Corneal Dystrophies1

Corneal dystrophies are a heterogenous group of rare, inherited corneal diseases that are typically bilateral, symmetric, noninflammatory, slowly progressive, and usually bear no relationship to environmental or systemic factors. The word dystrophy is derived from Greek literature (dys = wrong, difficult; trophe = nourishment). Clinically, the corneal dystrophies are divided into three groups-based on the principal anatomic location of the abnormalities. It may affect the corneal epithelium and its basement membrane or Bowman layer and the superficial corneal stroma (anterior corneal dystrophies), the corneal stroma (stromal corneal dystrophies), or Descemet's membrane and the corneal endothelium (posterior corneal dystrophies). Most corneal dystrophies have no systemic manifestations and present with variable shaped corneal opacities in a clear or cloudy cornea and they affect visual acuity to different degrees.

Most of the published reports derive their prevalence data from the number of cases of corneal dystrophy undergoing keratoplasty. Some of the recent reports are summarized in the Table 1.1. While this may be an indicator of the prevalence of cases severe enough to warrant a corneal graft, it is not a true estimate of the prevalence of corneal dystrophy in the entire population.

The increasing availability of genetic analyses highlighted the shortcomings of the phenotypic method of classification of corneal dystrophy. Abnormalities in different genes may produce a single phenotype, whereas various defects in a single gene can manifest as varying phenotypes.¹ The International Committee for Classification of Corneal Dystrophies (IC3D) was developed to incorporate the traditional classification of corneal dystrophies with new genetic, clinical, and pathologic information.² The anatomic classification continues to group dystrophies according to the structures predominantly involved. Each dystrophy carries a template summarizing genetic, clinical, and pathologic information.2

A category number from 1 through 4 is assigned depicting the level of evidence supporting the existence of the particular dystrophy. The most defined dystrophies belong to category 1 (a well-defined corneal dystrophy with a gene that has been mapped, identified and specific mutations are known) and the least defined belong to category 4 (a suspected dystrophy without substantial genetic evidence).²

Category 1: A well-defined corneal dystrophy in which the gene has been mapped and identified and specific mutations are known.

Category 2: A well-defined corneal dystrophy that has been mapped to 1 or more specific chromosomal loci, but the gene(s) remains to be identified.

Category 3: A well-defined corneal dystrophy in which the disorder has not yet been mapped to a chromosomal locus.

Category 4: This category is reserved for a suspected new, or previously documented, corneal dystrophy, although the evidence for it, being a distinct entity, is not yet convincing.

Alternative names: Map-dot-fingerprint dystrophy, Cogan microcystic epithelial dystrophy, Anterior basement membrane dystrophy, Dystrophic recurrent erosion.3

Most cases have no definite hereditary pattern. Autosomal dominant inheritance has been documented in a few cases.¹⁰

The genetic locus has been mapped to chromosome 5 (5q31); gene TGFBI has been isolated in a minority of cases.^11,12

The disease manifests in adult life around 30 years of age. Familial cases may manifest earlier in childhood.

This disease is characterized by the appearance of maps, dots and fingerprint lines.

Maps appear as gray geographical patches, best observed on broad tangential illumination (Fig. 1.2).

Dots (Cogan) are irregular round, oval or comma-shaped gray-white intraepithelial opacities; clustered like an archipelago in the central cornea. These occur in combination with other signs, especially with maps.5

Dots (Blebs of Bron and Brown) are small clear round dots clustered together, visible only on retroillumination.

Fingerprint lines are parallel, curvilinear branching lines with club shaped terminations. Refractile lines are seen on retroillumination.

Combination of maps and dots are noted most frequently, followed by maps alone (Fig. 1.3).6

The major pathology lies in the abnormal synthesis of the epithelial basement membrane. Recurrent erosions occur due to lack of hemidesmosomal connections between the epithelial cells and the abnormal basement membrane.

Corneal scrapping may be performed in cases of recurrent corneal erosions. Following the procedure, a soft contact lens is placed for 24 to 48 hours and topical antibiotics instilled. A five-year cumulative probability of recurrence of up to 44.7 percent has been reported following epithelial debridement for anterior basement membrane dystrophy.⁷

Alternative name: Franceschetti recurrent epithelial dystrophy²¹

Variant: Dystrophia Smolandiensis.

Inheritance pattern is autosomal dominant. The genetic locus remains unknown.²²

Most patients experience attacks of redness, photophobia, epiphora, and ocular pain due to corneal erosions (Fig. 1.4). Some may complain of sensitive eyes for years. Exposure to sunlight, dust and smoke and lack of sleep can precipitate attacks. Attacks generally decline in frequency and intensity and cease by the age of 50 years.7

Recurrent corneal erosions appear typically at 4 to 6 years of age but occasionally as early as 8 months of age. These may be precipitated by minimal trauma or may be spontaneous. The cornea may develop subepithelial haze or blebs between attacks. The Smolandiensis variant is characterized by recurrent corneal erosions, followed by the formation of central corneal keloid like opacities.²³

Light microscopic examination reveals epithelial hyperplasia, absence of Bowman's layer and subepithelial fibrosis in cases with dystrophia Smolandiensis; the specimen being positive for Congo red, suggesting an amyloid deposit. The general morphological pattern of pathology (true keloid formation, absence of Bowman's layer, subepithelial fibrosis and abnormal subbasal nerves) probably reflects a novel phenotypic expression of the healing response to recurrent erosion of the corneal epithelium.²³

Recurrent erosions are managed similar to cases with epithelial basement membrane dystrophy.

This dystrophy has an autosomal dominant pattern of inheritance. Genetic locus and gene remain unknown.²⁴

The onset is characterized by frequent, recurrent corneal erosions in the first decade. These subside during adolescence with the formation of subepithelial opacities, causing progressive decreased vision.²⁴

Bilateral, homogenous subepithelial haze is noted. The haze is most dense centrally, and fades towards the periphery.

Light microscopy reveals a subepithelial band of eosinophilic, periodic acid Schiff-positive, Alcian blue-positive, Masson trichrome-positive hyaluronidase-sensitive material anterior to the Bowman's layer. The overlying epithelium is thinned out. Immunohistochemistry staining is positive for combination of chondroitin-4-sulfate and dermatan sulfate.²⁴

Initial treatment includes management of recurrent corneal erosions. The superficial location of the pathology makes PTK a potential treatment modality.

Alternate name: Juvenile hereditary epithelial dystrophy.

This dystrophy was first described clinically by Pameijer.²⁵ The histopathological description was given by Meesmann.²⁶

Autosomal dominant with incomplete penetrance and variable expressibility is seen in a majority of cases. Autosomal recessive form has been reported by Stocker and Holt.²⁷

Clinical signs may be visible as early as 12 months of age and increase throughout life.9

Patients are usually asymptomatic till the fourth or fifth decade of life. Photophobia, redness and pain may occur due to recurrent corneal erosions with the rupture of the epithelial cysts. Most patients retain good functional vision, few may complain of blurred vision secondary to corneal irregularity and scarring.

Corneal involvement is usually bilateral. Multiple, tiny epithelial vesicles extend to the limbus and are most numerous in the interpalpebral area with clear surrounding epithelium. These appear as white spots on focal illumination and are seen as refractile cysts of retroillumnation. Cysts may coalesce to form refractile linear opacities with intervening areas of clear cornea.

Light microscopy demonstrates intraepithelial cysts filled with periodic acid Schiff-positive cellular debris. The epithelium may be thickened and disorganized. Bowman's layer and anterior stroma are unaffected.

Cremona et al³³ reported a rare case of bilateral and symmetric Meesmann corneal dystrophy concurrent with bilateral epithelial basement membrane dystrophy and bilateral but asymmetric posterior polymorphous corneal dystrophy in a patient of Armenian origin.

Most patients remain asymptomatic and may not require any treatment. Palliative treatment includes ocular lubricants, cycloplegia, and therapeutic contact lenses. In severe cases, management with epithelial debridement, phototherapeutic keratectomy, and lamellar keratoplasty has been advocated³⁴ Yeung et al³⁵ have suggested keratectomy with mitomycin C application in recurrent cases of Meesman's dystrophy.10

Alternative names: Band-shaped and whorled microcystic dystrophy of the corneal epithelium.³⁶

X-chromosomal dominant inheritance with genetic locus at Xp22.3 has been documented. The gene remains unknown.³⁷

The disease onset is in childhood with a slowly progressive course. Most patients are usually asymptomatic. Patients may report blurred vision if the pupillary zone is involved.

Direct illumination reveals localized gray opacities of varying patterns: whorl-like, radial, band-shaped, flame or feathery-shaped, or club-shaped.^38–40 Indirect illumination reveals intraepithelial multiple, densely crowded microcysts. The surrounding epithelium appears clinically normal. Similar degrees of opacities are noted in both men and women.

Light microscopy documents diffuse cytoplasmic vacuolization of all cells in the affected area.

The corneal abnormalities have been reported to recur after corneal scrapping.⁴¹

Alternative names: Subepithelial amyloidosis; Primary familial amyloidosis.⁴³

Inheritance pattern is autosomal recessive. The genetic locus has been isolated to 1p32; and tumor-associated calcium signal transducer 2 (TACSTD2, previously M1S1) gene has been implicated.^44,45

Patients present with significant decrease in vision, photophobia, irritation, redness, and lacrimation.

Onset of the disease is by the first to the second decade of life. Initial subepithelial lesions appear similar to band-shaped keratopathy. As they progress to form groups of small multiple nodules (Fig. 1.5), they acquire a mulberry configuration.11

These lesions show late staining with fluorescein, implying hyperpermeability of the corneal epithelium. Superficial vascularization may be noted. As the disease progresses, patients may develop stromal opacification (Fig. 1.6) or develop larger nodular kumquat-like lesions. This dystrophy is usually found in Japanese people, but has been reported in other regions of the world as well.⁴⁶12

Light microscopy demonstrates subepithelial and stromal amyloid deposits. Disruption of epithelial tight junctions in the superficial epithelium and the presence of amyloid in the basal epithelial layer is visible on transmission electron microscopy.

Corneal transplantation is required for visual rehabilitation.^47,48 Deep lamellar keratoplasty has been reported to successfully treat gelatinous drop-like corneal dystrophy.⁴⁹ Recurrence is common after keratoplasty, the disease may recur in nearly half the grafts. Lasram et al⁵⁰ reported that the five cases of GDLD treated by them required multiple keratoplasties at a mean interval of five years because of recurrence of the disease on the corneal graft.

This dystrophy primarily involves the Bowman's layer with secondary alterations in the epithelium and the stroma.

Alternative names: Corneal Dystrophy of Bowman layer, type 1; Geographic corneal dystrophy (Weidle); Superficial granular corneal dystrophy; Atypical granular corneal dystrophy; Granular corneal dystrophy, type 3; Anterior limiting membrane dystrophy, type 1.

This dystrophy was first reported by Reis in 1917.⁵² Detailed description was given by Buckler in 1949.⁵³

Autosomal dominant inheritance with variable expressibility has been noted. Genetic locus lies at 5q31; gene TGB1 has been implicated.^54–56

Recurrent corneal erosions manifest as pain, redness and tearing in the first decade of life. These attacks become less severe after the second decade with progressive deterio-ration of vision. The visual loss is attributable to the diffuse opaque irregular surface.

Irregular and coarse geographic-like opacities are seen in the Bowman's layer and superficial stroma (Fig. 1.7), secondary to generalized replacement of the Bowman's layer by irregular collagen fibers.⁵⁷ Opacities may be linear, geographical, honeycomb or ring like and are best seen with broad oblique illumination. Peripheral cornea is usually spared, although a diffuse haze extending up to the limbus may be seen in advanced cases. Corneal sensations are decreased and prominent corneal nerves may be noted.⁶13

The Bowman's layer is replaced by a mass of irregularly placed collagen fibers, which in advanced cases can extend to the subepithelial stroma. Epithelial cells and anterior stromal keratocytes show degenerative changes such as swelling of the endoplasmic reticulum and vacuole formation. The posterior epithelial layer shows a saw-tooth configuration.

Recurrent corneal erosions are treated in the initial stages. Phototherapeutic keratectomy has been reported to be an effective modality for the treatment of this dystrophy. Recurrence is common after this procedure. Dinh et al⁶⁰ reported that 47 percent of the eyes with Reis-Bucklers dystrophy developed clinically significant 14recurrence after an average of 21.6 months after PTK. Adjunctive application of topical Mitomycin-C 0.02 percent may be helpful in reducing the recurrence of the disease after PTK.⁶¹ Corneal electrolysis has been reported to effectively treat subepithelial opacities in RBCD.⁶² Keratoplasty may be required in severe cases.⁶³

Alternative names: Corneal dystrophy of Bowman layer, type 2 (CDB2); Honeycomb-shaped corneal dystrophy; Anterior limiting membrane dystrophy type 2; Curly fibers corneal dystrophy; Waardenburg-Jonkers corneal dystrophy.

Autosomal dominant inheritance with genetic locus at 10q24 has been demonstrated.⁶⁴ The gene remains to be isolated.

Recurrent erosions begin in childhood. Slowly progressive deterioration of vision occurs with increasing corneal opacification. The erosions are less frequent, and the onset of visual impairment is later than in RBCD.

Symmetrical subepithelial reticular honeycomb like opacities are noted, sparing the peripheral cornea.⁶⁵ Corneal sensations are normal. In advanced cases, opacities can progress to deep stromal layers and corneal periphery. It may be impossible to distinguish it clinically from Reis-Buckler corneal dystrophy.

A fibrillogranular material is deposited under the epithelium and projects into the overlying cells in a “saw-tooth” configuration. The epithelial basement membrane is thickened.

Autosomal dominant inheritance pattern is seen. The genetic locus remains unknown.

The onset of the disease occurs at 10 to 12 years, later than RBCD. Corneal erosions are less severe and less frequent than in RBCD and TBCD. Visual acuity is usually preserved.

Bowman's layer demonstrates diffuse gray-white moundlike opacities extending anteriorly into the epithelium. The intervening cornea is clear, and the peripheral cornea is spared. The corneal sensations are preserved, unlike in RBCD.^66,6715

Accumulation of abnormal material (PAS positive) in the basement membrane with disruptions in the Bowman's membrane is noted.

Corneal stromal dystrophies are a group of inherited disorders of the cornea (Table 1.3) that are caused by progressive accumulation of deposits within the stroma. These deposits are not caused by inflammation, infection, or trauma, but by genetic mutations that lead to abnormal proteins resulting in the accumulation of insoluble material within the stroma. The disorders may or may not affect vision and may or may not be symmetrical. They usually present in the second to third decade of life. The major corneal dystrophies include lattice, granular, and macular dystrophy.

Lattice dystrophy gets its name from an accumulation of amyloid deposits, or abnormal protein fibers, throughout the middle and anterior corneal stroma.

This dystrophy usually begins before the age of 20 years, and is inherited as an autosomal dominant disorder.

Early symptoms tend to be a ‘foreign body’ sensation and a slight deterioration in vision due to clear, comma-shaped overlapping dots and branching filaments in the corneal stroma, creating a lattice effect. As the dystrophy progresses, these lines become thicker and opaque that imparts a ground glass haze to the cornea and cause diminution of vision.

A network of delicate criss-cross branching filamentous opacities are seen within the cornea in two genetically distinct inherited disorders, one caused by specific mutations in the TGFBI (transforming growth factor-beta) gene with no systemic manifestations (LCD1) and the other resulting from a mutation in the gelsolin gene (LCD2). LCD 2 has systemic manifestations.

It is a rare form of human corneal dystrophy that becomes apparent in both eyes towards the end of the first decade of life, but occasionally it begins in middle life and is rarely seen in infancy. LCD1 was first described by Swiss ophthalmologist Hugo-Biber in 1890.⁶⁸ It has no systemic manifestations. The disease is bilateral, usually noted before the end of the first decade of life.

Inheritance: LCD1 is caused by mutations in TGFBI gene encoding keratoepithelin. Transforming growth factor, beta-induced, 68kDa, also known as TGFBI (initially called BIGH3, BIG-H3), is a protein which in humans is encoded by the TGFBI gene.⁶⁹ This gene encodes a protein that binds to type 1, 2 and 4 collagens. It is found in many extracellular matrix proteins modulating cell adhesion and serves as a ligand recognition sequence for several integrins.16

The protein is induced by transforming growth factor-beta and acts to inhibit cell adhesion.

Symptoms: Recurrent corneal erosions manifest as pain, redness and tearing in the first decade of life. These attacks become less severe after the second decade with progressive deterioration of vision.

Signs: Filamentous opacities appear in the cornea with intertwining delicate branching processes, particularly within the central corneal stroma, while the peripheral cornea remains relatively transparent. Corneal sensation is often diminished and the interwoven linear opaque filaments have some resemblance to nerves. Recurrent corneal erosions may precede the corneal opacities and even appear in individuals lacking recognizable stromal disease (Fig. 1.8). Both corneas are usually symmetrically involved, but sometimes one cornea remains clear or has discrete rather than the linear opacities.

Histopathology: On light microscopy, epithelial atrophy and disruption with degeneration of basal epithelial cells; focal thinning or absence of Bowman's layer that progressively increases with age; eosinophilic layer between epithelial basement membrane and Bowman's layer; and stromal deposition of amyloid substance distorts the architecture of corneal lamellae. Amyloid deposits have characteristic staining. Deposits stain positive with Congo red. Green birefringence is visible with a polarizing filter and red-green dichroism when a green filter is added with this stain. Metachromasia is noted with crystal violet and fluorescence is noted with use of thioflavin T-staining. Descemet's membrane and endothelium are normal.18

LCD2 is most common in Finland, where the disease was first discovered and most extensively studied.⁷⁴ In this disorder, both corneas contain randomly scattered short fine glassy lines, which are less numerous, more delicate and more radially oriented than those in LCD1 (Fig. 1.9). The peripheral cornea is chiefly affected and the central cornea is almost spared. The cornea has fewer amorphous deposits than LCD1.

Inheritance: Finnish type amyloidosis is a form of amyloidosis associated with gelsolin gene.⁷⁵ In persons homozygous for the relevant mutation in the GSN gene, the disorder begins earlier.

Symptoms and signs: The abnormal protein fibers in LCD1 accumulate under the outer corneal layer-the epithelium. This can cause erosion of the epithelium, manifesting as recurrent corneal erosion. These erosions alter the normal corneal curvature, resulting in temporary vision problems; and expose the nerves that line the cornea, causing severe pain. Even the involuntary act of blinking can be painful. Recurrent epithelial erosions are common particularly from the first decade of life.

Histopathology: The amyloid in LCD2 is composed of a mutated 71 amino acid long fragment of gelsolin and this protein accumulates in the corneal stroma. In LCD2, amyloid deposits are found in the cornea, scleral, choroidal and adnexal blood vessels as well as in the lacrimal gland and perineurium of ciliary nerves. The amyloid is also found in the heart, kidney, skin, nerves, wall of arteries, and other tissues.⁷⁸ Amyloid is deposited in the cornea in lattice lines, as a discontinuous band under Bowman layer and within the sclera. Streak-like deposits are seen between corneal lamellae, especially in the limbal cornea. Immunohistochemistry demonstrates deposition of mutated gelsolin in the conjunctiva, in the sclera, in the stroma of the ciliary body, along the choriocapillaris, in the perineurium of ciliary nerves, in the walls of ciliary vessels, and in the optic nerve. Extraocularly, amyloid is found in arterial walls, peripheral nerves and glomeruli. The amyloid within the cornea in LCD 2 reacts with the antigelsolin antibody.⁷⁹ Two single base substitutions in the GSN gene, located on human chromosome 9 (9q34), which encodes the actin modulating protein gelsolin are known to cause LCD2 (p. Asp187Asn, p. Asp187Tyr).

Management: Recurrent epithelial erosions are treated with preservative free tear substitutes, ointments, eye patching, bandage contact lens or amniotic membrane transplantation for persistent defects. With effective care, these erosions usually heal within three days, although occasional sensations of pain may occur for the next six to eight weeks. Phototherapeutic Keratectomy (PTK) may be tried in all patients with superficially accentuated opacities in lattice dystrophy before undergoing a more invasive procedure, such as lamellar or penetrating keratoplasty.⁸⁰

Subtle differences in the clinical appearance of the discrete corneal opacities permit two types of GCD to be recognized: GCD type I (GCD1) and GCD type II (GCD2). GCD2 tends to have fewer corneal deposits than GCD1 and the corneal deposits in GCD2 sometimes resemble a combination of GCD and LCD. GCD has been extensively studied in Denmark by Moller.⁸³

Granular corneal dystrophy shows an autosomal dominant mode of inheritance. It is caused by mutations in TGFBI gene encoding keratoepithelin.

It is a rare form of human corneal dystrophy. It was first described by German ophthalmologist Arthur Groenouw in 1890.⁸⁴

Symptoms: Light sensitivity and ‘foreign body’ sensation may be a problem. Vision is not usually severely affected under the age of 50 years.

Signs: It usually occurs before the age of 20 years. Early on, the vision is not affected but grayish dots can be seen through a microscope. Slowly the dots become larger and more apparent and become visible to the naked eye. The clinical picture is characterized by multiple, small, white discrete irregular-shaped sharply demarcated spots that resemble bread crumbs or snowflakes and become apparent beneath Bowman zone in the superficial central corneal stroma (Fig. 1.10). They initially appear within the first decade of life and may be evident by 3 years of age. The opaque spots are often arranged in lines and with time they gradually enlarge and become more numerous. In children, the external corneal surface is smooth, but in adults it may become uneven. While some patients have only a few corneal granules, others eventually have multiple opacities and subsequently, the cornea becomes markedly opaque. Visual acuity is more or less normal. By the end of the second decade, opacities are present in the central and superficial cornea but rarely in the deep stroma. Intervening tissue between the opacities and the peripheral 2 to 3 mm of the cornea usually remains crystal clear (Fig. 1.11). The opaque spots eventually extend throughout the central two-thirds of the cornea. On confocal microscopy, multiple, hyper reflective opacities are evident. Confocal microscopy with anterior segment optical coherence tomography may provide sufficient diagnostic information to diagnose corneal granular dystrophies in a clinical setting.⁸⁵

Histopathology: The light microscopic and transmission electron microscopic (TEM) appearance and staining attributes of the corneal deposits in GCD are diagnostic.21

Eosinophilic deposits in GCD consist predominantly of an extracellular deposition of mutant TGFB1 protein, which stains a brilliant red with the Masson trichrome stain. With the reticulin stain, the accumulations appear to contain tangles of argyrophilic fibers. The deposits react with histochemical methods for protein as well as with 22antibodies to TGFB1 protein. The granules stain positively with luxol fast blue and are reported to stain positively with antibodies to microfibrillar protein. By TEM, characteristic electron dense, discrete, rod-shaped or trapezoid bodies are evident.⁸⁶ Some rod-shaped structures appear homogeneous without a discernible inner structure; others, however, are composed of an orderly array of closely packed filaments (70–100 nm in width) orientated parallel to their long axis, while others appear moth-eaten with variable-shaped cavities containing fine filaments. Descemet's membrane and the corneal endothelium are unremarkable, and so is the cornea between the deposits.

Granular corneal dystrophy type II (GCD 2, Avellino corneal dystrophy, combined granular–lattice corneal dystrophy) was first described by Folberg et al in 1988.⁸⁷ The ancestry of some families with GCD2 have been traced to the Avellino district of Italy (hence the synonym Avellino corneal dystrophy).

Symptoms: Glare and photophobia are early symptoms. Visual acuity decreases as opacification progresses with age. Recurrent erosions are seen frequently. Homozygote has more severe symptoms and show rapid disease progression.

Signs: Slit lamp examination reveals well-defined granules that appear white on direct illumination. On retroillumination, these granules are composed of extremely small, translucent dots with the appearance of vacuoles, glassy splinters, or crushed bread crumbs. Opacities do not extend to the corneal limbus. In children, there may be a vortex pattern of brownish granules superficial to the Bowman's layer. In later life, granules may extend into the deeper stroma down to Descemet's membrane.

Histopathology: On light microscopy, corneal opacities extend from the basal epithelium to the deep stroma. Although, there is deposition of both typical GCD1 deposits and amyloid; individual opacities stain with either Masson trichrome or Congo red. Homozygotes demonstrate more severe findings. On TEM, anterior stromal rod-shaped, electron-dense deposits composed of extracellular masses of fine, electron-dense, highly aligned fibrils are noted. An extremely common ultrastructural finding is the presence of randomly aligned fibrils of amyloid.

Management: Many individuals with GCD never require corneal grafting because vision is usually not sufficiently impaired. Until relatively recently, a penetrating keratoplasty had been the traditional method for treating GCD, but postoperative recurrent disease can be detected in the donor tissue and even along the suture tracts within several years, particularly in GCD2.⁸⁸ After a penetrating keratoplasty, the graft usually remains free of recurrence for at least 30 months, but the opacities 23may recur in the grafts within a year, usually superficial to the donor tissue, even with lamellar grafts, or at the host-graft interface.

It is the least common but the most severe of the 3 major stromal corneal dystrophies.

This dystrophy is inherited in autosomal recessive fashion and is thought to be caused by the lack or abnormal configuration of keratan sulfate (KS). Keratan sulfate is one of the major glycosaminoglycans of the corneal stroma and plays an important role in corneal transparency. Most cases of MCD are caused by mutations in CHST6 (Carbohydrate sulfotransferase 6) gene.⁹⁴ The most frequent abnormalities are missense and nonsense single nucleotide polymorphisms in CHST6 that alter a conserved amino acid.

Eye pain from recurrent corneal erosions can occur but is much less common than in patients with lattice or granular dystrophies. Over time, the nontransparent areas progressively merge as the entire corneal stroma gradually becomes cloudy, causing severe visual impairment.

Macular corneal dystrophy involves the entire thickness of the cornea and is more superficial centrally and deeper peripherally. The first signs are usually noticed in the first decade of life, and progress afterwards, with opacities developing in the cornea.

Macular dystrophy is characterized by an intracellular storage of glycosaminoglycans within keratocytes and the corneal endothelium combined with an extracellular deposition of similar material in the corneal stroma and Descemet's membrane. The deposits stain with Alcian blue. Three immunophenotypes of MCD are recognized,⁹⁵ one has no detectable keratan sulfate (KS) in the serum or cornea (MCD type I), another has normal amounts of KS in the serum and cornea (MCD type II) and a third lacks detectable antigenic keratan sulfate in the serum, but has stainable KS in the keratocytes (MCD type IA). Because keratan sulfate in the serum appears to be predominantly derived from the normal turnover of cartilage, these studies strongly suggest that the defect in keratan sulfate synthesis in macular corneal dystrophy is not restricted to corneal cells and that this condition is one manifestation of a systemic disorder of keratan sulfate.⁹⁶

In MCD, vision can be restored by corneal grafting, but the disease may recur in the graft after many years. Conventionally, the condition affects the entire corneal stroma, Descemet's membrane and the corneal endothelium; a lamellar keratoplasty will not excise all of the pathologic tissue. However, DALK with the big-bubble technique can be considered for visual rehabilitation in cases with no significant Descemet's membrane and endothelial involvement (Fig. 1.13).⁹⁷

Congenital stromal corneal dystrophy (CSCD; Witschel dystrophy) is an extremely rare, nonprogressive form of corneal dystrophy.

Its inheritance is autosomal dominant and is linked to mutations in DCN gene encoding decorin. This protein is a component of connective tissue, binds to type I collagen fibrils, and plays a role in matrix assembly protein.

Corneal erosions, photophobia and corneal vascularization are absent. Strabismus or primary open angle glaucoma was noted in some of the affected patients.

The main features of the disease are numerous opaque flaky or feathery areas of clouding in the stroma that multiply with age and eventually preclude visibility of 26the endothelium. Thickness of the cornea stays the same, Descemet's membrane and endothelium are relatively unaffected, but the fibrills of collagen that constitute stromal lamellae are reduced in diameter.

In CSCD, the morphologic abnormalities include a peculiar arrangement of tightly packed lamellae having highly aligned collagen fibrils of an unusually small diameter.⁹⁸ The abnormally small stromal collagen fibrils and disordered lamellae suggest a disturbance in collagen fibrogenesis.

Penetrating keratoplasty or lamellar keratoplasty may be eventually required when vision becomes significantly impaired. Associated manifestations may be managed with spectacles or contact lenses for correction of refractive errors; patching and/or surgical correction for strabismus may be required in the initial stages of the disease.

It is caused by mutations in PIP5K3 gene.

The disease is nonprogressive and in most cases asymptomatic, with mild photophobia reported by some patients.

FCD affects males and females equally and has been observed throughout life and even in children as young as 2 years. Multiple nonprogressive, symmetric minute opacities, some of which resemble “flecks”, are scattered in the stroma of affected patients. Other opacities look more like snowflakes or clouds with distinct borders in the central and peripheral cornea with intervening portions of the cornea being normal. The corneal epithelium, Bowman layer, and Descemet's membrane are unremarkable. Corneal sensation is usually normal.

Corneal tissue with FCD has rarely been examined, but some keratocytes contain fibrillogranular material within intracytoplasmic vacuoles or pleomorphic electron-dense and membranous intracytoplasmic inclusions.⁹⁹ The stored material reacts positively with alcian blue, colloidal iron, Sudan black B and oil red O stains and is partially sensitive to hyaluronidase and β-galactosidase.

As it does not affect vision and is usually asymptomatic and does not require treatment. LASIK does not stimulate visually significant exacerbation of Fleck corneal dystrophy.¹⁰⁰27

The chromosomal locus of the gene responsible for the autosomal dominant PACD has not been determined.

Visual acuity is usually minimally impaired.

It is characterized clinically by irregular, amorphous sheet-like opacities in posterior corneal stroma and Descemet's membrane. The abnormalities are observed in infancy and childhood and, in contrast to the traditional corneal dystrophies, noncorneal manifestations have been reported including abnormalities of the iris (iridocorneal adhesions, corectopia, and pseudopolycoria). Transparent corneal stroma may intervene between opacities, while the Descemet's membrane and the corneal endothelium may show focal abnormalities.

Disorganized posterior stromal collagen lamellae, and an attenuated corneal endothelium have been observed.¹⁰¹ A zone of collagen fibers may interrupt the Descemet's membrane beneath the anterior banded layer.

Treatment is usually not required for this dystrophy as it does not affect vision.

Fuchs’ endothelial dystrophy is a bilateral, progressive disease involving the corneal endothelium manifesting as corneal edema and progressive deterioration of vision (Fig. 1.14). The condition was first described by Austrian Ernst Fuchs (1851–1930), after whom it is named.¹⁰²

The inheritance of FED is autosomal dominant with genetic and environmental modifiers such as increased prevalence in the elderly and in females. Cases without known inheritance may constitute the majority.

Genetic loci involved in Fuchs’ endothelial corneal dystrophy have been isolated at 13pTel-13q12.13, 15q and18q21.2-q21.32.

Fuchs’ dystrophy has been reported to be associated with cardiovascular disease, keratoconus, age-related macular degeneration, short axial length, narrow anterior chamber angles and open angle glaucoma.^107,108

Most cases begin in the fourth decade or later but the early variant starts in the first decade.¹⁰⁷ Most studies suggest that FED more commonly affects females, with as high as 4:1 female preponderance. The increased incidence in females has led to speculation about the role of hormones in the pathogenesis of FED.

Stage 1: This is the stage of cornea guttata. It occurs in the fourth or fifth decade of life when slit lamp examination by specular reflection reveals cornea guttata in the central part of the corneal endothelium. The excrescences of corneal guttata increase in number and may become confluent, resulting in a beaten metal appearance of the endothelial surface. Pigment dusting of the endothelium may be noted. The condition spreads from the center toward the periphery. The corneal thickness and visual acuity remain unaffected. The patient is asymptomatic.

Stage 2: This stage is characterized by deterioration in vision caused by incipient edema of the corneal stroma. As the stroma becomes edematous, the cornea acquires a ground glass appearance. The patients complain halos around lights, blurred vision and glare. Vision may improve as the day progresses owing to evaporation and subsequent corneal deturgescence.

Stage 3: The edema progresses to involve the epithelium at this stage. Epithelial microcysts manifest as bedewing on retroillumination. As these cysts enlarge and coalesce, they form larger intraepithelial or subepithelial bullae. When these bullae rupture, they cause pain and discomfort.29

Stage 4: This stage is characterized by corneal scarring following rupture of bullae cause diminution of vision, while ameliorating the pain. Peripheral vascularization may be noted.

Light microscopy reveals diffuse thickening and lamination of Descemet's membrane with hyaline excrescences on thickened Descemet's membrane (guttae). Degeneration, thinning, and reduction of endothelial cells is noted. Transmission Electron Microscopy demonstrates multiple layers of basement membrane like material on the posterior part of Descemet's membrane with degeneration of endothelial cells.¹⁰⁸ Stromal thickening secondary to edema causes disorganization and disruption of the lamellar pattern of collagen fibers. Confocal microscopy reveals polymegathism and pleomorphism of the endothelial cells. Subepithelial bullae formation may be seen on the anterior corneal surface. Subepithelial fibrosis may be seen subsequent to rupture of bullae. The Bowman membrane is normal, unless it has been involved in ulcer formation and keratitis, after the rupture of a bulla.

Stage 1: The guttate excrescences are seen as dark structures with sharply defined single bright spots at their center. They are smaller in size than a single endothelial cell and do not lie near the boundary wall of the cell.

Stage 2: The excrescence is almost the size of the endothelial cell. The surrounding cells have a stretched appearance.

Stage 3: The excrescence is considerably larger, and many cells are involved in one lesion. The dark structure is 5 to 10 times the size of an endothelial cell. The adjacent cells are abnormal and have missing boundaries. Many lesions are seen close to each other, but they do not coalesce. The excrescences are of 2 types, a smooth round shape or a rough excrescence.

Stage 4: The individual excrescences have coalesced. The net result is multilobed, rather than a round outline. The dark areas have many bright spots. The multilobulated structures cover considerable area. The cells between the excrescence masses tend to become abnormal. Coalesced areas contain both the smooth and the rough variety of excrescences.

Stage 5: An organized mosaic of endothelial cells is difficult to see. Many stages may be observed in the different areas of the same eye.

Patients of FCD with clear corneas (Stage 1) do not require treatment. When corneal decompensation sets in medical therapy may be initiated and can be continued till good functional vision is maintained; beyond which keratoplasty is necessary.

Corneal transplantation remains the definitive treatment for advanced cases of FCD. Penetrating keratoplasty (PK) has been performed for many years to restore vision in patients with FCD. Chung et al suggested in patients with insufficient endothelial cell density like in FCD, a large trephine size could reduce chronic endothelial cell loss.¹¹⁴

In posterior polymorphous corneal dystrophy, dystrophic endothelial cells acquire epithelial characteristics, leading to secondary abnormalities in the Descemet's membrane.¹²¹

Autosomal dominant inheritance with low penetrance and variable expression is seen.^122–126 Isolated unilateral cases have been reported, with similar phenotype but no heredity.

PPCD 1: Genetic locus isolated to 20p11.2–q11.2; gene remains unknown.

PPCD 2: Genetic locus mapped to 1p34.3–p32.3; gene collagen type VIII alpha 2, COL8A2 is involved.

PPCD 3: Genetic locus localized to 10p11.2; gene two-handed zinc-finger homeodomain transcription factor 8 is implicated.

Associations with Alport syndrome, keratoconus and keratoglobus have been reported.^127–129

Endothelial alterations often asymptomatic and are noted on slit lamp examination. Endothelial changes often unchanged over years. Rarely extensive and progressive visual impairment may occur due to stromal clouding (Fig. 1.15). Vision loss may also be secondary to iridiocorneal adhesions and glaucoma.

Disease onset is in childhood and involvement is often asymmetric. Deep corneal lesions of various shapes including nodular, vesicular (isolated, in clusters, or confluent) and blister-like lesions are observed.¹³⁰ Stromal and epithelial edema due to endothelial decompensation is rarely seen (Fig. 1.16). Peripheral iridocorneal adhesions have been reported in about 25 percent of cases, and elevated intraocular pressure in 15 percent of cases.¹³⁰ Lipid deposition or band keratopathy have been reported in advanced cases. A congenital variant may manifest with corneal edema at birth.

“Epithelialization” of endothelial cells occurs and they are seen to acquire characteristics like cytoplasmic keratin, desmosomal junctions and microvilli. Metaplastic fibroblast-like endothelial cells have also been reported.¹³¹ The altered endothelial cells are capable of migrating over the trabecular meshwork, thereby producing glaucoma. The posterior nonbanded layer of the Descemet's membrane is abnormal in cases of PPMD, thickened with deposition of abnormal collagen. Rare cases of the congenital variant may involve the anterior banded layer. Stromal and epithelial changes may occur secondary to edema due to endothelial dysfunction.

Most cases are asymptomatic and may not require any treatment. Corneal transplantation may be required in severe cases. In a series of 120 cases of PPMD, 10 percent were reported to require a corneal graft. Coexisting glaucoma and iridiocorneal adhesions may compromise graft survival in these cases.

Congenital hereditary endothelial dystrophy type 1 is characterized by bilateral, diffuse, noninflammatory corneal edema with markedly increased corneal thickness. It has not been consistently associated with any systemic disease.

Autosomal dominant inheritance with genetic locus at 20p 11.2-q11.2 (pericentromeric region) is seen. The gene involved remains to be isolated.¹³⁴

Children affected with CHED1 have clear corneas at birth. Corneal clouding with a diffuse haze begins from the first to second year of life and progresses to a ground-glass appearance over 5 to 10 years. Thickening of the cornea can be up to 2 to 3 times normal thickness. The corneal opacification extends up to the limbus and there are no interevening clear areas (Fig. 1.17). Bullae are unusual despite the extensive stromal edema, unlike in cases with FCD.¹³⁵ Co-existing congenital glaucoma and band keratopathy have also been reported.¹³⁶

Early symptoms include photophobia and tearing. Progressive corneal clouding leads to blurred vision. Visual acuity in cases of CHED1 tends to be better than in CHED2 and nystagmus is absent.¹³⁷

Diffuse thickening and lamination of Descemet's membrane and atrophic endothelial cells are seen on light microscopy. Stromal thickening is associated with disorganized arranged of the collagen fibers with disruption of the lamellar pattern.¹³⁵ Subepithelial fibrosis has been noted in some cases of CHED1.

Alternative name: Maumenee corneal dystrophy.¹³⁸

Autosomal recessive inheritance pattern is seen. Genetic locus has been localized to 20p13 (telomeric portion); the Solute carrier family 4, sodium borate transporter, member 11 gene has been implicated.^139,140

This form is more severe than CHED1 with onset at birth or in the neonatal period. Corneal clouding is dense at the time of presentation and does not tend to progress (Fig. 1.18). Nystagmus is usually present, possibly secondary to the severe visual impairment.¹³⁷ Congenital glaucoma may be co-existing but falsely elevated intraocular pressure measurement due to stromal edema may lead to misdiagnosis.

Band keratopathy and subepithelial amyloidosis has been reported in a few cases.^142–3

Diffuse thickening and lamination of Descemet's membrane with deposition of multiple layers of basement membrane—like material on the posterior part of Descemet's membrane has been noted. Endothelial cells appear atrophic and may be absent.

Corneal transplantation remains the definitive treatment for CHED. Pediatric keratoplasty, however, is a surgically challenging procedure and demands intensive postoperative monitoring and therapy. The timing of the surgery remains controversial in view of the possible challenges and complications. While some recommend early surgery, others suggest delaying the procedure as long as the patient demonstrates good fixation and normal alignment.^145,146

X-chromosomal dominant inheritance with genetic locus at Xq25 has been reported. The involved gene remains unknown.¹⁵⁰

Males may complain of progressive blurred vision while females are asymptomatic.

Congenital clouding ranging from a diffuse haze to a ground-glass, milky appearance have been reported in male patients with advanced involvement.¹⁵⁰ Moon crater–like endothelial changes have been observed in both males and females.

Light microscopy reveals irregular thickening of Descemet's membrane with small excavations and pits (moon crater endothelial changes).¹⁵⁰

Corneal transplantation may be required in advanced cases.36