The Crystalline Lens

Abstract

The human crystalline lens is the second most important refracting element of the eye. The lens functions primarily in accommodative vision. The lens doubles in volume between birth and age 70. Approximately at age 40, the lens loses its ability to accommodate because of loss of pliability, and at age 70 the transparency of the lens is reduced resulting in cataract formation.

The lens is a totally cellular structure with no extracellular space, vascular channels, nerves, or risk of malignant transformation. A dense basement membrane, the lens capsule, allows diffusion of nutrients from the aqueous into the lens fibers and establishes an immune barrier for the cortex. The lens is suspended in the visual axis by acellular zonular fibers composed of a nonelastic matrix originating in the neuroepithelium of the ciliary body.

Minor developmental abnormalities causing congenital cataracts commonly occur; however, this type of cataract rarely adversely affects vision. Most cataracts requiring surgical intervention are caused by inflammation, trauma, or degeneration. The most common type of cataract treated with surgical intervention is the nuclear sclerotic cataract characterized by progressive opacification of the central lens (nucleus) over a period of decades. Traumatic interruption of the lens capsule can cause instant formation of lens opacity. Lens cortex tissue dislocated into the posterior eye tissues can cause severe granulomatous endophthalmitis leading to loss of the eye.

The eye is a complex structure composed of many types of tissue of different densities and orientations. Fixation and tissue processing artifacts are common, and many easily lead to misinterpretation of tissue events.

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5.1 General Description

The crystalline lens is the second most powerful refracting structure of the eye. The cornea has the major refractive power. The lens is the optical element that allows voluntary variation of focusing from distance to near. At birth the lens is nearly totally transparent and is malleable (Fig. 5.1a, b). The lens doubles in volume between birth and age 70 years because of continuous addition of new lens fibers to the peripheral layers [1, 2]. Unlike the skin, the older layers cannot be desquamated to the exterior but accumulate in the central portion of the lens. At approximately age 40 years, the lens loses pliability and optical correction is necessary to focus at near (bifocals). At approximately age 70 years, the lens becomes progressively more opaque. When the loss of transparency affects activities of daily living, the lens is termed a cataract (Fig. 5.2a, b).

Fig. 5.1

The normal lens (a) examined by a slit lamp (biomicroscopy). No incident light is reflected by the lens tissue, as would be the case with a lenticular opacity (cataract). This shows the gross cross-sectional features of a lens (b) from a 50-year-old man without a significant clinical cataract. The lens contour is ovoid rather than spherical as found in more elderly individuals. The lens doubles in volume between birth and age 70 years

Fig. 5.2

A nuclear sclerotic cataract (a) as seen by direct illumination. The central portion of the lens (nuclear) has become opaque and is reflecting light (arrows). This degree of opacification may be associated with decreased visual acuity. A nuclear sclerotic cataract (b) as seen by slit beam illumination. The nuclear area of the lens (double arrows) has become brown-orange because of the deposition of adrenochrome pigment. The anterior lens capsule is indicated by the single arrow. The cornea is at the level indicated by C. The area between is the fluid-filled anterior chamber. The aqueous normally does not reflect light and the space is “optically empty”

A primary cataract is a lens opacity developing as an expected event in aging. Age-related cataracts many have variable clinical and histopathologic features such as nuclear sclerosis, cortical opacities, or posterior subcapsular opacities. A secondary cataract is a lens opacity developing as part of a systemic disease process or an external event. Examples include developmental (persistent fetal vasculature, or persistent hyperplastic primary vitreous), trauma (posterior subcapsular cataract), endocrine (galactosemic cataract), toxic (siderotic cataract), and neoplasia (zonal cataract from mechanical compression of a ciliary body melanoma). There are no absolute differentiating histopathologic features among the various groups; however, certain patterns many be suggestive of a possible cause. For example, posterior subcapsular cataracts are associated with the use of steroids, severe diabetes mellitus, and intraocular or idiopathic inflammation.

Generally, surgical removal of either a primary or secondary cataract restores functional vision. The opaque natural lens is replaced with an intraocular lens (IOL) made of biocompatible synthetic material (e.g., polymethylmethacrylate [PMMA], acrylic, or silicone) (Fig. 5.3). The lens is placed within the native lens capsule in the posterior chamber of the eye (Fig. 5.4).

Fig. 5.3

At the time of surgery the cataractous lens is replaced by a synthetic intraocular lens (IOL). Generally only the lens cortex is removed. The lens capsule is left in place and is used as a repository for the replacement lens. There are many different styles; however one of the most commonly used lens is this three-piece, posterior chamber intraocular lens. The central optic focuses light on the retina to form an image. The lens is supported by two lens loops (arrows) within the lens capsule

Fig. 5.4

Posterior view of an intraocular lens in situ. Ciliary processes (CP double arrow) are present in the peripheral posterior chamber. The intraocular lens optic (O double arrow) is roughly centered over the pupil. The tips of the arrows mark the insertion of the lens loops (L single arrow) into the lens optic. The lens loops are within the lens capsule, which is translucent except in an opaque region at the loop which has undergone focal fibrous metaplasia of equatorial lens epithelium

The current procedure for removal of a cataract is to use a double-lumen cannula with an ultrasound tip to fragment the lens cortical fibers while leaving the surface capsule intact. Irrigation fluid is introduced through the outer cannula lumen, and fragmented tissue is aspirated though the central lumen of the cannula. The IOL is positioned permanently within the original lens capsule. The fragmented lens tissue is usually of no diagnostic value and is not submitted for histopathologic evaluation.

The pathologist may encounter specimens containing lens material in cases of enucleation (removal of the entire eye), evisceration (removal of the cornea and intraocular contents), and exenteration (removal of all of orbital tissue including the globe). In many cases, evaluation of alteration of the lens position and character is helpful in determining mechanisms of end-stage glaucoma, a common final pathway leading to enucleation of the eye. Lens tissue may be an important finding in extruded intraocular contents from a ruptured globe, a vitreous aspirate, or surgical removal of a nonfunctioning IOL (Fig. 5.5). Malignant transformation of crystalline lens material has not been observed [3].

Fig. 5.5

This illustration demonstrates the desired position of an intraocular lens within the lens capsule. The optic (O) is placed in the visual axis. The intraocular lens loops (arrows) are encased in the residual cortex. The IOL is entirely within the lens capsule. This specimen is from an eye removed as part of an exenteration procedure in a case of adenoid cystic carcinoma of the lacrimal gland. The eye was not directly affected by the malignancy

5.2 Embryology, Anatomy, and Development

The crystalline lens is formed from the surface ectoderm at the 28th day of gestation at a point of physical contact with elements of neuroectoderm that have extended laterally from the anterior neural groove. The surface ectodermal cells elongate and penetrate internally to form a sphere of cells (the lens vesicle), which detaches from the surface. With the support of surrounding neural crest tissue, the lens matures by elongating the cells of the posterior hemisphere, which come to occupy the central lumen of the sphere to form a solid cellular structure. As the posterior cells elongate to form the primary lens fibers, most of the cell organelles and the entire lens nucleus involute creating an “anucleate” cell with homogeneous cytoplasm. These cell structure characteristics remain throughout life and contribute to the ability of lens tissue to efficiently transmit light [4].

The anterior hemisphere cells remain and function in proliferation of new lens fibers from stem cells near the lens equator and are essential for maintaining diffusion gradients for glucose and other molecules necessary to sustain lens fibers (Fig. 5.6). Initially, development of the lens is maintained by diffusion from surrounding tissues. As the structure enlarges, there is a transient vascular supply with contributions from the primitive iris vasculature and the posterior hyaloid artery system. Near the time of birth, this transient vascular system, the tunica vasculosa lentis, involutes by apoptosis, as the primary fibrovascular vitreous is replaced by acellular secondary vitreous (Figs. 5.7 and 5.8). Tight adhesions form between the lens capsule and the anterior vitreous in focal areas. Nutrition supplied by the temporary vascular system is replaced by a transudate of plasma (aqueous fluid which contains no red blood cells) produced by the nonpigmented epithelium of the ciliary processes. At this point of development, the fundamental organizational anatomy of the crystalline lens is complete and changes very little throughout life.

Fig. 5.6

In the developed lens, epithelial cells are only present on the anterior hemisphere. The posterior hemisphere is tightly adherent to the anterior vitreous face. New lens fibers are produced at the lens equator in the region of zonular insertions where cell nuclei separate from the lens capsule. These lens stem cells form a curvilinear arrangement, the lens “bow” indicated by the double headed arrow. COR indicates position of the cornea. CB indicates the position of the ciliary body

Fig. 5.7

The developing eye at an early stage of embryogenesis. The posterior lens epithelial cells have migrated anteriorly as primary lens fibers (P) to obliterate the cavity of lens vesicle. At this point nutrition to the lens is supplied by the anterior tunica vasculosa lentis (arrows) and the posterior tunica vasculosa lentis

Fig. 5.8

Early in the development of the eye, the nutritional support of the lens (L) is provided by a network of vessels (tunica vasculosa lentis) (arrows) until aqueous is produced by the ciliary body. The tunica vessels of the anterior hemisphere originate from the vascular system of the iris (I) via channels from the minor arterial circle of the ciliary body. The position of the cornea is indicated by (C)

The crystalline lens is located in the anterior segment of the eye bordered anteriorly by the cornea, laterally by the trabecular meshwork and the ciliary body, and posteriorly by the anterior vitreous face (Fig. 5.9). The anterior segment is divided into anterior and posterior chambers by the iris diaphragm. The pupil of the iris diaphragm allows aqueous fluid formed by the ciliary processes in the posterior chamber to circulate to the anterior chamber and exit the eye through the trabecular meshwork. The pupil also has optical functions in adjusting the quantity and quality of light entering the eye. The crystalline lens measures, in the adult, approximately 9–9.5 × 9–9.5 in diameter and ×3.5–4.5 from the anterior to the posterior surface. The lens is suspended in the posterior chamber by delicate, acellular elastic fibers, the zonules, which originate at the vitreous base and portions of the ciliary processes. The zonules insert directly to the lens capsule anteriorly and posteriorly near the equator but do not involve the central visual axis of the lens (Fig. 5.10a, b) [3].

Fig. 5.9

The lens (**) is located in the posterior chamber behind the iris diaphragm (i) and within the ring of the ciliary body (CB). The cornea (C) is the most powerful optical element of the eye. There is no cataract in this case

Fig. 5.10

The zonules suspend the lens in the posterior chamber. These acellular fibers (arrows) arise from the nonpigmented epithelium of the pars plana (CE) just anterior to the vitreous base (a) and pass through the fluid-filled posterior chamber. The zonular fibers insert onto the surface of the lens capsule (b) in the region of the lens equator. In addition, the zonules along with the muscles of the pars plicata participate in changing the lens contours in accommodation

The lens capsule, one of the thickest basement membranes of the body, is composed of type IV collagen, laminin, and heparin sulfate. This semipermeable membrane is thickest in the region of zonular insertion laterally and is thinnest at central anterior surface and the central posterior surface to maximize transmission of light. The anterior capsule thickens throughout life by the addition of basement membrane secreted by the anterior hemispheral epithelial cells. There are no similar cells on the posterior surface of the lens; therefore the posterior lens capsule remains thin throughout life (Fig. 5.11a, b) [5].

Fig. 5.11

The lens capsule of the anterior hemisphere (anterior) is associated with active lens epithelial cells, which add to the capsular thickness throughout life. The lens capsule of the posterior hemisphere is not associated with active lens epithelial cell and remains thin throughout life

The overall configuration of the lens is that of a biconvex oval that becomes more spherical with advancing age. The structure is completely cellular with essentially no extracellular space. There is no innervation. There is no direct vascular supply indicating that the metabolic demands of the lens are met completely by diffusion across the lens capsule from surrounding aqueous. Interruption of aqueous flow will cause degeneration of the lens as is observed in conditions such as acute narrow angle glaucoma.

The original intraocular lens was developed during World War II when surgeons caring for injured Spitfire pilots noted that intraocular foreign body fragments from the cockpit canopy material were well tolerated and appeared to be biostable. The material, Perspex or polymethyl methacrylate (PMMA), was used to fabricate a replacement lens of roughly the same dimensions as the native crystalline lens. The type of surgery commonly used during that time, extracapsular cataract extraction, allowed the lens to be placed in the posterior chamber without additional support. The lens, however, was quite heavy and tended to dislocate into the anterior chamber or into the vitreous. Despite these problems, many of the IOLs were retained and provided serviceable vision for decades. Over the last 50 years, the design of IOLs and the method of placement have improved considerably. A folded IOL is now injected through a large-bore cannula via a small (2.6 mm clear corneal incision) to spontaneously uncurl and position within the posterior chamber and within the lens capsule. Dislocation from the posterior chamber is currently an infrequent occurrence. Visual recovery from cataract surgery now generally restores vision to the full potential of the person’s retina. Coexisting macular degeneration is one of the major limiting factors to full vision rehabilitation [6].

Intraocular lenses are generally one of two basic designs (Fig. 5.12). The first is a lens constructed of three pieces: a central optic fabricated to the optical power needed to correct the cataract patient’s anticipated residual refractive error and two loops swedged into the optic to expand and support the optic within the lens capsule. The second category of design is a plate configuration that is a single flat piece of synthetic material with the optical power located in the center of the lens and the maximal dimensions of the lens calculated to optimally stabilize the device within the lens capsule. There are literally hundreds of other designs some with special applications such as implanting the lens anterior to the iris diaphragm in the anterior chamber [6].

Fig. 5.12

There are two general designs of intraocular lenses used commonly: the three-piece intraocular lens (two loops and a central optic) and a one-piece plate lens. Both of these types of lenses are placed in the lens capsule in the posterior chamber. Another type of lens may infrequently be placed in the anterior chamber

Except for silicone and Supramid, most of the intraocular lens materials are soluble in the organic solvents used for the preparation of paraffin-embedded material. Generally, the presence of an intraocular lens in sectioned tissue depends on recognizing the void in tissue (shadow) left by the intraocular lens material (Fig. 5.13). Generally, there is no tissue reaction to the material itself; however fibrous tissue may form in the immediate environment of the IOL (Fig. 5.14). Occasionally, there may be an inflammatory reaction to the materials of the lens loops (Fig. 5.15).

Fig. 5.13

A biconvex intraocular lens optic (IOL) was present in the posterior chamber; however the material was solubilized by the organic solvents used in tissue processing. Fibrous tissue has formed in the posterior capsule and in the space behind the lens (**) resulting in a cyclitic membrane. Osseous metaplasia (arrows) has formed in the abnormal fibrous tissue

Fig. 5.14

An intraocular lens has been placed in a lens capsule with a moderate amount of lens cortex remaining. The lens loop material has dissolved but the negative image of its cross section is apparent (black arrow). Lens zonules (Green arrows) and the tips of ciliary processes (CP) are evident

Fig. 5.15

An intraocular lens loop (arrow) has been placed in the posterior chamber posterior to the iris but outside of the lens capsule. The loop material has stimulated an inflammatory response either because of the loop material itself or because of some antigen on the surface of the material

Histopathologic features of congenital lens abnormalities are similar to those resulting from degeneration or injury. Congenital variations of the lens consist of failure of formation of transparent tissue, alteration of contours and refractive index affecting optical power, and abnormal positioning of the lens due to dysfunction of zonular support. Most of these features are readily apparent by clinical examination but are subtle or obscure by histopathologic examination (Fig. 5.16a, b) [7].

Fig. 5.16

Two cases of congenital cataract (lens opacity present at birth). The opacity in a is at level of the nucleus. The opacity surrounds the margin of the nucleus leaving the periphery relatively clear. The opacity in (b) is in the superficial cortex (A) and is associated with a defect (coloboma) of the iris (double arrow.) Estimating the vision in cases of congenital cataract is difficult; the vision in (a) was 20/30, while the vision in (b) was 20/80

Congenital absence of the crystalline lens in an otherwise normally developed globe has not been observed. The most likely reason is that the lens is one of two fundamental differentiating tissues necessary for eye development. In some cases the lens may have formed but then has degenerated. Malformation of lens fibers leading to focal opacification of the lens during gestation is a relatively common event and is usually dependent on toxic changes or microbial infection of the lens environment. If the event is brief and minimal, the opacity may be seen clinically but may not progress of cause loss of ocular function.

One of the clearest examples of histopathologic verification of a congenital lens abnormality is a phakomatous choristoma (Zimmerman tumor) [8]. This lesion consists of an asymptomatic area of palpable induration of the subcutaneous tissue the lower eyelid, usually nasally, and most often identified in early childhood. The indurated tissue evolves from an ectopic rest of primitive lens material characterized by a prominent PAS-positive membrane surrounding large epithelial cells that are similar in appearance to the cells of a posterior subcapsular cataract (Fig. 5.17). The entity is treated with total surgical excision and does not recur.

Fig. 5.17

Phakomatous choristoma (Zimmerman tumor) is an ectopic lens tissue in the lower eyelid presenting as an indurated tumor of childhood. It is composed of lens cortical cells (C) surrounded by irregular basement membrane (BM) forming a lens capsule

The most dramatic congenital abnormality of the eye is cyclopia or synophthalmos. This condition results from the failure of development the diencephalon that is most often associated with fetal death. In the autopsy specimens the eye tissue in synophthalmos generally preserves the anterior segments, while there is apparent “fusion” of the posterior segment characterized by major posterior tissue abnormalities. The crystalline lenses may appear to be remarkably normal (Fig. 5.18). Similarly, the lens of a cyclopean eye may have few abnormal features [9].

Fig. 5.18

Synophthalmos is a developmental abnormality of the development of the eye early in embryogenesis. There is a fault in the development of the intervening brain making the posterior segment appear to be “fused.” The anterior segment including the lens may be remarkably normal (Courtesy of Alan Prioa, MD, Eastern Ophthalmic Pathology Conference, Duke University, Durham, North Carolina, 2007)

Alteration of the shape of the lens because of abnormalities of the lens capsule can seriously disrupt the refractive function of the lens. One example is lenticonus associated with Alport’s syndrome. Alport’s syndrome is a rare genetically determined disorder generally with an x-linked pattern of inheritance that causes a defect in type IV collagen, a major component of basement membrane including the glomerulus of the kidney and the lens capsule [10]. The weakened capsule allows an increase in the radius of curvature of either the anterior or posterior lens surfaces (Fig. 5.19) causing a marked decrease in visual function. The alteration of curvature is clearly evident by biomicroscopy. The lens may contain a congenital or an acquired cataract. By light microscopy the lens capsular thickness is reduced by two-thirds and appears more fibrillar than the normal lens capsule. By electron microscopy large numbers of partial capsular dissidences are present throughout the lens capsule that contains cellular debris [11].

Fig. 5.19

A developmental abnormality of type IV collagen formation in the lens capsule has caused a thinning of the lens capsule. The thinning has caused an increase in the radius of curvature of the posterior surface of the lens significantly altering the optical qualities of the lens

A pyramidal cataract is a feature of failure of separation of the lens vesicle from the surface ectoderm. The cataract clinically appears as a well-demarcated and densely opaque pyramid projecting from the central anterior surface of the lens into the anterior chamber. The opacity is composed of a region of fibrous metaplasia of the anterior lens epithelium. The cataract is generally not progressive and may have a minimal effect on visual function [12].

5.3 Inflammation

Crystalline lens material does not excite an intraocular inflammatory response unless the cortical material is exposed to the immune system. If an entire crystalline lens is dislocated with the crystalline lens capsule intact, the lens will not induce an inflammatory response even though the position of the lens, particularly in the pupillary space, may induce secondary glaucoma (e.g., pupillary block glaucoma). If, however, the crystalline lens cortex is displaced from the protection of the lens capsule, the cortical material will induce a severe granulomatous inflammatory reaction (Fig. 5.20). In the setting of trauma, the condition is called lens-induced uveitis or phacoanaphylactic endophthalmitis. If the lens cortex is dislocated during cataract extraction, the condition is called a “dropped nucleus.”

Fig. 5.20

Lens cortex not covered by an intact lens cortex will induce granulomatous inflammation and potentially cause extensive destruction of intraocular tissue. There is an extensive inflammatory reaction on the surface of the lens nucleus (C, double arrows). The inflammatory reaction is characterized by epithelioid histiocytes (insert)

Phacoanaphylactic (phacoantigenic) endophthalmitis is an intraocular inflammation following disruption of the lens capsule in the setting of either accidental trauma or intraocular surgery [13–15]. Despite the implications of the name, the process is neither anaphylactic nor toxic. The inflammatory reaction is directed toward lens proteins, crystallins. Crystallins are found not only in the lens but also in the retina and skeletal muscle. The inflammatory reaction depends more on altered tolerance to lens protein than as an immune reaction to previously sequestered antigens [16, 17]. The histopathologic pattern of inflammation is zonal: a zone of polymorphonuclear leukocytes (PMN) directly adjacent to exposed lens protein, surrounded by a layer of epithelioid histiocytes, with a peripheral region of a lymphoplasmacytic infiltrate. The inflammation in the eye is generally limited to the anterior segment and vitreous (Fig. 5.21a, b). Only a mild reactive inflammatory infiltrate is usually present in other posterior segment structures [18]. This type of inflammatory reaction has the potential to completely destroy the internal contents of the eye. Treatment is usually directed to surgically removing the retained lens cortical remnants.

Fig. 5.21

(a) The lens capsule has become disassociated from the cortex (arrow) stimulating a massive inflammatory reaction. The reaction is in the posterior chamber and has completely destroyed the anterior uveal tract. (b) The inflammatory reaction is zonal: (1) a concentration of acute inflammatory cells in contact with lens cortical protein, (2) a region of accumulation of epithelioid histiocytes, and (3) a peripheral accumulation of lymphocytes and plasma cells

Inflammation in the anterior chamber (anterior uveitis, iridocyclitis) may result in either an anterior subcapsular cataract (fibrous metaplasia of the crystalline lens epithelium) or posterior subcapsular cataract (posterior migration of nucleated lens bow cells) (Fig. 5.22a, b). An anterior subcapsular cataract is located at the geographic center of the anterior surface of the lens. Lens epithelial cells rendered necrotic by the toxic effects of inflammation stimulate remaining viable epithelial cells to respond by fibrous metaplasia forming a subcapsular collagenous plaque. The remaining epithelial cells may form a posterior monolayer that secretes a new basement membrane on its basal surface. Contraction of myofibroblastic cells of the collagenous plaque results in wrinkling of the anterior contour of the lens capsule. The process is irreversible and may cause considerable loss of visual function. Aqueous status may occur if fibrinous adhesions form in the region of iris-lens contact (posterior synechiae) leading to additional epithelial cell damage because of depletion of nutrients. Treatment is limited to cataract extraction after inflammation is controlled or eliminated.

Fig. 5.22

Anterior chamber inflammation has caused a well-demarcated, elevated, totally opaque opacity of the anterior lens (a). In this case of necrotic malignant melanoma (b), fibrous metaplasia (arrow) of the anterior subcapsular lens epithelium has occurred. The epithelium has been replaced by collagenous tissue inside the lens capsule. Fibrous tissue has also been induced on the external surface of the capsule by anterior uveitis

A posterior subcapsular cataract is found not only in the setting of inflammation but also with the use of therapeutic cortical steroids, diabetes mellitus, and trauma and without apparent cause. The opacity may be very subtle consisting of granular opacities in the visual axis of the lens on the internal surface of the lens capsule (Fig. 5.23a, b). Epithelial cells migrating to the anterior hemisphere replace normally aging epithelial cells. If a toxic stimulus is concentrated in the posterior cortex, the lens epithelial cells may migrate posteriorly in the subcapsular space of the posterior hemisphere. In this circumstance, the lens cells do not lose their nucleus or cell organelles. The migrating cells do not form normal delicate strap cells but assume a pleomorphic globular configuration and congregate at the posterior pole of the lens (Fig. 5.24). Individual cells do not transmit light but reflect light giving the appearance of ground glass when viewed by biomicroscopy. This type of cataract is unpredictable; it may progress over months or may remain stable for decades. The process is irreversible and is treated by standard cataract extraction at a time when there is control of the original stimulating condition.

Fig. 5.23

Two cases of posterior subcapsular cataract are illustrated. This type of cataract presents as a “ground glass” opacity just anterior to the posterior capsule. The view (a) is by direct illumination and (b) by slit lamp biomicroscopy. Cataracts in this location tend to interfere with vision early in the natural history of cataract because of their location at the visual axis

Fig. 5.24

Lens epithelial cells (arrows) have migrated from the lens equator along the posterior capsular internal surface to the posterior axial region of the lens. The cells have retained their nuclei but have formed irregular globular cells (Wedl cells or bladder cells) instead of the uniform lens fibers normally found in this region

The most common type of microbial infection of the lens is acquired during cataract surgery when surface flora becomes established within the lens capsule and proliferates. The disrupted edges of the lens capsule fuse forming a pocket of basement membrane that protects the organism from innate inflammation. The organism is often S. epidermidis or P. acnes, both low-virulence bacteria (Fig. 5.25). Low-virulence endophthalmitis is recognized clinically several days to weeks following cataract surgery as a low-grade anterior uveitis associated with progressive opacification of lens capsular remnants. The inflammation may lead to secondary glaucoma or cystoid macular edema. Treatment consists of intraocular antibiotics or surgical removal of infected lens capsular and cortical remnants. Organisms within the lens remnants are clearly identified by Gram or Brown-Hopps stains.

Fig. 5.25

P. acnes organisms (**) mechanically introduced during the time of surgical extraction of the lens cortex have proliferated within residual lens capsule (arrows). The organisms (**) are protected from phagocytosis by the lens capsule

Of historical and possible future significance is infection of the developing crystalline lens by rubella virus. In the early 1960s in the United States and Europe, there was an epidemic of gestational rubella infections resulting in a large number of children with congenital cataracts, congenital glaucoma, congenital deafness, cardiac defects, and mental retardation [19]. The infection of the lens by live virus is recognized clinically as a densely opaque, “pearl-like” nuclear opacity with a relatively uninvolved peripheral cortex (Fig. 5.26). At the time of the epidemic, only primitive methods of cataract extraction were available. The common procedure was to lacerate the anterior capsule with a needle and intentionally disrupt the opaque cortex. The native cortical material could not be aspirated until several days later when due to the action of released proteases the material became less viscous. What was not recognized at the time was that the disrupted cortical cells exposed to the aqueous contained live virus, which was released and infected vulnerable intraocular tissue causing viral endophthalmitis. Many eyes were lost because of this complication. In intact lenses the infection was identified by retention of nucleated cells in the center of the embryonic nucleus. These nucleated cells provided the necessary environment for the obligate intracellular parasitic virus to proliferate [20]. It is now known that the rubella virus can remain viable under these conditions for many years. Current cataract extraction methods nearly completely remove the infected tissue at the time of cataract surgery, which considerably reduces the risk of subsequent viral endophthalmitis (see also page 30).

Fig. 5.26

The eye of this child was infected with the rubella virus during gestation. At birth a dense, well-demarcated nuclear opacity was present (double arrow). Lens nuclear cells retained their cellular nuclei indicating an arrest in normal development of anucleate lens fibers. The nucleated cells are infected with the rubella virus. In addition, the anterior chamber angle structures (AC) and iris are abnormal

5.4 Trauma

The crystalline lens has delicate biochemical mechanisms and anatomic structures all of which are easily damaged by trauma. The final common outcome of trauma to the crystalline lens is the formation of a cataract. The specific type of injury may cause characteristic patterns of damage that allow identification of the cause (Fig. 5.27).

Fig. 5.27

A linear laceration of the inferior cornea has been repaired with sutures. The iris architecture is severely disrupted. Cataractous lens remnants (arrow) are present behind the remaining iris tissue

Iron ions in high concentration either from a retained metal foreign body (siderosis) or from degenerating blood (hemosiderosis) are toxic to the metabolism of the lens epithelial cells. Iron oxide is Prussian blue-positive material that may accumulate in anterior subcapsular tissue. This “rust” is clearly visible by biomicroscopy.

Accidental contact with high concentrations of alkali agents (sodium hydroxide, anhydrous ammonia) may diffuse through the cornea and across the anterior chamber to cause generalized necrosis of the lens epithelial and strap cells to cause formation of a cataract. Contact with other high-energy forms including lightning and therapeutic radiation (200–500 cGy) may also opacify the crystalline lens.

Blunt injury to the eye may cause regional necrosis of lens epithelium and fibers (petaloid/rosette opacity). Occasionally pigment from the iris pigment epithelium is displaced during trauma to the anterior surface of the lens capsule (Vossius ring). The lens zonules are acellular extracellular matrix fibers that may rupture resulting in dislocation of the lens. Luxation is the total displacement from the normal anatomic site, while subluxation is the partial dislocation.

Perforating wounds of the sclera or cornea may be associated with significant loss of intraocular contents including the lens (Fig. 5.28).

Fig. 5.28

A well-healed perforating injury of the central cornea (arrow) contains partially extruded remnants of the lens. Only lens capsule remains (insert). The anterior chamber (yellow arrows) remains formed

Because the lens cortex is relatively dehydrated and the lens fiber cells are so highly organized, any mechanical disruption of the lens capsule will result in near instantaneous swelling and thus opacification of the lens fibers. Extremely small rents in the lens capsular barrier may, on occasion, spontaneously repair; however, that sequence of events leading to useful vision is unusual. Currently, surgical methods for removing a severely damaged lens are efficient and thorough even at the time of initial repair of a traumatic ocular wound. The problem arises in cases with less severe injury, and more potential for resorting vision, where hemorrhage obscures the surgical field and tissues are difficult to identify by macroscopic characteristics. For example, deoxygenated blood and uveal tract appear very similar when displaced to the ocular surface. Avulsed vitreous and retina are both transparent. The surgical repair strategy can be clarified by microscopic evaluation of any material extruded from an ocular wound. Frozen section evaluation may be indicated, but certainly permanent sections on all extruded tissue are obviously in the patient’s best interest. The information, particularly when portions of retina are identified, will aid in deciding whether vitrectomy/lensectomy or enucleation is the next indicated procedure.

In the time of less technical sophistication in tissue repair, significant amounts of lens could not be removed surgically and remained within the inflamed eye, and crystalline lens remnants remained in the field of injury. A Soemmering ring cataract is the retention of a large amount of tissue, usually cortex at the lens equator (Fig. 5.29). The anterior and posterior capsules may fuse by fibrous metaplasia (Fig. 5.30). Elschnig’s pearls on the other hand are small amounts of lens material that remains as small, smooth translucent, or opaque bodies at the site of injury.

Fig. 5.29

The central lens cortex has been lost during an episode of trauma. The retained peripheral cortex has become densely opaque. The disrupted anterior capsule has become adherent to the remaining central posterior capsule preventing granulomatous inflammation of the remaining cortical tissue

Fig. 5.30

The thick anterior capsule has become opposed to the thinner posterior capsule. The breach has been sealed by fibrous metaplasia of remaining viable lens epithelial cells (**). This case was further complicated by iris neovascularization. The neovascular channels (arrow) cover the anterior surface of the central Soemmering ring cataract

Trauma may cause total degeneration of the eye (phthisis bulbi). With loss of intraocular pressure, the globe shrinks in size and assumes a squared-off appearance due to external compression by the rectus muscles. The cornea and sclera may appear thickened. The lens may calcify. Generally, no other normal intraocular structures can be identified (Fig. 5.31). In other cases the lens may completely disintegrate. Cholesterol crystals are a sign of lipid degeneration often from hemorrhage (Fig. 5.32).

Fig. 5.31

The eye has degenerated and become shrunken (phthisical). The lens (single arrow) has become calcified by intrinsic dystrophic calcification. The sclera (double arrow) has thickened

Fig. 5.32

The lens has degenerated to the point where it is barely recognizable (black arrow). Cholesterol (yellow arrow) has precipitated in the posterior segment from vitreous hemorrhage

5.4.1 Degeneration

A cataract is a lens that has become sufficiently biochemically and anatomically altered to the point that the tissue no longer efficiently transmits light to the retina but increasingly reflects light. The opaque material of the lens nucleus is partially formed by pigments, which differentially block certain wavelengths of light, particularly in the blue region of visible electromagnetic spectrum. The lens also changes anatomically with the result of nearly doubling volume from birth to age 70 years. This opaque lens can be replaced with a synthetic lens in order to restore transmission of light to the retina. At this time intraocular lens technology is just beginning to address restoration of accommodation (i.e., surgical treatment for presbyopia). The most common types of age-related (degenerative) cataracts are cortical, nuclear, and posterior subcapsular [18, 21].

5.4.1.1 Cortical Cataract

A cortical cataract is a regional opacification of the superficial, peripheral lens cortex usually presenting during middle age (Fig. 5.33a, b). This type of opacity is thought to be due a disorder of oxidative metabolism. The opacity is initially translucent and limited to an apparent single bundle of fibers or a partially demarcated opacity in the peripheral regions of the crystalline lens.

Fig. 5.33

One of the earliest signs of clinically significant cataract occurs at the lens cortex as translucent to opaque curvilinear opacities perpendicular to the periphery of the lens (a). The opacities are caused by circumscribed areas of lens fiber degeneration (b)

The light microscopic appearance is of regional clefts containing low-viscosity eosinophilic material (disassociated lens protein) and cell fragments (Morgagnian globules). The changes are similar to processing artifacts commonly seen in the lens, which tend to be more angular than the naturally occurring change. There is generally no reaction by adjacent lens epithelial cells. Focal areas of dystrophic calcification may be present. Ultrastructural features include linear breaks of the lens fibers perpendicular to the long axis of the fiber and splitting of suture lines.

5.4.1.2 Nuclear Cataract (Nuclear Sclerosis)

A nuclear sclerotic cataract presents as a region of opacification in the geographic center of the crystalline lens (Fig. 5.34). This is the most common type of cataract. The opacity can be identified in early middle age but generally does not significantly interfere with visual function until the sixth or seventh decade.

Fig. 5.34

With aging a nuclear opacity develops. The central nuclear area becomes orange (a) due to the accumulation of adrenochrome pigments. In addition the nuclear region becomes progressively more opaque (b) due to compression of spent cortical fibers (double arrow). These changes in the lens cause loss of color perception, particularly at the blue end of the spectrum, and vision loss due to opacification and alterations of the optical characteristics of the lens

Light microscopic characteristics include a loss of lamellar character of the lens fibers centrally with some variable preservation of the lens fiber pattern peripherally. The central area of the lens is homogeneous and may contain multiple artifactual cracks. A considerable amount of adrenochrome pigment may accumulate in the nuclear region making the cataract appear black (cataracta nigra) (Fig. 5.35). The ultrastructural characteristics of this process are those of nonspecific degeneration.

Fig 5.35

With progressive accumulation of pigment in the lens nucleus, the lens becomes black (cataracta nigra)

Degeneration of a nuclear cataract is progressive. As the lens enlarges (intumescent lens), it may impinge upon the iris diaphragm limiting the exit of aqueous into the anterior chamber (pupillary obstruction glaucoma, narrow angle glaucoma) (Fig. 5.36a, b). The cortical lens fibers undergo proteolysis forming globules of protein of irregular size and shape. This process in its early stages is characterized by a sharp demarcation from adjacent, normal appearing lens fibers (Fig. 5.37a, b). The lens cortex ultimately liquefies, and protein diffuses across an intact lens capsule into the surrounding aqueous (hypermature cataract) (Fig.5.38a, b). The nucleus is resistant to the proteolysis that affects the peripheral cortex and remains suspended in a location within the lens capsule determined by gravity (Morgagnian cataract) (Fig. 5.39 LM hypermature lens). The liberated lens protein is phagocytized by macrophages in the anterior chamber. The macrophages or toxic products of protein degeneration can cause dysfunction of the trabecular meshwork and increased intraocular pressure (phacolytic glaucoma).

Fig. 5.36

Two cases of nuclear sclerosis. As the cataractogenesis progresses, the lens becomes more spherical (a), which may displace the iris diaphragm anteriorly. The lens cortical fibers (b) begin to fragment and form large globules (black arrows). This process does not occur in the hardened nuclear region (double yellow arrow)

Fig. 5.37

In this case (a), the cortex adjacent to the posterior capsule (single arrow) is intact. More centrally the lens fibers have fragmented into globules (Morgagnian globules) of protein of irregular size and shape. Because these elements are no longer homogeneous, they will reflect light (appear opaque) rather than transmit light. In the second case (b), the demarcation between the tissue undergoing degeneration and normal appearing fibers (double arrow) is often well defined. Clinically, these areas of degeneration may appear as translucent “waterclefts” or opaque “spokes” in the lens cortex

Fig. 5.38

Lens cortical degeneration has progressed to total liquefaction of the lens cortex resulting in a spherical shape (a). With loss of cortical fluid, the lens assumes a partially shrunken shape (b). The nucleus, which is not affected by the liquefaction process, is visible as a poorly defined orange spheroid surrounded by lens capsule (arrow)

Fig. 5.39

With tissue processing the elements of the cataractous lens have disassembled. The sclerotic lens nucleus (N) maintains its integrity and shape. The residual protein debris of the degenerated lens cortex (double arrow) remains as an amorphous, slightly granular mass. The lens capsule (single arrow) is not affected by the degenerative process

One of the clinically most important types of cataract is the exfoliative cataract [22–24]. The fundamental abnormality in this case is a defect in basement membrane production. Particulate material accumulates on the surface of the lens capsule, which appears as fragments of dandruff (Fig. 5.40). This type of cataract is found more commonly in Scandinavia and Saudi Arabia, but is present in all ethnic groups. Exfoliative glaucoma may be more unpredictable and more aggressive than the more common chronic open angle glaucoma. Exfoliative material has been found in many tissues throughout the body.

Fig. 5.40

Biomicroscopy of an exfoliative cataract (a). The arrows indicate the presence of pathologic protein accumulation on the anterior surface of the lens. The material on the central portion of the lens has been swept away by contraction and dilation of the iris. A faint nuclear sclerotic cataract is also present. Light microscopy of exfoliative material (b). The material appears as linear accumulations of protein (arrow) perpendicular to the lens capsule from which the protein originated

In this condition, the iris cannot dilate fully because of degeneration of the iris musculature making cataract extraction difficult. In addition the lens zonules are defective and support of the lens is weak. These factors combine to increase the risk of lens dislocation at the time of cataract extraction.

By light microscopy the material can be readily identified on the surface of the lens capsule and zonules as irregular eosinophilic “iron filings.” The posterior contour of the iris pigment epithelium in cross sections of the eye has a serrated appearance reflecting the biochemical dysfunction of the iris musculature.

5.4.1.3 Posterior Subcapsular Cataract

A posterior subcapsular cataract presents as a region of opacification just anterior to the posterior lens capsule (Fig. 5.24). This is the most infrequently encountered type of degenerative cataracts and is indistinguishable clinically and histopathologically from trauma-induced, diabetes-induced, and corticosteroid-induced posterior subcapsular opacities. The opacity may present in early middle age. The rate of progression is unpredictable over a range of months to decades. Treatment is the standard cataract extraction with intraocular lens implantation.

The light microscopic characteristics are distinctive, composed of a layer of large bizarrely shaped cells with vesicular cytoplasm and small nuclei, accumulating in a region internal to and parallel with the posterior lens capsule (Wedl cells or bladder cells) [25]. Characteristic organelles of fibroblasts are found in the more mature cells although extracellular matrix production is rarely seen. Once formed the plaque of abnormal cells generally remains stable.

5.5 Tissue Processing and Artifacts

The crystalline lens is easily dislocated during gross sectioning. This is best avoided by opening the globe from posterior to anterior from a point 2 mm lateral to the optic nerve on the scleral surface to exit the globe 2 mm inside the limbus. This maneuver allows the lens to be supported by the iris diaphragm and cornea instead of dislocating the lens into the vitreous cavity as often occurs during anterior to posterior cutting (Fig. 5.41). If the lens is totally dislocated during gross sectioning, it can be repositioned during the time of final paraffin embedding.

Fig. 5.41

The lens (yellow arrow) has been dislocated during gross sectioning. Pigment from the iris pigment epithelium (white arrow) has been transferred from the iris to the anterior lens capsule. A serous detachment of the retina (black arrow) has developed in the region of a uveal melanoma

A formalin-fixed lens is translucent. Truly cataractous lenses are at least focally opaque and may be darkly opaque. Advanced cataracts may be dark orange or even black due to accumulation of phenochrome pigment in the lens during degeneration. The degenerated lens is composed of frail tissue, and the capsule may become separated from the cortex during tissue preparation (Fig. 5.42). Dystrophic calcification of the lens may make sectioning difficult and decalcification necessary.

Fig. 5.42

The lens cortex has degenerated to total opacity. The lens capsule was separated from the cortex during gross tissue preparation. A small portion of lens capsule remains intact (arrow)

Only in the case of the lens of an infant is lens structure physically preserved during sectioning with a microtome. The nuclear lens tissue is brittle and fragmentation during microscopic sectioning is the rule. The lens capsule is often intact, but parallel cracking, dislocation, and loss of cortical tissue are common. Areas of focal calcification only increase the number and extent of artifact formation. Periodic acid/Schiff stain highlights features of the lens capsule and is routinely used in histopathologic. Many of the features of certain types of cataract formation, e.g., anterior subcapsular cataract and posterior subcapsular cataract, are the result of fibrous metaplasia or posterior migration of the lens epithelial cells and are generally affected less by tissue processing and sectioning. Lens tissue is frequently lost during perforating trauma to the eye. The lens tissue may be reduced to small sections of PAS-positive membrane encased in fibrous reactive tissue. In many cases differentiating residual lens capsule from residual Descemet’s membrane may be difficult.

With the exception of silicone and some Supramid and metal loops, the intraocular lens material totally dissolves in the organic solvents used to process tissue for paraffin infiltration. Some of the original designs for iris-supported intraocular lenses were supported by metal loops (platinum) attached to the iris diaphragm at the pupil. This metal can seriously damage microtome knife cutting edges. Either the material needs to be identified and removed prior to sectioning or disposable blades should be used.

The position of intraocular lenses or any other implantable device is generally recognized by the negative image of the material within fibrous reactive tissue. The most common site with the presence of IOL loop material is within the native lens capsule or in the region of fibrous reaction anterior to the vitreous base. The IOL generally remains within the posterior chamber but may be dislocated to any site in the anterior or posterior segments. Foreign body granulomatous reaction may be found associated with suture material or retained cortex, but the material of the IOL does not excite an inflammatory response.