Ординатура / Офтальмология / Английские материалы / Ocular Pathology_6th edition_Yanoff, Sassani_2009
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286 Ch. 8: Cornea and Sclera
genetic basis, dystrophies are more likely to recur in the graft following corneal transplantation than other corneal disorders. Bowman’s membrane dystrophy has the highest rate of recurrence followed by granular and lattice dystrophies respectively.
The tiny intraepithelial cysts (vacuoles) appear relatively transparent on retroillumination by slit-lamp examination. Only the cysts that reach the surface and rupture take up fluorescein and stain; those below the surface do not stain.
Epithelial
I.Heredofamilial—primary in cornea
A.Meesmann’s (Figs 8.29 and 8.30) and Stocker–Holt dystrophy are the same.
1.The condition is inherited as an autosomaldominant trait and appears in the first or second year of life.
A fragility of the corneal epithelium where K3 and K12 keratins are specifically expressed is found. Dominantnegative mutations in the K3 and K12 keratins (K3 maps to the type II keratin gene cluster on 12q, and K12 to the type I keratin gene cluster on 17q) may be the cause of
Meesmann’s corneal dystrophy. A clinically similar corneal
dystrophy, Lisch corneal dystrophy, maps to Xp22.3. A family with a novel missense mutation (423T > G) in exon 1 of the cornea-specific keratin 12 (KRT12) gene has been reported.
2.Myriad, tiny, punctate vacuoles are present in the corneal epithelium that only rarely cause vision problems, and then not until later in life.
3.The involved corneas are prone to recurrent irritations.
4.Histologically, the characteristic findings consist of a “peculiar substance” in corneal epithelial cells and a vacuolated, dense, homogeneous substance, most commonly in corneal intraepithelial cysts and less commonly in corneal epithelial cells.
The primary disturbance probably involves the cytoplasmic ground substance of the corneal epithelium and, ultimately, results in complete homogenization of cells and formation of intraepithelial cysts. Thickening of the corneal epithelial basement membrane varies, and is a nonspecific response by the epithelial basal cells.
B.Dot, fingerprint, and geographic patterns (microcystic dystrophy; epithelial basement membrane dystrophy; Figs
8.31 through 8.34)
1.The condition mainly occurs in otherwise healthy people.
A B
Fig. 8.29 Meesmann’s dystrophy. A and B show tiny, fine, punctate, clear vacuoles in the corneal epithelium. C, Histologic section shows an intraepithelial cyst that contains debris (called peculiar substance in electron microscopy). The epithelial basement membrane is thickened here. (C, periodic acid–Schiff stain; case reported in Fine BS et al.: Am J Ophthalmol 83:633. Copyright Elsevier 1977.)
C
Dystrophies 287
A
B
Fig. 8.30 Meesmann’s dystrophy. A, In this thin, plastic-embedded section, numerous tiny cysts of uniform size and one surface pit are present in the epithelium. One cyst to the right of center resembles a cell. B, Characteristic intracytoplasmic degeneration—”peculiar substance”—involves cytoplasmic filaments (i.e., “cytoskeleton”). C, Cyst contains vacuolated, homogeneous, dense material (i.e., filament-free). (Modified from Fine BS et al.: Am J Ophthalmol 83:633. Copyright Elsevier 1977.)
C
Fig. 8.31 Schematic appearance of dot, map, and fingerprint dystrophies.
Dot, fingerprint, and geographic patterns predispose to sloughing of the corneal epithelium during laser in situ keratomileusis, with subsequent wound healing complications.
2.Clinically, at least three configurations may be found, or any combinations thereof:
a.Groups of tiny, round or comma-shaped, puttylike grayish-white superficial epithelial opacities of various sizes are seen in the pupillary zones of one or both eyes.
b.A fingerprint pattern of sinuous, translucent lines, best seen with retroillumination.
c.A maplike or geographic pattern, best seen on oblique illumination.
3.Inheritance is uncertain.
4.Histologically, three corresponding patterns can be observed:
a.The grayish dots represent small cystoid spaces in the epithelium into which otherwise normal, superficial corneal epithelial cells desquamate.
Microcystic dystrophy is easily differentiated from Meesmann’s dystrophy in that, in the former, the epithelial cells are not morphologically abnormal and contain a normal amount of glycogen.
288 Ch. 8: Cornea and Sclera
m
d
A B C
Fig. 8.32 Dot, fingerprint, and map patterns. A, The dot pattern (d) is shown in the lower central cornea. A map pattern (m) is seen above and to the left of the dot pattern. B, The dot pattern resembles “putty” in the epithelium. C, The fingerprint pattern, best seen with indirect lighting, is clearly shown. (B, Courtesy of Dr. WC Frayer.)
e |
f |
f
b
s
A B
Fig. 8.33 Dot, fingerprint, and map patterns. A, Histologic section shows that the dot pattern is caused by cysts that contain desquamating surface epithelial cells. B, The fingerprint pattern (f) is caused by extensive aberrant production of basement membrane material in the epithelium (e) (b, Bowman’s membrane; s, stroma). C, The map pattern is caused by accumulated ribbons of subepithelial basement membrane and collagenous tissue that resemble a subepithelial fibrous plaque. (PD stain; cases reported in Rodrigues MM et al.: Arch Ophthalmol 92:475, 1974. © American Medical Association. All rights reserved.)
C
b.The fingerprint pattern is formed by both normally positioned and inverted basal epithelial cells producing abnormally large quantities of multilaminar basement membrane. The latter cells have migrated into the epithelial superficial layers.
c.The map pattern is produced beneath the epithelium by basal epithelial cells and possibly a few keratocytes that have migrated from the superficial stroma to elaborate both multilaminar basement membrane and collagenous material.
Dystrophies 289
n
ep
c
m-bm
ep
m-bm
c
A B C
Fig. 8.34 Dot, fingerprint, and map patterns. A, Cyst contents consist of almost normal desquamating surface epithelial cells (ep) (n, nucleus of flattened epithelial cell near inverted surface). B, Basement membrane consists of two separate multilaminar basement membranes (m-bm) produced by aberrant basal cell. Collagenous filaments separate two basement membranes and epithelial cells from their own multilaminar basement membrane. C, Multilaminar nature of irregular whorls of basement membrane (m-bm). Collagenous filaments (c) interspersed between epithelial cells and basement membrane and throughout whorls of poorly formed multilaminar basement membrane (ep, basal cells of epithelium). (B and C, From Rodrigues MM et al.: Arch Ophthalmol 92:475, 1974, with permission. © American Medical Association. All rights reserved.)
Similar epithelial abnormalities are frequently encountered on routine histopathologic examination of corneal buttons from penetrating keratoplasty surgery for chronic edema and bullous keratopathy.
II.Heredofamilial—secondary to systemic disease: Fabry’s disease (angiokeratoma corporis di usum; see Table 11.5, p. 454)
A.The typical maculopapular skin eruptions (angiokeratoma corporis di usum) are seen in a girdle distribution and start in early adulthood.
B.Whorl-like (vortex-like) epithelial corneal opacities are seen.
Cornea verticillata (Fleischer–Gruber), the corneal manifestation of Fabry’s disease, is the term found in the older literature. Quite similar corneal appearances are seen in chloroquine, amiodarone, indomethacin, atovaquone, and suramin keratopathies.
ciency results in intracellular storage of ceramide trihexoside.
E.Inheritance is X-linked recessive.
Amniotic fluid can be analyzed during early gestation for levels of α-galactosidase, thereby detecting the condition during early pregnancy.
F.Histologically, lipid-containing, finely laminated inclusions are present in corneal epithelium, lens epithelium, endothelial cells in all organs, liver cells, fibrocytes of skin, lymphocytes, smooth-muscle cells of arterioles, and capillary pericytes.
On light microscopy, material is noted between the epithelium and Bowman’s membrane. Oil red-O positive material is present in the subepithelial layer. Duplication of basal lamina is detected on electron microscopic examination.
C.The fundus shows tortuous retinal vessels containing visible mural deposits. The deposits may be so pronounced as partially to occlude the lumen, resulting in sausage-shaped vessels; the blood in the arterioles becomes much darker than normal from stasis.
D.Fabry’s disease is caused by a generalized inborn error of glycolipid metabolism wherein α-galactosidase defi-
Subepithelial and Bowman’s Membrane (Anterior Limiting Membrane or Layer)
I.Subepithelial mucinous corneal dystrophy (SMCD)
A.SMCD has its onset in the first decade, has an autoso- mal-dominant inheritance, is characterized by frequent, recurrent corneal erosions, and shows progressive visual loss.
290 Ch. 8: Cornea and Sclera
B.The cornea shows bilateral subepithelial opacities and haze that involve the entire cornea but are most dense centrally.
C.Histology
1.An eosinophilic, periodic acid–Schi (PAS)- positive and Alcian blue-positive, hyaluronidasesensitive material lies anterior to Bowman’s membrane.
2.Immunohistochemical analysis demonstrates chondroitin 4-sulfate and dermatan sulfate in the material.
3.Electron microscopy shows deposition of a fine
fibrillar material consistent with glycosaminoglycan.
SMCD resembles Grayson–Wilbrandt dystrophy, which differs in having clear intervening stroma, stromal refractile bodies, and Alcian blue negativity, and honeycomb dystrophy (Thiel–Behnke), which differs in having its onset in the second decade, a subepithelial honeycomb opacity, a clear peripheral cornea, and no characteristic histologic staining pattern.
II.Reis–Bücklers corneal dystrophy—see later discussion of granular dystrophies
Stromal (Table 8.3)
I.Heredofamilial–primary in cornea:
A. Genetic overview:
1.Mutations in the transforming growth factor-β- induced gene (TGFBI: BIGH3) can produce the granular corneal dystrophy (GCD) phenotype or that of LCD. Mutation of codon 124 of TGFBI from arginine to cysteine (R124C), histidine
(R124H), or leucine (R124L) is associated with type I LCD, Avellino dystrophy, and superficial
GCD respectively. In one French study, GCD was
produced by mutations R124L, R124H, and
R124L+delT125-delE126. LCD was produced by mutations R124C, H626R, and A546T. BIG-h3 genetic analysis may be required to determine the mutation in the keratoepithelin gene in order to diagnose related corneal dystrophies properly.
B.The granular dystrophies (Groenouw type I; Bücklers type I; hyaline; Fig. 8.35; see Table 8.3) can be divided into at least three types: classic, Avellino (see later discussion of LCD), and superficial (Reis–Bücklers and
Thiel–Behnke)
1.Classic (CGCD/R555W)
a.Sharply defined, variably sized, white opaque granules are seen in the axial region of the super-
ficial corneal stroma; the intervening stroma is clear.
b.At least two clinical phenotypes exist.
c.Family members with the R555W mutation
(C1710T) in exon 12 may present with an unusual vortex pattern of corneal deposits. Another atypical phenotype of GCD demonstrates white dotlike opacities scattered in the anterior and mid-stroma of the central cornea.
The mutation resulted in a nucleotide transversion at codon 123 (GAC → CAC), causing Asp
→ His substitution (D123H); however, there is low penetrance for GCD.
1). An early-onset, superficial variant begins in childhood and is characterized by confluent subepithelial and superficial stromal opacities, frequent attacks of recurrent erosion, and early visual loss.
The peripheral stroma is clear. The variant may be confused histologically with Reis–Bücklers dystrophy. Electron microscopic examination clarifies the diagnosis by demonstrating rod-shaped granules in a plane localized to, or near, Bowman’s membrane. The granules may be enveloped by amyloid (9- to 11-nm filaments)
2). A milder, late-onset variety is characterized by multiple, crumblike stromal opacities, slow progression, fewer attacks of recurrent erosion, less visual disturbance, and less need for corneal grafting.
The peripheral stroma is clear.
TABLE 8.3 Histopathologic Differentiation of Granular, Macular, and Lattice Dystrophies
Dystrophy |
Trichrome |
AMP* |
Periodic Acid–Schiff |
Amyloid† |
Birefringence‡ |
Heredity |
|
|
|
|
|
|
|
Granular |
+ |
− |
− |
− or +§ |
− |
Dominant |
Macular |
− |
+ |
+ |
− |
− |
Recessive |
Lattice |
+ |
− |
+ |
+ |
+ |
Dominant |
*Stains for acid mucopolysaccharides (e.g., Alcian blue and colloidal iron).
†Stains for amyloid (e.g., Congo red and crystal violet).
‡To polarized light.
Periphery of granular lesion (and occasionally within the lesion) stains positively for amyloid.
Dystrophies 291
A B
C D
Fig. 8.35 Granular dystrophy. A, Clear cornea is present between the small, sharply outlined, white stromal granules. B, Histologic section shows that the granules stain deeply with hematoxylin and eosin and (C) stain red with the trichrome stain. The periodic acid–Schiff stain and stain for both glycosaminoglycams and amyloids are negative. The condition is inherited as an autosomal-dominant trait. D, The granules seen by light microscopy also appear as granules by electron microscopy. Many granules are “apertured.”
d.Inheritance is autosomal dominant.
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 gene (BIGH3). In classic granular dystrophy, the specific mutation in the BIGH3 gene is a R555W mutation. The TGFBI gene may also be involved in Reis–Bücklers.
A unique corneal dystrophy involving Bowman’s layer and stroma has been reported to be associated with the Gly623Asp mutation in the TGFBI gene. Clinical features include findings of LCD and a Bowman’s layer dystrophy.
e.Histologically, granular, eosinophilic, trichrome red-positive deposits are scattered throughout the stroma.
The periphery of the granule may show positive Congo red staining. Granular dystrophy may recur in otherwise normal donor material after a corneal graft. The recurrence is quite slow and is believed to be caused by the host keratocytes slowly replacing those of the donor. Some recurrences appear more commonly as a localized avascular subepithelial membrane with no involvement of Bowman’s membrane or corneal stroma. These superficial membranes can often be stripped away to restore corneal transparency. The deposits may originate in part from the corneal epithelium.
1). In addition, unesterified cholesterol is found in the superficial stroma.
292 Ch. 8: Cornea and Sclera
2). Electron microscopy shows electron-dense polygonal granules, some of which may be “apertured,” scattered throughout the stroma.
2.Reis–Bücklers (Fig. 8.36) and Thiel–Behnke corneal dystrophies
a.Acute attacks of red, painful eyes caused by recurrent erosions commence in early childhood.
1). Multiple, minute, discrete opacities are seen early just beneath the epithelium.
2). These become confluent, often producing the characteristic subepithelial honeycomb pattern.
3). Usually, by the fifth decade, a marked opacification of the corneas occurs.
b.Inheritance is autosomal dominant.
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
(BIGH3) gene. In classic granular dystrophy, the specific mutation in the BIGH3 gene is a R555W mutation.
1). Reis–Bücklers dystrophy [also known as superficial variant of corneal granular dystrophy or corneal dystrophy of Bowman’s layer type 1
(CDB1)] is caused by the R124L mutation of the BIGH3 gene.
2). Thiel–Behnke dystrophy [also known as hon- eycomb-shaped dystrophy or corneal dystrophy of
Bowman’s layer type 2 (CDB2)] is caused by the R555Q mutation of the BIGH3 gene.
c.Histology
1). Epithelial abnormalities may underlie the pathologic process of both conditions.
2). The corneal changes are limited to levels in and around Bowman’s membrane (layer).
The membrane is slowly replaced by scarring or increased layering of collagenous tissue that extends beneath the epithelium. Loss of hemidesmosomes and associated basement membrane appears to lead to the recurrent desquamations or erosions with consequent additional trauma to Bowman’s membrane.
A B
e
d
b |
b |
C D
Fig. 8.36 Reis–Bücklers dystrophy. A, The characteristic honeycomb corneal pattern is seen. B, Slit-lamp view shows very superficial location of opacity. C, Histologic section in another case shows central degeneration of Bowman’s membrane and irregularity of overlying epithelium. D, Trichrome stain demonstrates disruption (d) of Bowman’s membrane by fibrous tissue, along with a fibrous plaque between Bowman’s membrane (b) and epithelium (e). (A and B, Courtesy of Dr. IM Raber.)
Dystrophies 293
3). Electron microscopy shows involvement in the subepithelial area, Bowman’s layer, and anterior stroma. The involvement consists of masses of peculiar curly filaments that have a diameter of approximately 10 nm and indeterminate length.
Reis–Bücklers dystrophy may recur in the donor button of a corneal graft. By both light and electron microscopy, hereditary recurrent erosions may appear similar to Reis–Bücklers dystrophy.
C.Macular (Groenouw type II; Bücklers type II; primary corneal acid mucopolysaccharidosis; Fig. 8.37; see Table 8.3)
1.Macular dystrophy is a localized corneal mucopolysaccharidosis caused by a disorder of keratin sulfate metabolism. Unsulfated keratin sulfate is deposited both within keratocytes and corneal endothelial cells and in the extracellular corneal stroma.
a.A wide range of keratocyte-specific proteoglycan and glycosaminoglycan remodeling processes are activated during degeneration of the stromal matrix in MCD.
2.Di use cloudiness of superficial stroma and aggregates of gray-white opacities in the axial region are seen; the intervening stroma is also di usely cloudy.
A decrease in N-acetylglucosamine 6-O-sulfotransferase (GlcNAc6ST) activity in the cornea may result in the occurrence of low-sulfate or nonsulfated keratan sulfate and thereby cause the corneal opacity.
The cloudiness usually develops rapidly so that vision in most patients is seriously impaired by 30 years of age, necessitating corneal grafting.
Macular dystrophy may recur in the donor button after corneal graft.
ep
A
bl
nug
B C
Fig. 8.37 Macular dystrophy. A, The corneal stroma between the opacities is cloudy. B, Histologic section shows that keratocytes and vacuolated cells beneath the epithelium (stained yellow) are filled with glycosaminoglycam (stained blue). In this condition, the trichrome stain and stains for amyloid are negative, but the periodic acid–Schiff stain is positive. The condition is inherited as an autosomal-recessive trait. The cornea and serum of most patients who have type I macular dystrophy lack detectable antigenic keratan sulfate, whereas it is present in the cornea and serum in type II. C, Keratocyte beneath Bowman’s layer (bl) filled with vesicles containing acid mucopolysaccharide (AMP)-positive substance (ep, epithelium; nug, nucleus of keratocyte). (A, Courtesy of Dr. JH Krachmer; B, AMP stain.)
294 Ch. 8: Cornea and Sclera
3.Type I, the most prevalent type, shows a lack of detectable antigenic keratan sulfate in the cornea and serum.
A type IA has been described in which a lack of detectable antigenic keratan sulfate occurs in the corneal stroma and serum, but in which corneal fibroblasts do react with keratan sulfate monoclonal antibody. A further subdivision of this type can be achieved on the basis of reactivity to monoclonal antibody 3D12/H7.
4.Type II shows detectable antigenic keratan sulfate in the cornea and serum.
5.Inheritance is autosomal recessive. The gene (CHST6) for this dystrophy is located on chromosome 16 (16q22).
Macular dystrophy is thought to result from an inability to catabolize corneal keratan sulfate (keratan sulfate I). Keratan sulfate may be absent from the serum of patients who have macular corneal dystrophy.
6.Histologically, basophilic deposits, which stain positively for acid mucopolysaccharides (glycosami-
noglycams), are present in keratocytes, in endothelial cells, and in small pools lying extracellularly in or between stromal lamellae.
a.In addition, unesterified cholesterol is found throughout the stroma and amyloid is sometimes present in the deposits.
b.Some cases show excrescences of Descemet’s membrane.
7.Concomitant keratoconus and macular corneal dystrophy have been reported in two siblings.
D.Lattice (type I,Bücklers type III; Biber–Haab–Dimmer; primary corneal amyloidosis; Figs 8.38 and 8.39; see
Table 8.3, and p. 238 in Chapter 7)—six forms exist:
(1) LCD type I; (2) LCD type III; (3) LCD type IIIA,
(4) gelatinous droplike corneal dystrophy; (5) LCD type II (OMIM 204870); and (6) polymorphic corneal amyloidosis.The R124C mutation frequently accompanies LCD. Two mutations in the TGFBI gene have been reported to segregate with LCD in a family having two heterozygous single-nucleotide mutations in exon
12of the TGBI gene (C1637A and C1652A), leading to amino acid substitutions in the encoded TGF-β- induced protein (A546D and P551Q). This family lacked the common R124C mutation. A late-onset
A B
C D
Fig. 8.38 Lattice dystrophy. A, Translucent branching lines of typical lattice dystrophy [lattice corneal dystrophy (LCD type I)] seen best by retroillumination. B, Another patient shows an accentuated form of lattice, perhaps LCD type III. C and D, Corneal deposits appear as granules, similar to granular corneal dystrophy. Histology of cornea, however, is consistent with lattice dystrophy (see Fig. 8.39A). This is the Avellino-type corneal dystrophy. (A, Courtesy of Dr. JH Krachmer; C and D, case reported in Yanoff M et al.: Arch Ophthalmol 95:651, 1977. © American Medical Association. All rights reserved.)
Dystrophies 295
A B
C D
Fig. 8.39 Lattice dystrophy (Avellino type). A, Histologic section shows focal areas of “hyalin” irregularities. B, Top and bottom taken with both polarizers in place in Congo red-stained section. Birefringence is demonstrated by a change in color when the bottom polarizer is turned 90° (when only one polarizer is in place, the corneal amyloid deposit—stained with Congo red—acts as second polarizer and dichroism is demonstrated by a change in color when the one polarizer is turned 90°). Electron microscopy shows that lesions are composed of myriad individual filaments either in disarray and therefore nonbirefringent (C), or (D) highly aligned and therefore birefringent.
form of LCD involved the leu527Arg mutation of the
TGFBI gene.
Typically, the deposits in LCD are in the mid-stroma, with a mean distance of 79 μm from the epithelium. In contrast, deposits in GCD are mostly superficial, having a mean distance from the epithelium of 28 μm.
1.LCD type I (classic primary LCD) shows corneal lines forming a lattice configuration present centrally in the anterior stroma, leaving the peripheral cornea clear.
a.The central lattice lines are di cult to visualize with direct illumination.
Some authors believe that the lattice lines may represent nerves or nerve degeneration. Proof for this hypothesis is lacking.
b.LCD type I can progress to involve deeper stromal layers.
c.Also seen are epithelial abnormalities (e.g., recurrent erosion, band keratopathy, and loss of surface luster), which may be caused by epithelial basement membrane abnormalities.
d.The autosomal-dominant condition begins in the first decade or early second decade and may progress fairly rapidly; many a ected people have marked vision impairment by 40 years of age. LCD is rarely unilateral; however, it may be extremely asymmetrical at the time of presentation.
Chromosome linkage analysis shows that Reis–Bück- lers, Thiel–Behnke, superficial granular, 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.
e.Although lattice lines are typical of LCD type I, presentation as a di use opacification of the central corneal stroma without lattice lines may occur. Molecular genetic analysis revealed LCD I-associated heterozygous missense change (C417T) replacing arginine in codon 124 with cysteine (R124C) in the TGFBI gene.
f.Amyloid deposition may recur in a corneal transplant graft. Examination of two grafts 20