Accumulating yellow pigment together with increasing cellular compaction decreases the transmission of light and so decreases vision The same aging changes filter out ultraviolet (UV) light preferentially, which may help protect the foveomacular region of the neural retina from light damage.

D. Normally, no blood vessels or nerves are present in or attached to the lens.

General Information

I. A clinically significant opacity of the lens is called a cataract.

II. Cataracts, which do not cause an afferent pupillary defect, cause light scattering and transmit only a portion of light at all wavelengths.

III. Risk factors for development of a cataract include heredity, age, diabetes, oral or inhaled steroid therapy, exposure to UV-B radiation, poor nutrition, cigarette smoking, iris color (nuclear cataracts are more likely to develop in eyes with a dark brown iris), and high serum levels of the antioxidant enzymes plasma glutathione peroxidase and erythrocyte superoxide dismutase.

IV. Increased intake of protein, vitamin A, niacin, and riboflavin may reduce the risk of nuclear cataract.

Congenital Anomalies

Introduction

I. Congenital anomalies of the lens are usually associated with other ocular anomalies.

II. Such entities as coloboma of the lens, spherophakia, and congenital dislocation of the lens may be related to problems of zonular development rather than lenticular development.

A true coloboma of the lens probably does not exist. A coloboma of the zonules results in a deformed equator of the lens, simulating a lens coloboma.

The flecks tend to occur in the anterior and posterior cortex, are blue instead of white, and are called cerulean flecks.

II. Frequently, pigment cells are present on the anterior surface of the lens capsule in the pupillary area at the site of attachment of the pupillary membrane overlying the opacity.

All degrees of changes can be seen (especially with the slit lamp): sometimes only the blue flecks, other times only the membrane adhesions or the pigment cells, or any combination.

III. Most rarely, the same type of fleck cataract can occur in the posterior subcapsular area associated with remnants of the hyaloid vessels or the posterior tunica vasculosa lentis.

Anterior Polar Cataract

I. Anterior polar cataracts (Fig. 10.2) constitute approximately 3% of congenital cataracts.

Fig. 10.2 Congenital cataracts. A, Congenital anterior and posterior polar cataracts. B and C, Congenital posterior cataract. D, Congenital anterior Y suture. E and F, Congenital nuclear cataract.

II. Clinically and histologically, it appears similar to an acquired anterior subcapsular cataract. It is almost always stationary.

Rarely, congenital anterior polar cataract may be secondary to intrauterine keratitis. The capsule of the lens may become adherent to the inflamed cornea, causing lens traction during fetal development. The traction may distort the lens by drawing its axial area out to form an anterior pyramidal cataract. Even more rarely, spontaneous anterior capsular rupture may occur.

III. Often, the cause of the cataract is unknown, although occasionally it may be inherited as an autosomal-dominant, autosomal-recessive, or X-linked trait, or it may be associated with a reciprocal translocation between chromosomes 2 and 14. In an autosomal-dominant variant, anterior polar cataract is associated with cornea guttata.

Posterior Polar Cataract

I. Clinically and histologically, a posterior polar cataract appears similar to an acquired posterior subcapsular cataract (PSC: Fig. 10.3; see Fig. 10.2).

II. The cataract, rarer than its anterior counterpart, is usually stationary but may be progressive when associated with persistent hyperplastic primary vitreous (see Chapter 18). When this occurs, a dehiscence in the lens capsule may be seen posteriorly, with fibrovascular tissue within the posterior lens substance.

Anterior Lenticonus (Lentiglobus)

I. The anterior surface of the lens can assume an abnormal conical (lenticonus) or spherical (lentiglobus) shape.

More than 90% of cases of bilateral anterior lenticonus are associated with Alport’s syndrome.

II. Either condition predominates in boys, is usually present as the only ocular anomaly, and is usually bilateral.

III. Clinically, an “oil globule” reflex is seen in the pupillary area of the lens, similar to that seen in posterior lenticonus (see later), keratoconus, and, most commonly, nuclear cataract.

IV. The cause is unknown, except rarely it may be inherited as an autosomal-recessive trait.

Anterior lenticonus has been reported in familial hemorrhagic nephritis (Alport’s syndrome). Alport’s syndrome is probably inherited as an autosomal-dominant trait, with incomplete penetrance and varying expressivity of the mutant gene. The syndrome shows kidney disease, perceptive deafness, and ocular lesions. It is much more severe in men, who usually die before 40 years of age. Ocular lesions include spherophakia, anterior polar cataract, anterior lenticonus, posterior cortical cataract, rubeosis iridis, and fundus lesions such as drusen, retinal flecks (macular and midperiphery) similar to fundus albipunctatus, degeneration of macular pigment epithelium, and retinal neovascularization.

V. Histologically, thinning of the anterior lens capsule, a decreased number of anterior lens epithelial cells, and bulging of the anterior cortex are seen.

Posterior Lenticonus (Lentiglobus)

I. Posterior lenticonus (see Fig. 18.24), more properly called lentiglobus, consists of a spherical elevation or ridge on the posterior surface of the lens and is more common than its anterior counterpart. Clinically, an oil globule-like reflex is seen in the pupillary area of the lens.

II. The condition predominates in girls, occurs sporadically, is usually present as the only ocular anomaly, and is usually, but not always, unilateral.

Sometimes, posterior lenticonus is associated with other congenital anomalies, such as microphthalmos, microcornea, iris and retinal pigment epithelial colobomas, anterior chamber angle anomalies, hyaloid system remnants, axial myopia, and skull deformities.

III. The cause is unknown; the condition may occur in Lowe’s syndrome (see later).

IV. Histologically, the capsule is thinned in the central part posteriorly; the lens cortex bulges posteriorly; and often abnormal nuclei, resembling either lens epithelium or pigmented and nonpigmented ciliary epithelium, can be seen in the area of the anomaly.

A bulging or umbilicated posterior polar lens abnormality is frequently encountered in enucleated infant eyes. The abnormality is due to a fixation artifact.

Other Congenital Cataracts

I. Autosomal-dominant congenital cataract (ADCC)

Although dominant and recessive autosomal- and X-linked recessive types of congenital cataracts have been described, most familial cataracts are inherited in an autosomal-dominant manner. At least 15 loci have been reported for various primary forms of ADCC, including on chromosomes 3, 12, and 17.

A. ADCC is usually bilaterally symmetric but may be unilateral.

B. The lens opacity may be zonular, fetal nuclear pulverulent, nuclear, or sutural (or any combination; see Fig. 10.2).

II. Congenital cataracts such as zonular, sutural, axial, membranous, and filiform types have nonspecific histologic changes.

III. Cataracts secondary to intrauterine infection

A. Anterior subcapsular cataract (see later in this chapter)

B. Posterior subcapsular cataract (see later in this chapter)

C. Rubella cataract (see Fig. 2.12)

IV. Galactosemia cataract (see later in this chapter)

V. Transient neonatal lens vacuoles (Fig. 10.4)

A. Bilateral, symmetric lens vacuoles are situated predominantly in the posterior cortex near the Y suture close to the lens capsule.

B. The vacuoles, seen mainly in premature infants, are not present at birth, appear between days 8 and 14, and persist for approximately two weeks but may remain up to nine months before disappearing completely.

C. Histologically, swelling of lens cortical cells in several lamellae of both anterior and posterior (mainly) cortex is seen.

1. Large, “watery” cortical vacuoles with a nonstaining content are found.

2. Lipoidal degenerative products are also seen in the involved areas.

If the vacuoles do not disappear and become exaggerated, they may be responsible for zonular cataracts. The lipoidal degenerative products may cause the punctate opacities seen clinically.

Fig. 10.4 Transient neonatal lens vacuoles. A, Vacuoles in posterior lens of infant. B, Vacuoles have disappeared 20 days later. C, Periodic acid–Schiff stain shows multiloculated posterior subcapsular cortical cysts. D, Plastic-embedded thin section shows swollen lens cortical cells, ruptured artifactitiously, adjacent to edge of cyst. E, Electron micrograph shows edematous cortical cells containing dense bodies. Anteriormost cells in figure are relatively normal. (A and B, Courtesy of Dr. DB Schaffer; C–E, modified from Yanoff M, Fine BS, Schaffer DB: Histopathology of transient neonatal lens vacuoles: A light and electron microscopic study. Am J Ophthalmol 76:363. © Elsevier 1973.)

Capsule (Epithelial Basement Membrane)

General Reactions

I. The lens capsule, which is the thickest basement membrane in the body, is elastic, easily molded, and resists rupture (Fig. 10.5). It is impermeable to the passage of most particulate matter (e.g., bacteria and inflammatory cells).

Fig. 10.5 Lens capsule elasticity. A, This patient had bullous keratopathy secondary to glaucoma. The cornea then became ulcerated and perforated, resulting in an expulsive choroidal hemorrhage. The eye was enucleated. Gross examination shows the massive choroidal hemorrhage and the lens protruding through the ruptured cornea. B, Histologic section demonstrates molding of the lens through the corneal opening. The lens capsule is intact.

II. The lens capsule can undergo marked thinning, as in a mature cataract, or focal thickening, as in Lowe’s syndrome.

A. Oculocerebrorenal syndrome of Lowe (Fig. 10.6)

1. Lowe’s syndrome consists of systemic acidosis, organic aciduria, decreased ability to produce ammonia in the kidneys, renal rickets, generalized hypotonia, and buphthalmos.

a. The syndrome is transmitted as an X-linked recessive trait. The defect is in the distal long arm of the X chromosome (the OCRL1 gene) at positions 24 to 26 (Xq24–q26).

b. Female carriers show characteristic lens opacities—equatorial and anterior cortical clusters of smooth, off-white opacities of various sizes distributed in radial wedges.

2. Ocular findings include congenital cataract, glaucoma, and miotic pupil.

Most cases of genetic congenital cataract are not associated with glaucoma and, conversely, most cases of genetic congenital glaucoma are not associated with cataract. The combination of congenital cataract and congenital glaucoma, therefore, is highly suggestive of either Lowe’s syndrome or congenital rubella.

3. Histology

a. The cataractous lens is small and discoid, frequently containing a posterior lenticonus. The fetal nucleus may show retention of lens nuclei similar to the cataract in rubella, Leigh’s disease, and trisomy 13.

b. Lens capsular excrescences, similar to those seen in trisomy 21 and Miller’s syndrome, may be found.

Fig. 10.6 Lowe’s syndrome. A, Small, discoid, cataractous lens seen. Note Lange’s fold, a fixation artifact, at ora serrata. B and C, Cataractous lens contains artifactitious fissures. Note retention of lens nuclei in fetal nucleus of lens, similar to rubella (see Fig. 2.12). D, Periodic acid–Schiff stain shows abnormal lens capsular excrescences just posterior to the equator on the right. Note generalized posterior lens capsular thickening. E, Anterior chamber angle shows “infantile” (late embryonic) configuration. (Case courtesy of Dr. VT Curtin.)

III. Rupture of the lens capsule (Fig. 10.7) may be sealed over by the underlying lens epithelium or by the overlying iris, if the rent is small enough.

Most capsular ruptures result from trauma. Rarely, rupture may be spontaneous (e.g., in a hypermature cataract or in lenticonus) or, even more rarely, it may be secondary to a purulent infection.

Fig. 10.7 Trauma. A, Thickened, globular capsule marks site of sealed capsular rent. B, Traumatically ruptured lens capsule has allowed lens cortical material to “spill out” into anterior chamber. (A and B, Periodic acid–Schiff stain.)

Exfoliation of the Lens Capsule

I. True exfoliation of the lens capsule is a rare condition that results from prolonged ocular exposure to infrared radiation (a condition once common in glass and steel workers).

Today, true exfoliation of the lens capsule may be found more frequently as an idiopathic aging change than as a result of long-term exposure to infrared radiation.

II. The anteriormost layers of the anterior lens capsule split off into one or more sheets that curl into the anterior chamber. The exfoliated lamellae can be seen clinically waving in the aqueous as a “scroll” on the anterior surface of the lens.

III. Exfoliation of the lens does not affect the zonules and is not specifically associated with glaucoma.

Pseudoexfoliation Syndrome (Pseudoexfoliation of Lens Capsule, Exfoliation Syndrome, Basement Membrane Exfoliation Syndrome, Fibrillopathia Epitheliocapsularis) (Figs. 10.8–10.11)

I. The pseudoexfoliation (PEX) syndrome has a worldwide distribution, but it seems to be most common in Scandinavian people (especially in Norway and Finland) and is quite rare in black people.

A. It is probably inherited, possibly as an autosomal-dominant trait with incomplete penetrance and varying expressivity. The LOXL1 gene on chromosome 15q24.1 is strongly associated with PEX.

B. Low selenium levels in the aquous humor and conjunctiva may support the role of impairment in the antioxidant defense system in the pathogenesis of PEX.

C. Increasing age and female gender are significant risk factors.

D. The ocular component appears to be the most dramatic part of a systemic disorder (see later).

II. PEX syndrome occurs mainly in people between 60 and 80 years of age (although rarely it can be seen in young people) and is characterized by a deposition of a peculiar, white, fluffy material on the lens capsule, the zonules, the ciliary epithelium, the iris pigment epithelium, and the trabecular meshwork (i.e., limited to the anterior compartment of the eye).

PEX is a risk factor for cataract development.

A. Clinically, the anterior surface of the lens shows a characteristic thin, homogeneous white deposit centrally, called the central disc, corresponding in extent to the smallest size of the pupil. Often, an inrolled edge defines the end of the central disc, which is surrounded by a relatively clear zone.

The concentration of ascorbic acid, a major protective factor against free radicals, is reduced in the aqueous humor of PEX patients. Free radical action may play a role in the development of PEX. Also, plasma homocysteine, a risk factor for cardiovascular disease, is elevated in PEX with or without glaucoma.

B. On the outer third of the anterior lens surface is a peripheral band of a coarse, granular, “hoarfrost” material giving a frosted appearance to the lens surface. The band extends to the lens equator, is not seen unless the iris is dilated, and tends to have radial depressions that correspond to the radial furrows on the posterior surface of the iris.

C. Powdery, dandruff-like particles are commonly seen on the pupillary margin of the iris and occasionally attached to the corneal endothelium.

A consistent finding and essential sign (Naumann’s sign) of PEX syndrome are the corneal endothelial changes: small flakes or clumps of pseudoexfoliative material (PEXM) and usually a diffuse, nonspecific melanin pigment deposition on the corneal endothelial surface; reduced endothelial density; morphologic changes in cell size (polymegathism) and in cell shape (pleomorphism); endothelial cell damage; cell detritus; intraendothelial inclusions; and retroendothelial accumulations. Even with only moderate intraocular pressure elevation, a diffuse corneal decompensation that resembles cornea guttata (Fuchs’) may develop in these corneas.

D. The iris tends to be leathery and to dilate poorly because of fusion and atrophy of groups of circumferential ridges on its posterior surface and because of degenerative tissue changes and iris muscle cell atrophy.

Pupillary ruff defects may be seen. Iridodonesis and phacodonesis are noted in many patients and, rarely, spontaneous subluxation and dislocation of the lens may occur. Because of zonular weakness, cataract surgery on PEX eyes carries an increased risk of surgical complications. Before surgery, a shallow anterior chamber may be an indicator of zonular instability and should alert the surgeon to possible intraoperative complications.

E. An early sign of the condition is Sampaoelesi’s line, a pigmented line lying on the corneal side of Schwalbe’s line.

III. In slightly more than 50% of people, the condition is bilateral.

The uninvolved eye in patients who have unilateral PEX will develop PEX approximately 38% of the time if followed for 10 years. Although only one eye may seem affected clinically, autopsy analysis has shown that, histologically, the clinically unaffected eye can indeed be affected.

IV. Approximately 8% have glaucoma (glaucoma capsulare), and approximately 12% have ocular hypertension.

A. The cumulative probability of the development of increased intraocular pressure in PEX eyes is approximately 5% in five years and 15% in 10 years.

B. Degeneration of iris pigment epithelium and subsequent dense pigmentation of the anterior chamber angle is often seen, resembling that of the pigment dispersion syndrome (rarely, true pigment dispersion syndrome can coexist with PEX syndrome).

C. The cause of the glaucoma is unknown.

PEXM is apparently produced locally by trabecular cells and may cause a direct obstruction of aqueous outflow. The severity of glaucoma in PEX syndrome may be related to the amount of PEXM in the middle portion of the trabecular meshwork.

2. Alternatively, the glaucoma may be caused by a separate gene on a locus close to the gene that causes the other changes, or, conversely, it may be caused by a single gene bearing three characteristics: (1) an abnormality of the aqueous drainage pathways that causes glaucoma, (2) an abnormality that causes production of the PEXM, and (3) an abnormality that causes degeneration of the iris pigment epithelium. Variations in the expressivity of this single gene would explain why the three events are usually found together but sometimes only one or two are present.

3. Marked and site-specific elastosis in the lamina cribrosa of patients who have PEX syndrome and glaucoma suggests that an abnormal regulation of elastin synthesis or degradation, or both, occurs in the optic nerves.

V. Considerations

A. PEX syndrome appears to be part of a systemic disorder. PEXM is found histologically in the uninvolved fellow eye. In addition, extraocular PEXM has been found in the following sites: around posterior ciliary vessels, palpebral and bulbar conjunctiva of the involved eye, lid and nonlid skin, orbital tissue, lung, heart, liver, gallbladder, kidney, and cerebral meninges.

Almost always, PEXM is found in association with the fibrovascular stroma of the involved organs, most often adjacent to elastic tissue. Elevated plasma homocysteine (a risk factor for cardiovascular disease) is found in patients who have PEX, and increased levels of homocysteine in the aqueous may be involved in the pathogenesis of the glaucoma. PEX is associated with aortic aneurysm in up to 10% of patients.

B. Delayed intraocular PEXM development

1. White, fluffy PEXM may appear on the anterior hyaloid and pupillary border years after intracapsular cataract extraction in eyes where no PEXM had been present before cataract surgery (see Fig. 10.9A).

2. PEXM may develop on the anterior vitreous and on the anterior and posterior surfaces of a lens implant after extracapsular cataract extraction and lens implantation.

C. Currently, the most appealing hypothesis is that PEXM is a product of abnormal metabolism of extracellular matrix, particularly abnormal basement membranes and elastic fibers.

1. Chemical analysis indicates that PEXM has a complex carbohydrate composition, with both O-linked sialomucin-type and N-linked oligosaccharide chains.

2. PEXM reacts with monoclonal antibodies to the HNK-1 epitope. This carbohydrate epitope is characteristic of many extracellular matrix and integral membrane glycoproteins that are implicated in cell adhesion.

3. Whatever the cause, PEXM results in defective or abnormal zonular attachment to the lens capsule so that these patients are in a high-risk group for extracapsular cataract surgery and lens implantation.

Fibrillin appears to be an intrinsic component of pseudoexfoliative fibers, suggesting that enhanced expression of fibrillin or abnormal aggregation of fibrillin-containing microfibrils may be involved in the pathogenesis of PEX syndrome.

VI. Histologically, eosinophilic PEXM is found on the anterior surface of the lens, on the zonular fibers, on and in both surfaces of the iris and ciliary body, in the anterior chamber, on the corneal endothelium and incorporated in Descemet’s membrane, and in the trabecular meshwork.

A. In the central disc area of the lens, the small, straight, thin PEXM lines up parallel with but perpendicular to the lens (it looks much like iron filings lining up on a magnet).

B. In the area of the peripheral band and on the other ocular structures in the anterior segment, the deposits tend to have a dendritic appearance, usually at right angles to the surface to which they are attached. The deposits are prominent over the free surface of the iris pigment epithelium and are characteristically in atrophic clusters of circumferential ridges.

C. Electron microscopically, a fibrogranular material is found in the deep (posterior) part of the anterior lens capsule.

1. It is most marked toward the equator and in the region of the zonular attachments. The abnormal material also seems to be present near the underlying lens epithelium.

2. The material is made up of bundles of exceedingly fine filaments that are banded together and have a periodicity of 50 nm—a type of basement membrane.

Fig. 10.8 Pseudoexfoliation (PEX) syndrome. A, The earliest hint of PEX in the undilated pupil is the presence of dandruff-like material on the pupillary edge of the iris and on the anterior surface of the lens in the region of the pupillary margin. B, Partial dilatation shows the beginning (from 6 to 8 o’clock) of the peripheral rim of PEX material. Another case shows the slit-lamp (C) and red reflex (D) appearance of the central and peripheral deposits.

Fig. 10.9 Pseudoexfoliation (PEX) syndrome. A, Throughout the years, PEX material developed on the anterior face of the vitreous in an aphakic patient who did not have PEX syndrome at the time of an intracapsular cataract extraction. B, In the central disc area, the PEX material is deposited as small slivers that line up parallel to each other and perpendicular to the lens capsule. C, In the peripheral granular area, the material is abundant and has a thick dendritic appearance. D, Scanning electron micrograph of anterior lens surface shows a relatively clear zone (z) surrounded by a central edge of peripheral granular area. (B and C, Periodic acid–Schiff stain; D, courtesy of Dr. RC Eagle, Jr.)

Fig. 10.10 Pseudoexfoliation syndrome. A, The exfoliation material deposits on the posterior surface of the iris, causing the iris to have a sawtooth posterior configuration. The deposited material often acts as a strut, limiting dilatation of the iris. The material can also be seen deposited on the zonular fibers of the lens (B) and on the ciliary epithelium (cp, ciliary processes; l, lens; e, exfoliation material on zonules) (C) . (B, Courtesy of Dr. RC Eagle, Jr.; C, periodic acid–Schiff stain.)

Fig. 10.11 Pseudoexfoliation (PEX) syndrome. A, Scanning electron microscopy shows coarse ridging of posterior iris surface. Encrusted ciliary crests lie below. Compare abnormal iris (B) with relatively normal iris (C) (same patient). Note compression of several ridges into single coarse ridge in B. D, In single coarse ridge, pigment epithelium is compressed into core by accumulating PEX material. E, PEX material (p) entering into trabecular (uveal) meshwork (tr).

Epithelium

Proliferation and Migration of Epithelium

Anterior Subcapsular Cataract (ASC) (Figs. 10.12–10.15)

I. After an injury (traumatic or noxious, e.g., iritis or keratitis) to the anterior lens, the following sequence of events may take place and result in an ASC.

A. The lens epithelial cells in the region of the anterior pole of the lens become necrotic.

B. Adjacent cells migrate into the subcapsular area, proliferate, and form an epithelial plaque.

C. The epithelial cells, except the most posterior layer, undergo fibrous metaplasia to become fibroblasts. They then lay down a connective tissue plaque containing collagen. With time, the fibroblasts largely disappear and the scar tissue shrinks, wrinkling the overlying lens capsule.

D. Simultaneously, the remaining epithelial cells, which now line the posterior edge of the fibrous plaque, lay down a new lens capsule (basement membrane). The final result is a fibrous plaque at the anterior pole of the lens between a duplicated lens capsule, called an anterior subcapsular cataract.

E. An ASC cataract is rarely seen clinically because an occluded pupil is most often superimposed.

II. Frequently, the same injury that initially caused the ASC also causes an anterior cortical cataract. The combination of an ASC cataract and an anterior cortical cataract is called a duplication cataract (see Fig. 10.14).

Fig. 10.12 Anterior subcapsular cataract. A–D, Changes from normal lens epithelium through proliferating epithelial cells to final subcapsular fibrous plaque and formation of new continuous lens capsule.

Fig. 10.13 Anterior subcapsular cataract (ASC). A, The patient had an ASC some years after blunt trauma to the eye. B, Histologic section of another case shows early proliferation of the lens epithelium beneath the capsule. C, In yet another case, continued proliferation of the lens epithelium has occurred along with fibroblastic metaplasia (fm, pigmented, vascularized fibrous membrane; lc, lens capsule; e, proliferation of the lens epithelium; c, cortex). D, Electron micrograph of ASC shows filamentous spindle cell and adjacent irregular patches of basement membrane (bm). (B and C, Periodic acid–Schiff stain.)

Fig. 10.14 Anterior subcapsular cataract (ASC). A, An intumescent cataractous lens shows ASC on its anterior surface. B, An anterior subcapsular fibrous plaque and a wrinkled capsule are prominent. The combination of ASC and underlying cortical morgagnian (globular) degeneration is called a duplication cataract. C, Alizarin red stain demonstrates calcium (red color) in the ASC. D, The proliferated epithelium has largely disappeared and has laid down collagen tissue. The original lens capsule is thrown into folds, and the original lens epithelium has laid down a new, periodic acid–Schiff-positive lens capsule (olc, original lens capsule; asc, anterior subcapsular cataract; nlc, new lens capsule; le, lens epithelium; c, lens cortex).

Fig. 10.15 Anterior and posterior subcapsular cataract in two different cases. The blue color of the trichrome stain demonstrates the fibrous plaques. A and B, Anterior and posterior subcapsular cataract in same lens. C and D, Another case shows the combination of anterior and posterior subcapsular cataract in same lens.

Posterior Subcapsular Cataract (PSC) (Figs. 10.16 and 10.17; See Fig. 10.15)

I. The following sequence of events may result in a PSC, either idiopathically (most common) or after an injury to the posterior or equatorial area of the lens (usually noxious, e.g., with choroiditis or retinitis pigmentosa).

Other increased risk factors for a PSC include oral or inhaled steroid therapy, diabetes, and increased UV-B exposure.

A. In all probability, the subcapsular posterior cortical cells degenerate early.

B. Later, the lens epithelial cells proliferate and migrate posteriorly, frequently reaching the posterior pole of the lens.

Any lens epithelial cells present between lens capsule and lens cortex posterior to the equator are always in an abnormal location and represent a pathologic change. The epithelial cells may proliferate abnormally until the entire lens capsule appears lined by a continuous layer of cells.

C. The abnormally positioned epithelial cells enlarge in a grossly aberrant manner and produce large, bizarrely shaped cells that contain abundant, pale-staining, vesicular cytoplasm and small nuclei [i.e., bladder cells (of Wedl)]. The changes, mainly bladder cell formation, constitute a PSC.

Pre-age-related PSC is an early finding in Werner’s syndrome, a rare autosomal-recessive disease that has multiple progeroid characteristics.

II. The proliferating epithelial cells, including the aberrant forms (bladder cells), may move anteriorly into the posterior cortex and result in a posterior cortical cataract in addition to the PSC.

Fig. 10.16 Posterior subcapsular cataract (PSC). A, The patient had been on long-term steroid therapy after receiving a renal transplant. PSC developed over many years. B, Red reflex view of same case. C, Moderate PSC changes in lens from patient with primary retinitis pigmentosa. D, Periodic acid–Schiff-stained histologic section shows marked PSC changes, including cortical bladder cell formation (Wedl’s cells).

Fig. 10.17 Posterior subcapsular cataract (PSC). A, Gross specimen shows early PSC. Eye enucleated because of ciliary body melanoma. B, Same case shows posterior migration of lens epithelium and minimal posterior subcapsular cortical degeneration.

Elschnig’s Pearls (See Fig. 5.12)

Degeneration and Atrophy of the Epithelium

I. Degeneration and atrophy of the lens epithelium may occur as the result of aging or secondary to acute or chronic glaucoma, iritis or iridocyclitis, hypopyon, hyphema, chemical injury (especially alkali burn), noxious products in the aqueous (e.g., with anterior segment necrosis), or stagnation of the aqueous (e.g., with posterior synechiae and iris bombé).

A. The epithelial damage may be minimal, resulting in no clinically detectable opacity, or it may be extensive, resulting in widespread cortical degeneration and opacification. Between the two extremes, a wide range of abnormalities may occur.

B. Neighboring normal epithelial cells may proliferate to heal a small epithelial defect and sometimes form irregular tufts dipping into the lens substance, or they may overproliferate and form ASC or PSC cataracts.

C. Localized focal areas of epithelial necrosis, as often occur after an attack of closed-angle glaucoma, may result in multiple, discrete, stationary, permanent subcapsular opacities called glaukomflecken (cataracta disseminata subcapsularis glaucomatosa). Undoubtedly, stagnation of aqueous secondary to aqueous outflow blockage, along with a buildup of noxious materials in the aqueous (especially from iris necrosis), plays a role in the development of glaukomflecken (see Fig. 16.8).

Cortex and Nucleus (Lens Cells or “Fibers”)

Cortex (“Soft Cataract”)

I. Biochemical changes in the lens cortex from any cause (congenital, inflammatory, traumatic) may result in clinically detectable opacities (i.e., cortical cataracts) (Figs. 10.18–10.22).

Fig. 10.18 Types of changes that lens “fibers” (i.e., cells) undergo.

Fig. 10.19 Cortical cataract. A, Peripheral cataractous clefts, presumably caused by liquefaction of cortex. B, Scanning electron microscopic appearance of morgagnian globules in liquefied cortex. C, Periodic acid–Schiff-stained histologic section shows morgagnian globules between fragmented lens “fibers” in cortex. (B, Courtesy of Dr. RC Eagle, Jr.)

Fig. 10.20 Cortical cataract. A, Lens appears white (mature cataract) secondary to complete liquefaction of cortex; no clear cortex is detectable beneath anterior lens capsule. Note gravity has caused brown nucleus to sink inferiorly in liquid cortex. B, Liquid cortex has escaped through intact capsule, resulting in a wrinkled capsule, called hypermature cataract. C, Histologic section of a removed mature lens shows no cortex (except lower right) surrounding the nuclear cataract. The capsular rupture is an artifact of fixation and processing.

Fig. 10.21 Cortical changes by electron microscopy. A, Gross irregularities of cortical cells and few globules above. Normal (n) cells present below. B, Cell fragmentation and morgagnian globules (g) present. C, Dense (d) and lucent (l) globules present. Lucent globules appear watery. D, Watery cell or possibly “hypermature” cell protein (h).

Fig. 10.22 Christmas tree cataract. A, Patient had glistening, shimmering crystals in the cortex of both eyes. B, Polarization of unstained frozen section of removed lens demonstrates birefringence. Previously thought to be areas of cholesterol, evidence suggests that crystals are cystine.

UV irradiation may play a role in the development of cortical cataracts. Matrix metalloproteinase-1 may be upregulated by UV-B light and contribute to cortical cataract formation.

II. Many clinical types of cataracts are recognized (e.g., cuneiform, coronal, and spokelike), but they do not have well-characterized pathologic counterparts in specific histologic findings.

III. Histologically, the following pathologic changes may be found.

A. Clefts seen clinically and histologically are made up of diffuse, watery, or eosinophilic material, probably representing altered or denatured cell proteins (Morgagnian globules—see later).

B. Cell fragments represent pieces of broken-up lens cortical cells.

1. They are distinguished from artifactitious fragments by the rounding off of their fractured ends from retraction of the tenacious cytoplasm of the cell.

2. Cortical fragmentation and rounding, or liquefaction, of their cytoplasm results in the production of morgagnian globules.

C. Morgagnian globules represent small or large fragments of cortical cells that appear rounded from the increased liquidity of the cytoplasm.

1. They may be present in small or large clefts in otherwise normal-appearing cortex, or they may completely replace the entire cortex.

2. As increasingly more morgagnian globules, together with altered or denatured protein, replace the normal lens cortex, the lens becomes hyperosmolar and absorbs fluid.

3. A swollen (mainly in the anteroposterior diameter) intumescent cataract ¹ results.

4. The globules or abnormal protein may replace the entire cortex and result in a mature (morgagnian or liquefied) cataract. The nucleus then sinks, by gravity, inferiorly (see Fig. 10.20A). The whole lens looks clinically like a milk-filled sac.
During the process of cortical liquefaction, if the fluid is of sufficiently small molecular size, it may escape through the intact capsule and result in a smaller-than-normal lens with a wrinkled capsule (hypermature cataract; see Fig. 10.20B).

Rarely, the capsule of a mature cataract may rupture spontaneously and spill its contents into the aqueous fluid. In both a mature and a hypermature cataract, the capsule is frequently thinned and the epithelial cells are often degenerated. It is rare to see a hypermature lens in which all of the lens substance has been resorbed, leaving only the capsule.

D. Numerous crystals, such as calcium oxalate, cholesterol, and cystine, may become deposited in long-standing cataracts.

A Christmas tree cataract (see Fig. 10.22) consists of highly refractile, multicolored needles throughout the cortex. The needles are thought probably to be cystine. Christmas tree cataract may be associated with uncombable hair syndrome, an autosomal-dominant condition.

E. Calcium salts may impregnate long-standing cataracts (cataracta calcarea). The abnormal calcification of the lens is an example of dystrophic calcification. Disruption of the lens capsule can result in intraocular dispersion of calcified lens particles, resulting in a condition called calcific phacolysis.

F. A break in the anterior capsule may result in cortical material becoming trapped in the equatorial region of the lens (i.e., a Soemmerring’s ring cataract; see Fig. 5.12). After an acquired break in the lens capsule, or congenitally, mesenchymal tissue may grow into the cataract, leading to bone formation (cataracta ossea) or the formation of adipose tissue (cataracta adiposa or xanthomatosis lentis).

Nucleus (“Hard Cataract”)

I. The increasing pressure of cell on cell, the breakdown of intercellular membranes in the lens nucleus, the slow conversion of soluble to insoluble protein, and the dehydration and accumulation of pigment (urochrome) all lead to optical and histologic densification of the nucleus and a nuclear cataract (Figs 10.23 and 10.24; see Fig. 10.20).

Cigarette smokers have an increased risk for development of nuclear lens opacities.

A. With increasingly more accumulation of pigment in the nucleus, the nuclear color changes from clear to yellow to brown (cataracta brunescens) to black (cataracta nigra).

B. Both the change in color and the increase in refractive index of the nucleus impede light from entering the eye and cause a decrease in visual acuity.

The increase in index of refraction also causes greater bending of the entering light and results in a lens-induced myopia (“second sight”).

Fig. 10.23 Nuclear cataract. A, The red reflex shows the “oil droplet” effect of the nuclear cataract. B, Slit-lamp examination of another case shows the cataractous yellow pigmented nucleus. C, A histologic section of yet another case shows the homogeneous appearance of the compacted cells in the nuclear cataract.

Fig. 10.24 Nuclear cataract. A, Dark nucleus floating in liquefied, “milky” cortex (mature cataract) has settled inferiorly because of gravity. Gross appearance of cataracta brunescens (B) and cataracta nigra (C). D and E, Calcium oxalate crystal in nucleus before (D) and after (E) polarization. (A, Courtesy of Prof. GOH Naumann.)

II. Histologically, the changes are usually subtle. Disappearance of the usual artifactitious nuclear clefts is noted.

A. The nucleus appears as an amorphous, homogeneous mass, with increased eosinophilia.

Crystals such as calcium oxalate (see Fig. 10.24) may be deposited in the nucleus.

B. As seen by electron microscopy, the cells are very electron-dense, exceedingly folded, and tightly packed, with obliteration of the intercellular spaces.

Age-Related (Senile) Cataracts

A. Clinically, age-related cortical cataracts can be divided into three main types: (1) cuneiform (in the peripheral cortex), (2) punctate perinuclear (in the cortex next to the nucleus), and (3) cupuliform (in the posterior cortex).

B. A nuclear cataract is merely the acceleration of the normal densification process of the innermost lens fibers.

Fig. 10.25 Schematic comparison of histologic features in normal and abnormal lenses. (Courtesy of Dr. RC Eagle.)

Secondary Cataracts

Intraocular Disease

I. Uveitis, malignant intraocular tumors (see Fig. 10.17), glaucoma, and retinitis pigmentosa (see Fig. 10.16C) can cause secondary cataracts.

The cataract secondary to intraocular disease has been termed a complicating cataract (cataracta complicata). Diseases in the anterior part of the eye tend to cause anterior cataract (ASC, anterior cortical, or both), whereas diseases in the posterior part of the eye tend to cause posterior cataract (PSC, posterior cortical, or both).

II. Histologically, the lens changes are nonspecific and are the same as those described previously.

Trauma

See Chapter 5.

Toxic

I. Drugs such as steroids (topical, inhaled, and systemic), MER 29, phospholine iodide, Myleran, the phenothiazines and dinitrophenol, amiodarone, and allopurinol, along with toxic substances such as ergot or metallic foreign bodies [e.g., iron (Fig. 10.26; see also Figs 5.49 and 5.50) or copper (see Fig. 8.58)], can cause cataracts.

Fig. 10.26 Siderosis lentis (see Figs. 5.49 and 5.50). A, Gross specimen of cataract caused by intraocular iron foreign body. B, Anterior lens nuclei stain blue with Perl’s stain for iron. Note lens capsule and cortex do not stain for iron. C, Cells in siderotic nodule. Necrotic cell above contains a large number of iron bodies. Cell below viable but iron is accumulating (arrows) near segments of granular endoplasmic reticulum (n, nucleus). D, Anterior lens capsule and base of epithelial cell (ep). Note line of iron accumulating in capsule (arrows). More anteriorly, iron is diffusely distributed throughout lens capsule. However, the iron in the capsule is not concentrated enough to see by light microscopy. E, Nodule of basement membrane produced by epithelial cells in epithelial nodule. Basement membrane is mostly homogeneous.

II. Histologically, the lens changes are nonspecific except in siderosis and hemosiderosis lentis, in which iron is present in lens epithelial cells (see Fig. 10.26), and in chalcosis, in which copper is deposited in the lens capsule.

Endocrine, Metabolic, and Others

I. Cataracts occur in conditions such as diabetes mellitus (see Chapter 15), galactosemia, hypoparathyroidism, hypothyroidism, aminoacidurias such as Lowe’s syndrome (see section Capsule, earlier), myotonic dystrophy (see Chapter 14), dermatologic disorders (e.g., atopic dermatitis, chronic eczema, and erythema multiforme), and chromosomal abnormalities.

A. Galactosemia

1. Galactosemia is an autosomal-recessively inherited condition (homozygous) resulting from a deficiency of the enzyme galactose-1-phosphate uridyl transferase.

2. The cataract is usually noted a few days to a few months after birth.

a. In latent galactosemia, however, cataracts may not develop in some patients until they are one year of age or even older. In such cases of juvenile cataract, the galactosemia may not be evident and can only be discovered by means of an abnormal galactose loading test result or a raised fasting blood galactose.

b. Galactosemia may be associated with cataracts that develop in early and middle adulthood in heterozygous patients.

B. Clinically and histologically, the lens changes tend to be nonspecific.

Complications of Cataracts

Glaucoma

I. Mechanical

A. An intumescent cataract may cause pupillary block and secondary angle closure.

B. A cataract may spontaneously dislocate anteriorly and cause a pupillary block directly (see Fig. 5.38), or it may dislocate posteriorly and cause a pupillary block indirectly by prolapsing vitreous into the pupil.

II. Phacolytic glaucoma

A. Phacolytic glaucoma (Fig. 10.27) is a secondary open-angle glaucoma characterized clinically by signs and symptoms of acute glaucoma, except that the anterior chamber angle is open, a white cataract is noted, and a milky material may be seen in the anterior chamber. The glaucoma may resemble open-angle glaucoma secondary to anterior uveitis, except that keratic precipitates are usually absent.

Fig. 10.27 Phacolytic glaucoma. A, Patient presented with signs and symptoms of acute closed-angle glaucoma. Chalky material seen in anterior chamber. B, Slit-lamp picture of another case shows lens-filled macrophages in anterior chamber. The angle was open. C, Histologic section of a third case shows hypermature cataract. Most of the cortex has leaked through the intact capsule. Lens-filled macrophages present in anterior chamber, on iris surface, in iris stroma, and clogging anterior chamber angle, shown at increased magnification in D. (A, Courtesy of Dr. TR Thorp.)

B. Phacolytic glaucoma occurs in an eye with a hypermature (white) cataract.

1. Liquefied, denatured lens material leaks out of the lens through a generally intact lens capsule into the aqueous fluid.

Often, polychromatic, hyperrefringent crystalline particles are noted on the milky material in the anterior chamber. The particles are presumably composed of cholesterol.

2. The lens material in the aqueous incites a macrophagic cellular response.

Liquefied or denatured protein does not seem capable of inciting an antigen–antibody response, only a macrophagic response. Relatively normal lens protein (i.e., not liquefied or denatured), if an abrogation of tolerance to lens protein has occurred, is capable of inciting an antigen–antibody reaction. The result is phacoanaphylactic endophthalmitis (see Chapter 4).

3. The macrophages engulf the liquefied lens material and obstruct an open anterior chamber drainage angle, causing an acute rise in the intraocular pressure.

In addition to macrophages filled with denatured lens material, aggregates of high-molecular-weight soluble protein (molecular weight 1.5 × 10⁸) in the anterior chamber angle may play a role in obstructing aqueous outflow.

C. In 25% of enucleated eyes that show phacolytic glaucoma, a postcontusion deformity of the anterior chamber angle suggests that trauma may have been the event initiating cataract formation.

D. Histologically, a hypermature cataract is found. Macrophages filled with eosinophilic lens material are seen in the aqueous fluid and on and in the iris, occluding the anterior chamber angle, but are not seen in the form of keratic precipitates.

Phacoanaphylactic Endophthalmitis

See Chapter 4.

Ectopic Lens

Congenital

I. Congenital ectopia of the lens is usually bilateral and associated with generalized malformations or systemic disease such as homocystinuria, Marfan’s syndrome, or Weill–Marchesani syndrome, or less frequently with cutis hyperelastica (Ehlers–Danlos syndrome), proportional dwarfism, oxycephaly, Crouzon’s disease, Sprengel’s deformity, genetic spontaneous late subluxation of the lens, or Sturge–Weber syndrome. Only the first three are described.

A. Homocystinuria (Fig. 10.28)

1. Homocystinuria is a systemic disease characterized by fair hair and skin, malar flush, poor peripheral circulation, frequent skeletal abnormalities (osteoporosis, arachnodactyly, pectus excavatum, or pectus carinatum), mental retardation, shortening of platelet survival time, and progressive arterial thrombosis, especially during or after general anesthesia.

2. Ocular findings include ectopia lentis (often luxated into the anterior chamber or subluxated inferonasally) and peripheral chorioretinal degeneration.

3. The disease, which is caused by a deficiency or absence of cystathionine synthetase, is transmitted by an autosomal-recessive gene. A metabolic block between homocysteine and cystathionine results in the accumulation of homocysteine.

4. Histology

a. A thick, periodic acid–Schiff (PAS)-positive, amorphous material overlies the nonpigmented ciliary epithelium.

b. The material is made up of short segments of normal zonules composed of oriented filaments intermingled with myriad short filaments in disarray; the number of abnormal filaments appears to increase with age as the number of normal zonular fiber fragments decreases.

A similar collection or fringe of a mixture of very short, disorganized filaments, together with a few aligned groups of filaments like those present in normal zonules, is found attached to the anterior lens capsule (see Fig. 10.28A). The lens fringe of white zonular remnants is characteristic of homocystinuria. The zonular breakdown and degeneration, even dissolution, result in the ectopic location of the lens.

c. Degeneration of the nonpigmented ciliary epithelium and peripheral neural retina is often present and increases in severity with age.

Fig. 10.28 Homocystinuria. A, Fringe of white zonular remnants present at equator of lens. These remnants tend to undulate slowly with eye movement. B, Histologic section of another case shows a thrombus in the greater arterial circle of the ciliary body. Patient died from a thrombotic episode during general anesthesia (t, thrombus; p, patent blood vessel; cp, ciliary process). C, A thick layer of material covers the nonpigmented ciliary epithelium of the pars plana. D, Electron micrograph shows a portion of thick, abnormal zonular material lying on normal, multilaminar, internal basement membrane (m-bm) of ciliary epithelium. The abnormal zonular material consists of myriad fragments of zonular filaments. (A, From Ramsey MS, Daitz LD, Beaton JW: Lens fringe in homocystinuria. Arch Ophthalmol 93:318, 1975. © American Medical Association. All rights reserved; D, from Ramsey MS, Fine BS, Yanoff M: The ocular histopathology of homocystinuria: A light and electron microscopic study. Am J Ophthalmol 74:377. © Elsevier 1972.)

B. Marfan’s syndrome (arachnodactyly, dystrophia mesodermalis hypoplastica; Figs. 10.29 and 10.30)

1. Marfan’s syndrome consists of ocular, skeletal, and cardiovascular abnormalities.

2. Urinary excretion of hydroxyproline may be present or even excessive, but it may also be normal (i.e., absent).

An attenuation, probably of nonenzymatic steps involved in the maturation of collagen, causes defective collagen organization in the connective tissue of patients. The defect resides on chromosome 15q15–21. The responsible gene is fibrillin-1 (FBN1). The estimated prevalence is 2 to 3 per 10,000 individuals.

3. The lens may be subluxated in any direction, but usually superotemporally. Other ocular anomalies include iridodonesis, hypoplasia of the iris, increased positive transillumination of the iris, miosis with decreased ability to dilate, and a fetal anterior chamber angle.

4. The condition is usually inherited as an autosomal-dominant trait, often with variable degrees of expression.

The condition can also occur de novo, with a mutation rate of 0.7 per 100,000 births.

5. Histology

a. The anterior chamber angle shows an immature configuration, but this is variable and nonspecific.

b. The iris may show segmental hypopigmentation or absence of pigment from the posterior layer of the pigment epithelium, especially toward the periphery, with accompanying hypoplasia of the overlying iris dilator muscle.

The hypopigmentation of the posterior iris pigment epithelial layer, when present, is highly characteristic and explains the clinical observation of increased positive retroillumination of the iris diaphragm where stromal pigmentation is not too dense.

c. The ciliary body processes or crests may extend sporadically onto the back of the iris and may be maldeveloped.

d. The lens is subluxated in the posterior chamber or dislocated into the anterior chamber or vitreous compartment.

The area of interface between lens capsule and zonular fibers appears abnormal. The zonular attachments seem blunted and rounder than in the normal attachment. It is probably the abnormality of the lens capsule–zonular adhesion area that results in the ectopia of the lens.

e. Qualitative abnormalities in fibrillin-1 staining can be seen in the conjunctiva.

Fig. 10.29 Marfan’s syndrome. A, Transillumination of enucleated child’s eye shows widespread lucency of most of iris leaf. B, Posterior epithelium pigmented slightly and thin dilator muscle present. C, Posterior epithelium amelanotic; dilator muscle appears absent. D, Scanning electron micrograph of posterior iris near its root. Ciliary crests extend onto peripheral iris. Circumferential ridges and furrows of iris have disappeared, and the iris surface has become smooth in its periphery. (B and C, Plastic-embedded thin sections. From Ramsey MS, Fine BS, Shields JA et al.: The Marfan syndrome: A histopathologic study of ocular findings. Am J Ophthalmol 76:102. © Elsevier 1973.)

Fig. 10.30 Marfan’s syndrome. A, The lens has dislocated into the anterior chamber (although in Marfan’s syndrome the lens usually subluxates superotemporally in the posterior chamber). Anterior dislocation is more common in homocystinuria. B, A histologic section from an infant shows a relatively normal anterior segment. C, Electron microscopic examination of a normal lens shows the zonular fibers spread out over the anterior lens capsule. Note the fanning out and the tapering of the fibers (z, zonular fibers fan out and taper). D, The zonular fibers intruding into the anterior capsule of a patient with Marfan’s syndrome show a flattening and rapid attenuation of the fibers, along with a lack of wide separation, probably representing a weakened attachment site (z, flattened zonular fibers). E, Electron micrograph shows normal arrangement of myriad filaments, highly aligned, that make up fragment of zonular fiber. (A, Courtesy of Dr. AC Wulc; B, reticulum stain; C and D, scanning electron micrographs; D and E, from Ramsey MS, Fine BS, Shields JA et al.: The Marfan syndrome: A histopathologic study of ocular findings. Am J Ophthalmol 76:102. © Elsevier 1973.)

C. Weill–Marchesani syndrome

1. Weill–Marchesani syndrome is a generalized disorder of connective tissues characterized by spherophakia, ectopia lentis, brachymorphism, and joint stiffness.

2. The spherophakic lens subluxates frequently, usually in a down-and-in direction. High myopia is often present.

Spherophakia may be part of the Weill–Marchesani syndrome and may occur independently or, rarely, may occur in Marfan’s syndrome. The small lens can cause pupillary block glaucoma. Such glaucoma is worsened by miotics but ameliorated by mydriatics. Peripheral anterior synechiae may form secondarily to the pupillary block. The small lens may dislocate into the anterior chamber.

3. It is inherited as an autosomal-recessive trait.

4. Histologically, a filamentary degeneration of zonular fibers produces a thick PAS-positive layer overlying the ciliary epithelium.

The picture may be almost identical to that seen in homocystinuria.

II. Congenital ectopia of the lens without associated systemic problems

A. Simple ectopia lentis

1. Simple ectopia lentis is usually bilateral and symmetric, with the lenses subluxated upward and laterally.

2. Iridodonesis is often present.

3. It has an autosomal inheritance pattern, occasionally with decreased penetrance.

4. Associated ocular problems include dislocation of the lens into the anterior chamber, secondary glaucoma, and neural retinal detachment.

B. Ectopia lentis et pupillae is quite similar to simple ectopia lentis but with the additional feature of ectopia of the pupil.

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