or free radical damage when appropriate.

Sunlight, aging, and cortical cataracts

Although exposure to higher levels of sunlight over a lifetime is one of the best-validated environmental risks of cortical cataract, the mechanism by which light exposure contributes to cortical opacities in humans is not understood. We do not know if sunlight has its effect by damaging DNA, inhibiting enzyme activity, decreasing protein stability, increasing lipid oxidation, or some combination of these. We do not even know whether it is the direct interaction of light with the lens or another component of the anterior segment, the iris for instance, that increases cataract risk. Unlike the skin, which shows clear evidence of light-induced DNA damage in sun-exposed areas,49,50 no similar “signature” of light damage has been identified in cortical cataracts. Paradoxically, the equatorial region of the lens, where cortical cata-

racts originate, is better protected from light exposure than regions that show no apparent susceptibility to sunlightinduced cataract, like the nucleus. Dark iris color, which might be expected to protect the lens from light exposure, has been identified as a risk factor for cortical cataracts in some studies,26,51 although not in others.52,53 Lack of understanding of the causal chain between sunlight exposure and cortical cataract formation in humans makes it difficult to speculate whether there are biochemical similarities between the cause of sunlight-induced cortical cataracts and the cortical cataracts that are associated with smaller lens size, diabetes, or genetic variation. Each of these disparate risk factors may contribute separately to cortical cataract or may be connected through an, as yet, unidentified mechanism.

An alternative view of cortical cataract formation is based on the frequent occurrence of these cataracts at the onset of presbyopia. Shearing force between the soft cortex and stiffer nucleus, generated during attempted accommodation in the increasingly presbyopic eye, could cause local rupture of cortical fiber cells.54–57 This initially focal damage then spreads along damaged fiber cells and to nearby fiber cells, leading to the spoke-like pattern of damage that is often seen in cortical opacities. If this view is correct, it can be related to the epidemiologic risk factors for cortical cataracts. The increased glycation of lens proteins seen in diabetics might further stiffen nuclear fiber cells or weaken cortical fiber cells. Smaller lens size might be associated with higher strain on the lens during disaccommodation, as the zonules of smaller lenses could be more taut. High sunlight exposure could exacerbate the hardening of the lens nucleus, thereby indirectly contributing to cortical cataracts without exposing the cortical cells to light. Further tests of this view of cortical cataract formation seem warranted.

Diabetes and cataract

Diabetes is one of the most widely recognized risk factors for age-related cataracts, although other diabetic complications are more clinically significant.30,58–60 Rapid-onset, uniformly distributed cortical opacities are seen in patients or experimental animals with acute hyperglycemia. While this type of opacity is important because it may alert patients to the need for treatment, it is not the typical presentation for diabetic patients with reasonably well-controlled blood glucose.30 In general, diabetics have earlier-onset opacities than nondiabetics. These are usually cortical or posterior subcapsular cataracts. Although nuclear cataracts can occur in diabetics, epidemiologic studies suggest that diabetes may provide modest protection against nuclear opacification.61 Because they impair vision at an earlier stage, posterior subcapsular cataracts often account for a disproportionate percentage of cataract surgery in diabetics.60,62

The natural history of nuclear opacification

With increasing age, the lens nucleus gradually increases in opacity and hardness in all individuals.63–65 When nuclear opacities become visually significant they are often called nuclear sclerotic cataracts. Thus, nuclear cataract formation

Oxygen, the vitreous body and nuclear cataracts

can be thought of as an acceleration or exacerbation of changes that occur during aging. This is not the case for cortical and posterior subcapsular cataracts. Although more cortical and posterior subcapsular cataracts occur in older individuals, most older patients will never have even a trace of either type.44 In this way, nuclear cataracts are fundamentally different from cortical or posterior subcapsular cataracts.

Increasing nuclear opacification correlates with a decline in reduced glutathione and an increase in the oxidized form of this important intracellular antioxidant in the lens nucleus.66,67 Experimental depletion of glutathione causes rapid opacification of the lens.68 Glutathione is synthesized and converted to its protective, reduced form in the metabolically active cells near the lens surface. It then diffuses through abundant gap junctions in the fiber cell membranes to the center of the lens, where it can protect lens crystallins and membrane proteins from oxidation. Once glutathione is oxidized, it diffuses down its concentration gradient to the lens surface, where it can again be reduced (Figure 30.3). This glutathione cycle slows with age, due to a decrease in the apparent viscosity of the lens cytoplasm, appearing as a diffusion barrier between cells at the lens surface and the nucleus69,70 The resulting decrease in access of reduced glutathione to the nucleus places the proteins there at greater risk of oxidative damage. It is likely that this decline in antioxidant capacity contributes to the age-related increase in opacification and hardening of the nucleus, seen in virtually all lenses. Other antioxidant systems may decline with aging,71,72 possibly contributing to increased risk of nuclear cataract.

Oxygen, the vitreous body and nuclear cataracts

During hyperbaric oxygen (HBO) therapy, patients breathe pure oxygen at two or more times atmospheric pressure. This is likely to cause oxygen levels around the lens to increase dramatically, since intraocular oxygen levels increase greatly when patients breathe 100% oxygen at normal pressure.73 If HBO treatment is protracted, the refractive power of the lens increases, causing a “myopic shift.”74–76 This effect may reverse after therapy is discontinued.74,77 If therapy persists for over a year, the lens develops increased nuclear opacity or frank nuclear cataract.74 In these cases, it appears that exposure to elevated oxygen causes rapid hardening of the lens, the presumed cause of the myopic shift76 and progression to nuclear cataracts (Box 30.4). Both are typical properties of age-related nuclear cataracts. However, these pathological changes occur more rapidly after HBO treatment than during aging.

The lens normally exists in a hypoxic environment.73,78–80 Given the demonstrated toxicity of oxygen to the lens, it is worth considering how the low level of oxygen around the lens is maintained. Recent measurements in patients undergoing cataract or glaucoma surgery revealed that oxygen levels in the posterior chamber, the space between the ciliary epithelium, iris, and lens, and in the anterior chamber, at the anterior surface of the lens, are also usually less than 1% (Siegfried et al, unpublished results). In rabbits and

B

Figure 30.3  Diagrams representing the distribution of reduced (GSH) glutathione, and its oxidized form (GSSG) in young and older lenses and the hypothetical role of oxygen in altering the ratio of these metabolites in

the lens nucleus. (A) The distribution of GSH and GSSG in young lenses.

(B) The distribution of GSH and GSSG in older lenses. (C) The distribution of GSH and GSSG in older lenses exposed to increased oxygen. Oxygen or its metabolites diffuse from the vitreous body to the center of the lens, reducing GSH and increasing GSSG, which is postulated to lead to nuclear opacification. The red bars in (B) and (C) represent the barrier to diffusion resulting from the increased viscosity of the lens cytoplasm that occurs with age.

humans, oxygen levels in the vitreous body at the posterior of the lens are normally very low, 1% or less.78 These measurements suggest that oxygen levels are already low in freshly secreted aqueous humor, placing the entire anterior of the lens in a hypoxic environment. They also suggest that the vitreous body protects the lens from exposure to the higher levels of oxygen found near the surface of the retinal vessels.81,82

Diverse studies suggest that the gel structure and biochemical activities of the vitreous body protect the human lens from oxygen and the formation of nuclear cataracts. As indicated above, severe myopia is associated with early degeneration of the vitreous body and increased risk of nuclear cataract.41,48,83 Examination of eyes postmortem

showed that the level of vitreous degeneration varied greatly in older individuals.42,44 Increased liquefaction of the vitreous body was associated with increased nuclear opacification, but not with other types of cataract.44 Many studies have shown that removal of the vitreous body during retinal surgery (vitrectomy) leads to the formation of nuclear cataracts within 2 years in 60–98% of older individuals.84–88 However, if retinal surgery is performed without damaging the structure of the vitreous body, there is no detectable increase in nuclear opacification.89 Oxygen levels near the lens increase dramatically during vitrectomy and remain significantly elevated for years after destruction of the vitreous gel.73 Recent studies showed that the vitreous body metabolizes oxygen in a reaction that is dependent on the high level of ascorbate (vitamin C) that is normally present there. Vitrectomy and the slower degeneration of the vitreous gel seen during aging are associated with decreased levels of ascorbate, decreased ability of the vitreous to consume oxygen and increased risk of nuclear cataract.90 Therefore, the gel structure of the vitreous body appears to maintain low oxygen levels at the posterior of the lens and protects the lens against nuclear cataract. A model that provides a possible explanation for the protective effect of the vitreous gel is shown in Figure 30.4.

Recent studies showed that elevating the level of oxygen around the rodent lens markedly increases its rate of growth, especially in older individuals.91 If a similar relationship between oxygen and lens growth exists in humans, the increased oxygen levels that accompany the degeneration of the vitreous body could lead to larger lenses. Summarizing from the data mentioned above, larger lens size is associated with increased risk of nuclear cataract. Oxygen exposure causes a myopic shift, similar to that which occurs early in the formation of a nuclear cataract. In these cases, the myopic shift is probably due to hardening of the lens, thereby increasing its refractive power. Hardening of the lens decreases the rate of diffusion from the lens surface to the nucleus. Larger lens size and decreased diffusion through lens cytoplasm should reduce the level of reduced glutathione in the lens nucleus, thereby hastening nuclear opacification (Figure 30.3). It seems possible that exposing the lens to increased oxygen accelerates nuclear cataract formation by directly causing oxidative damage and/or by making the lens more susceptible to oxidative damage.

If the vitreous gel protects the lens against nuclear cataract formation, it follows that factors that promote the stability of the vitreous body could decrease the risk of nuclear cata-