Secondary cataract, also known as posterior capsule opacification (PCO), is the most common complication after cataract surgery, resulting from migration and proliferation of residual lens epithelial cells (LECs) onto the central posterior capsule, leading to decrease in visual function, and ultimately in visual acuity. Opacification within the capsular bag also may present as anterior capsule opacification (ACO) or interlenticular opacification (ILO).
Introduction
Secondary cataract or posterior capsule opacification (PCO) is the most common postoperative complication of cataract surgery. Its incidence has decreased over the past few decades as the understanding of its pathogenesis has evolved. Advances in surgical technique and intraocular lens (IOL) design and materials all have contributed to the gradual decline in PCO incidence. However, it remains a major cause of decreased visual acuity after cataract surgery, occurring at a rate of between 3% and 50% in the first 5 postoperative years.
Pathogenesis
PCO results from migration and proliferation of residual lens epithelial cells (LECs) onto the central posterior capsule. When the cells invade the visual axis as pearls, fibrotic plaques, or wrinkles, the patient experiences a decrease in visual function and, ultimately, in visual acuity. The epithelium of the crystalline lens consists of a sheet of anterior epithelial cells (“A” cells) that are in continuity with the cells of the equatorial lens bow (“E” cells). The latter cells comprise the germinal cells that undergo mitosis as they peel off from the equator. They constantly form new lens fibers during normal lens growth. Although both the anterior and equatorial LECs stem from a continuous cell line and remain in continuity, it is useful to divide these into two functional groups. They differ in terms of function, growth patterns, and pathological processes. The anterior or “A” cells, when disturbed, tend to remain in place and not migrate. They are prone to a transformation into fibrous-like tissue (pseudo-fibrous metaplasia).
In contrast, in pathological states, the “E” cells of the equatorial lens bow tend to migrate posteriorly along the posterior capsule (e.g., in posterior subcapsular cataracts, and the pearl form of PCO). In general, instead of undergoing a fibrotic transformation, they tend to form large, balloon-like bladder cells (the cells of Wedl). These are the cells that are clinically visible as “pearls” (Elschnig’s pearls). These equatorial cells are the primary source of classic secondary cataract, especially the pearl form of PCO. In a clinical study by Neumayer et al., significant changes in the morphology of Elschnig’s pearls were observed within an interval of only 24 hours. Appearance and disappearance of pearls, as well as progression and regression of pearls within such short intervals illustrate the dynamic behavior of regeneratory PCO.
The “E” cells also are responsible for formation of a Soemmerring’s ring, which is a doughnut-shaped lesion composed of retained/regenerated cortex and cells that may form following any type of disruption of the anterior lens capsule. This lesion was initially described in connection with ocular trauma. The basic pathogenic factor of the Soemmerring’s ring is the anterior capsular break, which may then allow exit of central nuclear and cortical material out of the lens, with subsequent Elschnig’s pearl formation. A Soemmerring’s ring forms every time any form of extracapsular cataract extraction (ECCE) is done, as manual, automated, or phacoemulsification (“phaco”) procedures. For practical purposes, it is useful to consider this lesion as the basic precursor of classic PCO, especially the “pearl” form. The LECs have higher proliferative capacity in the young compared with the old; therefore, the incidence of PCO formation is higher in younger patients.
The same cell types mentioned above are involved in other processes of opacification within the capsular bag ( Fig. 5.17.1 ). These include anterior capsule opacification (ACO) and interlenticular opacification (ILO). The latter is the opacification of the space between two or more IOLs implanted in the bag (piggyback implantation).
Treatment and Prevention
The treatment of PCO is typically neodymium:yttrium–aluminum–garnet (Nd:YAG) laser posterior capsulectomy. This is a simple procedure in most cases but is not without risks. Complications include IOL damage, IOL subluxation or dislocation, retinal detachment, and secondary glaucoma. Therefore, prevention of this complication is important, not only because of the risks associated with its treatment but also because of the costs involved in the procedure. Extensive research has been performed on the inhibition of LEC proliferation and migration by pharmacological agents through various delivery systems, or IOL coatings, in vitro and in vivo animal studies. Use of pharmacological and nonpharmacological agents for this purpose in an unsealed system may increase the risk of toxicity to surrounding intraocular structures, especially corneal endothelial cells. The Perfect Capsule, a silicone device that reseals the capsular bag allowing isolated safe delivery of irrigating solutions into its inner compartment, therefore, was developed. Immunotherapy and gene therapy, as well as physical techniques to kill/remove LECs, have been investigated. We evaluated in our laboratory the efficacy of an Nd:YAG laser photolysis system in removing LECs by using eyes from human cadavers. Light microscopy and immunohistochemistry revealed that the laser photolysis system removed LECs from the anterior lens capsule and capsule fornix. Along with the cells, laminin, fibronectin, and cell debris remained in the untreated areas but were removed by the treatment, which may be useful for PCO prevention.
While basic research on an effective mechanism for PCO eradication is evolving, the practical surgeon can apply some principles to prevent it. Studies done in our laboratory, as well as clinical studies done in other centers, have helped in the definition of three surgery-related factors that help in the prevention of PCO:
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Hydrodissection-enhanced cortical cleanup.
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In-the-bag IOL fixation.
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Performance of a capsulorrhexis slightly smaller than the diameter of the IOL optic ( Fig. 5.17.2 ).
Fig. 5.17.2
Human Eye Obtained From Cadaver (Posterior View) 19 Months After Implantation of a Single-Piece Hydrophobic Acrylic Lens.
This is an example of application of the three surgery-related factors for prevention of posterior capsule opacification. The lens was symmetrically implanted in the bag, via capsulorrhexis smaller than the optic diameter of the lenses (ideally, the capsulorrhexis margin should cover the edge of the lens for 360°). No significant Soemmerring’s ring formation is present.
The same studies helped in the definition of three IOL-related factors for PCO prevention:
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Use of a biocompatible IOL to reduce stimulation of cellular proliferation.
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Enhancement of the contact between the IOL optic and the posterior capsule.
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An IOL with a square, truncated optic edge.
Hydrodissection-Enhanced Cortical Cleanup
Howard Fine introduced this technique and coined the term cortical cleaving hydrodissection. The edge of the anterior capsule is slightly tented up by the tip of the cannula while the fluid is injected. The technique is used by many surgeons to facilitate cortex and equatorial LEC (“E” cell) removal, also enhancing the safety of the operation. Experimental studies used different solutions during the hydrodissection step of the phacoprocedure (e.g., preservative-free lidocaine 1%, antimitotics, etc.). Further studies are necessary to establish the safety and utility of these solutions in terms of PCO prevention.
Although a careful cortical cleanup and elimination of as many “E” cells as possible is fundamental to reducing the incidence of PCO, the role of anterior capsule polishing and elimination of “A” cells remains to be demonstrated. Indeed, Sacu et al. have performed a randomized, prospective study to evaluate the effect of anterior capsule polishing on PCO. The anterior capsule was extensively polished in one eye and was left unpolished in the other eye. Digital slit lamp photographs taken 1 year postoperatively by using a standardized photographic technique showed that anterior capsule polishing caused no significant difference in the outcome of PCO. Some authors actually believe that the postoperative fibrous metaplasia of remaining “A” cells would push the IOL against the posterior capsule, and that would explain the relatively low PCO rates of eyes implanted with silicone lenses having rounded optic edges.
In-the-Bag IOL Fixation
The hallmark of modern cataract surgery is the achievement of consistent and secure in-the-bag or endocapsular IOL fixation. The most obvious advantage of in-the-bag fixation is the accomplishment of good lens centration. However, endocapsular fixation functions primarily to enhance the IOL–optic barrier effect, as will be discussed later. In a series of human cadaver eyes implanted with different IOLs and analyzed in our laboratory, central PCO and Nd:YAG rates were both influenced by IOL fixation, that is, less PCO and Nd:YAG capsulectomies in eyes where the IOLs were in the bag.
Marie-José Tassignon proposed a variation of the in-the-bag IOL fixation concept for PCO prevention, named “bag-in-the-lens” implantation. This involves the use of a twin-capsulorrhexis IOL design and performance of anterior and posterior capsulorrhexes of the same size. The biconvex lens has a circular equatorial groove in the surrounding haptic, for placement of both capsules after capsulorrhexis. If the capsules are well stretched around the optic of this lens, the LECs will be captured within the remaining space of the capsular bag, and their proliferation will be limited to this space, so the visual axis will remain clear ( Fig. 5.17.3 ). Experimental and clinical studies showed that bag-in-the-lens implantation was highly effective in preventing PCO when the anterior and posterior capsules were properly secured in the IOL groove.
Capsulorrhexis Size
There is evidence that PCO is reduced if the capsulorrhexis diameter is slightly smaller than that of the lens optic so that the anterior edge rests on the optic. This helps provide a tight fit of the capsule around the optic analogous to “shrinkwrapping,” which has beneficial effects in maximizing the contact between the lens optic and the posterior capsule. In a retrospective clinical study performed at the John A. Moran Eye Center, University of Utah, on patients implanted with different IOLs, including lenses with round or square optic edges, the degree of postoperative PCO was correlated with the degree of anterior capsule overlap. Considering all patients, including the patients distributed in different IOL groups, there was always a significant negative, linear correlation between the degree of overlap and PCO.
Biocompatible Intraocular Lens
Many definitions for the term “biocompatibility” exist. With regard to PCO, materials with the ability to inhibit stimulation of cell proliferation are more “biocompatible.” The “sandwich” theory states that a hydrophobic acrylic IOL with a bioadhesive surface would allow only a monolayer of LECs to attach to the capsule and the lens, preventing further cell proliferation and capsular bag opacification. We performed two immunohistochemical studies on the adhesion of proteins to different IOLs that had been implanted in human eyes from cadavers. Analyses of histological sections have demonstrated that fibronectin mediates the adhesion of this hydrophobic acrylic lens to the anterior and posterior capsules. Analyses of explanted lenses have confirmed the presence of greater amounts of fibronectin on the surfaces of the same lens. However, even though differences among materials exist, in terms of PCO prevention it appears that the geometry of the lens, with a square posterior optic edge is the most important factor (see IOL optic geometry below).
The adhesiveness of the material may have a more direct impact on the development of ACO. This generally occurs much earlier in comparison to PCO, sometimes within 1 month postoperatively. When the continuous curvilinear capsulorrhexis (CCC) is smaller than the IOL optic, the anterior surface of the optic’s biomaterial maintains contact with the adjacent posterior aspect of the anterior capsule. Any remaining anterior LECs (“A” cells) in contact with the IOL have the potential to undergo fibrous proliferation; thus, ACO is essentially a fibrotic entity. Studies in our laboratory using pseudo-phakic eyes obtained from cadavers showed that ACO is more common with silicone IOLs, especially the plate designs, because of the larger area of contact between these lenses and the anterior capsule (see Fig. 5.17.1C ). However, the same studies showed that the plate design resists contraction forces within the capsular bag better than three-piece silicone lenses with flexible haptics (polypropylene). These latter showed the higher rates of capsulorrhexis phimosis and IOL decentration as a result of excessive capsular bag fibrosis. Therefore, a tendency exists in IOL manufacture favoring haptic materials with higher rigidity, such as polymethyl methacrylate (PMMA), polyimide (Elastimide), and poly(vinylidene) fluoride (PVDF). In the same studies, ACO was less significant with hydrophobic acrylic lenses having an adhesive surface.
ACO has been considered a clinical problem when anterior capsular shrinkage associated with constriction of the anterior capsulectomy opening (capsulorrhexis contraction syndrome or capsular phimosis) accompanies excessive anterior capsule fibrosis. This has been especially observed in conditions associated with zonular weakness (e.g., pseudo-exfoliation and advanced age, and with chronic intraocular inflammation. Besides phimosis of the CCC opening, excessive zonular traction, and its sequelae, IOL dislocation and retinal detachment can occur because of excessive capsular fibrosis. Excessive opacification of the anterior capsule is problematic in that it hinders visualization of the peripheral fundus during retinal examination. Otherwise, a certain degree of ACO is sometimes considered an advantage because it can prevent potential dysphotopsia phenomena caused by the square edge of some IOL optic designs. Additionally, anterior capsule fibrosis with contraction of the capsular bag will push the IOL optic against the posterior capsule, helping in the prevention of PCO according to the “no space, no cells” theory. This mechanism would explain the relatively low PCO rates with some silicone lenses, in the absence of a square optic edge profile, as noted above (hydrodissection-enhanced cortical cleanup).
The adhesiveness of the IOL material may also have an influence on ILO formation. To date, all cases of ILO that we have analyzed in our laboratory seem to be related to two hydrophobic acrylic IOLs being implanted in the capsular bag through a small capsulorrhexis, with its margins overlapping the optic edge of the anterior IOL for 360°. When these lenses are implanted in the capsular bag through a small capsulorrhexis, the bioadhesion of the anterior surface of the front lens to the anterior capsule edge and of the posterior surface of the back lens to the posterior capsule prevents the migration of the cells from the equatorial bow onto the posterior capsule. This migration may be directed toward the interlenticular space. In this scenario, the two IOLs are sequestered together with aqueous and LECs in a hermetically closed microenvironment. In addition, the adhesive nature of the material seems to render the opacifying material very difficult to remove by any surgical means (see Fig. 5.17.1D ).
Based on the common features of different cases of ILO, some surgical methods were proposed for its prevention. The first option would be to implant both IOLs in the capsular bag but with a relatively large-diameter capsulorrhexis. The other possibility is to implant the anterior IOL in the sulcus and the posterior IOL in the bag with a small rhexis. These should help sequester the retained/proliferated equatorial LECs within the equatorial fornix. Reassessment of factors leading to ILO formation is important because of the development of dual-optic accommodating IOLs to be implanted in the capsular bag. Additionally, piggyback implantation for correction of residual refractive errors appears to be increasing in popularity, including implantation of a multifocal IOL in patients with pseudo-phakia. However, in these cases the second (anterior) IOL is generally fixated in the ciliary sulcus.
Contact Between the IOL Optic and the Posterior Capsule
Different factors can help maximize the contact between the IOL and the posterior capsule, contributing to the so-called “no space, no cells” concept. Optic/haptic angulation displacing the optic posteriorly and stickiness of the IOL optic material are the most important lens features for obtaining a tight fit between lens and capsule. Three-piece lenses manufactured from the different haptic materials currently available today have in general a posterior optic/haptic angulation ranging 5°–10°. To keep the advantages of the two above-mentioned factors, it is important to achieve endocapsular lens fixation and to create a capsulorrhexis smaller than the diameter of the lens optic.
Capsular tension rings may have a role in the prevention of PCO. Equatorial capsular tension rings have the ability to maintain the contour of the capsular bag and to stretch the posterior capsule. Thus, they have primarily been used in cases of zonular rupture or dehiscence, secondary to trauma, or when inherent zonular weakness is present, such as in pseudo-exfoliation syndrome. It has been demonstrated by high-resolution laser interferometric studies that a space exists between the IOL and the posterior capsule with different lens designs. With a capsular tension ring in place, this space was found to be smaller or nonexistent. Thus, LECs would not find a space to migrate and proliferate onto the posterior capsule. Capsular tension rings also produce a circumferential stretch on the capsular bag, with the radial distention forces equally distributed. Formation of traction folds in the posterior capsule, which may be used as an avenue for cell ingrowth is thus avoided.
Capsular tension rings may also have a role in the prevention of opacification of the anterior capsule. The presence of a broad, band-shaped, capsular ring would keep the anterior capsule leaf away from the anterior optic surface and the posterior capsule. This would ultimately lead to less metaplasia of LECs on the inner surface of the anterior capsule with less fibrous tissue formation, as well as less opacification and contraction of this structure. IOLs with design features that also help maintaining the anterior capsule away from the anterior surface of the lens have been evaluated in our laboratory. A capsular tension ring designed to prevent opacification within the capsular bag was evaluated in two centers, one in Japan (Nishi O) and the other in Austria (Menapace R). Both centers reported a significant reduction in PCO and ACO with the rings, in comparison to the contralateral eyes implanted with the same lens design.
Intraocular Lens Optic Geometry
The square, truncated lens optic edge acts as a barrier, preventing migration of proliferative material from the equatorial region onto the posterior capsule. The barrier effect is absent in lenses having rounded edges, and proliferative material from the equatorial region has greater free access to the posterior capsule, opacifying the visual axis. The barrier effect of the square optic edge is functional when the lens optic is fully in the bag, in contact with the posterior capsule. When one or both haptics are out of the bag, a potential space that is present allows an avenue for cellular ingrowth toward the visual axis. Different modern lenses manufactured from different materials currently on the market present this important design feature. Some of them have a square edge on the posterior optic surface, whereas the anterior optic edge has remained round to prevent dysphotopsia. Findings from experimental studies which demonstrate that the square edges of different lenses on the market are not equally “sharp,” even when the same class of materials is considered, are noteworthy.
The optic–haptic junctions of square-edged single-piece lenses may represent a site for cell ingrowth and PCO formation. At the level of those junctions, the barrier effect of the square edge appears to be less effective. We obtained better results regarding PCO formation with a hydrophilic acrylic single-piece lens having an “enhanced” square edge than with the standard model of the same design. The enhanced edge provided the lens with a peripheral ridge around the lens optic for 360°. In the standard model, the square edge profile appeared to be absent at the level of the optic–haptic junctions ( Fig. 5.17.4 ). Therefore, the square optic edge is probably the most important IOL design feature for PCO prevention. It appears, however, that it should be present for 360° around the IOL optic in order to provide an effective barrier effect.
Treatment and Prevention
The treatment of PCO is typically neodymium:yttrium–aluminum–garnet (Nd:YAG) laser posterior capsulectomy. This is a simple procedure in most cases but is not without risks. Complications include IOL damage, IOL subluxation or dislocation, retinal detachment, and secondary glaucoma. Therefore, prevention of this complication is important, not only because of the risks associated with its treatment but also because of the costs involved in the procedure. Extensive research has been performed on the inhibition of LEC proliferation and migration by pharmacological agents through various delivery systems, or IOL coatings, in vitro and in vivo animal studies. Use of pharmacological and nonpharmacological agents for this purpose in an unsealed system may increase the risk of toxicity to surrounding intraocular structures, especially corneal endothelial cells. The Perfect Capsule, a silicone device that reseals the capsular bag allowing isolated safe delivery of irrigating solutions into its inner compartment, therefore, was developed. Immunotherapy and gene therapy, as well as physical techniques to kill/remove LECs, have been investigated. We evaluated in our laboratory the efficacy of an Nd:YAG laser photolysis system in removing LECs by using eyes from human cadavers. Light microscopy and immunohistochemistry revealed that the laser photolysis system removed LECs from the anterior lens capsule and capsule fornix. Along with the cells, laminin, fibronectin, and cell debris remained in the untreated areas but were removed by the treatment, which may be useful for PCO prevention.
While basic research on an effective mechanism for PCO eradication is evolving, the practical surgeon can apply some principles to prevent it. Studies done in our laboratory, as well as clinical studies done in other centers, have helped in the definition of three surgery-related factors that help in the prevention of PCO:
- •
Hydrodissection-enhanced cortical cleanup.
- •
In-the-bag IOL fixation.
- •
Performance of a capsulorrhexis slightly smaller than the diameter of the IOL optic ( Fig. 5.17.2 ).
