The Stromal Dystrophies

Clinical Features

First described in 1890 by Groenouw and later differentiated from macular dystrophy with which it was initially linked, granular dystrophy (Groenouw type 1) is a bilateral corneal disorder characterized by the deposition of small, discrete, sharply demarcated, grayish-white opacities in the anterior central stroma ( Fig. 71.1 ). The opacities of granular dystrophy may vary in shape but are usually grouped into three basic morphologic types: drop-shaped, crumb-shaped, and ring-shaped ( Fig. 71.2 ). The overall pattern of deposition is ray-shaped or disk-shaped, although the deposits may also present in a vortex pattern originating from the inferior paracentral cornea ( Fig. 71.3 ). Initially, the stroma between the opacities remains clear. Although there is usually no associated discomfort or decrease in vision in the early stages of the disease, some patients may have mild photophobia from light scattering by the stromal deposits.

As the condition advances, individual lesions increase in size and number and may coalesce. Although they frequently extend into the deeper and more peripheral stroma, 2–3 mm of the peripheral cornea usually remains free of deposits ( Fig. 71.4 ). With more advanced disease, the intervening cornea develops a diffuse, ground-glass appearance. Although the lesions can involve Bowman layer and result in superficial irregularity, recurrent erosions are unusual.

Visual impairment is rare before the fifth decade and usually occurs secondary to the coalescence of the dystrophic deposits or opacification of the intervening stroma. Corneal sensation is variably affected. Individuals who are homozygous for the mutant allele typically demonstrate an earlier onset and more severe manifestation of the affected phenotype. Variants of granular dystrophy with atypical appearance and the association of the dystrophy with lesions of the fundus consistent with cone dystrophy have also been described.

Slit lamp examination in early stages of the disease reveals fine dots, which appear opaque on focal illumination and may appear translucent on retroillumination, and radial lines in the superficial stroma. The lesions usually occur in a random distribution and may be individual or may aggregate into different patterns. The intervening stromal opacification that develops can best be seen as a slight haze with oblique illumination or as a discrete granularity on retroillumination. The surface may stain negatively with fluorescein over the superficial lesions, or there may be areas of rapid tear film break-up.

Epidemiology and Heritability

GCD1 (MIM 121900) is an autosomal dominant disorder associated with the p. (Arg555Trp) mutation in the TGFBI gene on chromosome 5q31. Corneal stromal opacities appear in the first or second decade of life. Although a positive family history is nearly always obtained from individuals with a TGFBI dystrophy, spontaneous mutations in the TGFBI gene have been reported in association with several of the TGFBI dystrophies, including GCD1.

Histopathology

The histopathology of granular dystrophy is characteristic. Light microscopy demonstrates eosinophilic, rod-shaped, or trapezoidal hyaline deposits beneath the epithelium and in the stroma. These deposits stain bright red with Masson trichrome and stain weakly with periodic acid–Schiff (PAS) ( Fig. 71.5 ). The peripheral portions of the deposits may also stain with Congo red. Immunohistochemical staining with antibodies to the TGFBI protein ( TGFBI p) demonstrates that the stromal deposits that characterize GCD1 consist of the mutated TGFBI p. ^, Electron microscopy demonstrates rod-shaped or trapezoidal extracellular structures 100–500 μm wide, which may display a homogeneous, filamentous, or moth-eaten pattern in their inner structure ( Fig. 71.6 ). Given the presence of these characteristic rod-shaped structures in both epithelial cells and stromal keratocytes, and because epithelial findings are prominent in recurrent granular dystrophy, it has been suggested that GCD1 actually is of an epithelial genesis. Surrounding these lesions may be 8–10-nm tubular microfibrils that usually lack the typical orientation of amyloid, despite staining with Congo red. Stromal keratocytes may be normal in appearance or may be in various stages of degeneration, with dilation of the endoplasmic reticulum and Golgi apparatus as well as vacuolation of the cytoplasm.

Management

Recurrent epithelial erosions should be managed routinely with therapeutic contact lenses, topical antibiotic therapy, and artificial tears. If vision is markedly reduced, surgical management may be considered, which varies depending on the depth and extent of the stromal lesions. If the opacities are extremely superficial, superficial keratectomy may be performed. However, excimer laser phototherapeutic keratectomy (PTK) is the preferred treatment for the management of visually significant dystrophic deposits located in the anterior 100 μm of the corneal stroma. In the setting of visually significant stromal deposits that are located more than 100 μm from the corneal surface, deep anterior lamellar keratoplasty (DALK) or penetrating keratoplasty (PK) can be performed, although these procedures are uncommonly required before the fifth decade.

Granular dystrophy can recur in the grafts as early as 1 year after surgery, and the recurrence-free interval seems to be independent of the diameter and type of graft performed. Recurrent deposits typically first appear in the central, superficial region, occasionally in a vortex pattern suggestive of an epithelial origin ( Fig. 71.7 ). Recurrent opacities located in the middle and posterior portions of the donor stroma usually appear similar to more typical granular lesions. The recurrent superficial lesions may be removed by PTK with restoration of good vision.

Clinical Features

GCD2 ( Fig. 71.8 ) is a variant of granular dystrophy associated with stellate and dendritic stromal opacities. Although histopathologic examination of excised corneas demonstrates amyloid deposits characteristic of LCD, lattice deposits are typically not observed clinically. Folberg et al. reported four patients from three families who demonstrated well-circumscribed central stromal opacities similar to those seen in GCD1. On histologic examination, however, they had lattice-like deposits in addition to the granular lesions. Holland et al. described the clinical manifestations and natural history of this disorder. They reported the three clinical signs that characterize GCD2: (1) anterior stromal, discrete gray-white granular deposits; (2) mid to posterior stromal lattice lesions; and (3) anterior stromal haze. The earliest clinical evidence of this condition is discrete granular deposits. With increasing age, the granular lesions become larger and more prominent, often coalescing to form linear opacities, especially in the inferior cornea. If lattice lesions develop, they do so after the granular deposits appear and become more prominent with age. No patient was seen with lattice lesions without granular opacities. Initially, the lattice deposits are found in the mid and deep stroma and later involve the entire stroma. As it is the last clinical sign to emerge, stromal haze is typically seen only in patients with advanced granular opacities and also becomes more prominent with age.

Patients with GCD2 experience foreign body sensation, pain, and photophobia secondary to recurrent corneal erosion formation. More patients with GCD2 experience recurrent corneal erosion formation than patients with GCD1. Homozygous patients have an earlier onset, as early as 3 years of age, and demonstrate more rapid progression. Recurrent granular deposits have been noted in donor corneal tissue after PK for this condition.

Epidemiology and Heritability

GCD2 (MIM 607541 ) is an autosomal dominant disorder associated with the p.Arg124His mutation in the TGFBI gene on chromosome 5q31. ^{, ,} Its prevalence is significant in Asia, with the mutation identified in 5 of 2068 (0.24%) Chinese refractive surgery candidates, and estimated to be present in 11.5 individuals per 10,000 (0.12%) individuals in Korea, constituting the most common corneal dystrophy in Korea.

Histopathology

The stromal opacities stain with either Masson trichrome or Congo red, indicating deposition of both typical GCD1 deposits and amyloid. Transmission electron microscopy shows deposits similar to GCD1 and LCD, with opacities extending from the basal epithelium to the deep stroma. Confocal microscopy demonstrates findings that are a combination of those observed in GCD1 (hyperreflective round or trapezoidal deposits) and LCD (hyperreflective linear and branching deposits) in the corneal stroma.

Management

Initially, recurrent epithelial erosions should be managed with therapeutic contact lenses and artificial tears. In patients with reduced vision secondary to anterior stromal opacities, excimer laser PTK may provide good visual results, either performed alone or in combination with femtosecond laser-assisted lamellar keratectomy. Anterior segment ocular coherence tomography (AS-OCT) can be a useful tool to determine the desired depth of excimer laser ablation and to ensure adequate residual stromal thickness following treatment. Different studies have given conflicting results on the potential utility of topical mitomycin-C (MMC) to delay the recurrence of dystrophic deposits after PTK. In cases in which the majority of the visually significant stromal deposits are located more than 100 μm from the corneal surface, PTK should not be performed, and instead, ALK or PK should be the preferred management strategies. Elective keratorefractive surgery should be avoided in patients with GCD2, given the association with accelerated deposition of dystrophic opacities. ^, For individuals with a family history of GCD2 or with unexplained corneal opacities, molecular genetic analysis to exclude the presence of the p.Arg124His mutation in the TGFBI gene is advisable before considering performing elective keratorefractive surgery.

Clinical Features

Published descriptions of families with LCD reveal considerable variation in both the corneal manifestations and the clinical course. Early clinical features include discrete ovoid or round subepithelial opacities, anterior stromal white dots, and small refractile filamentary lines that may appear in the first to second decade of life ( Fig. 71.9 ). ^, With further progression, the stromal opacities can appear as small nodules, dots, thread-like spicules, or thicker, radially oriented branching lines. At the slit lamp, the lattice lines are typically refractile with a double contour and a clear core on retroillumination. They are radially oriented with dichotomous branching near their central terminations ( Fig. 71.10 ). The lines overlap one another, creating a latticework pattern, and can extend superficially into epithelium as well as into the deep stroma and may become opacified. While the stroma between the lines and dots is clear initially, the opacities coalesce with time, and a diffuse ground-glass haze may develop in the anterior and mid stroma ( Fig. 71.11 ). The peripheral perilimbal stroma remains largely uninvolved. The subepithelial location of many of the dystrophic deposits commonly leads to recurrent erosions and irregularity of the epithelial surface with accompanying discomfort, pain, and decreased visual acuity ( Fig. 71.12 ). Central corneal sensitivity can also be decreased, and superficial and/or stromal vascularization may develop in unusual cases. Over time, the majority of patients develop a central, panstromal haze.

Classic LCD is characterized by branching stromal lattice figures with subepithelial opacities and anterior stromal haze. ^, While the clinical features of variant LCD are diverse, those that are associated with a later onset of the affected phenotype and/or dystrophic deposition in the deeper layers of the cornea are less likely to be associated with recurrent epithelial erosions, and thus epithelial irregularity and subepithelial scarring are less common and less severe. Other variant forms of LCD have been reported in which the lattice lines are much thicker than those usually observed in classic LCD and in which dystrophic deposits may be present in only one cornea.

Epidemiology and Heritability

Lattice corneal dystrophy (LCD; MIM 122200), first described by Biber, Haab, and Dimmer in the 1890s, is an autosomal dominant disorder, the classic form of which is associated with the p.(Arg124Cys) mutation in the TGFBI gene. In contrast, the variant forms of LCD have been associated with more than 40 different TGFBI mutations in four of the 17 exons of TGFBI. ^, Thus while diagnostic assays to identify the conserved mutations associated with GCD1, GCD2, and LCD in codons 124 and 55 of TGFBI are commercially available, genetic testing in an individual with a suspected variant LCD would require Sanger sequencing of at least these four exons of TGFBI or next-generation sequencing of TGFBI . Lattice corneal deposits have also been reported in individuals in four families in which neither parent was reported to be affected, with affected siblings in two of the families, consistent with an autosomal recessive mode of inheritance. The affected individuals in these families developed visual impairment late in life, and demonstrated thick, midstromal, lattice-like lines that extend from limbus to limbus. Screening of the TGFBI gene in these families has not been reported.

Nondystrophic corneal amyloid deposits may also occur in association with primary localized deposition (polymorphic amyloid degeneration), primary systemic amyloid deposition (Meretoja syndrome), and secondary localized amyloid deposition (local ocular trauma). In distinction to LCD, polymorphic amyloid degeneration is associated with the appearance of polymorphic punctate and filamentous opacities in the deep stroma of the central cornea in patients in the fourth decade of life or older. The intervening stroma is normal, and the deposits do not impair visual function. There is no pattern of heritability in these patients, and screening of TGFBI has not revealed any pathogenic coding region mutations. Interestingly, an association between lattice dystrophy and keratoconus has been described. ^,

Histopathology

Histopathologic examination reveals an atrophic and disarrayed epithelium with degeneration of the basal epithelial cells, degenerative pannus, and focal disruption in the thickness or absence of Bowman layer that is progressive with age. An eosinophilic layer separating the epithelial basement membrane from Bowman layer is present and is composed of amyloid and collagen ( Fig. 71.13 ). Irregular, eosinophilic deposits that distort the configuration of the corneal lamellae are seen in the stroma ( Fig. 71.14 ). The central, superficial corneal stroma may have a crater-like appearance with fine, short, branching, or crisscrossing lines.

Due to the structure of the dystrophic amyloid deposits, in which the fibrils are highly aligned with a diameter of 8–10 nm ( Fig. 71.15A ), they demonstrate characteristic features using histochemical staining and polarization microscopy. The deposits stain orange-red with Congo red, and also stain with PAS, Masson trichrome, and fluorochrome thioflavin T. When viewed with a polarizing filter, the amyloid deposits demonstrate green birefringence (see Fig. 71.15B ). Red-green dichroism is also a characteristic feature when the tissue is examined with both green and polarizing filters. With crystal violet staining, metachromasia is apparent. Immunostaining of the stromal amyloid deposits using antibodies to the TGFBI protein reveals that the stromal deposits represent aggregations of mutant TGFBI protein, which is still produced even in the presence of the missense mutations associated with the classic and variant forms of LCD. Ultrastructural examination of classic LCD demonstrates elastotic degeneration (elastin) within the amyloid deposits that stains positive with Verhoeff-van Gieson and Movat pentachrome stains and shows autofluorescence. ^, Extracellular masses of fine, electron-dense fibrils with a diameter of 80–100 Å are seen as well. Keratocytes in the involved areas are decreased in number and may show cytoplasmic vacuolation and degeneration, whereas others appear metabolically active. Descemet membrane and endothelium are usually normal. ^,

In a variant form of LCD, numerous amyloid deposits are scattered throughout the corneal stroma. These deposits, which stain positively with Congo red, are predominantly located midway between the epithelium and the endothelium. Bowman layer usually has only one or two small disruptions, and in the superficial stroma, a discontinuous band of amyloid (15–25 μm wide) can be seen. ^, Descemet membrane and the endothelium are normal.