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. According to the World Health Organization, 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. 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).
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. 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. 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 acuity ( Figure 31.1 ). The time between surgery and PCO development varies considerably, ranging from a few months to 4 years. 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.
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The most common complication of primary cataract surgery is secondary cataract, also known as, posterior capsular opacification (PCO)
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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
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. 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. 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 (Nd-YAG) posterior capsulotomy. 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.
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. 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. 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.
In PCO, the “E cells” are those derived from the pre-equatorial 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. Thus, clinically, two morphological types of PCO have been documented, including wrinkling and fibrosis of 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 ). 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 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. The potential consequences of these factors are discussed in greater detail in the next section on pathophysiology.
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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
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. 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. 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 al 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.
The majority of recent studies have focused on IOL design effects. The observation that the incorporation of a square edge in an acrylic IOL results in a significantly lower incidence of PCO has led to significant changes in lens design. 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 silicones and polymethyl methacrylate (PMMA). Results also suggest that an edge effect is present in acrylic lens materials, although the effect is less clear with these materials. The work of Hayashi and Hayashi 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. 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.
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 oxide and poly methacryoyloxyethyl phosphorylcholine (MPC), 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. Various patents have examined the modification of IOL materials with materials which can lead to interactions with the lens capsule. These include tackiness coatings, functional end groups which react with the components of the capsule, and biological glues to stimulate adhesion to the lens capsule.
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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%
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Surgical improvements include the implementation of hydrodissection-enhanced cortical cleanup and the surgical approach, continuous curvilinear capsulorrhexis (CCC)
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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
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