Ординатура / Офтальмология / Английские материалы / Ocular Pathology_6th edition_Yanoff, Sassani_2009

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.

b.The fetal nucleus may show retention of lens nuclei similar to the cataract in rubella, Leigh’s disease, and trisomy 13.

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

d.The anterior-chamber angle resembles that seen in genetic congenital glaucoma.

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.

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 longterm exposure to infrared radiation.

II.The anteriormost layers of the anterior lens capsule split o 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 a ect 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 to 10.11)

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

A.It is probably inherited, possibly as an autosomaldominant trait with incomplete penetrance and varying expressivity.

B.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, flu y 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, dandru -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 as observed with the slit lamp; and reduced endothelial density, morphologic changes in cell size (polymegathism) and in cell shape (pleomorphism), endothelial cell damage, cell detritus, intraendothelial inclusions, and retroendothelial accumulations, as observed with specular microscopy. 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.

1.Pupillary ru defects may also be seen.

2.Iridodonesis and phacodonesis are seen 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 5 years and 15% in 10 years.

B.Degeneration of iris pigment epithelium and subsequent dense pigmentation of the anterior-chamber angle is often seen.

The picture resembles that of the pigment dispersion syndrome (rarely, true pigment dispersion syndrome can coexist with PEX syndrome).

C.The cause of the glaucoma is unknown.

1.A suggested cause is the accumulation of the PEXM or pigment in the angle.

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 is present.

Thorleifsson and colleagues have identified two nonsynonymous single nucleotide polymorphisms in exon 1 of the gene, lysyl oxidase-like 1 (LOXL 1), located on chromosome 15q24, as associated with pseudoexfoliation and pseudoexfoliation glaucoma in individuals from Iceland and Sweden. About 25% of the general population studied is homozygous for the highest-risk haplotype and the population-attributable risk is more than 99%. Thus, an individual who is homozygous for both of the highest-risk haplotypes is a 700 times more likely than those with the lowest-risk variants to have pseudoexfoliation. The authors further noted that the product of LOXL 1 catalyzes the formation of elastin fibers, which are a major component of the lesions in pseudoexfoliation.*

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.Cause

A.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.

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.

1.Almost always, PEXM is found in association with the fibrovascular stroma of these organs, most often adjacent to elastic tissue.

2.PEX syndrome appears to be part of a systemic disorder.

B.Delayed intraocular PEXM development

1.White, flu y PEXM may appear on the anterior hyaloid and pupillary border years after intracapsu-

*Damji KF. Progress in understanding pseudoexfoliation syndrome and pseudoexfoliation-associated glaucoma. Can J Ophthalmol 42:657, 2007;

Thorleifsson G, Magnusson KP, Sulem P et al.: Common sequence variants in the LOXL1 gene confer susceptibility to exfoliation glaucoma. Science

317:1397, 2007.

lar cataract extraction in eyes where no PEXM had been present before cataract surgery (see Fig. 10.9A).

If, therefore, the lens epithelium is a source of PEXM, it is not the only source.

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, in particular 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, in the eye, 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.

2.The abnormal material also seems to be present near the underlying lens epithelium.

3.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.

anterior subcapsular cataract (the end-stage fibrous plaque between a duplicated capsule), also causes an anterior cortical cataract. The combination of an anterior subcapsular cataract and an anterior cortical cataract is called a duplication cataract (see Fig. 10.14).

EPITHELIUM

Proliferation and Migration of Epithelium

Anterior Subcapsular Cataract (Figs 10.12 to 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 anterior subcapsular cataract.

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.

D.With time, the fibroblasts largely disappear and the scar tissue shrinks, wrinkling the overlying lens capsule.

E.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.

An anterior subcapsular cataract is rarely seen clinically because an occluded pupil is most often superimposed.

II.Frequently, the same injury that initially caused the damage to the epithelial cells, leading to the previously described

Posterior Subcapsular Cataract

(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)].

D.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.

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, to 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 anterior subcapsular or PSC.

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 to 10.22).

A.UV irradiation may play a role in the development of cortical cataracts

B.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, spokelike), but they do not have well-char- acterized pathologic counterparts in specific histologic findings.

III.Histologically, the following pathologic changes may be found in cortical cataracts.

A.Clefts seen clinically and histologically are made up of di use, watery, or eosinophilic material, probably representing altered or denatured cell proteins.

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

1.They are distinguished from artifactitious fragments by the rounding-o 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 more and 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* 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 (the free-floating nucleus cannot usually be seen clearly through an opacified liquid cortex).

During the process of cortical liquefaction, if the fluid is of su ciently small molecular size, it may escape through the intact capsule and result in a

*Clinically, the term mature cataract refers to the appearance of a swollen (intumescent) lens as well as to the fact that no clear cortex is detectable beneath the anterior capsule. An immature cataract clinically has some clear cortex between the anterior cortical opacity and the lens capsule. The lens may be normal in size or swollen. If swollen, it is an intumescent cataract.

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, previously thought to be cholesterol, are now thought probably to be cystine. Christmas-tree cataract may be associated with uncombable hair syndrome, an autosomaldominant condition.

E.Calcium salts may impregnate long-standing cataracts

(cataracta calcarea). The abnormal calcification of the lens is an example of dystrophic calcification.