PATHOLOGY

The deposits in macular dystrophy are glycosaminoglycans (GAGs), or acid mucopolysaccharides, and they stain with colloidal iron and alcian blue (see Table 7-4). They accumulate in the endoplasmic reticulum and not in lysosomal vacuoles, as seen in systemic mucopolysaccharidoses. Electron microscopy reveals keratocytes and endothelial cells that stain positive for GAGs, as well as extracellular clumps of fibrogranular material that also stains for GAGs. On confocal microscopy, blurred accumulations of light-reflective material are seen in the anterior corneal stroma.

CLINICAL PRESENTATION

Macular dystrophy occurs less frequently than the stromal dystrophies associated with mutations in the TGFBI gene. Unlike most corneal dystrophies, it has an autosomal recessive inheritance. It involves all layers of the cornea, including the endothelium, and extends to the periphery. The corneas are clear at birth and begin to cloud between 3 and 9 years of age.

Patients with macular dystrophy initially show superficial, irregular, whitish, flecklike opacities that evolve into focal, gray-white, superficial stromal opacities with intervening haze. The opacities tend to be more superficial centrally and more posterior peripherally. Macular spots have indefinite edges (Fig 7-13). Involvement of the Descemet membrane and endothelium is indicated by the presence of guttate excrescences, but corneal edema does not occur. Dystrophic opacities in the periphery may also appear similar to keratic precipitates. Epithelial erosions rarely develop, but a severe decrease in vision typically occurs between 10 and 30 years of age. Hypoesthesia has been noted. Central corneal thinning is common and may appear similar to long-standing interstitial keratitis (IK), but the ghost vessels and thickened Descemet membrane seen in IK help differentiate the conditions.

There are 3 variants of macular dystrophy, and they are distinguished based on bio-chemical differences. In type I, the most prevalent form of macular dystrophy, antigenic keratan sulfate (AgKS) is lacking in the cornea, serum, and cartilage. In affected patients, there is normal synthesis of dermatan sulfate proteoglycan. Errors occur in the synthesis of keratan sulfate and in the activity of specific sulfotransferases involved in the sulfation of the keratan sulfate lactose aminoglycan side chain. In type IA, keratocytes show AgKS reactivity, but the extracellular material does not. There is no AgKS in the serum. In macular dystrophy type II, all of the abnormal deposits react positively with AgKS, and the serum has normal or lower levels of AgKS.

Figure 7-13 Macular dystrophy. A, Diffuse illumination shows involvement to the limbus with diffuse haze. B, Slit view. Typically, the cornea is thin with dense opacities that occur more posteriorly in the periphery.

(Courtesy of Robert S. Feder, MD.)

An enzyme-linked immunosorbent assay (ELISA) measures sulfated keratan sulfate. This test can help in the diagnosis of macular dystrophy, even in preclinical forms and carriers.

MANAGEMENT

Recurrent erosions should be treated, and photophobia may be reduced with tinted contact lenses. PTK may be used for symptomatic anterior macular dystrophy. Definitive treatment requires PK or DALK, and recurrences are uncommon.

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.

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

PATHOLOGY

This condition is thought to be a local disorder of corneal lipid metabolism. Pathologically, the opacities are accumulations of unesterified and esterified cholesterol and phospholipids. Lipids stain with oil red O and Sudan black B (see Table 7-4). In the normal process of embedding tissue in paraffin, cholesterol and other fatty substances are dissolved; therefore, fresh tissue should be submitted to the pathologist for special lipid stains. Electron microscopy shows abnormal accumulation of lipid and dissolved cholesterol in the corneal epithelium, in the Bowman layer, and throughout the stroma. Confocal microscopy reveals disruption of the basal epithelial/subepithelial nerve plexus, with highly reflective intracellular and extracellular deposits.

CLINICAL PRESENTATION

Schnyder corneal dystrophy is a rare, slowly progressive stromal dystrophy that may become apparent as early as in the first year of life. The diagnosis is usually made by the second or third decade of life, although it may be further delayed in patients who have the crystalline form of the disease. Central subepithelial crystals are seen in only 50% of patients and do not involve the epithelium. For this reason, the name Schnyder crystalline dystrophy has been replaced. Vision and corneal sensation decrease with age. Glare increases because of progressive corneal haze.

Changes are progressive and predictable by age, beginning with central corneal opacification:

• ring or disclike central corneal opacification (can affect the entire corneal stromal thickness) ± subepithelial crystals (Fig 7-14A); individuals younger than 23 years

• dense corneal arcus lipoides (Fig 7-14B); third decade of life

• midperipheral corneal opacification (affects entire corneal stromal thickness); fourth decade

• corneal sensation that decreases with age

• abnormal lipid profile

Figure 7-14 Schnyder corneal dystrophy. A, Central subepithelial crystalline deposition. B, Central panstromal corneal opacity and arcus lipoides. No crystals are present.

(Courtesy of Jayne S. Weiss, MD.)

MANAGEMENT

Schnyder corneal dystrophy disproportionately reduces photopic vision (despite maintenance of excellent scotopic vision); thus, most SCD patients older than 50 years require corneal transplant surgery. The dystrophy can recur after PK or DALK. PTK has been used to treat decreased vision from subepithelial crystals, but it does not reduce panstromal haze. A fasting lipid profile should be done to detect possible hyperlipoproteinemia or hyperlipidemia. Patients with abnormal serum lipid levels are managed with dietary changes and/or medication, but the progression of the corneal dystrophy is unaltered. Unaffected family members may also have an abnormal lipid profile.

Weiss JS. Visual morbidity in thirty-four families with Schnyder crystalline corneal dystrophy (an American Ophthalmological Society thesis). Trans Am Ophthalmol Soc. 2007;105:616–648.

PATHOLOGY

The stromal lamellae are separated from each other in a regular manner, sometimes with areas of amorphous deposition. On electron microscopy, the collagen fibril diameter is approximately half the normal size in all lamellae. Abnormal lamellar layers consisting of thin filaments arranged in an electron-lucent ground substance separate the lamellae of normal appearance. The keratocytes and endothelium are normal. The absence of the anterior banded zone of Descemet membrane has been reported. The epithelial cells are normal on confocal microscopy. Stromal evaluation is not possible because of increased reflectivity.

CLINICAL PRESENTATION

Congenital diffuse, bilateral corneal clouding with flakelike, whitish opacities is found throughout the stroma (Fig 7-15). The corneas are thickened. The course is nonprogressive or slowly progressive, with moderate to severe vision loss.

MANAGEMENT

Penetrating keratoplasty is recommended in advanced cases.

Bredrup C, Knappskog PM, Majewski J, Rødahl E, Boman H. Congenital stromal dystrophy of the cornea caused by a mutation in the decorin gene. Invest Ophthalmol Vis Sci. 2005; 46(2):420–426.

Figure 7-15 Congenital stromal corneal dystrophy: diffuse clouding with flakelike opacities throughout the stroma.

(Reproduced with permission from Weiss JS, Møller HU, Lisch W, et al. The IC3D classification of the corneal dystrophies. Cornea. 2008;27(10:Suppl 2):S22.)

PATHOLOGY

Affected keratocytes are vacuolated and contain 2 abnormal substances: excess glycosaminoglycan, which stains with alcian blue and colloidal iron; and lipids, which stain with Sudan black B and oil red O. Transmission electron microscopy shows membrane-based inclusions with delicate granular material. Confocal microscopy shows an accumulation of pathologic material in stromal cells and inclusions in the basal nerves.

CLINICAL PRESENTATION

Fleck corneal dystrophy is a nonprogressive condition that may be congenital or may present early in the first decade of life. Discrete, flat, gray-white, dandrufflike (sometimes ring-shaped) opacities appear throughout the corneal stroma to its periphery (Fig 7-16). The epithelium, Bowman layer, Descemet membrane, and endothelium are not involved. Fleck dystrophy may be unilateral or bilateral but asymmetric. Symptoms are minimal, and vision is usually not reduced. Fleck dystrophy may be associated with decreased corneal sensation, limbal dermoid, keratoconus, central cloudy dystrophy, punctate cortical lens changes, pseudoxanthoma elasticum, or atopy.

MANAGEMENT

None is required.

Purcell JJ Jr, Krachmer JH, Weingeist TA. Fleck corneal dystrophy. Arch Ophthalmol. 1977; 95(3):440–444.

Figure 7-16 Dandrufflike opacities seen in Fleck corneal dystrophy.

(Reproduced with permission from Weiss JS, Møller HU, Lisch W, et al. The IC3D classification of the corneal dystrophies. Cornea. 2008;27(10:Suppl 2):S23.)

PATHOLOGY

Focal attenuation of corneal endothelial cells and irregular stromal architecture anterior to the Descemet membrane are seen on light microscopy. On electron microscopy, there is disorganization of the posterior stromal lamellae. A fibrillar layer interrupts the Descemet membrane. On confocal microscopy, there are microfolds and a hyperreflective layer in the posterior stroma.

CLINICAL PRESENTATION

Posterior amorphous dystrophy presents in the first decade of life with a diffuse, sheetlike, gray-white opacity, usually in the posterior cornea (Fig 7-17). The condition is usually nonprogressive. The cornea is flat (<41 D) and thin (as thin as 380 μm), and there is associated hyperopia. Cornea plana, a bilateral familial disease caused by a mutation in the KERA gene, also has marked flattening of the cornea and is also stationary. In PACD, the Descemet membrane and the corneal endothelium may be indented by opacities. Focal endothelial abnormalities, a prominent Schwalbe line, fine iris processes, pupillary remnant, iridocorneal adhesions, corectopia, pseudopolycoria, and anterior stromal tags have been noted. There is no associated glaucoma. Visual acuity is usually 20/40 or better.

Figure 7-17 Posterior amorphous corneal dystrophy. A, Central, deep stromal pre-Descemet opacity. B, Slit-lamp photograph shows a diffusely thin, flat cornea with a posterior stromal opacity.

(Part A reproduced with permission from Weiss JS, Møller HU, Lisch W, et al. The IC3D classification of the corneal dystrophies. Cornea. 2008;27(Suppl 2):S24.)

MANAGEMENT

Although usually no treatment is required, PK is sometimes performed.

Dunn SP, Krachmer JH, Ching SS. New findings in posterior amorphous corneal dystrophy. Arch Ophthalmol. 1984;102(2):236–239.

Johnson AT, Folberg R, Vrabec MP, Florakis GJ, Stone EM, Krachmer JH. The pathology of posterior amorphous corneal dystrophy. Ophthalmology. 1990;97(1):104–109.

PATHOLOGY

Large keratocytes are seen in the posterior stroma, with vacuoles and intracytoplasmic inclusions containing lipidlike material. On electron microscopy, there are membrane-bound intracellular vacuoles containing electron-dense material suggestive of secondary lysosomes, and there are inclusions consistent with lipofuscin-like lipoprotein, suggesting a degenerative process.

CLINICAL PRESENTATION

Onset is usually after 30 years of age, but it has been reported in children as young as 3 years old. Focal fine, polymorphic, gray opacities that may be central, annular, or diffuse are seen in the deep stroma just anterior to the Descemet membrane (Fig 7-18). The rest of the cornea is unaffected. Vision is normal. Similar opacities have been described in pseudoxanthoma elasticum, X-linked and recessive ichthyosis, keratoconus, posterior polymorphous corneal dystrophy, and EBMD.

Figure 7-18 Pre-Descemet corneal dystrophy: punctate opacities just anterior to the Descemet membrane.

(Courtesy of Robert S. Feder, MD.)

MANAGEMENT

None is indicated.

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.