PATHOLOGY

On light microscopy, the Bowman layer is disrupted or absent and replaced by a sheetlike connective tissue layer with granular deposits that stain red with Masson trichrome stain. Transmission electron microscopy shows subepithelial electron-dense, rod-shaped bodies, which are immunopositive for the TGFBI protein, keratoepithelin. Electron microscopy is needed to histologically distinguish RBCD from Thiel-Behnke corneal dystrophy (TBCD), which has curly fibers (see the next section). On confocal microscopy, distinct deposits are found in the epithelium and Bowman layer. The basal epithelial cell layer shows high reflectivity associated with small granular deposits without any shadows (Fig 7-6A), which would be typical of TBCD. The Bowman layer is replaced with highly reflective irregular material. Greater hyperreflectivity is seen at the Bowman layer in RBCD than in TBCD.

Figure 7-6 Reis-Bücklers corneal dystrophy. A, Confocal microscopy reveals highly reflective material without shadows in the basal epithelium. B, Coarse geographic opacity of the superficial cornea. C, Broad, oblique illumination shows a dense, reticular, superficial opacity. D, Slit-lamp photograph showing irregularities at the level of the Bowman layer.

(Part A reproduced with permission from Weiss JS, Møller HU, Aldave AJ, et al. IC3D classification of corneal dystrophies—edition 2. Cornea. 2015;34(2):132. Parts B–D reproduced with permission from Weiss JS, Møller HU, Lisch W, et al. The IC3D classification of the corneal dystrophies. Cornea. 2008;27(suppl 2):S1–S42.)

CLINICAL PRESENTATION

Reis-Bücklers corneal dystrophy appears in the first few years of life and mainly affects the Bowman layer. Confluent, irregular, and coarse geographic opacities with varying densities develop at the level of the Bowman layer and superficial stroma, mostly centrally (Fig 7-6B). With time, the opacities may extend to the limbus and deeper stroma (Fig 7-6C, D).

The posterior cornea appears normal. In advanced cases, stromal scarring can lead to surface irregularity. Symptoms often begin in the first or second decade of life with painful recurrent epithelial erosions. The erosions in RBCD are usually more severe and more frequent than those in TBCD, but they recur less often over time. Anterior scarring and associated surface irregularity both contribute to reduced vision.

MANAGEMENT

Initial treatment is aimed at the recurrent erosions. Superficial keratectomy, LK, phototherapeutic keratectomy (PTK), or, in rare instances, PK may be performed. Recurrence in the graft is common. Elective LASIK and PRK are contraindicated in all TGFBI dystrophies because these procedures accelerate deposit formation.

Laibson PR. Anterior corneal dystrophies. In: Mannis MJ, Holland EJ, eds. Cornea. Vol 1. 4th ed. Philadelphia: Elsevier; 2017:770–780.

PATHOLOGY

Light microscopy shows irregular thickening and thinning of the epithelial layer, which offset the ridges and furrows in the underlying stroma and the focal absences of the epithelial basement membrane. The Bowman layer is replaced with fibrocellular material in a pathognomonic wavy, “sawtoothed” pattern. On electron microscopy, curly fibers (9–15 nm) rather than rod-shaped bodies are apparent, distinguishing this dystrophy from RBCD. These curly fibers are immunopositive for the TGFBI protein, keratoepithelin, which is associated with the 5q31 locus. On confocal microscopy, distinct deposits are found in the epithelium and Bowman layer. The deposits in the basal epithelial cell layer show reflectivity, with round edges and dark shadows not seen in RBCD (Fig 7-7A). The Bowman layer is replaced with irregular reflective material that is less reflective than in RBCD. Optical coherence tomography (OCT) shows hyperreflective material at the level of the Bowman layer in the characteristic sawtoothed configuration that also distinguishes TBCD from RBCD (Fig 7-7B).

CLINICAL PRESENTATION

Onset is in the first or second decade of life as solitary flecks at the level of the Bowman layer. Over time, symmetric subepithelial reticular opacities develop in a honeycomb pattern, sparing the peripheral cornea (Fig 7-7C). The opacities may progress to the deep stromal layers and the corneal periphery. Clinically distinguishing TBCD from RBCD is difficult, but noninvasive OCT and confocal microscopy may help differentiate these entities. Recurrent erosions in TBCD, which are less frequent and less severe than those in RBCD, cause ocular discomfort and pain. Vision decreases secondary to increased corneal opacification.

Figure 7-7 A, In vivo confocal microscopy shows that hyperreflective material is less reflective in Thiel-Behnke corneal dystrophy than in Reis-Bücklers dystrophy and reveals dark shadows in the basal epithelium not seen in Reis-Bücklers dystrophy. B, Anterior segment optical coherence tomography shows typical hyperreflective deposits in the characteristic sawtoothed configuration at the level of the Bowman layer. C, Subepithelial reticular (honeycomb) opacities of Thiel-Behnke corneal dystrophy.

(Parts A and B reproduced with permission from Weiss JS, Møller HU, Aldave AJ, et al. IC3D classification of corneal dystrophies—edition 2. Cornea. 2015;34(2):134. Part C reproduced with permission from Weiss JS, Møller HU, Lisch W, et al. The IC3D classification of the corneal dystrophies. Cornea. 2008;27(suppl 2):S1–S42.)

MANAGEMENT

Management is similar to the approach used in RBCD.

Kobayashi A, Sugiyama K. In vivo laser confocal microscopy findings for Bowman’s layer dystrophies (Thiel-Behnke and Reis-Bücklers corneal dystrophies). Ophthalmology. 2007; 114(1):69–75.

Küchle M, Green WR, Völcker HE, Barraquer J. Reevaluation of corneal dystrophies of Bowman’s layer and the anterior stroma (Reis-Bücklers and Thiel-Behnke types): a light and electron microscopic study of eight corneas and a review of the literature. Cornea. 1995;14(4):333–354.

Weiss JS, Møller HU, Aldave AJ, et al. IC3D classification of corneal dystrophies—edition 2. Cornea. 2015;34(2):117–159.

PATHOLOGY

Light microscopy of classic lattice dystrophy shows arborizing amyloid deposits concentrated most heavily in the anterior stroma. Amyloid may also accumulate in the subepithelial area, giving rise to poor epithelial–stromal adhesion. Epithelial atrophy and disruption, with degeneration of basal epithelial cells, and focal thinning or absence of the Bowman layer increase progressively with age. An eosinophilic layer develops between the epithelial basement membrane and Bowman layer, with stromal deposition of the amyloid substance distorting the corneal lamellar architecture. Amyloid stains rose to orange-red with Congo red dye and metachromatically with crystal violet dye (Table 7-4). It exhibits dichroism (shift from red-orange to apple green in response to a single rotating polarizing filter) and birefringence (property of amyloid to change the axis of light polarization). (See BCSC Section 4, Ophthalmic Pathology and Intraocular Tumors, Chapter 6, for further discussion of birefringence). Electron microscopy reveals extracellular masses of fine 8–10-μm fibrils that are electron dense and randomly aligned. In vivo confocal microscopy reveals characteristic linear images that should be differentiated from those seen in infection with fungal hyphae (Fig 7-8). Corneal deposits caused by monoclonal gammopathy may resemble lattice lines.

CLINICAL PRESENTATION

Lattice dystrophy is relatively common and is characterized by refractile branching lines in the corneal stroma. The spectrum of corneal changes is broad, and the classic branching lattice lines may not be present in all cases. Subtle refractile lines, central and subepithelial ovoid white dots, and diffuse anterior stromal haze appear early in life and, in a corneal graft, these may be the first signs of recurrence. The typical branching refractile lines, so-called lattice lines, develop as the condition progresses and are best seen against a red reflex or with indirect illumination (Fig 7-9). These lines start centrally and superficially and spread centrifugally, becoming deeper. The stroma can take on a “ground-glass” appearance, but the peripheral cornea typically remains clear. Epithelial erosions recur often and may occur as early as the first decade of life. Stromal haze and epithelial surface irregularity may decrease vision, typically in the fourth decade. Familial amyloidosis with lattice corneal changes (formerly lattice corneal dystrophy type 2) is no longer considered a dystrophy (see Chapter 8). Variant lattice dystrophy type IIIA is associated with severe erosions occurring later in life. Thick, ropy lattice lines and heavy amyloid deposits are seen (Fig 7-10). The findings in lattice dystrophy type IV occur more posteriorly than those in type IIIA and therefore type IV is less likely to be associated with erosions.

Table 7-4 Histologic Differentiation of Granular, Lattice, Schnyder, and Macular Dystrophies

Figure 7-8 In vivo confocal microscopy image demonstrates filamentous lines that correspond to corneal stromal lattice lines.

(Reproduced with permission from Weiss JS, Møller HU, Aldave AJ, et al. IC3D classification of corneal dystrophies— edition 2. Cornea. 2015;34(2):136.)

Figure 7-9 Classic lattice corneal dystrophy (LCD1).

Figure 7-10 Variant lattice dystrophy type IIIA. A, Coarse linear opacities. B, Thick lattice lines are well seen on retroillumination.

(Courtesy of Robert S. Feder, MD.)

MANAGEMENT

Recurrent erosion and irregular astigmatism can be managed with therapeutic contact lenses, superficial keratectomy, or PTK. PTK may stimulate deposit formation. Severe cases of lattice dystrophy with vision loss are treated with deep anterior lamellar keratoplasty (DALK) or PK. Dystrophy recurrence in the corneal graft is common.

Aldave AJ, Vo RC, de Sousa LB, Mannis MJ. The stromal dystrophies. In: Mannis MJ, Holland EJ, eds. Cornea. Vol 1. 4th ed. Philadelphia: Elsevier; 2017:781–799.

Pradhan MA, Henderson RA, Patel D, McGhee CN, Vincent AL. Heavy chain amyloidosis in TGFBI-negative and Gelsolin-negative atypical lattice corneal dystrophy. Cornea. 2011; 30(10):1163–1166.

Stock EL, Feder RS, O’Grady RB, Sugar J, Roth SI. Lattice corneal dystrophy type IIIA: clinical and histopathologic correlations. Arch Ophthalmol. 1991;109(3):354–358.

PATHOLOGY

Microscopically, the granular material is hyaline, and it stains bright red with Masson trichrome stain. An electron-dense material made up of rod-shaped bodies immersed in an amorphous matrix is seen on electron microscopy. Histochemically, the deposits are noncollagenous protein that may derive from the corneal epithelium and/or keratocytes. Hyperreflective opacities are seen on confocal microscopy. Although the exact cause is unknown, a mutation different from that in RBCD, LCD1, and granular corneal dystrophy type 2 (GCD2; granular-lattice) has been identified in the TGFBI gene on 5q31, which is responsible for the formation of keratoepithelin.

CLINICAL PRESENTATION

Onset occurs early in life with crumblike opacities in the superficial cornea. With direct illumination, the opacities appear white; however, indirect illumination reveals small translucent dots with vacuoles and a glassy splinter or “crushed bread crumb” appearance. The lesions are separated by clear spaces early in the disease process but later become more confluent. The lesions do not extend to the limbus but can extend anteriorly through focal breaks in the Bowman layer (Fig 7-11). The dystrophy is slowly progressive, with most patients maintaining good vision and visual acuity, and only rarely dropping to 20/200 after age 50 years. Patients report glare and photophobia. Recurrent erosions occur and vision decreases as the opacities become more confluent.

Figure 7-11 Granular corneal dystrophy type 1.

(Courtesy of Robert S. Feder, MD.)

MANAGEMENT

Early in the disease process, no treatment is needed. Recurrent erosions may be treated with therapeutic contact lenses and superficial keratectomy. PTK may be effective but may accelerate deposit formation. When vision is affected, DALK or PK has a good prognosis. The disease may recur in the graft after several years, presenting as fine subepithelial opacities anteriorly and peripherally in contrast to the original presentation. Elective LASIK and PRK are contraindicated.

PATHOLOGY

Pathologically, both the hyaline deposits typical of granular dystrophy and the amyloid deposits typical of lattice dystrophy are seen. These lesions extend from the basal epithelium to the deep corneal stroma. Individual opacities stain with the Masson trichrome or Congo red stain. The deposits appear as rod-shaped bodies on electron microscopy; randomly aligned fibrils of amyloid are also seen. Findings on confocal microscopy are a combination of those seen in GCD1 and LCD.

CLINICAL PRESENTATION

Affected patients have a granular dystrophy both histologically and clinically, with shorter, whiter lattice lesions in addition to the granular lesions. Clinical findings in GCD2 differ from those in GCD1. Stellate-shaped, snowflake-like, and icicle-like opacities appear between the superficial stroma and midstroma (Fig 7-12). Lattice lines are also seen deeper than the snowflake opacities. Older patients have anterior stromal haze between deposits, which reduces vision. Pain may occur with mild corneal erosions.

Figure 7-12 Granular corneal dystrophy type 2. Stellate-shaped opacities with intervening clear spaces can be seen in direct illumination (left) and in retroillumination (right).

(Reproduced with permission from Weiss JS, Møller HU, Aldave AJ, et al. IC3D classification of corneal dystrophies—edition 2. Cornea. 2015;34(2):141.)

MANAGEMENT

Lamellar or penetrating keratoplasty may be useful, depending on the depth of the deposits. PTK may be considered as an alternative to reduce surface irregularity and increase corneal clarity. Laser in situ keratomileusis (LASIK) and PRK are contraindicated.

Aldave AJ, Vo RC, de Sousa LB, Mannis MJ. The stromal dystrophies. In: Mannis MJ, Holland EJ, eds. Cornea. Vol 1. 4th ed. Philadelphia: Elsevier; 2017:781–799.

Holland EJ, Daya SM, Stone EM, et al. Avellino corneal dystrophy. Clinical manifestations and natural history. Ophthalmology. 1992;99(10):1564–1568.

Kim TI, Hong JP, Ha BJ, Stulting RD, Kim EK. Determination of treatment strategies for granular corneal dystrophy type 2 using Fourier-domain optical coherence tomography. Br J Ophthalmol. 2010;94(3):341–345.

Weiss JS, Møller HU, Aldave AJ, et al. IC3D classification of corneal dystrophies—edition 2. Cornea. 2015;34(2):117–159.

Excerpted from BCSC 2020-2021 series: Section 10 - Glaucoma. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.