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

years after the original transplants revealed deposits confined to the basement membrane regions in contrast to the initial specimens in which amyloid deposits were present throughout the stroma.

2.LCD type III primary corneal lattice dystrophy has an autosomal-recessive inheritance pattern, has thicker lines extending from limbus to limbus, and has a later onset than type I.

A similar entity, except for an autosomal-dominant inheritance and the presence of corneal erosions, has been called LCD type IIIA. Chromosome linkage analysis shows Reis–Bücklers, Thiel–Behnke, granular, superficial granular, Avellino, and lattice type I dystrophies are linked to a single locus on chromosome 5q31. These dystrophies may represent different clinical forms of the same entity. The severe phenotype of granular dystrophy is caused by homozygous mutations in the keratoepithelin [TGFBI

(BIGH3)] gene. In classic granular dystrophy, the specific mutation in the TGFBI gene is an R555W mutation.

3.Primary gelatinous droplike dystrophy (familial subepithelial amyloidosis),the third form of primary lattice dystrophy, has an autosomal-recessive inheritance pattern, is most common in Japan, and shows a striking corneal picture. It has been divided into four types: band keratopathy type, stromal opacity type, kumquat-like type, and typical mulberry type.

a.The gene responsible for primary gelatinous droplike dystrophy, MI1S1, is localized to chromosome 1p.

b.The bilateral dystrophy presents in the first decade of life as subepithelial, mulberry-like opacities that grow with age.

c.The Q118X mutation of the M1S1 gene can result in a corneal phenotype with either droplike or band-shaped opacities.

4.LCD type II (Meretoja) is a dominantly inherited, familial form of systemic paramyloidosis or secondary corneal amyloidosis, mainly in people of Finnish origin, and consists of lattice corneal changes (more peripheral than in LCD type I) plus progressive cranial neuropathy and skin changes. It is also known as gelsolin-related amyloidosis.

a.Clinical confocal microscopy (CFM) confirms that symptom levels and slit-lamp findings correlate positively with corneal haze intensity, and correlate inversely with visibility of epithelial and stromal nerves. In severe cases, stromal and epithelial nerves are not visible, suggesting progressive neural degeneration.

b.The lattice lines have been attributed to amyloid deposits and not to corneal nerves based on CFM.

c.Nerve damage is the probable cause of decreased corneal mechanical and, to a lesser degree, thermal sensitivity.

The disorder is also called type IV familial neuropathic syndrome, familial amyloid polyneuropathy type IV, or amyloidotic polyneuropathy. Vitreous opacities do not occur. LCD type II is caused by mutations in the gelsolin gene on chromosome 9 (9q32–34).

5.Polymorphic corneal amyloidosis is caused by an

A546D mutation in the TGFBI gene

a.Multiple polymorphic, polygonal, refractile, chipped ice-appearing gray and white opacities are seen at multiple depths of the cornea.

b.Occasional deep, filamentous lines that do not form a distinct lattice pattern are noted.

c.A phenotypic variant of LCD characterized by bilateral, symmetric, radially arranged branching refractile lines within and surrounding an area of central anterior stromal haze accompanied by polymorphic refractile deposits in the mid and posterior stroma may be seen.

1). Light and electron microscopy demonstrates amyloid and excludes material characteristic of GCD.

2). Ala546Asp and Pro551Gln missense changes in exon 12 of the TGFBI gene may be seen.

d.Corneal amyloidosis can be associated with lactoferrin, and a Glu561Asp mutation with or without accompanying Aal11Thr and

Glu561Asp mutations.

6.Histology

a.An eosinophilic, metachromatic, PAS-positive and Congo red-positive, birefringent, and dichroic deposit is present in the stroma, mainly superficially.

b.The epithelium is abnormal and shows areas of hypertrophy and atrophy along with excessive basement membrane production.

It seems that not only keratocytes but, on occasion, corneal epithelial cells have the ability to elaborate the abnormal material considered to be amyloid. LCD may recur in the donor button after corneal graft.

c.In addition, unesterified cholesterol is found in areas corresponding to the Congo red positivity.

The stromal lesions are characteristic of amyloid in all respects. Amyloidosis may be classified into two basic groups: systemic (primary and secondary) and localized (primary and secondary). Secondary systemic amyloidosis, the most frequently encountered type, rarely involves the eyes and is not an important ophthalmologic entity. Lattice dystrophy of the cornea is now considered by many to be a hereditary form of primary localized amyloidosis. The epithelial basement membrane abnormalities are responsible for secondary epithelial erosions and are partially responsible for the vision impairment.

d.Electron microscopy shows masses of delicate filaments, many in disarray, whereas others are highly aligned.

Filaments also infiltrate between collagen fibrils of normal diameter, and alignment is at the edges of lesions.

e.LCD type III shows larger amyloid deposits than types I and II, and contains a ribbon of amyloid between Bowman’s membrane and the stroma.

E.Avellino corneal dystrophy (combined granular–lattice dystrophy; see Figs 8.38C and D, and 8.39)

1.Many patients who have granular and lattice dystrophy changes in the same eye can trace their origins to the region surrounding Avellino, Italy.

2.Chromosome linkage analysis shows Reis– Bücklers, Thiel–Behnke, granular, superficial granular, Avellino, and lattice types I and IIIA dystrophies are linked to a single locus on chromosome 5q31 (associated with the R124H mutation of the BIGH3 gene). These five dystrophies may represent di erent clinical forms of the same entity.

3.Clinically, well-circumscribed granular lesions are seen along with corneal lesions that are larger than lattice type I opacities and appear snowflake-like.

4.Three signs characterize Avellino corneal dystrophy: anterior stromal discrete, grayish-white deposits; lattice-like lesions located in the mid to posterior stroma; and anterior stromal haze

The granular lesions occur early in life, whereas the lattice component appears gradually, maturing later in life.

5.Histologically, both eosinophilic, trichromepositive granular deposits and Congo red-positive fusiform deposits are found.

Electron microscopy shows discrete, homogeneous, electron-dense deposits and apertured deposits enclosing lacunae of filaments in the superficial stroma.

Loosely arranged fibrils, many of which are oriented randomly, are seen at the periphery of the superficial deposits, as contrasted to the parallel packing of amyloid fibrils seen in the fusiform deposits of deeper stroma.

F.Congenital hereditary stromal dystrophy (Table 8.4)

1.The condition is a congenital, nonprogressive corneal opacification with di use and homogeneous small opacities.

2.Inheritance is autosomal dominant.

3.Histologically, the characteristic changes consist of a rather widespread, uniform clefting of the stromal lamellae, composed of collagen filaments of small diameter.

a.The stroma is thickened.

1). Electron microscopy demonstrates thickened stroma due to cleaving of the lamellae by alternating layers of small-diameter collagen

fibrils arranged in random fashion.

b.The remaining corneal layers (epithelial, Bowman’s, endothelial, and Descemet’s membrane) are normal.

G.Hereditary fleck dystrophy (François and Neetens’ hérédodystrophie mouchetée)

1.Clinically, the condition is characterized by small ringlike or wreathlike opacities that contain clear

centers and distinct margins, and are present throughout all layers of the corneal stroma. The opacities vary in size, shape, and depth.

2.Hereditary fleck dystrophy is congenital, bilateral, and nonprogressive with little or no interference with vision.

3.Inheritance is autosomal dominant.

Rarely, affected members of families may also have posterior crocodile shagreen, keratoconus, lens opacities, pseudoxanthoma elasticum, or atopic disease.

4.Histologically, the keratocytes are abnormal, and appear swollen and vacuolated. They contain mem- brane-limited intracytoplasmic vacuoles of a granular to fibrogranular material that stains positively for acid mucopolysaccharides and complex lipids.

H.Schnyder’s corneal crystalline dystrophy (central stromal crystalline corneal dystrophy)

1.Clinically, five morphologic phenotypes have been described:

a.A disc-shaped central opacity lacking crystals

b.A central crystalline disc-shaped opacity with an ill-defined edge

c.A crystalline discoid opacity with a garland-like margin of sinuous contour

1). A central full-thickness disciform lesion having a mosaic pattern instead of the more typical collection of crystals or di use haze may also occur.

d.A ring opacity with local crystal agglomerations with a clear center

e.A crystalline ring opacity with a clear center

2.The bilateral, symmetric, relatively nonprogressive condition (it may progress significantly over time) is probably not related to blood lipoprotein abnormalities, but occasionally may coexist with a hyperlipoproteinemia.

Rarely, the crystals can regress (e.g., after corneal epithelial erosion).

3.Inheritance is autosomal dominant.

4.Histologically, lipids (predominantly phospholipid, unesterified cholesterol, and cholesterol ester) are seen in Bowman’s membrane (layer) and corneal stroma.

a.The deposits stain positively with oil red-O and filipin (a fluorescent probe specific for unesterified cholesterol).

b.The dystrophy appears to be related to a primary disorder of corneal lipid metabolism.

I.Decorin gene-associated stromal dystrophy

1.Clouded corneas present shortly after birth.

2.No associated systemic or congenital abnormalities.

3.Autosomal-dominant inheritance with linkage to chromosome 12q22, with a maximum logarithm of odds (LOD) score of 4.68 at D12S351 and a

frameshift mutation in the DCN gene (c967delT) that encodes for decorin, and predicting a C-termi- nal truncation of the decorin protein (p.S323fsX5) is seen.

4.Transmission electron microscopy: normal collagen fiber lamellar arrangement separated by abnormal fibrillar layers.

J.Central discoid corneal dystrophy

1.Clinically: bilateral, symmetrical central, discoid, corneal opacification.

2.Symptoms: decreased vision, glare, and photophobia.

3.Histopathology: multiple extracellular vacuoles are located in the anterior one-half of the central corneal stroma.

a.The material within the vacuoles is intensely positive to Alcian blue and colloidal iron stains, compatible with glycosaminoglycan deposits.

b.Electron microscopy demonstrates nonmem- brane-bound vacuoles in the stroma containing faintly osmophilic matrix and black circular profiles.

4.Chondroitin sulfate is demonstrated on immunohistochemical analysis. Systemic evaluation fails to disclose a systemic storage disorder.

5.Identical clinical findings in other family members suggest dominant inheritance.

6.Genetic analysis does not demonstrate a mutation in the coding region of CHST6.

K.Posterior crocodile shagreen (central cloudy dystrophy of François)

1.It is characterized by large, polygonal gray lesions that are separated by relatively clear lines, seen in the axial two-thirds of the cornea, and most dense in the deep stroma.

2.Inheritance is autosomal dominant.

3.In vivo CFM has demonstrated multiple dark striae and abnormal stromal deposits in the disorder.

4.Histologically, an extracellular deposit of mucopolysaccharide and lipid-like material is seen.

5.Electron microscopy shows an irregular, sawtoothlike configuration of the collagen lamellae interspersed with areas of 100-nm spaced collagen, along with extracellular vacuoles, some of which contained fibrillogranular material.

L.Posterior amorphous corneal dystrophy

1.It is characterized by broad, sheetlike opacification, with intervening clear areas, of the posterior stroma associated with corneal flattening and thinning.

2.Inheritance is autosomal dominant.

3.Histologically, by both light and electron microscopy, an irregularity of the stroma is seen just

anterior to Descemet’s membrane, whereas the endothelium is normal.

II.Heredofamilial—secondary to systemic disease

A.Mucopolysaccharidoses (Fig. 8.40) can be divided into seven major classes (Table 8.5).

1.They all have mucopolysacchariduria.

2.In all but mucopolysaccharidosis IV, degradation of acid mucopolysaccharides is impaired.

A

C

3.These genetic mucopolysaccharidoses may be considered as intralysosomal storage diseases with deficiencies of lysosomal hydrolases.

4.Histologically, vacuolated cells (histiocytes, corneal epithelium and endothelium, keratocytes, and iris and ciliary body epithelia) contain acid mucopolysaccharides in the vacuoles. The di erent classes show varying pathologic findings, fairly consistent within each class.

In Maroteaux–Lamy syndrome, donor corneal grafts reaccumulate mucopolysaccharides as early as 1 year postgrafting, but some patients may remain clear up to 5 years. Partial clearing of the host cornea may occur after transplantation. Proteoglycans may be present in the corneal epithelium, intercellular spaces, and in swollen desmosomes. Keratocytes may be abnormal. Betaig-h3 labeling is around electron-lucent spaces in the stroma. CFM has detected abnormal keratocytes, particularly in the middle and posterior stroma in this condition in which macular retinal folds are also described.

B.Mucolipidosis (see p. 450 in Chapter 11)

1.An unusual case of mucolipidosis IV a ected an

African American patient resulting in the formation of intracytoplasmic inclusions in the corneal epithelium and endothelium. Usually, the disorder a ects individuals of Jewish descent.

C.Sphingolipidosis (see p. 451 in Chapter 11)

D.Ochronosis (see p. 314 in this chapter)

E.Cystinosis (Lignac’s disease; Figs 8.41 and 8.42)

B

Fig. 8.40 Mucopolysaccharidoses. A, The cornea is diffusely clouded in a case of Hurler–Scheie syndrome. B, Histologic section of a case or Maroteaux–Lamy syndrome shows acid mucopolysaccharides (AMP; stained blue) deposited in epithelial cells and in stromal keratocytes, and in C in endothelial cells. (A, Courtesy of Dr. HG Scheie; B and C, AMP stain, courtesy of Dr. GOS Naumann.)

1.The disease, a rare congenital disorder of amino acid metabolism, is characterized by dwarfism and progressive renal dysfunction resulting in acidosis, hypophosphatemia, renal glycosuria, and rickets.

The precise biochemical defect in cystinosis is not known, but it is believed to be primarily a deficiency of lysosomal enzymes and, hence, a lysosomal disease.

2.Three types of cystinosis are recognized:

a.Childhood type (nephropathic)—characterized by renal rickets, growth retardation, progressive renal failure, and death usually before puberty; autosomal-recessive inheritance

By biomicroscopy, narrowing of the angle and a ciliary body configuration similar to plateau iris may be seen. Also, by gonioscopy, crystals may be seen in the trabecular meshwork.

The activity of the cystine transport system in patients’ leukocytes is deficient.

b.Adolescent type—onset in the first or second decade,mild nephropathy,diminished life expectancy; probably autosomal-recessive inheritance

c.Adult (benign) type—onset from late second to sixth decade, typical corneal crystals but no renal disease, normal life expectancy; no known hereditary pattern

3.Patients who have childhood cystinosis may show a retinopathy that does not seem to cause any

C

A

C

abnormality of retinal function. The retinopathy consists of a very fine pigmentation accompanied by tiny, multiple refractile crystals, probably at the level of retinal pigment epithelium and choroid.

4.Histologically, cystine crystals are deposited in many ocular tissues, including the conjunctiva and cornea.

B

Fig. 8.42 Cystinosis. A, Myriad tiny crystals seen in retinal fundus. B, Unstained histologic section of sclera, choroid, and retina shows abundant gray crystalline bodies throughout the choroid. C, The choroidal bodies are birefringent to polarized light. (B and C, Case

presented by Dr. FC Winter to the meeting of the Verhoeff Society, 1975.)

Cystine can be seen clinically with a slit lamp as tiny, multicolored crystals. Although cystine crystals are stored in the liver, spleen, lymph nodes, bone marrow, eyes (conjunctiva, cornea, retina, and choroid), and kidneys (and probably other organs), they seem to be relatively innocuous. Progressive renal failure starts in the first decade of life with proximal tubular involvement (Toni–

Febré–Fanconi syndrome), but it does not seem to be directly related to renal cystine storage. The underlying enzyme defect is not yet known, but the accumulating cystine is often found in the lysosomal components of the cell.

F.Hypergammaglobulinemia

1.Corneal crystalline deposits (see subsection Crystals, later) are a rare manifestation of hypergammaglobulinemic states such as may be found in multiple myeloma, benign monoclonal gammopathy, Hodgkin’s disease, and other dysproteinemias.

2.Histologically, positive deposits of immunoglobulin may be seen in corneal stroma (at all levels), conjunctiva, ciliary processes, pars plana, and choroid.

3.The term “immunotactoid keratopathy” has been used to describe corneal immunoglobulin G kappa deposits that appear as tubular, electron-dense, crystalloid deposits having a central lucent core on electron microscopy associated with paraproteinemia.

G.Lecithin cholesterol acyltransferase (LCAT) deficiency

1.LCAT deficiency results from an inborn error of metabolism and consists of a normochromic anemia, proteinuria, renal failure, arteriosclerosis, a high serum level of free cholesterol and lecithin, and greatly reduced esterified cholesterol and lysolecithin.

2.LCAT enzyme is absent.

3.The cornea has a cloudy appearance because of the myriad, tiny, grayish stromal dots, evenly distributed except for being more concentrated near the limbus, where they mimic an arcus.

a.Vision is not severely a ected until late in life.

b.In addition, retinal hemorrhages, optic disc protrusions, and ruptures in Bruch’s membrane may be the result of lipid deposits.

4.Light microscopy shows a vague, mild, di use, tiny vacuolation of the corneal stroma.

a.Electron microscopy strikingly demonstrates myriad tiny vacuoles, many containing membranes and particles, in Bowman’s membrane and stroma (larger vacuoles in stroma).

b.The corneal epithelial basement membrane is thickened.

c.Amyloid deposition may be found in addition to the other corneal changes.

III.Nonheredofamilial

A. Keratoconus (Figs 8.43 through 8.45)

1.Ectasia of the central cornea usually becomes manifest in youth or adolescence, progresses for 5 to 6 years, and then tends to arrest. Approximately 90% of cases are bilateral.

The condition progresses most rapidly during the second and third decades of life. A high irregular astigmatism is common, an increased incidence of keratoconus occurs in

Down’s syndrome (see p. 39 in Chapter 2), and human leukocyte antigen (HLA)-327 may be found. Unilateral keratoconus is rare, and most patients with so-called unilateral keratoconus, if followed long enough, eventually acquire keratoconus in the other eye.

2.Most cases (70%) occur in girls.

It is uncertain if keratoconus is not an inherited condition.

a.Multiple overand underexpressed genes have been related to this disorder.The upregulation of keratocan expression may be specific for keratoconus. Keratocan is said to be one of three keratan sulfate proteoglycans important for structure of the stromal matrix and maintenance of corneal transparency.

3.The apex of the cone is usually slightly inferior and nasal to the anterior pole of the cornea and tends to show stromal scarring.

4.Munson’s sign occurs when the lower lid bulges on downward gaze.

5.Vogt’s vertical lines are seen in the stroma. CFM suggests that Vogt’s striae, which are seen to radiate from the center of the cone, represent stressed collagen lamellae.

6.Fleischer ring (see Fig. 8.44) is caused by iron deposition in the epithelium circumferentially around the base of the cone.

a.It is best seen with the light of the slit lamp through a cobalt-blue filter.

b.The iron is mainly deposited in the basal layer of epithelium, but is also found in epithelial wing cells.

7.Ruptures in Bowman’s membrane (early, giving rise to anterior clear spaces), and in Descemet’s membrane (late), and increased visibility of corneal nerves are common.

Ruptures in Descemet’s membrane may result in acute keratoconus (see Fig. 8.45), a condition characterized by the abrupt onset of severe central corneal edema (hydrops), especially in Down’s syndrome. With extreme rarity, the cornea may perforate, which has even occurred bilaterally.

8.Most cases are not inherited, although autosomalrecessive and dominant inheritance patterns may occur.

9.Keratoconus may be associated with, or accompanied by, vernal keratoconjunctivitis, pellucid marginal corneal degeneration, mitral valve prolapse, and, rarely, Fuchs’ combined dystrophy. It has also been reported in association with distal arthrogryposis type IIB.

10.Elevated levels of terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) immunoreactivity suggest that apoptosis may play a role in the pathogenesis of keratoconus.

11.Clinical and histopathologic features compatible with keratoconus have been demonstrated in trans-

plant grafts as long as 40 years after the initial corneal transplant for keratoconus. Population of the graft stroma by host keratocytes and/or aging of the graft has/have been postulated to cause this phenomenon.

12.Protein-related abnormalities are present in keratoconus corneas (e.g., molecular weights of abnormal proteins of 12, 14, and 39 kD); in addition, some normal corneal protein components may be increased, whereas others may be decreased. The level of type XII collagen is reduced in the epithelial basement membrane zone and stromal matrices in keratoconus corneas.

A reduction occurs in highly sulfated keratan sulfate epitopes.

Keratoconus corneas contain a reduced level of α2-mac- roglobulin, lending support to the hypothesis that degradation processes may be aberrant in these corneas.

13.Histologically, the central cornea is thinned, the central portion of Bowman’s membrane is destroyed, the central stroma is scarred, and the central portion of Descemet’s membrane often shows ruptures.

a.The stromal lamellae have a significant change in their organization, and the collagen fibrillar mass has been demonstrated to be unevenly distributed, particularly at the apex of the cone, indicating interand intralamellar slippage and displacement leading to the clinical morphologic changes characteristic of keratoconus.

b.Guttata may occur.

c.In the periphery of keratoconic corneas, fine cellular processes of keratocytes can be seen to penetrate Bowman’s membrane. These cells may have elevated levels of cathepsins B and G.

d.CFM has demonstrated a significant reduction in the density of keratocytes in the stroma.

Reduced anterior keratocyte density is particularly associated with a history of atopy, eye rubbing, and the presence of corneal staining. CFM has also shown corneal epithelial abnormalities in this disorder, that have been confirmed by light microscopy.

e.Iron is found in epithelial cells at all levels in the peripheral region of the thinned central cornea (Fleischer ring).

f.Three acid hydrolases—acid phosphatase, acid esterase, and acid lipase—are significantly elevated in the corneal epithelium, especially in the basal layer.

B.Keratoglobus

1.Keratoglobus is a rare, bilateral, globular configuration of the cornea. The cornea shows generalized thinning from limbus to limbus, but most markedly peripherally.

2.The cornea is transparent, and an iron ring is absent.

3.The condition tends to be stationary, but hydrops can develop.

4.Keratoglobus is probably a variant of keratoconus and may occur in di erent members of the same family.

Keratoglobus may be associated with vernal keratoconjunctivitis, idiopathic orbital inflammation, chronic marginal blepharitis with eye rubbing, glaucoma after penetrating keratoplasty, Leber’s congenital amaurosis, blue sclera syndrome, and thyroid ophthalmopathy.

C.Pellucid marginal degeneration

1.Pellucid marginal degeneration is a progressive, bilateral, inferior, peripheral thinning of the cornea in a crescentic fashion; rarely, it can occur superiorly.

2.The area of involved cornea is clear with no scarring, infiltration, or vascularization.

3.Protrusion of the cornea occurs above a band of thinning located 1 to 2 mm from the limbus and measuring 1 to 2 mm in width, usually from 4 to 8 o’clock. Acute hydrops may occur.

4.The condition becomes apparent between 20 and

40 years of age; it occurs in both men and women, and results in high irregular astigmatism.

A

5.Scleroderma has been reported in association with a case of pellucid marginal degeneration.

6.Pellucid marginal degeneration may be an atypical form of keratoconus.

7.Spontaneous hydrops and even perforation may occur rarely.

It differs from keratoconus in that it has no iron ring; its thinning is in an inferior arc without a cone; and the corneal protrusion is located above (rather than in) the area of thinning; however, it has been reported in association with keratoconus.

Endothelial

I.Cornea guttata (Fuchs’ combined dystrophy; Figs 8.46 and 8.47)

In 1910, Ernst Fuchs described the epithelial component, which is really a degeneration, secondary to the primary endothelial dystrophy (cornea guttata). Koeppe, in 1916, noted the endothelial changes. Vogt coined the term guttae in 1921.

A.It occurs predominantly in elderly women and is bilateral.

B