Corneal dystrophies. II. Endothelial dystrophies

SURVEY OF OPHTHALMOLOGY

VOLUME 23. NUMBER 3 *NOVEMBER-DECEMBER

1978

REVIEW Cornea1

Dystrophies.

II. Endothelial

Dystrophies

GEORGE 0. WARING III, M.D., MERLYN M. RODRIGUES, M.D., Ph.D., AND PEYER R. LAIBSON, M.D. Department of Ophthalmology, University of California. Davis, California, Section of Clinical Eye Pathology, Clinical Branch, National Eve Institute, Bethesda, Maryland, and the Cornea Service, Wills Eye Hospital, Philadelphia, Pennsylvania

Abstract. In general, endothelial dystrophies present three types of clinical manifestations: 1) production of collagenous tissue posterior to Descemet’s membrane which appears as cornea guttata, polymorphic excrescences or gray sheets; 2) a disrupted endothelial mosaic in specular reflection; and 3) cornea1 edema as a reflection of decreased endothelial barrier and pump functions. In this review, the authors discuss three endothelial dystrophies - Fuchs’, posterior polymorphous and congenital hereditary. They describe the clinical, histopathologic and biochemical features, and il-

lustrate each dystrophy with a composite drawing. Dystrophies of the epithelium, Bowman’s layer, and stroma were reviewed separately in the September-October 1978 issue of this journal.

(Surv Opbtbalmol 23:147-168,

1978)

Key words. cornea - cornea guttata * cornea1 dystrophy (congenital hereditary, endothelial, Fuchs’, posterior polymorphous) - electron microscopy pathology l

E

ndothelial dystrophies manifest them- polymorphic excrescences, or gray sheets.75 selves in three ways. (1) Most common- Ultrastructurally, it appears as abnormal ly, the stressed endothelial cell produces basement membrane or fibrillar tissue excess collagen posterior to Descemet’s mem- between the original Descemet’s membrane brane. We have called this new tissue the and the dystrophic endothelial cells. (2) The posterior collagen layer (PCL) of the cornea. endothelial cells become larger, more polyClinically, this tissue appears as thickening of morphic, and disrupted by the excrescences Descemet’s membrane - cornea guttata, from Descemet’s membrane; these findings are most apparent in specular reflection with Part I of this review, covering dystrophies of the the slitlamp, with the specular microscope, and by scanning electronmicroscopy. (3) Bowman’s layer, epithelium and stroma, appeared in the September-October 1978 issue of this jour- Stromal and epithelial edema occur with nal. breakdown of the endothelial barrier and 147

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pump, reducing visual acuity. I. Endothelial Dystrophies A. FUCHS’ENDOTHELIAL

DYSTROPHY

(FIG. 1)

1.Terminology

We prefer the term “Fuchs’ endothelial dystrophy” because the eponym is so widely used, because the endothelium is the primary site of involvement, and because the term also includes the stromal and epithelial changes. “Late hereditary endothelial dystrophy” is the most descriptive term, since it also emphasizes the onset in middle age, but it will not easily displace Fuchs’ historical priority. “Combined epithelial-endothelial dystrophy” is an outdated term that emphasizes the later secondary anterior cornea1 changes. “Cornea guttata” designates a focal, clinically refractile accumulation of collagen posterior to Descemet’s membrane, commonly called a wart or excrescence of Descemet’s membrane.33 Primary cornea gut-

FUCHS’ ENDOTHELIAL

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tata occur in three clinical patterns.O (1) A few cornea guttata pepper the posterior cornea as part of normal endothelial aging.26.4g (2) Larger numbers, often accompanied by flecks of endothelial pigment, form confluent patches and are simply called “endothelial dystrophy.“46 (3) Increasing numbers of cornea guttata accompanied by cornea1 edema constitute Fuchs’ endothelial dystrophy. Secondary cornea guttata appear after corcharacteristically in neal inflammation, syphylitic interstitial keratitis.77 2. Clinical Course The disorder is probably inherited as an autosomal dominant, but only three pedigrees have been reported with sufficient information for genetic analysis.15 Krachmer and colleagues46 examined 228 relatives of individuals with confluent cornea1 guttata and found 38% of those over age 40 affected. It occurs most often in post-menopausal women; the female to male ratio has been

DYSTROPHY

Light microscopy

Electron microscopy

Climcal ki

Collagen

FIG. 1. Fuchs’ endothelial dystrophy, Composite drawing emphasizes major features. Clinical: (clockwise) Isolated cornea guttata - refractile in retroillumination; fine pigment granules - dark in retroillumination; fine epithelial edema; epithelial bullae; stromal edema, thickening and subepithelial fibrocellular tissue; stromal scarring. Light microscopy: Anterior - epithelial edema within, between, and beneath cells; subepithelial fibrocellular tissue; stromal edema. Posterior - new layers of PAS positive collagen material forming cornea guttata. Electron microscopy: Anterior - subepithelial fibrocellular tissue; subepithelial fluid. Posterior - layers of abnormal basement membrane and fibrillar collagen on posterior surface of Descemet’s membrane; attenuated endothelial cells; intracellular pigment granules.

CORNEA1 DYSTROPHIES

reported to be as high as 4 to 1,15an unusual distribution in an autosomal dominant disease. There is some racial variation, since it is extremely rare in Japanese.33 It is not clear whether isolated cornea guttata are part of the spectrum of Fuchs’ endothelial dystrophy. Primary cornea guttata occur in 5 to 70% of the normal population, the frequency rising with age.26,48*4gWhether these individuals exhibit only a degenerative change of the aging cornea1 endothelium or manifest a less severe form of Fuchs’ endothelial dystrophy can best be answered by careful family studies. Dohlman’* described a family in which autosomal dominant cornea guttata associated with anterior polar

FIG 2. Fuchs’ endothelial dystrophy. A. Moderately advanced case demonstrates central circular zone of cornea1 edema and subepithelial fibrosis. B. Slitlamp photograph demonstrates full-thickness central cornea1 edema (arrow) with minimal stromal swelling. C. Cornea guttata stand out as focal refractile dots against red fundus reflection. Endothelial pigment deposits appear as dark spots in direct illumination (arrows). D. In specular reflection, cornea guttata give Descemet’s membrane beaten-metal appearance (arrow) with distortion of endothelial mosaic.

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cataracts did not progress to stromal and epithclial edema. Fuch’s endothelial dystrophy is bilateral, but usually asymmetric. This is fortunate, as keratoplasty can be performed in the worse eye while the better eye continues to provide useful vision. Although the cornea guttata associated with Fuchs’ dystrophy may be present from age 30, symptoms rarely appear before age 50, an exception to the generality that cornea1 dystrophies appear early in life. Three phases characterize the clinical course of Fuchs’ dystrophy, which usually spans 10 to 20 years.2os71In the first phase, the patient remains asymptomatic, and the posterior cornea manifests central, irregu-

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larly distributed guttate excrescences and fine pigment dusting. Later, Descemet’s membrane may appear gray and thickened. In the second stage, the patient experiences hazy visual acuity and symptoms of glare as stromal and epithelial edema develop. Initially, stromal edema appears in front of Descemet’s membrane and just behind Bowman’s layer, but gradually the entire stroma develops a ground-glass appearance with water clefts as it swells to produce wrinkles in Descemet’s membrane. Epithelial edema initially imparts a fine pigskin texture to the corneal surface (“bedewing”) and gradually progresses to large oval or sinuous subepithelial bullae that burst to produce attacks of pain. Visual acuity falls dramatically because of the stromal opacification and irregular astigmatism. It is worse on awakening because decreased tear evaporation during sleep reduces tear osmolarity, allowing increased cornea1 edema. In the third phase,

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ET AL

subepithelial connective tissue appears and is associated with decreased epithelial edema, such that the patient is more comfortable, even though vision may fall to hand motions. Secondary complications, such as epithelial erosion, microbial ulceration, peripheral vascularization, and elevated intraocular pressure complicate this phase. Other cornea1 disorders can resemble Fuchs’ dystrophy. Endothelial edema associated with anterior segment inflammation simulates cornea guttata, but the pattern is more irregular, may extend outside the central cornea, and disappears with healing of the endothelium. Disciform stromal edema from herpes simplex keratitis is distinguished from Fuchs’ dystrophy by the accompanying iridocyclitis, keratic precipitates, and preexisting subepithelial herpetic scars. No systemic diseases regularly accompany Fuchs’ dystrophy. However, ocular hypertension and chronic open angle glaucoma

FIG 3. Specular microscopy of Fuchs’ endothelial dystrophy. Clinical photomicrographs demonstrate progressively severe cornea guttata and endothelial disruption. A. Endothelial cells demonstrate fairly uniform hexagonal shape. Small black spots are guttate excrescences (arrows). B. Larger cornea guttata (arrow) appear as black areas with central white dot. C. Cornea guttata (arrow) disrupt endothelial mosaic which demonstrates marked cellular pleomorphism. D. Only a focal patch of endothelium retains its mosaic pattern. E. The endothelium mosaic is not identifiable, because of stromal edema, new collagen posterior to Descemet’s membrane, and disruption by guttate excrescences. (X 200)

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may be more common in these patients than in the general population. Buxton1o performed tonography on 34 eyes with Fuchs’ dystrophy and found that 82% had a facility of outflow below 0.18 whereas approximately 2.5% of the normal population have this lowered value. He postulated that the trabecular endothelium might also be involved with the dystrophic process. Acute angle closure glaucoma also complicates the dystrophy, possibly because the thick peripheral cornea further compromises narrow angles. 3. Slitlamp Appearance (Figs. 2 and 3)

The progressive involvement of all cornea1

tissues during the course of Fuchs’ dystrophy makes detailed description complex. The changes commence centrally, and spread toward the periphery. A paracentral sectorshaped area of endothelial dystrophy occurs in unusual instances. From posterior to anterior, the following alterations occur: (1) cornea guttata with thickening and wrinkling of Descemet’s membrane; (2) endothelial pigmentation; (3) stromal edema with appearance of subepithelial connective tissue and superficial peripheral vascularization; and (4) epithelial edema and bullae. Cornea1 guttata in direct focal illumination appear as small, glittering golden-brown spots on the posterior cornea1 surface. In

FIG. 3 (continued)

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retroillumination, they light up like small dew drops (Fig. 2C). On very narrow slit examination, minute glittering reflections appear posterior to the cornea1 surface, suggesting that the guttata act as convex lenses. In specular reflection, they form black dots that disrupt the endothelial mosaic (Fig. 2D), a pattern best appreciated by specular photomicroscopy (Fig. 3). As Descemet’s membrane thickens, it assumes an uneven gray appearance; its irregular crinkled texture is best seen in broad tangential illumination. With an extremely narrow slit, the dark adapted observer may actually see laminations, sometimes glimpsing a thin refractile layer behind the gray tissue. In retroillumination, a diffuse beaten metal appearance replaces the distinct cornea guttata. Increasing stromal edema displaces Descemet’s membrane posteriorly with resultant refractile wrinkles and folds. Endothelial pigment exhibits a line, faint dusting that sometimes forms a central geographic pattern with discrete brown borders. Early stromal edema produces a central faint gray haze in front of Descemet’s membrane and later a gray zone behind Bowman’s layer. Scleral scatter detects this slight edema most sensitively. Increasing stromal edema creates a central round ground-glass area (Fig. 2A and B) studded with dark flat, fusiform crisscrossed water clefts. The cornea1 thickness, measured with a pachometer, may reach 1.0 mm - twice the normal thickness. Mild epithelial edema displays a fine dewdrop pattern, each droplet surrounded by a dark ring. Topical fluorescein accentuates the

ET AL

irregular epithelial surface by pooling in the small crevices between focal epithelial vesicles. Gradually, large lakes of fluid appear both within and beneath the epithelium, producing bullae that sometimes hang down like bags of water and frequently burst to leave a large painful epithelial defect. Some bullae contain debris (flare, cells, hypopyon, hyphema) and manifest small vesicles in their epithelial walls. The avascular subepithelial connective tissue springs up diffusely over the stromal surface; it does not migrate from the periphery like a post-inflammatory pannus. In broad tangential illumination, it appears as an irregular dense, gray, swirling sheet of scar tissue, while in the narrow slit beam it appears as a loose connective tissue layer separating the epithelium from the stroma. As stromal scarring increases, the epithelial and stromal edema gradually decrease, and the cornea degenerates into a peripherally vascularized sheet of scar tissue. 4. Clinicopathologic

Correlation (Figs. 4-7)

Epithelium. As cornea1 edema develops, the basal epithelial cells swell to produce the tine bedewing seen clinically. Initially, little edema occurs between the cells, but as epithelial cells swell and burst, intercellular edema accumulates to form large lakes of fluid that appear clinically as bullae. Subsequently, stromal fluid moves forward to lift the epithelium off Bowman’s layer and create subepithelial bullae (Fig. 4). In general, the epithelial basement membrane remains intact and adjacent to the epithelial cells and

FIG. 4. Histopathology of Fuchs’ endothelial dystrophy. Thin layer of fibrocellular tissue and focal pockets of fluid elevate epithelium from underlying stroma (open arrows). Inset: multilaminar fibrous tissue has accumulated on the posterior surface of Descemet’s membrane. Anterior layer stains darkly and forms focal excrescences, cornea guttata (arrow), that are buried in lighter staining posterior layers. Inset: (PAS, X 100, PAS X 400).

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becomes as thick as 2.5 microns (average 0.5-1.0 micron). As bullae and subepithelial connective tissue appear, the epithelium becomes irregular and varies from 2 to 10 cells in thickness. The superficial epithelial cells retain their tight intercellular junctions and continue to form a barrier to fluid penetration, accounting for the retention of fluid within the basal epithelium and the stroma. The coagulated fibrillar material that appears within the large bullae corresponds to the hypopyon-like appearance seen clinically. Bowman’s Layer and Stroma. Bowman’s layer remains intact, except for a few focal breaks filled with connective tissue.35.5gThe avascular subepithelial connective tissue which accumulates between the epithelial basement membrane and Bowman’s layer reaches a thickness of up to 350 pm (seven times the normal epithelial thickness). It consists of active fibroblasts, 30 nm diametercollagen fibrils, lo-20 nm diameter-collagen fibrils, and basement membrane-like material - all loosely arrayed with wide interfibrillar spaces.35 In some areas, the connective tissue extends into the epithelium to form septae and islands that appear clinically as large epithelial vesicles.28J5.66 Stromal edema disrupts the architecture of the collagen lamellae and widens the interfibrillar spaces - changes that scatter light

and produce the ground-glass appearance seen clinically. Fine fibrillogranular material accumulates adjacent to keratocytes. As cicatrization occurs, the stroma resumes a more compact morphology with marked irregularity of the collagen lamellae and an increased number of stromal cells.71 Descemet’s

Membrane

and

Endothelium

(Figs. 5 and 6). The most striking histopathologic features of Fuchs’ dystrophy are posterior to Descemet’s membrane, where endothelial cells produce new collagenous tissue that gives the clinical appearance of thickening of Descemet’s membrane (Fig. 4). Descemet’s membrane (8-10 pm thick) and the new collagen tissue (4-5 pm thick) form a multilaminar configuration that appears as alternating dark and light layers with PAS stain and produces the gray swirling pattern seen clinically. Focal thickenings of the new collagen tissue create discrete excrescences or warts that correspond to cornea guttata (Fig. 5). Four patterns OCCU?~:(1) simple warts that protrude into the anterior chamber; (2) multilaminar warts; (3) warts buried within the multilaminar tissue; and (4) multilaminar tissue without warts. Some excrescences form a simple nub-shaped protrusion. Others develop a mushroom shape with the posterior surface flaring out from a central broad stalk,

FIG. 5. Scanning electron micrograph of Fuchs’ endothelial dystrophy. A. Guttate excrescences (arrows) protrude from the posterior surface of the cornea. Endothelial cells appear to bridge the spaces between the warts. (X 1650). B. Single guttate excrescence is covered by cellular debris and exhibits central depression. Arms of lateral cell junctions reach from its base. Excrescence appears suspended over posterior surface of Descemet’s membrane because its mushroom shape hides the underlying stalk. (X 10,000)

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FIG. 6. Histopathology of Fuchs’ endothelial dystrophy. A. Transmission electron micrograph demonstrates stroma (S) and normal Descemet’s membrane (D). Newly produced layer of abnormal basement membrane material contains 110 nm broad spacing collagen (arrow) and focal posterior guttate excrescence (G). Posterior layer of more loosely fibrillar collagen tissue (F) contains fibrils lo-20 nm in diameter. (X 5289). B. High. magnification of posterior surface of guttate excrescence shows tine collagen fibrils (f), 110 nm wide-spacing collagen with horizontal tibrils (arrows), and 50 nm banded collagen (asterisk) adjacent to degenerating endothelial cell (E) that contains pigment granules. (X 35,000)

so that a cross-section through the edge will show a piece unattached to Descemet’s membrane, while a section through the middle will demonstrate an anvil shape. The endothelium overlying the apex of an excrescence may be too thin for detection by light microscopy, but it is usually present on electron microscopy. The distribution of these focal excrescences over the posterior cornea1 surface can be studied by flat preparations of Descemet’s membrane,” phase contrast microscopy,ll scanning electron microscopy,58 and, clinically, by specular microscopy7 (Fig. 3). The guttate excrescences interrupt the endothelial mosaic by pushing the endothelial nuclei into dumbbell or sickle shapes, by thinning the overlying endothelial cells, and by producing irregular cell borders. Even though the endothelial cells enlarge up to 1000 ym2,

(normal - 400 pm*) and lose their characteristic hexagonal shape, they usually maintain an intact covering of the posterior corneal surface. The number of endothelial cells is inversely proportional to the number of guttate excrescences.62 Seen by electron microscopy,28~33~34~41~51~61~82 Descemet’s membrane consists of its normal anterior 110 nm banded and posterior nonbanded portions (Fig. 6A). The junction between the normal Descemet’s membrane and the newly produced collagen tissue is usually indistinct. The layer of abnormal basement membrane material adjacent to Descemet’s membrane forms cornea guttata and contains fusiform bundles and broad sheets of 55 or 110 nm banded wide-spacing collagen that manifest sub-bands with a periodicity of about 30-40 nm (Fig. 6B). Within this material, horizontal fibrils run

FK, 6B

perpendicular to the vertical bands. In tangential section, the wide-spacing collagen forms a hexagonal pattern similar to that seen in horizontal section of the normal anterior banded Descemet’s membrane. Adjacent to the broad-spacing bundles are groups of lo-20 nm diameter collagen fibrils that may fuse with the horizontal fibrils of the widespacing collagen. An amorphous material is present in the background. In some areas, fissures containing cellular debris penetrate the guttate excrescences, giving an appearance similar to Hassall Henle warts.

In more advanced cases, an additional layer of fibrillar collagen appears; it consists of a ioose feltwork of 20 nm diametercollagen fibrils scattered within basement membrane-like material (Fig. 6A). Sometimes, collagen fibrils 20-30 nm in diameter with 64 nm banding are present. The endothelium consists of both normal and degenerating cells (Fig. 6B). The degenerating cells show wide intercellular of intercellular junctions, spaces, absence membrane-bound vacuoles and swollen mitochondria, myelin figures, dilated endo-

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plasmic reticulum containing finely granulated material, phagocytosed pigment granules, and increased cytoplasmic lilaments .33a+41*61 These have been interpreted as cells with fibroblastic function that may produce the collagen tissue posterior to Descemet’s membrane. Rarely, endothelial cells exhibit microvilli, desmosomes and cytoplasmic filaments similar to epithelial cells. 5. Pathogenesis (Fig. 7) Although the basic endothelial abnormality in Fuchs’ endothelial dystrophy is unknown, the pathogenesis of the clinical findings has two main aspects. (1) Collagen tissue production is increased posterior to Descemet’s membrane and beneath the epithelium. As in many other cornea1 diseases,75 the abnormal endothelium of Fuchs’ dystrophy produces excess collagen, both abnormal basement membrane with long-spacing collagen and layers of looser fibrillar collagen. The subepithelial connective tissue arises from libroblasts that migrate from the limbus or from the stroma, although some of it could be epitheliogenous. (2) Endothelial barrier and pump functions are decreased as

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the endothelium undergoes its abiotrophic deterioration. Excess aqueous humor penetrates the endothelial barrier to enter the stroma and epithelium, probably because the tight gap junctions at the cell apices deteriorate. Since the diseased endothelium cannot pump this fluid out and since the epithelial barrier prevents the loss of fluid across the anterior surface, cornea1 edema results. In the late stages, the cornea becomes more compact and the patient more comfortable as subepithelial scarring prevents fluid from entering the epithelium, as stromal scarring prevents the cornea from becoming thicker, and as the posterior collagen tissue makes the posterior cornea more rigid and less easily swollen. 6. Management

Patients with cornea guttata and no cornea1 edema remain asymptomatic. Slight epithelial edema blurs vision and produces discomfort, especially upon awakening. Since this occurs because decreased nocturnal tear evaporation produces more dilute tears which osmotically draw less fluid from the cornea,

i___________-____________-----___________---_____---------__~

r----

ET AL

----- --------- -____-----_ ---_________________--_____--_ 1

FIG. 7. Fuchs’ endothelial dystrophy. Composite drawing relates major clinical stages to histopathologic changes. Beginning on left, cornea guttata appear as focal excrescences posterior to Descemet’s membrane. As endothelial decompensation occurs, stromal and epithelial edema thicken cornea. Clinically, Descemet’s membrane appears thick and gray, because of excess collagen tissue. Endothelium phagocytoses pigment. Intraepithelial edema and subepithelial bullae appear, followed by subepithelial connective tissue. Collagen tissue posterior to Descemet’s membrane becomes multilaminar. In end stages, cornea1 edema diminishes as subepithelial and stromal scarring increase.

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hypertonic ointments like 5% sodium chloride used before retiring will increase the tonicity of the tear film, dehydrate the cornea1 epithelium, and may decrease morning symptoms.” Warm air gently blown into the eyes with a hair dryer upon awakening increases evaporation of the tears and osmotically removes water from the epithelium, but few patients use this therapy regularly. Topically applied hypertonic solutions like 5% sodium chloride reduce epithelial edema during the day, but persistent blurred vision may leave the patient dissatisfied. A loosely fit, thin, high water content soft contact lens will smooth the irregular astigmatism and decrease the pain from broken epithelial bullae. while allowing oxygen to reach the diseased epithelium. A glued-on contact lens has been reported as helpfu1.25 Since elevated intraocular pressure will force more fluid into the stroma across the endothelium, appropriate compromised pressure reduction with carbonic anhydrase inhibitors, topical miotics or epinephrine, or /3-adrenergic blockers may decrease cornea1 edema. Pressure is most accurately measured by electronic applanation (MacKay-Marg) tonometry because the edematous epithelium may cause the Goldmann applanation tonometer to read falsely low. As visual acuity approaches an unacceptable level, penetrating keratoplasty is indicated. Fuchs’ dystrophy accounts for about 10% of all cornea1 grafts and about 80% will remain clear for two years.3 However, the surgeon should perform keratoplasty while the guttate changes and edema are confined to the central cornea, since extensive involvement of host tissue reduces longterm graft survival.7’ Even with appropriately timed surgery, the duration of graft clarity seems limited. For example, in 12 carefully selected patients operated on between the ages of 50 and 67, Stocker observed that all grafts became cloudy l-9 years postoperatively, while 6 grafts performed during the same period for keratoconus remained clear for 1l-l 5 years.7o Keratoplasty in eyes with narrow angles should include lens removal to avoid angle closure with the formation of peripheral anterior synechiae. In patients with both Fuchs’ endothelial dystrophy and cataract, a combined procedure gives visual results as good as those obtained with keratoplasty followed later by cataract extraction.3 Patients with advanced painful bullous

keratopathy in whom keratoplasty and soft contact lens therapy are inappropriate will often regain comfort after a conjunctival flap or cautery of Bowman’s layer. 7. Summary

Fuchs’ endothelial dystrophy is probably inherited as an autosomal dominant, but it affects females more often than males. It appears in middle life as bilateral, central, sometimes asymmetric, dewdrop-like cornea guttata, which are focal accumulations of abmembrane between normal basement Descemet’s membrane and the endothelium. Over the next lo-20 years, endothelial function declines with resultant cornea1 edema, manifested as thickened central stroma with a ground-glass haze. The edematous epithelium initially has a fine pigskin appearance caused by intracellular edema of the basal cells, but later becomes studded by large clear blisterlike lakes of intercellular and subepithelial fluid. A layer of tibrillar collagen also appears posterior to Descemet’s membrane. Visual acuity declines gradually as epithelial bullae burst to cause painful cornea1 erosions. Subepithelial and stromal scarring ensue. Penetrating keratoplasty will give best results if performed before the process reaches the cornea1 periphery. B. POSTERIOR

POLYMORPHOUS

DYSTROPHY

(FIG. 8) 1. Terminology

A variety of terms has described this entity - a fact consistent with its variable clinical appearance and natural history. The entities called posterior polymorphous dystrophy (of deep Schlichting), 9,21,32,53,65,72,73 hereditary dystrophy, grouped vesicles or Schnyder’s posterior herpes,5,‘4*64.68and hereditary corneal edema, form a clinical spectrum. Table 5, published in Part I of this review, compares the clinical and histopathologic features of three congenital cornea1 dystrophies: congenital hereditary endothelial; the hereditary cornea1 edema variant of posterior and congenital hereditary polymorphous; stromal. 2. Clinical Course

Posterior polymorphous dystrophy is usually inherited as an autosomal dominant53 with extremely wide expression.‘3 In some families it is propagated as an autosomal

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Et AL

POSTERIOR POLYMORPHOUS DYSTROPHY

Clinical

/

I

FIG. 8. Posterior polymorphous dystrophy. Composite drawing emphasizes major features. Clinical: (clockwise) Isolated grouped vesicles surrounded by gray haze; beaten-metal appearance of irregular Descemet’s membrane in retroillumination; geographically shaped discrete gray lesions; band configuration; stromal edema; peripheral iridocorneal adhesions. Light microscopy: Periodic Acid Schiff positive material posterior to Descemet’s membrane with fusiform excrescence. Electron microscopy: fibrillar collagen tissue on posterior surface of very thin Descemet’s membrane; epithelial-like cells with microvillae and desmosomes.

recessive.‘3*53Generally bilateral, it may be asymmetrical or unilateral, so that one cornea demonstrates advanced polymorphic changes while the other possesses only an area of grouped vesicles. The age of onset is difficult to determine, since most patients remain asymptomatic and are identified either during routine ophthalmologic examination or as part of family studies. The disorder is probably congenital, since cases of cornea1 edema at birth and congenital posterior vesicular changes occur in families with posterior polymorphous dystrophy.13 In addition, ultrastructural studies demonstrate a normal anterior banded fetal Descemet’s membrane but little or no posterior amorphous Descemet’s membrane, suggesting abnormal endothelial function at, or shortly after, birth.eJ0*e*73

Posterior polymorphous dystrophy usually does not reduce visual acuity, since it rarely produces stromal opacities or epithelial edema. Although it has been described as stationary,32~53 the disorder can progress slowly. For example, the number of grouped vesicles may increase,‘jg and there are more polymorphic vesicles and greater thickness of Descemet’s membrane in older patients who retain normal visual acuity. In some patients, stromal edema gradually blurs vision and progresses to epithelial edema with secondary band keratopathy requiring keratoplasty.9*13 Broad peripheral iridocorneal adhesions with overlying cornea1 edema spread around the angle covering 60-120” in a small percentage of cases.**‘2Elevated intraocular pressure occurs in about 15% of patients with posterior polymorphous dystrophy, both with

CORNEA1 DYSTROPHIES

FIG. 9. Posterior polymorphous dystrophy. A. Cluster of grouped vesicles at level of Descemet’s membrane (arrow) stand out against red fundus reflection. B. Gray discrete, irregular lesions of varying size spread across the posterior cornea. C. Slit view of B demonstrates focal thickenings (arrow) at level of Descemet’s membrane. D. High power view of single lesion in B shows small vesicular (arrow) areas surrounded by denser gray focal thickenings zone. E. In retroillumination, take on refractile vesicular appearance. In one area, two roughly parallel lines form band (arrow).

\

\

and

peripheral iridocorneal without adhesions. In one family, components of the

anterior chamber cleavage syndrome (prominent Schwalbe’s ring, diffuse hypoplasia of the anterior iris stroma, scleralization of the cornea, and posterior keratoconus) accompanied posterior polymorphous dystrophy.*’ No systemic diseases are consistently present, although vitiligo of the eyebrows and eyelashes sometimes occurs.

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3. Slitlamp Appearance (Fig. 9)

The configurations of posterior polymorphous dystrophy include small grouped vesicles, larger geographically shaped blisterlike lesions, broad bands, and sheets of gray material that appear as a thickening of Descemet’s membrane.13 Cornea guttata are absent. Because these alterations occur at the level of Descemet’s membrane, they stand out most strikingly in retroillumination from the iris or fundus. Broad oblique illumination accentuates the gray areas and specular reflection accentuates the posterior surface irregularities. The simplest form of the disorder is grouped vesicles, sometimes called herpes posterior or linear vesicles (Fig. 9A). Two to 20 small (0.2-0.4 mm) discrete round lesions with the optical quality of blisters or vesicles cluster together, surrounded by a diffuse gray halo. They may appear anywhere on the posterior cornea and may remain stationary, increase in number, or regress; they do not affect visual acuity. The larger geographic lesions are a more severe form of grouped vesicles in which the gray halo is denser and sometimes nodular and in which the round or elliptical vesicles are less discrete (Fig. 9B). The distribution varies from a peripheral ring to a focal wedge to a diffuse Swiss cheese-like pattern over the posterior cornea. They protrude posteriorly in a very narrow slit beam, have optical qualities of a convex surface (the shadow from each vesicle is on the side opposite the retroilluminating light) and correspond histopathologically to posterior cornea1 excrescences. Sometimes optical distortion makes them appear as concavities or pits in the posterior cornea1 surface. Broad 1 mm-wide bands, distinctive lesions in posterior polymorphous dystrophy, extend across the posterior cornea1 surface. These consist of two translucent scalloped, elevated ridges that run roughly parallel to each other, but lack the straight railroad track appearance characteristic of traumatic breaks in Descemet’s membrane, with which they have been confused (Fig. 9E)?* When the area of Descemet’s membrane becomes gray and irregular, it appears like a frozen lake surfaced by focal patches of snow. In retroillumination, the entire posterior cornea takes on the peau d’orange appearance of beaten metal and, on specular reflection, a quality of

glassy undulation. The stromal and epithelial edema resemble that in other types of cornea1 edema. The stromal edema begins posteriorly, becomes more dense and, as the epithelial surface becomes irregular, visual acuity falls. In some instances, mild stromal edema appears in the neonatal period as hereditary cornea1 edema.3sq3gThe clinician can distinguish this entity from congenital hereditary endothelial dystrophy by identifying family members with lesions typical of posterior polymorphous dystrophy48 and contrasting their mild stromal haze to the extreme edema and stromal thickness that characterize congenital hereditary endothelial dystrophy. Rarely, the cornea1 edema in adults decreases spontaneously with improvement in visual acuity, l3 a phenomenon that highlights the extremely variable course of posterior polymorphous dystrophy. In some cases, broad peripheral iridocorneal adhesions occupy the peripheral 1 mm of the posterior cornea, sometimes accompanied by a glassy membrane that extends down the adhesion onto the surface of the iris to produce ectropion of the iris epithelium and an irregular pupil.13 The atrophic iris is easily visible at the slitlamp through the overlying cornea1 edema. These broad adhesions are different from the finer iris strands that attach to a prominent Schwalbe’s ring in Axenfeld’s and Rieger’s anomalies. 5. Clinicopathologic

Correlation (Figs. 10 and 11)

As expected, the histopathologic findings vary widely, depending upon the severity of the disease at the time of keratoplasty. Epithelium and Basement Membrane. In cases without cornea1 edema, the epithelium appears normal,29~31*54 while more advanced cases demonstrate intracellular and intercellular edema with some free ribosomes in the cytoplasm and distention of the rough endoplasmic reticulum.3s The epithelial basement membrane is present, although it thickens and fragments in advanced cases. Bowman’s Layer and Stroma. Bowman’s layer is usually normal, although subepithelial fibrous tissue fragments it in advanced cases?? Stromal edema increases distance between collagen fibrils, creates lakes of fluid, and produces irregularity of the collagen lamellae. Keratocytes appear nor-

CORNEA1 DYSTROPHIES

FIG 10. Histopathology of posterior polymorphous dystrophy. Inset: collagen tissue (arrow) accumulates posterior to Descemet’s membrane. Double layer of cells lines posterior cornea. (Toluidine blue, X 500) Electron micrograph: multilayered epithelial-like cells (E) manifest microvilli and desmosomes (arrow). Collagen posterior to Descemet’s membrane (DM) forms 110 nm banded broad-spacing pattern anteriorly (box), layer of loosely packed fibrillar tissue centrally (F), and layer of basal-laminar material with broad-spacing collagen (box, asterisk) posteriorly. (X 10,800)

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sometimes occurs.39

Membrane

and

Endothelium.

Descemet’s membrane is immature and multiple layers of collagen appear on its posterior surface. By light microscopy, these layers of PAS positive material manifest focal fusiform or nodular excrescences.31,54 Ultrastructurally, Descemet’s membrane consists of the anterior 3 pm thick, 110 nm banded portion that appears in utero, but the posterior non-banded layer that appears after birth is extremely thin or absent.3g Two types of collagenous tissue posterior to this immature Descemet’s membrane form layers up to 25 pm thick~.27,30~32.38.3s,63,73 The most common is a tibrillar tissue in which non-banded collagen fibrils lo-20 nm in diameter (and occasionally 30 nm in diameter with 64 nm banding) form a loose feltwork against a background of basement membrane-like material. Rarely, fibroblast-like cells and fusiform bundles of 110 nm widespacing collagen are present. The second type of collagenous tissue consists of basement membrane-like material with fusiform or diffuse bundles of 110 nm or 55 nm banded wide-spacing collagen and some lo-20 nmdiameter collagen tibrils. These collagenous layers form the gray tissue seen clinically at the level of Descemet’s membrane. The histopathologic basis for the vesicular appearance is unknown; it may reflect focal nodular thickenings of the posterior collagenous layers with the more refractile basement membrane material producing the vesicular appearance, as it does in cornea guttata of Fuchs’ endothelial dystrophy. No reports on the histopathology of the iridocorneal adhesions have been published. The most distinctive histopathologic finding in posterior polymorphous dystrophy is the multilayered epithelial-like morphology of the cells surfacing the posterior cornea:9.30.32,36,63,73 numerous surface microvilli, abundant intracellular keratofibrils, multiple desmosomes instead of the usual apical gap junctions, minimally interdigitated cell borders, and sparse organelles. Scanning electron microscopy of the endothelial surfacez7 shows a forest of microvillae (Fig. 11). However, these epithelial-like cells are not diagnostic for posterior polymorphous dystrophy, since fibroblast-like cells may occur in this disorder36 and since endothelial microvillae occur in other disorders.

FE. 1I. Scanning electron micrograph of posterior polymorphous dystrophy. Cells lining posterior cornea manifest numerous microvillae. (X 5000) 6. Pathogenesis

The basic defect in posterior polymorphous dystrophy is in the epithelial-like cells on the posterior cornea. We have speculated that the mesenchymal cells from which the endothelium is derived are pluripotential and can transform into epithelial-like cells.63 These cells probably produce the multilaminar, focally thickened collagen layers posterior to Descemet’s membrane. The association with the anterior chamber cleavage syndromez7 and with the broad iris adhesions13 suggests a more general ocular mesenchymal dysgenesis. The presence of a normal thickness 110 nm banded anterior Descemet’s membrane suggests that the abnormal development commences in the late gestational or the neonatal period. Stromal and epithelial edema result from loss of the barrier and pump functions of these cells. The superficial degenerative changes like band keratopathy are nonspecific. 7. Management

Visual acuity remains normal in most patients with posterior polymorphous dystrophy. Patients with mild stromal or

CORNEA1 DYSTROPHIES

163

CONGENITAL HEREDITARY ENDOTHELIAL

Clinical

FIG. 12. Congenital hereditary endothelial dystrophy. Composite drawing emphasizes major features. Clinical: thick, edematous stroma. Light microscopy: Periodic Acid Schiff positive tissue on posterior surface of Descemet’s membrane; suarse endothelial cells. Electron microscopy: fibrillar collagen on posterior surface of thin Descemet’s membrane. epithelial edema may obtain comfort and some improved vision from hypertonic solutions or soft contact lenses. Elevated ocular pressure is managed as in chronic open angle glaucoma. Cataract extraction may be successful.” When the edema is severe enough, penetrating keratoplasty will often restore visual acuity,13 but the prognosis is poorer in eyes with peripheral iridocorneal adhesions. There are no reports of posterior polymorphous dystrophy recurring in cornea1 grafts. 8. Summary Posterior polymorphous dystrophy is a congenital, bilateral, often asymmetrical, autosomal dominant disorder. Epithelial-like cells on the posterior cornea produce abnormal collagen that appears clinically as small groups of vesicles, focal geographic blisterlike excrescences, broad refractile bands, and sheets of grayish material with a diffuse

beaten metal appearance. In some instances broad peripheral iridocorneal adhesions accompany overlying cornea1 edema. Generally, the disorder is stationary and does not affect visual acuity, but it may progress to diffuse stromal edema with secondary cornea1 degeneration so that the patient requires penetrating keratoplasty. Glaucoma is more frequent in these individuals than in the general population. (‘. CONGENITAL HEREDITARY ENDOTHELIAL DYSTROPHY (FIG. 12) 1. Terminology

Ophthalmologists have classified this congenital cornea1 opacity in a variety of ways. Early investigators considered it a variant of intrauterine interstitial keratitis;47 later it took a place among the stromal dystrophies as congenital stationary (or congenital macular) cornea1 opacity.18~22~23~67~78

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Recently, ultrastructural studies have demonstrated the dystrophic endothelium and Descemet’s membrane that provide the basis for the appellation, congenital hereditary endothelial dystrophy.‘,52*43-45v56 Current studies have suggested distinctive clinical patterns for both the dominant and the recessive types3’ and have distinguished this disorder from a congenital hereditary stromal dystrophy.78 2. Clinical Course

This congenital cornea1 dystrophy is inherited as either an autosomal domior an autosomal recesnant 16*37+2*55+56 sive. 8*2s*31 Isolated cases occur.52 The clinical picture of the two genetic patterns may differ.37 The autosomal recessive type is present at birth, remains stationary and asymptomatic, and is accompanied by nystagmus; the dominant type appears in the first or second year with photophobia and tearing, progresses slowly over 5 to 10 years and lacks nystagmus. Although additional observations are necessary to confirm these differences, the term “autosomal dominant hereditary endothelial dystrophy”37 is more suitable, since this form is not congenital. The symmetrically edematous corneas have a diffuse gray-blue ground glass appearance occasionally studded with focal gray spots. While the stromal edema sometimes remains stable, it usually progresses gradually over 5-10 years, with secondary changes such as band keratopathy or epithelial erosion that can reduce visual acuity to light perception.42,52*56There is no consistently associated systemic abnormality, although one family manifested autosomal dominant progressive high-tone sensory neural deafness.31 During the neonatal period, the clinician may mistake this disorder for congenital glaucoma without buphthalmos and perform glaucoma surgery.42 The absence of inflammation and photophobia, of elevated pressure by electronic tonometry (using ketamine or nitrous oxide anesthesia to avoid falsely low readings), and of progressive cornea1 enlargement make congenital glaucoma an unlikely diagnosis. Both posterior polymorphous dystrophy and congenital hereditary endothelial dystrophy may manifest diffuse corneal clouding at birth, but cornea1 thickness is usually normal in posterior polymorphous dystrophy, while it is 2-3 times normal in congenital hereditary endothelial dystrophy.

FIG. 13. Congenital hereditary endothelial dystrophy. Diffuse ground-glass edema occupies segmental portion of cornea.

If the focal gray spots are prominent, it can resemble macular dystrophy, although the different time of onset distinguishes the two. 3. Slitlamp Appearance (Fig. 13)

Congenital hereditary endothelial dystrophy consists of epithelial and stromal edema that involves the entire cornea, with a gray thickening at the level of Descemet’s membrane. The epithelium manifests a diffuse pigskin-like roughness, while the groundglass stroma may have a different density from one area to another, but is homogeneous across its anterior-posterior axis. Focal stromal macular opacities and discrete white dots sometimes appear. When the stromal edema allows visualization of the posterior surface, the area of Descemet’s membrane appears gray and thickened, with a peau d’orange texture devoid of guttate and vesicular excrescrences. The endothelial mosaic is visible in some cases, but endothelial cells seem absent in others. 4. Clinicopathologic

Epithelium

Correlation (Fig. 14)

and Basement Membrane. The thickness of the epithelium varies from 3-7 layers. Individual cells demonstrate loss of polarity, increased numbers of mitochondria, and intercellular edema. Fluid clefts separate the basal epithelium from Bowman’s layer. Even though the basement membrane is focally absent, the basal epithelial cells adhere to the cornea, since epithelial cornea] erosions are unusual. Bowman’s Layer and Stroma. Bowman’s layer is usually intact, although irregularly thick and sometimes fragmented. Homogeneous granular material and fluid pockets separate the stromal collagen fibrils and dis-

165

CORNEA1 DYSTROPHIES

Fro. 14. Histopathology of congenital hereditary endothelial dystrophy. Inset: Periodic Acid Schiff positive tissue lies posterior to Descemet’s membrane (DM) and is lined by sparse atrophic endothelial cells (arrows). (PAS, X 640) Electron micrograph: normal 110 nm banded anterior Descemet’s membrane (arrow) separates stroma (S) from layer of amorphous basement membrane-like material (asterisk) that extends to atrophic endothelial cells (X 14,600) (Reprinted from Rodrigues MM et ale3 with permission of Am J Uphthalmoi)

tort the collagen lamella into undulating fragmented bundles, a finding more marked posteriorly. Although most collagen librils have a normal diameter and periodicity, some enlarge to 60-80 nm, twice the normal diameter. The fibril density is about half the normal value of 504 fibril cross-sections/~m2.‘3.‘5 All these alterations produce light scattering that creates the ground-glass appearance clinically. Keratocytes appear normal; inflammatory cells and blood vessels are absent; glycosaminoglycans are not inCreaSed.45S5,60.74 Descemet’s

Membrane

and

Endothelium.

Descemet’s membrane consists of the normal anterior 110 nm banded portion and a very narrow layer of posterior non-banded material. In one eye enucleated from a newborn,2,43 the area of Descemet’s membrane consisted of multiple layers of tine filamentous material similar to that seen in the developing fetus. In most specimens with preserved cornea1 endothelium, the collagen tissue present posterior to Descemet’s membrane consists of an acellular feltwork of fibrils 20-40 nm in diameter, the larger with 64 nm banding, interspersed among small amounts of basement membrane-like material. In some areas the basement membrane-like material becomes densely packed and simulates an extra layer of Descemet’s membrane without guttate excrescences.45 This entire layer varies from 2.0-35.0 pm in thickness and corresponds to the gray tissue seen on the posterior cornea clinically. A detailed description of the cornea1 endothelial cells is not available, since the cells are often missing or atrophic, even in an intact

globe; this makes it difficult to see an endothelial mosaic clinically. 5. Pathogenesis The degeneration and focal absence of cornea1 endothelium in a globe enucleated from a newborn with congenital hereditary endothelial edema pinpoints abnormal endothelial development as responsible for the tremendous stromal edema. The presence of a normal 3 pm thick anterior banded Descemet’s membrane suggests that the endothelial cells were able to synthesize a normal basement membrane during their development. Wide variation in postnatal endothelial function is reflected by the variable amount of stromal edema in early childhood, by the highly variable thickness of the posterior collagen tissue, and by the unpredictable clinical course. 6. Management

Like others with epithelial and stromal edema, these patients have worse visual acuity in the morning because of decreased tear film evaporation during sleep. Topical hypertonic ointment upon retiring and warm air from a hair dryer on arising may improve acuity, but are often unsatisfactory. Fortunately, painful epithelial erosions are unusual. Patients who have miid cornea1 edema and useful vision early in life may avoid keratoplasty, especially if the edema remains stationary; however, if cornea1 opacification is moderately severe, keratoplasty in childhood diminishes the severity of the amblyopia and may prevent nystagmus and esotropia. Unfortunately, cornea1 grafts per-

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formed for congenital hereditary endothelial dystrophy often gradually opacify months to years after surgery,42 possibly because of the severely compromised host endothelium. Recently, long-term clear grafts have been possible in this disorder,76 maybe because of improved microsurgical techniques and sutures. 7. Summary

Congenital hereditary endothelial dystrophy is an autosomal dominant or autosomal recessive disorder that exhibits bilaterally symmetrical full-thickness stromal edema and diffuse nonbullous epithelial edema extending to the limbus. The cornea is 2-3 times normal thickness. The area of Descemet’s membrane may appear thickened because of new collagen tissue on the posterior surface. and cornea1 inflammation Ocular vascularization are present. Nystagmus and esotropia may occur. Although the edema sometimes remains stationary, it usually keratoprogresses, requiring penetrating plasty. II. Other Dystrophies We have omitted many reports of cornea1 dystrophies in isolated individuals and in few members of a family. For example, annular endothelial dystrophy, characterized by posterior peripheral flat ring-shaped opacities, has been described in a mother and daughter.24 Attentive clinicians will discover more. References 1. Akiya S, Brown SI: Granular dystrophy of the cornea. Characteristic electron microscopic lesion. Arch Ophthalmol 84:179-192, 1970 2. Antine B: Histology of congenital cornea1 dystrophy. Am J Ophthalmol 69:964-969, 1970

3. Arentsen JJ, Laibson PR: Penetrating keratoplasty and cataract extraction. Combined vs. nonsimultaneous surgery. Arch Ophthalmol 96:75-76,

1978

4. Babel J, Pouliquen Y, Bisson J, et al: Dystrophie congenitale de la corn&e. Arch Ophtalmol

(Paris)

29:683-698,

1969

5. Bergman GD: Posterior polymorphous degeneration of the cornea. Am J Ophthalmol 58:125-128, 1964 6. Berliner ML: Biomicroscopy of the Eye, Vol I. New York, Paul B Hoeber, 1949, pp 3 16-320 I. Bigar F, Schimmelpfennig B, Hurzeler R: Cornea guttata in donor material. Arch Ophthalmol

96:653-655,

1978

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8. Blum JD: Relations entre les degenerescences hCrtdofamiliales et les opacites congenitales de la corn&e (&de clinique et genealogique). Ophthalmologica

109:123-136,

1945

9. Boruchoff SA, Kuwabara T: Electron microscopy of posterior polymorphous degeneration. Am J Ophthalmol 72:879-887, 1971 10. Buxton JN, Preston RW, Riechers R, et al: Tonography in cornea guttata. A preliminary report. Arch Ophthalmol 77:602-603, 1967 1 I. Chi HH, Teng CC, Katzin HM: Histopathology of primary endothelial-epithelial dystrophy of the cornea. Am J Ophthalmol45: 518-535,

1958

12. Cibis GW, Krachmer JA, Phelps CD, Weingeist TA: Iridocorneal adhesions in posterior polymorphous dystrophy. Trans Am Acad 1976

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81:770-777,

JA, Phelps CD, 13. Cibis GW, Krachmer Weingeist TA: The clinical spectrum of posterior polymorphous dystrophy. Arch Ophthalmol

95: 1529-l 537, 1977

14. Collier M: La dystrophie vtsiculiform goupCe en ilots et en bandes de I’endothClium cornten (herpes posterior de Schnyder). Bull Sot Ophtalmol

Fr 80:95-125,

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15. Cross HE, Maumenee AE, Cantolino SJ: Inheritance of Fuchs’ endothelial dystrophy. Arch Ophthalmol 85:268-272, 197 1 16. Desvignes P, Vigo A: A propos d’un cas de dystrophie cornkenne parenchymateuse familiale ti htrCditt: dominate. Bull Sot Ophtalmol Fr 68:220-225, 1955 17. DeVoe AG: The management of endothelial dystrophy of the cornea. Am J Ophthalmol 61:1084-1089, 1966 18. Dohlman CH: Familial congenital cornea guttata in association with anterior polar cataract. Acta Ophthalmol (Kbh) 29:445-473, 1951 19. Duke-Elder S: Normal and abnormal development, in Duke-Elder S (ed): System of Ophthalmology, Vol III, Part 2. St. Louis, CV Mosby, 1963, p 529 20. Duke-Elder SS, Leigh AG: Diseases of the outer eye, in Duke-Elder SS: System of Ophthalmology, Vol VIII, Part 2. St. Louis, CV Mosby, 1965, pp 921-976 21. Eggers C: Dystrophia cornealis posterior polymorpha (Hornhautdystrophie von Schlichting). Ophthalmologica 154:1-5, 1967 22. Franceschetti A: Classification and treatment of hereditary cornea1 dystrophies. Arch Ophthalmol 52:1-12, 1954 23. Franceschetti A, Babel J: Essai de classification anatomique des dig6n&rescences familiales de la cornte. Ophthalmologica 109:169-202, 1945 24. Franqois J, Evens A: H&do-dystrophie annulaire de’ l’endothblium cornken. J Genet Hum 9:78-86, 1960

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scopic studies of the cornea1 granular dystrophy. Acta Sot Ophthalmol Jap 81:

25. Girard LJ, Lopez 0: Regression of Fuchs’ dystrophy with a glued on contact lens. Ann Ophthalmol 7:943-944, 26. Goar EL: Dystrophy

1975

of the cornea1 endothelium (cornea guttata), with a report of a histological examination. Am J Ophthalmol

17:215-221, 1934 27. Grayson M: The nature

of hereditary deep polymorphous dystrophy of the cornea. Its association with iris and anterior chamber dysgenesis. Trans Am Ophthalmol Sot 72: 516-559, 1974 28. Hamada R. Giraud JP, Pouliquen Y: Electron microscopic study on the Fuchs’ dystrophy. Acta Sot Ophthalmol Jap 77:531-545, 1973 29. Hanselmayer H: Zur Histopathologie der

hinteren polymorphen Hornhautsdystrophie nach Schlichting. I. Licht mikroskopische Befunde in Beziehung zum Klinischen Bild. Alhrecht von Graefes Arch Klin Ophthalmol 184:345-357, 1972 30. Hanselmayer H: Zur Histopathologie der

hinteren polymorphen Hornhautsdystrophie nach Schlichting. II. Ultrastrukturelle Befunde. pathogenetische und pathophysiologische Bemerkungun. Albrecht von Graefes Arch Klin Ophthalmol 185:53-65, 1972 31. Harboyan G, Mamo J, Der Kaloustian

V, Karam F: Congenital cornea1 dystrophy: Progressive sensorineural deafness in a family.

Arch Ophthalmol 85:27-32, 197 1 32. Hogan MJ. Bietti G: Hereditary

dystrophy of the cornea (polymorphous).

deep

145-154, 1977 41. Kayes J, Holmberg

A: The line structure of the cornea in Fuchs’ endothelial dystrophy.

Invest Ophthalmol 3:47-67, 1964 42. Keates RH, Cvintal T: Congenital hereditary cornea1 dystrophy. Am J Ophthalmol 60: 892-894, 1965 43. Kenyon KR, Antine B: The pathogenesis of

congenital hereditary endothelial dystrophy of the cornea. Am J Ophthalmol 72:787-795, 1971 44. Kenyon KR, Maumenee AE: The histological and ultrastructural pathology of congenital hereditary cornea1 dystrophy: A case report. Invest Ophthalmol 7:475-500, 1968 45. Kenyon KR, Maumenee AE: Further studies

of congenital hereditary endothelial dystrophy of the cornea. Am J Ophthalmol 76:419-439, 1973 46. Krachmer JH, Purcell JJ, Young CW, Bucher

KD: A study of sixty-four families with corneal endothelial dystrophy. Arch Ophthalmol (in press) 47. Laurence GZ: Klin Monatsbl Augenheilkd 1:351, 1863. (cited by Pearce56)

48. Levenson JE, Chandler JW, Kaufman HE: Affected asymptomatic relatives in congenital hereditary endothelial dystrophy. Am J Ophthalmol 76:967-971, 1973 49. Lorenzetti DWC, Uotila MH,

Am

J Ophthalmol 68:777-788, 1969 33. Hogan MJ, Wood I, Fine M: Fuchs’ endothelial dystrophy of the cornea. Am J Ophthalmol 78:363-383, 1974 34. Iwamoto T. DeVoe A: Electron microscopic

50.

studies on Fuchs’ combined dystrophy: I. Posterior portion of the cornea. invest Ophthalmol 10:9-28, 197 I 35. Iwamoto T, DeVoe AG: Electron microscopic studies on Fuchs’ combined dystrophy: II. Anterior portion of the cornea. Invest

5 I.

Ophthalmol 10:29-40. 1971 36. Johnson BL, Brown SI: Posterior

52.

polymorphous dystrophy: A light and electron microscopic study. Br J Ophthalmol 62:89-96, 1978 37. Judisch GF, Maumenee IH: Clinical differentiation of recessive congenital hereditary endothelial dystrophy and dominant hereditary endothelial dystrophy. Am J Ophthalmol

85:606-612, 1978 38. Kanai A: Further electron microscopic study of hereditary cornea1 edema. Invest Ophthalmol 10:545-554, 197 1

39. Kanai A, Waltman S, Polack FM, Kaufman HE: Electron microscopic study of hereditary cornea1 edema. Invest Ophthalmol 10:89-99. 1971 40. Kanai A, Yamaguchi

histochemical

A: The electron micro-

T, Nakajima

and analytical

53.

Parikh N, Kaufman HE: Central cornea1 guttata. Incidence in the general population. Am J Ophthalmol 64:1155-l 158, 1967 Magruder GB: Lens extraction in hereditary deep cornea1 dystrophy. Am J Ophthalmol 52:677-681, 1961 Marquardt R, Doden W: Histologische Untersuchungen zu Verilnderungen am DescemetEndothel bei Cornea Guttata und Fuchsscher. Kornbinierter adematiiser Hornhautdystrophie. Klin Monatsbl Augenheilkd 165: 709-714, 1974 Maumenee AE: Congenital hereditary cornea1 dystrophy. Am J Ophthalmol 50:1114-l 124, 1960 McGee HB, Falls HF: Hereditary polymorphous deep degeneration of the cornea. Arch

Ophthalmol 50:462-467, 54. Morgan G, Patterson

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A: Pathology of posterior polymorphous degeneration of the cornea. Br J Ophthalmol 51:433-437, 1967 55. Odland M: Dystrophia corneae parenchymatosa congenita. A clinical, morphological and histochemical examination. Acta Ophthalmol 46:477-485, 1968 56. Pearce WG, Tripathi RC,

Morgan G: Congenital endothelial cornea1 dystrophy: Clinical, pathological and genetic study. Br J Ophthalmol 53:577-59 1, 1969 57. Pippow G: Zur Erbbedingtheit der cornea

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66. Schroeder GT, Hanna C: Unusual epithelial changes in a case of combined cornea1 dystrophy of Fuchs. Am J Ophthalmol 72:542-548, 197 1 cornea1 dystrophy; 61. Schutz S: Hereditary history of the condition and presentation of pedigree. Arch Ophthalmol 29:523-534, 1943 68. Snell AC Jr, Irwin ES: Hereditary deep dystrophy of the cornea. Am J Opbthalmol 45:636-638,

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69. Staz L: An unusual condition of the posterior surface of the cornea (posterior herpes of the cornea). Br J Ophthalmol 23:622-626, 1939 70. Stocker FW, Irish A: Fate of successful cornea graft in Fuchs’ endothelial dystrophy. Am J Ophthalmol

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71. Stocker FW: The Endotbelium of the Cornea and its Clinical Implications. Springfield, III, Charles C Thomas, 1971, ed 2, pp 79-109 12. Strachan IM, Maclean H: Posterior polymorphous dystrophy of the cornea. Br J Ophthalmol

structural

and clinical report. Trans OphUK 94:21 l-225, 1974 74. Victoria-Troncoso V, Malbran E: RCcherche Histochimique sur la dystrophie edCmateuse cong&itale de la cornte (Son rapport avec les mucopolysaccharidoses). Bull Sot Belge thalmol .Soc

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15. Waring G, Laibson P, Rodrigues M: Clinical and pathological alterations of Descemet’s membrane with emphasis on endothelial metaplasia. Surv Ophthalmol l&325-368, 1974 76. Waring GO, Laibson PR: Keratoplasty in infants and children. Trans Am Acad Ophthalmol

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78. Witschel H, Fine BS, Grutzner P, McTigue JW: Congenital hereditary stromal dystrophy of the cornea. Arch Ophthalmol96:1043-1051, 1978

Supported in part by grants from the Commonwealth Fund and the American Academy of Ophthalmology. Reprints are not available of Part I or Part II of this review.

1975

64. Rubenstein RA, Silverman JJ: Hereditary deep dystrophy of the cornea associated with glaucoma and ruptures in Descemet’s membrane. Arch Ophthalmol 79:123-126, 1968 65. Schlichting H: Blasen und Dellenformige Endotheldystrophie der Hornhaut. Klin Monatsbl Augenheilkd

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1978

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73. Tripathi RC, Casey TA, Wise EG: Hereditary posterior polymorphous dystrophy. An ultra-

Outline

PART I [Vol 23 (2) 19781 I. Definition and classification A. Definition B. Classification II. Epithelial dystrophies A. Epithelial basement membrane dystrophy B. Meesmann’s juvenile epithelial dystrophy 111. Bowman’s layer dystrophies A. Reis-Biicklers’ ring-shaped dystrophy B. Anterior mosaic dystrophy IV. Stromal dystrophies A. Granular dystrophy B. Lattice dystrophy C. Macular dystrophy D. Central crystalline dystrophy E. Fleck dystrophy F. Pre-Descemet’s “dystrophy” G. Polymorphic stromal “dystrophy” H. Central cloudy dystrophy I. Posterior amorphous dystrophy J. Congenital heriditary stromal dystrophy PART II I. Endothelial Dystrophies A. Fuchs’ endothelial dystrophy B. Posterior polymorphous dystrophy C. Congenital hereditary endothelial dystrophy II. Other dystrophies