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

PVD

↑O2

A B

Figure 30.4  Diagram illustrating the proposed effect of vitreous degeneration on the distribution of oxygen in the eye. (A) The vitreous gel is intact, there are standing gradients of oxygen near the retinal vessels, and some of the oxygen that diffuses into the vitreous gel is consumed by reacting with ascorbate (AsA). The ultimate products of this reaction are dehydroascorbate (dhAsA) and its eventual degradation products and water. After extensive vitreous liquefaction (B) due to syneresis of the vitreous gel, the vitreous separates from the retina (posterior vitreous detachment; PVD), allowing fluid to circulate in the fluid-filled spaces at

the surface of the retina and within the liquid parts of the vitreous body. This overwhelms the ability of ascorbate to maintain low oxygen, increases the Po2 near the lens, and results in nuclear cataract formation.

ract. This makes it important to understand why the vitreous body degenerates at an early age in some individuals and remains intact in others. Some of the hereditary risk of nuclear cataracts might result from genetic variations that promote the early degeneration of the vitreous gel. Smoking might increase the risk of nuclear cataracts by promoting vitreous degeneration, although this possibility has not been examined. In summary, interventions that preserve or restore the mechanical and biochemical properties of the vitreous body should protect against age-related nuclear cataract.

Key references

Summary and conclusions

Age-related cataract is at least three different diseases. Each occurs in different locations in the lens, involves a distinct pathogenic mechanism, and is associated with different risk factors. Although several common environmental risk factors have been identified, each appears to contribute to a relatively small fraction of the total cataract burden. Heredity plays a major role in the risk of age-related cataract. Identifying the genes involved may lead to treatments that augment or suppress the pathways in which these genes function. Much research has centered on the potential role of oxidative stress and sunlight in cataract etiology. Greater sunlight exposure accounts for only a small percentage of cortical cataracts and constitutes little or no risk for the other types. Little evidence has been offered for increased oxidative stress as an inciting factor in cortical or posterior subcapsular cataract. Anatomic changes with aging, particularly hardening of the lens nucleus and degeneration of the vitreous body, provide insight to the etiology of nuclear cataracts and suggest interventions for their prevention. Closer collaboration between basic scientists, clinicians, epidemiologists, and geneticists could help clarify the etiology of age-related cataracts and provide the first steps toward delaying or preventing them.

Acknowledgments

Support for the authors’ research was provided by Research to Prevent Blindness, the Department of Ophthalmology and Visual Sciences, the Barnes Retina Institute Research Fund, and NIH grants EY015863, EY04853, and core grant EY02687.

17.AREDS. A randomized, placebocontrolled, clinical trial of high-dose supplementation with vitamins C and E and beta carotene for age-related cataract and vision loss: AREDS report no. 9. Arch Ophthalmol 2001;119:1439–1452.

26.AREDS. Risk factors associated with age-related nuclear and cortical cataract: a case-control study in the Age-Related Eye Disease Study, AREDS report no. 5. Ophthalmology 2001;108:1400–1408.

27.West SK, Duncan DD, Munoz B, et al. Sunlight exposure and risk of lens opacities in a population-based study: the Salisbury Eye Evaluation project. JAMA 1998;280:714–718.

30.Bron AJ, Sparrow J, Brown NA, et al. The lens in diabetes. Eye 1993;7:260–275.

34.Hammond CJ, Duncan DD, Snieder H, et al. The heritability of age-related cortical cataract: the Twin Eye Study. Invest Ophthalmol Vis Sci 2001;42:601– 605.

35.Hammond CJ, Snieder H, Spector TD, et al. Genetic and environmental factors in age-related nuclear cataracts in

monozygotic and dizygotic twins. N Engl J Med 2000;342:1786–1790.

40.Klein BE, Klein R, Moss SE. Lens thickness and five-year cumulative incidence of cataracts: The Beaver Dam Eye Study. Ophthalm Epidemiol 2000;7:243–248.

44.Harocopos GJ, Shui Y-B, McKinnon M, et al. Importance of vitreous liquefaction in age-related cataract. Invest Ophthalmol Vis Sci 2004;45:77–85.

55.Michael R, Barraquer RI, Willekens B, et al. Morphology of age-related cuneiform cortical cataracts: the case for mechanical stress. Vision Res 2008;48:626–634.

64.Heys KR, Cram SL, Truscott RJ. Massive increase in the stiffness of the human lens nucleus with age: the basis for presbyopia? Mol Vis 2004;10:956–963.

67.Truscott RJW. Age-related nuclear cataract

– oxidation is the key. Exp Eye Res 2004;80:709–725.

73.Holekamp NM, Shui YB, Beebe DC. Vitrectomy surgery increases oxygen exposure to the lens: a possible mechanism for nuclear cataract formation. Am J Ophthalmol 2005;139: 302–310.

74.Palmquist BM, Philipson B, Barr PO. Nuclear cataract and myopia during hyperbaric oxygen therapy. Br J Ophthalmol 1984;68:113–117.

89.Sawa M, Ohji M, Kusaka S, et al. Nonvitrectomizing vitreous surgery for epiretinal membrane: long-term follow-up. Ophthalmology 2005;112: 1402–1408.

90.Shui et al. Arch Ophthalmol (in press)

Clinical background

Cataract, a pathology of the ocular lens, is the leading cause of blindness worldwide despite the availability of effective surgery in developed countries.1,2 According to the World Health Organization,1,2 up to 40 million people are blind worldwide, and of these, 47% of them are blind due to cataract. A total of 82% of the blind are more than 50 years of age. Thus, the number of blind people worldwide, and likely those with cataracts, is expected to increase further as the population ages. Cataract surgery provides quick restoration of vision and is the most frequently performed surgical procedure in the developed world.3 However, it is not without its problems and can lead to a number of complications, the most common of which is secondary cataract, also known as posterior capsular opacification (PCO).4–7

Modern cataract surgery, also known as extracapsular cataract extraction (ECCE), involves removing a circular anterior portion of the lens capsule, breaking up and removing the fiber mass it contains, and placing a synthetic lens implant (intraocular lens: IOL) into the remaining capsular bag (Figure 31.1). This newer procedure replaced intracapsular cataractous lens extraction (ICCE), in which the whole lens and capsule were removed and often resulted in a number of significant complications, including retinal detachment and macular edema.8,9 ECCE avoids such complications, yet frequently leaves behind lens epithelial cells (LECs) on the remaining portion of the anterior capsule; these cells can proliferate, transdifferentiate, and migrate on to the otherwise cell-free zone of the posterior capsule surface (Figure 31.1; Box 31.1). Here the cells deposit aberrant matrix and also cause capsular wrinkling, two important features of PCO.7 Both of these events obstruct or alter the path of light entering the eye by decreasing the amount of available light, decreasing contrast and color intensity, and increasing light scatter, culminating in a reduction in visual acuity10 (Figure 31.1). The time between surgery and PCO development varies considerably, ranging from a few months to 4 years.8 Interestingly, the visual symptoms do not always correlate with the degree of PCO observed, and some patients with significant PCO as determined by slit-lamp examination are less symptomatic as compared to others who have only mild haze observed.8

PCO was diagnosed following the beginnings of ECCE surgery and was fairly common in these early days (late 1970s and early 1980s) with incidence in up to 50% of patients.11 Advances in IOL design and surgical technique over the last 20 years have resulted in a dramatic reduction in reported PCO rates, to occurrence in 14–18% of patients.6,7 However, PCO remains a major medical problem with profound consequences for the patient’s well-being and is a significant financial burden due to the costs of follow-up treatment. The most common postoperative treatment for PCO is neodymium-doped yttrium aluminum garnet (NdYAG) posterior capsulotomy.8 This treatment involves using the Nd-YAG laser to cut an opening in the posterior capsule to clear the visual axis and restore vision. Complications, although rare, include IOL damage and pitting, postoperative IOP elevation, cystoid macular edema, retinal detachment, and IOL subluxation. Access to this procedure is also not widely available in developing countries.8

Pathology

The intact lens is composed of an anterior monolayer of epithelial cells (referred to earlier as LECs) and an underlying fiber cell population, making it a relatively simple tissue (Figure 31.2). The lens continues to grow throughout life, albeit at a much slower rate in the adult. This continued growth is attributed primarily to the proliferation of the LECs in the germinative zone of the lens, a region just anterior to the lens equator.12 In PCO, LECs from the anterior and equatorial regions left behind after surgery have the capacity to survive, proliferate, and transdifferentiate. Cells derived from the anterior lens epithelium, referred to as “A cells,” are those thought to transdifferentiate into spindle-shaped myofibroblasts, through a process known as epithelial-to-mesenchymal transformation (EMT) (Figure 31.2). These myofibroblasts express contractile elements such as alpha-smooth-muscle actin (α-SMA), and are therefore thought to contribute to the capsular wrinkling detected in PCO.13,14 Unlike epithelial cells, myofibroblasts also stop producing type IV collagen and the highly organized crystallin proteins and begin to secrete abnormal amounts of extracellular matrix (ECM) proteins, including type I and type III collagen. The abnormal ECM deposition contributes to the capsular fibrosis observed in PCO.

B

Figure 31.2  Schematic diagram of the adult mammalian lens. The germinative zone, just anterior to the lens equator, is where the majority of the active proliferation takes place in the adult lens. Following cataract surgery, cells from the anterior monolayer, referred to as “A cells,” are those thought to undergo epithelial to mesenchymal transition into myofibroblasts, expressing alpha-smooth-muscle actin (αSMA). The “E cells”

are derived from the pre-equatorial region of the lens and tend to transition into fiber-like cells, referred to as Elschnig pearls. LECs, lens epithelial cells.

C

Figure 31.1  (A) Schematic diagram of the capsular bag with an implanted intraocular lens (IOL) following surgery. Remaining lens epithelial cells (LECs) on the anterior lens capsule can proliferate, transition, and then migrate to the posterior capsule where they multilayer and deposit aberrant matrix. (Modified from Wormstone IM. Posterior capsule opacification: a cell biological perspective. Exp Eye Res 2002;74:337–347.) (B) The clinical appearance of a posterior capsular opacity as viewed through the slit-lamp biomicroscope. (Courtesy of Mike Feifarek, MD.) (C) Appearance of posterior capsular opacification with retroillumination. (Courtesy of Rakesh Ahuja, MD.)

In PCO, the “E cells” are those derived from the preequatorial region of the lens. Although fibrosis may also occur in these cells, they have a stronger tendency to form “epithelial pearls” (also called Elschnig pearls) in which the cells transform into swollen and opacified cells known as “bladder cells” or “Wedl cells” that do not express α-SMA and are considered to be LECs attempting to form fiber cells.8,13 Thus, clinically, two morphological types of PCO have been documented, including wrinkling and fibrosis of

Box 31.1  Clinical background

•The most common complication of primary cataract surgery is secondary cataract, also known as, posterior capsular opacification (PCO)

•PCO results from lens epithelial cells remaining on the anterior capsule following cataract surgery; these cells migrate on to the posterior capsule, deposit aberrant matrix, and cause capsular wrinkling

the capsule, from the transformed A cells, and epithelial pearls from improper proliferation and differentiation of E cells. The former phenomenon is often referred to as fibrotic PCO, whereas the latter is called regeneratory PCO.

Etiology

As discussed above, considerable evidence has shown that the LECs remaining after cataract surgery are the cells that contribute to the development of PCO. The histology surrounding these cells has been relatively well documented. However, knowledge regarding the mechanisms that lead to their survival and fibrotic phenotype is more limited. What is clear is that age plays an important role in the incidence of PCO, with patients over the age of 40 having a significantly lower incidence than those under 40 (Box 31.2).8,15,16 Furthermore, in pediatric patients PCO occurrence is nearly universal if the posterior capsule is left intact, as is the case in ECCE surgery. This difference may be related to the role of inflammation in PCO, since children and younger patients typically have a more marked inflammatory response after

Box 31.2  Etiology

•Patients over 40 have a significantly lower incidence of posterior capsular opacification (PCO) than those under 40 and in pediatric patients PCO occurrence is nearly universal

cataract surgery. Another contributing factor may be that the LECs in younger patients produce more autocrine growth factors that stimulate their survival and fibrotic phenotype.7 The potential consequences of these factors are discussed in greater detail in the next section on pathophysiology.

Changes in surgical technique and design and placement of IOLs have been important in minimizing PCO. Surgical improvements include the implementation of hydrodissection-enhanced cortical cleanup, a technique allowing for more efficient removal of the cortex and LECs, and placement of the IOL in the capsular bag such that direct contact is made with the posterior capsule.17 A surgical approach, referred to as continuous curvilinear capsulorrhexis (CCC), has aided with the IOL placement. In this case, a continuous circular tear is made in the anterior capsule of the cataractous lens to allow for phacoemulsification (surgical breakup) and removal of the lens material, while maintaining the integrity of the posterior capsule. The diameter of the CCC incision is slightly smaller than that of the IOL inserted such that a tight fit is made, sequestering the IOL in the bag from the surrounding aqueous humor.3,8 This type of placement of the IOL is thought to act as a barrier, preventing the edge of the anterior capsule from adhering and fusing to the posterior capsule. It is also thought to prevent the posterior capsule from being exposed to any inflammatory or fibrotic mediators in the aqueous humor. The development of newer surgical techniques is also being considered, such as primary posterior capsulorrhexis, which would prophylactically eliminate the possibility of PCO.

Considerations for the IOL design have also been important for minimizing PCO. Numerous studies have examined the role of IOL materials, both the optic and the haptic, on the development of PCO. Foldable IOL materials can be broadly categorized into three areas: silicone materials, hydrogel materials, and nonhydrogel acrylic materials. A range of materials exists in each of the categories. Regardless of the material type, however, all are susceptible to PCO to some extent and as a result a number of clinical studies have examined the role of IOL material in PCO development. While material specific effects have been shown in some cases, there are a number of contradictions in the literature and it is far from clear whether one material is superior to the others with respect to PCO prevention. Much of the contradiction has occurred due to the lack of appropriate controls, and that factors such as lens design were not kept constant in these studies. The work of Nishi et al18,19 suggests that the effects of materials are much less significant than design effects. However, there are some limited data suggesting that silicone IOLs may have lower PCO rates than acrylic.20

The majority of recent studies have focused on IOL design effects. The observation that the incorporation of a square edge in an acrylic IOL21 results in a significantly lower incidence of PCO has led to significant changes in lens design.

240

Box 31.3  Intraocular lens (IOL) design and surgical

technique

•Advances in IOL design and surgical technique over the last 20 years have resulted in a dramatic reduction in reported posterior capsular opacification (PCO) rates, from an occurrence of over 50% to 14–18%

•Surgical improvements include the implementation of hydrodissection-enhanced cortical cleanup and the surgical approach, continuous curvilinear capsulorrhexis (CCC)

•A significant effect of different IOL materials on PCO has not been determined, whereas the incorporation of a square edge in an acrylic IOL has been shown to lower the incidence of PCO significantly

Implantation of sharp-edged IOLs causes postoperative capsular bag closure, fusion, and wrapping of the bag around the optic periphery, resulting in the tight apposition of the posterior capsule along the posterior optic rim. This barricades lens epithelial cell migration, effectively inhibiting PCO caused by migration and proliferation of residual lens cells into the area between the lens capsule and the IOL.

The effect of incorporating a square edge has been shown for various materials, including silicones20 and polymethyl methacrylate (PMMA).22 Results also suggest that an edge effect is present in acrylic lens materials,23,24 although the effect is less clear with these materials.25 The work of Hayashi and Hayashi26 suggests that an anterior round edge and a posterior square edge are particularly advantageous. There is some controversy, however, as to whether the square-edged IOLs lead to an increased incidence of anterior capsular contraction (ACC), which can hinder postoperative procedures such as fundoscopy, retinal photocoagulation, and vitreal surgery.27,28 The area of anterior capsule opening (ACO), related to ACC, has in fact been shown to be independent of the incidence and severity of PCO.26

Surface modification of IOL materials is used to improve lens properties for various reasons, including to allow for ease of insertion and to reduce tackiness (Box 31.3). Modification of the IOL materials has also been used as a method of reducing PCO. Modification with cell-resistant polymers, such as polyethylene oxide29 and poly methacryoyloxyethyl phosphorylcholine (MPC),30 provided in vitro results suggesting that adhesion of lens cells is inhibited. However, others have demonstrated that polyethylene glycol (PEG) coatings, even at high density, are not sufficient to inhibit completely protein adsorption or cell adhesion.31,32 Various patents have examined the modification of IOL materials with materials which can lead to interactions with the lens capsule. These include tackiness coatings,33 functional end groups which react with the components of the capsule,34 and biological glues to stimulate adhesion to the lens capsule.

Pathophysiology

Primary cataract surgery often results in a breach of the blood–aqueous barrier and a subsequent influx of inflam-

matory cells, erythrocytes, and other cell types into the aqueous humor. A consequence of this is a reported increase in the protein levels in the aqueous humor. In fact, some proteins are only detected in the aqueous humor following such trauma to the eye.7 The implanted IOL can also elicit an inflammatory response as a foreign body and thereby further contribute to the increased cellularity and protein content in the aqueous humor following surgery.7,13 The production of these proteins/peptides, namely growth factors and cytokines, has been the focus of much of the research related to PCO. Numerous studies using multiple models have therefore been aimed at determining which factors control the pathophysiological features of PCO, namely LEC proliferation, migration, and EMT.

Transforming growth factor-ß (TGF-ß), specifically isoforms 1 and 2, is detected in the aqueous humor under normal circumstances, mainly in their latent forms, whereas the active forms have been detected in the ocular media from patients following cataract surgery.35,36 TGF-ß 1 and 2 can affect multiple cellular processes, including cell adhesion, proliferation, apoptosis, migration, and fibrosis.37,38 In particular, it is the strong association of TGF-ß with fibrosis that has caused increased attention regarding the role that it may play in promoting PCO. Multiple models have been developed to investigate this, many of which involve the seeding of LECs on to structures such as Plexiglas, plastic, or bovine capsules with or without IOLs to determine their effects on proliferation and migration.39,40 A capsular bag model similar to that produced in vivo following cataract surgery has also been developed to monitor LEC migration as it occurs during PCO from the anterior equatorial margin on to the posterior capsule.41–43 Other derivations of this capsular bag model have been undertaken by Wormstone et al44 and Saxby et al.45 Importantly, utilizing their capsular bag model, Wormstone et al14 were able to demonstrate that addition of TGF-ß accelerated LEC transformation and capsule wrinkling, both of which are thought to induce light scattering. Furthermore, co-culturing with an anti-TGF-ß antibody (CAT-152) suppressed TGF-ß-in- duced development of PCO, implicating TGF-ß in its etiology.14

Additional support for the involvement of TGF-ß in PCO includes the fact that connective tissue growth factor (CTGF), a factor closely associated with TGF-ß, has been detected in human postmortem capsular bags.46 TGF-β has been shown to induce CTGF and CTGF on its own has been shown to induce EMT, reminiscent of that induced by TGF-β (Box 31.4). Thus, CTGF may serve as mediator of TGF-β’s effects on LECs and may play a prominent role in PCO; however this has yet to be confirmed.

Basic fibroblast growth factor (FGF-2) and acidic FGF (FGF-1) are additional growth factors detected in the ocular media bathing the lens and are known to regulate normal lens structure and function. FGF-2 has been shown to stimulate LEC proliferation, migration, and differentiation in vitro.47 These three different cellular responses to FGF occur in a sequential fashion as the concentration of FGF is increased. For example, when LEC explants from the rat lens are cultured with a lower concentration of FGF, LEC proliferation is induced whereas a higher concentration of FGF stimulates differentiation of LECs into lens fiber cells.47 Interestingly, an FGF concentration gradient is evident in

Pathophysiology

Box 31.4  Pathophysiology

•Primary cataract surgery often results in an influx of inflammatory cells, erythrocytes, and other cell types into the aqueous humor and an accompanying increase in the

production of autocrine and paracrine growth factors and cytokines, including transforming growth factor-β (TGF-β, fibroblast growth factor (FGF), epidermal growth factor (EGF), hepatocyte growth factor (HGF) and connective tissue growth factor)

•TGF-β accelerates lens epithelial cell (LEC) transformation and causes capsule wrinkling

•FGF has been shown to exacerbate the ability of TGF-β to induce posterior capsular opacification (PCO) by promoting LEC survival

•Like FGF, HGF and EGF have been shown to regulate LEC proliferation and likely act together with FGF to promote LEC proliferation during PCO

Box 31.5  Matrix metalloproteinases (MMPs) and

posterior capsular opacification (PCO)

•MMPs are a family of zinc-dependent matrix-degrading enzymes, involved in multiple fibrotic diseases, with emerging roles in a variety of cataract phenotypes, including PCO

•Broad-spectrum and specific MMP inhibitors (MMPIs) have been shown to suppress the development of PCO effectively in an vitro animal model setting

vivo with lower levels in the aqueous humor and higher levels in the vitreous humor.47 Thus, the concentration of FGF in the aqueous is thought to stimulate LEC proliferation. Indeed, FGF has been shown to exacerbate the ability of TGF-ß to induce PCO in vitro, and this is thought to occur due to the fact that FGF promotes LEC survival by counteracting the apoptotic effects of TGFß.48,49

Hepatocyte growth factor (HGF) and its receptor, c-met, have been found to be expressed in human postmortem capsular bags and LECs remaining on the anterior and posterior capsules showed elevated levels following surgical trauma.7 Like FGF, HGF has also been shown to regulate LEC proliferation and likely acts together with FGF to promote LEC proliferation during PCO. Similarly, the application of epidermal growth factor (EGF) to LECs has been shown to induce proliferation. In some cases, EGF was also found to induce LECs to differentiate into lens fiber-like lentoid bodies in vitro, which could have relevance to the appearance of regenerated lens fiber cells observed in the capsular bag in some cases of PCO.

The matrix metalloproteinases (MMPs) are a family of zinc-dependent matrix-degrading enzymes, involved in multiple diseases, including fibrosis, and emerging roles in a variety of cataract phenotypes, including PCO (Box 31.5).50 In particular, the gelatinases, MMP-2 and MMP-9, have been shown to be induced by TGF-ß in capsular bags.14,51 Studies that directly test whether MMPs promote PCO include that in which the broad-spectrum MMP inhibitor, GM6001, was shown to inhibit LEC migration significantly on human

donor lens capsules.51 A significant reduction in capsular contraction was also observed in the GM6001-treated capsular bags. The ability of MMPIs to prevent another related, fibrotic cataract, anterior subcapsular cataract (ASC), has also been shown. Like PCO, ASC involves a transformation and proliferation of LECs and an aberrant deposition of matrix beneath the anterior lens capsule. A common model of ASC, employing excised rat lenses cultured with active TGF-β, was used to provide further evidence for a causative role(s) for MMPs in the development of ASC: Dwivedi and colleagues52 showed that co-treatment of excised rat lenses with TGF-β and either of two commercially available MMP inhibitors (MMPIs), GM6001, a broad MMPI, or a MMP2/9-specific inhibitor, significantly suppressed formation of the cataractous plaques typically observed in ASC.

As outlined above, the cellular changes that occur in PCO are likely regulated in a paracrine manner by factors in the ocular media. Interestingly, while the levels of these factors peak shortly after cataract surgery, and typically return to basal levels within a few weeks or months, PCO can develop years after.53 This suggests that the events contributing to PCO persist after the initial exposure to paracrine factors. Thus, it is proposed that autocrine signals from the LECs themselves also contribute to PCO. Indeed, it has been shown using a human capsular bag model that LECs cultured in serum-free media, and devoid of any proteins/peptides, proliferate well on the capsule.44 Candidate autocrine signaling systems in the capsular bag include those normally expressed in the native lens epithelium, including EGF and its receptor EGFR, FGF and the FGF receptor 1, and also HGF and the c-met receptor.7

In summary, significant progress has been made in identifying the factors that contribute to the development of PCO. While surgical and IOL improvements have signifi-

Box 31.6  Treatment

•A number of pharmacological antagonists to posterior capsular opacification have been explored but none has gone beyond phase I clinical trials

•Delivery of these agents is likely to be a key factor in their success in the clinic

•The most promising is delivery from an intraocular lens, which offers the advantage of controlled release of the modulating agent and perhaps reduced toxicity to surrounding ocular tissues

cantly minimized the incidence of PCO, it still remains an important problem. A number of pharmacological antagonists have thus been explored, including agents that affect cell growth, such as ethylenediaminetetraacetic acid (EDTA), and thapsigargin, as well as those that inhibit multiple aspects of PCO, including LEC proliferation, migration, EMT, and capsular contraction, such as the MMPIs, and the proteosome inhibitor, MG132.51,54–56 However, to date, agents that inhibit PCO have not gone beyond phase I clinical trials (Box 31.6). Delivery of these agents is likely to be a key factor in their success in the clinic. Potential delivery mechanisms include injection into the anterior chamber or incorporation of the agent into the irrigation solution used during surgery, or modification of the IOL. The most promising of these appears to be delivery from an IOL, which offers the advantage of controlled release of the modulating agent and perhaps reduced toxicity to surrounding ocular tissues. Of course an important requirement for this type of delivery system would be that, following incorporation of the agent in the IOL, the optic of the IOL would need to retain its transparency.

5.Kappelhof JP, Vrensen GF. The pathology of after-cataract. A minireview. Acta Ophthalmol 1992;(Suppl.):13–24.

7.Wormstone IM. Posterior capsule opacification: a cell biological perspective. Exp Eye Res 2002;74:337– 347.

8.Pandey SK, Apple DJ, Werner L, et al. Posterior capsule opacification: a review of the aetiopathogenesis, experimental and clinical studies and factors for prevention. Ind J Ophthalmol 2004;52: 99–112.

11.Apple DJ, Solomon KD, Tetz MR, et al. Posterior capsule opacification. Surv Ophthalmol 1992;37:73–116.

13.Saika S. Relationship between posterior capsule opacification and intraocular lens biocompatibility. Prog Retin Eye Res 2004;23:283–305.

14.Wormstone IM, Tamiya S, Anderson I, et al. TGF-beta2-induced matrix

modification and cell transdifferentiation in the human lens capsular bag. Invest Ophthalmol Vis Sci 2002;43:2301–2308.

19.Nishi O, Nishi K, Menapace R, et al. Capsular bending ring to prevent posterior capsule opacification: 2 year follow-up. J Cataract Refract Surg 2001;27:1359–1365.

31.Chen H, Brook MA, Chen Y, et al. Surface properties of PEO-silicone composites: reducing protein adsorption. J Biomater Sci Polym Ed 2005;16:531– 548.

35.Wallentin N, Wickstrom K, Lundberg C. Effect of cataract surgery on aqueous TGF-beta and lens epithelial cell proliferation. Invest Ophthalmol Vis Sci 1998;39:1410–1418.

44.Wormstone IM, Liu CS, Rakic JM, et al. Human lens epithelial cell proliferation in a protein-free medium. Invest Ophthalmol Vis Sci 1997;38:396–404.

51.Wong TT, Daniels JT, Crowston JG, et al. MMP inhibition prevents human lens epithelial cell migration and contraction of the lens capsule. Br J Ophthalmol 2004;88:868–872.

52.Dwivedi DJ, Pino G, Banh A, et al. Matrix metalloproteinase inhibitors suppress transforming growth factor-beta-induced subcapsular cataract formation. Am J Pathol 2006;168:69–79.

55.Duncan G, Wormstone IM, Liu CS, et al. Thapsigargin-coated intraocular lenses inhibit human lens cell growth. Nat Med 1997;3:1026–1028.

Clinical background

Diabetes mellitus (DM) is an expanding major health problem. By the year 2030, it is anticipated that the worldwide incidence of DM will roughly double to 366 million, with 75% of all diabetics residing in developing countries.1 Diabetic adults 18 years of age and older have a 21% increased prevalence of visual impairment while those 50 years or older have a higher prevalence of vision loss from retinopathy, cataracts, and glaucoma.2 Cataracts develop earlier and more rapidly in diabetics. According to the Wisconsin Beaver Dam Study, the Australian Blue Mountains Eye Study, the Barbados Eye Study, the French Pathologies Oculaires Liées à l’Age (POLA) Study, and the West African Countries (Ghana and Nigeria) Study, diabetics have up to a fivefold increase in the prevalence of cataracts with cortical and/or posterior subcapsular opacities, with women developing cataracts slightly more than men.3–5

It is anticipated that the worldwide increase in DM will lead to an upsurge of cataracts and need for cataract surgery. While cataract surgery generally results in a favorable visual outcome, the visual potential in diabetics is often less and the surgical management more complex because of preexistent retinopathy, macular edema, or prior laser surgery.6 Hyperglycemia along with the duration of DM are important risk factors for cataract development (Box 32.1). The risk for cataracts is reduced fivefold when children and adolescents with type 1 DM are treated with intensive insulin therapy while tight control of hyperglycemia in adults with type 2 DM lowers the need for cataract extraction.7,8

Pathology

Precataractous changes

Clear lenses in diabetics are often larger in size with a widened subcapsular clear zone (Box 32.2). The cortex and nucleus of these lenses are also more fluorescent due to protein glycation that is proportional to glycemic control. This fluorescence is reduced with tight control.9 Transient refractive changes are also linked to glycemic control, with hyperglycemia primarily associated with myopia and hyperopia associated with a reduction in hyperglycemia. These

changes may be linked to the lenticular accumulation of sorbitol, a sugar alcohol metabolite of glucose.10 Sorbitol plays an osmoregulatory role in the kidney by helping cells adjust to intraluminal hyperosmolality during urinary concentration. In the lens, sorbitol may similarly diminish the dehydrational effects of increased aqueous osmolarity due to hyperglycemia.11 Sorbitol, however, is not rapidly removed from lens cells. As a result, an osmotic gradient favoring lens hydration is formed when hyperglycemia is reduced. The osmotic differences between the lens and aqueous are accentuated by rapid decreases in blood and aqueous glucose levels and this can lead to an additional accumulation of water and hyperopia. If severe enough, these changes can result in lens opacification.

Appearance of diabetic cataracts

While hyperglycemia is the common factor in cataract development in both type 1 and 2 diabetics, the appearance of cataracts in these patients differs depending on the individual’s age and the severity of the hyperglycemia (Figure 32.1). Experimental studies indicate that the appearance of diabetic cataracts is also affected by species differences, as discussed below (Figure 32.2). Clinically, the most common diabetic cataracts contain cortical and/or posterior subcapsular opacities. In children and adolescents with type 1 DM, the lenses contain numerous flaky white cortical deposits which give the appearance of a snowstorm. Alternatively, posterior subcapsular opacities with radial striae extending from the equatorial zone are present. As the opacities progress to the more advanced stages, the lens fibers become distinct with the formation of vacuoles and clefts.12 These opacities are often referred to as “true” diabetic cataracts because they rapidly evolve bilaterally over a period of days or weeks and are osmotic in nature.10 Cataract development in type 1 diabetics appears primarily dependent on the severity and prolonged poor control of the hyperglycemia rather than on the duration of DM.13

In adults, cataracts from diabetics are often difficult to differentiate from those from nondiabetics. In addition to cortical and/or posterior subcapsular opacities, adult-onset diabetic cataracts often contain nuclear sclerosis which closely resembles the typical senile cataracts of nondiabetics.13 Comparison of posterior cortical subcapsular cataracts from elderly individuals with type 2 DM and nondiabetics

shows similar morphological changes.14 Moreover, the cataractous regions in both the diabetic and nondiabetic lenses contain similar spherical globules, which are estimated to account for most light scatter, with the remainder from fiber degeneration. Similar morphological changes have also been observed in comparisons of the inner nuclear fiber cells from diabetic and nondiabetic lenses with nuclear sclerosis. However, the epithelial cell densities are lower in cataractous lenses from diabetics compared to nondiabetics.15

Pathophysiology

The specific mechanism(s) of how hyperglycemia initiates human cataracts has not been established (Box 32.3). To date, sorbitol pathway hyperactivity, oxidative stress and the generation of reactive oxygen species (ROS), and nonenzymatic glycation/glycooxidation have been implicated in diabetic cataract development. These pathways are summarized in Figure 32.3.

Box 32.1  Clinical background

•Diabetics have a fivefold increase in the prevalence of cataracts with cortical and/or posterior subcapsular opacities

•The anticipated worldwide doubling of patients with diabetes by 2030 will lead to an upsurge of cataracts and need for cataract surgery

•Hyperglycemia is the primary risk factor for diabetic cataracts and its tight control reduces the risks of cataract development and progression

•Transient refractive changes can occur with hyperglycemia, primarily associated with myopia, and a reduction of hyperglycemia associated with hyperopia

•Sorbitol may serve as an osmolyte in protecting lens epithelia against dehydrational effects of hyperglycemia-increased aqueous osmolarity

Box 32.2  Appearance of cataracts

•Appearance of diabetic cataracts depends on age, hyperglycemia, and species

•Children and adolescents with type 1 diabetes demonstrate “snowstorm” cortical opacities or “true” osmotic cataracts where posterior subcapsular opacities with radial striae and eventually vacuoles and clefts develop

•Adults with type 2 diabetes demonstrate cortical and/or posterior subcapsular opacities, often with nuclear sclerosis, that are similar to typical senile cataracts of nondiabetics. Although morphologically similar, epithelial cell densities in cataractous lenses from diabetics are lower than those from nondiabetics

Box 32.3  Pathophysiology of diabetic cataracts

•The specific mechanism(s) of how hyperglycemia initiates human cataracts has not been established

•Animal studies demonstrate that sorbitol formation associated with aldose reductase (AR) activity occurs in the epithelium and superficial cortical fibers. This can initiate localized osmotic changes that trigger biochemical cascades, leading to cataract formation. Sorbitol is also produced in human epithelial cells and biochemical similarities and clinical observations have linked both AR activity and sorbitol formation with the development of diabetic cataracts

•Oxidative stress and the generation of reactive oxygen species can result from hyperglycemia-associated mitochondrial dysfunction and sorbitol accumulation-initiated endoplasmic reticular stress, both of which are localized to the lens epithelium and bow region where the endothelial cells are differentiating into lens fibers

•Protein glycation and the formation of advanced glycation end products occur in both human and animal lenses and are directly linked to the levels of hyperglycemia present. However, animal studies with aldose reductase inhibitors and the observed absence of cataracts in some diabetic animals, such as hyperglycemic mice or diabetic cats, fail to support a central role for glycation in cataract development

Aldose reductase and sorbitol pathway activity

The sorbitol pathway converts glucose to fructose. In the first step, aldose reductase (AR) utilizes NADPH to reduce glucose to sorbitol. Then sorbitol dehydrogenase (SDH) using NAD+ oxidizes sorbitol to fructose. In the lens glucose is rapidly phosphorylated by hexokinase and undergoes glycolysis. Hyperglycemia results in rapidly increased lens glucose levels because glucose uptake is insulin-independent. As a result, hexokinase becomes saturated while AR is activated through gene expression by hypertonicity changes associated with excess glucose; however, SDH is not activated. Since glucose is reduced faster than sorbitol is oxidized, the net effect is the intracellular accumulation of the osmolyte sorbi-

tol. Excess formation of sorbitol has been directly linked to the onset and progression of diabetic complications, and the clinical development of select diabetic complications has been linked to the presence of AR alleles that are associated with increased enzyme activity.16

The importance of AR in initiating diabetic complications such as cataracts has been experimentally established by taking advantage of the broad substrate specificity of this enzyme. In addition to glucose, AR reduces galactose to its sugar alcohol galactitol. Galactose-induced tissue changes occur faster and are more severe than glucose-induced changes.5 This is because AR reduces galactose more rapidly than glucose and because higher intracellular levels of this osmolyte are achieved because galactitol is not further metabolized by SDH. Combining observations that similar

cataracts develop in diabetic and galactosemic rats and that AR is present in the lens, Kinoshita et al established that these “sugar” cataracts are initiated by the intracellular accumulation of sorbitol or galactitol.17,18 Moreover, these authors demonstrated that the accumulation of sorbitol or galactitol results in localized lens swelling, membrane permeation, vacuole and cleft formation, intracellular biochemical changes, protein aggregation/modification, and light scatter. This is known as the osmotic hypothesis, aldose reductase hypothesis, or sorbitol hypothesis.

This hypothesis is supported by extensive studies utilizing AR inhibitors (ARIs), animal models, and in vitro lens culture studies.18,19 Prevention studies utilizing a broad range of structurally diverse ARIs demonstrate that sugar cataracts can be dose-dependently delayed or inhibited. Animal studies show that the onset and severity of sugar cataract formation are directly linked to the levels of lens AR activity, which decreases with age.5,20 Cataracts develop faster and are more severe in young animals and they develop faster and under milder hyperglycemic conditions in animals possessing high lens AR levels. In contrast, cataracts do not clinically appear in hyperglycemic mice where AR levels are low. However, when AR is introduced into the lenses of transgenic mice, sugar cataracts rapidly form under both diabetic and galactosemic conditions.20,21 In vitro lens culture studies indicate that lens opacification is not only prevented by reducing lens polyol formation with ARIs, but also by preventing the formation of osmotic gradients between the lens and medium in iso-osmotic experiments.17,19 This suggests

246

that lens opacification does not directly result from AR activity.

The specific mechanism(s) of how sorbitol (or galactitol) formation and increased AR activity initiate cataract formation remains unclear. While sorbitol or galactitol as osmolytes can initiate localized osmotic stress, increased flux through AR, SDH or both have also been proposed to initiate oxidative stress and generate ROS.22 Reduced NADPH levels are associated with reduced levels of the antioxidant glutathione, the synthesis of nitric oxide (NO), and the activation of protein kinases. Since SDH only metabolizes sorbitol and not galactitol, it has also been suggested that alternate mechanisms of sugar cataract formation may occur with galactosemia linked to osmotic stress and diabetes linked to oxidative stress-associated ROS. This premise is not supported by animal studies, which show that sorbitol pathway activity is not altered by the administration of antioxidants and potent superoxide scavengers.

It has been proposed that sorbitol is formed through a free radical auto-oxidation of glucose rather than through the enzymatic reduction of glucose by AR; however, glucose auto-oxidation does not occur in the lens at physiological pH and sorbitol (or galactitol) is only enzymatically formed by AR.13,23 Sorbitol and galactitol formation has also been linked to oxidative stress24 and oxidative damage attributed to free radical scavenger formation has been observed in sugar cataracts . Both osmotic and oxidative stress in the lens is reduced by ARIs. Recent studies indicate that ROS is not directly generated by glucose metabolism but by the induc-