Alternative names Combined granular-lattice corneal dystrophy, Avellino corneal dystrophy

Inheritance Autosomal dominant

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 stroma. Individual opacities stain with either the Masson trichrome or Congo red stain. Rodshaped bodies are seen on electron microscopy, as are randomly aligned fibrils of amyloid. Findings on confocal microscopy are a combination of GCD1 and LCD.

CLINICAL FINDINGS Affected patients have a granular dystrophy both histologically and clinically, with lattice lesions in addition to the granular lesions. Clinical findings differ from those of GCD1. Stellate-shaped, snowflake-like, and icicle-like opacities appear between the superficial stroma and midstroma (Fig 10-11). 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 10-11 Granular corneal dystrophy type 2. Stellate-shaped opacities with intervening clear spaces can be seen in

retroillumination. (Reproduced with permission from Weiss JS, Møller H, Lisch W, et al. The IC3D classification of the corneal dystrophies. Cornea. 2008;27(10:Suppl 2):S18.)

MANAGEMENT LK or PK may be useful, depending on the depth of the deposits. PTK may result in increased opacification and is not recommended.

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.

Stromal Dystrophies: Non-TGFBI Dystrophies

Macular corneal dystrophy (MCD)

Alternative names Groenouw corneal dystrophy type II, Fehr spotted dystrophy

Inheritance Autosomal recessive

PATHOLOGY The deposits in macular dystrophy are glycosaminoglycans (GAGs; acid mucopolysaccharide), and they stain with colloidal iron and Alcian blue. 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 FINDINGS Macular dystrophy is the least common of the 3 classic stromal dystrophies (lattice, granular, and macular). Unlike most corneal dystrophies, it has an autosomal recessive inheritance, involves the entire corneal stroma and periphery, and may involve the corneal endothelium. The corneas are clear at birth and begin to cloud between the ages of 3 and 9.

Patients with macular dystrophy show focal, gray-white, superficial stromal opacities that progress to involve full stromal thickness and extend to the corneal periphery. Macular spots have indefinite edges, and the stroma between the opacities is diffusely cloudy (Fig 10-12). Involvement of the Descemet membrane and endothelium is indicated by the presence of cornea guttae. Epithelial erosions are possible, but symptoms usually involve a decrease in vision, between the ages of 10 and 30. Central corneal thinning and hypoesthesia have been noted. There are 3 variants of macular dystrophy, and they are distinguished based on biochemical differences.

Figure 10-12 Macular dystrophy, showing involvement to the limbus with diffuse haze.

Patients with type I macular dystrophy, the most prevalent form of macular dystrophy, lack antigenic keratan sulfate (AgKS) in their cornea, serum, and cartilage. These patients have a 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 macular dystrophy, keratocytes manifest AgKS reactivity, but the extracellular material does not. There is no AgKS in the serum.

Patients with type II macular dystrophy synthesize a normal ratio of keratan sulfate and dermatan sulfate–proteoglycans, but total synthesis is 30% below normal. Moreover, the dermatan sulfate– proteoglycan chains are 40% shorter than normal.

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 are treated like other stromal dystrophies, and photophobia may be reduced with tinted contact lenses. PTK may be used for symptomatic anterior macular dystrophy. Definitive treatment requires PK, although recurrences may be seen.

Schnyder corneal dystrophy (SCD)

Alternative names Schnyder crystalline corneal dystrophy (SCCD), Schnyder crystalline dystrophy sine crystals, hereditary crystalline stromal dystrophy of Schnyder, crystalline stromal dystrophy, central stromal crystalline corneal dystrophy, corneal crystalline dystrophy of Schnyder

Inheritance Autosomal dominant

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. Oil red O stains the phospholipids red. In the normal process of embedding tissue in paraffin, cholesterol and other fatty substances are dissolved; therefore, the pathologist must be made aware of the requirement for special stains. Electron microscopy shows abnormal accumulation of lipid and dissolved cholesterol in the 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 FINDINGS Schnyder corneal dystrophy is a rare, slowly progressive stromal dystrophy that may become apparent as early as the first year of life. However, diagnosis is usually made by the second or third decade, although it may be further delayed in patients who have the acrystalline form of the disease. Central subepithelial crystals are seen in only 50% of patients and do not involve the epithelium. Vision and corneal sensation decrease with age. Glare complaints increase due to progressive corneal haze.

Affected patients show predictable progressive changes on the basis of age, beginning with central corneal opacification (Fig 10-13):

1.central corneal opacification (can affect the entire corneal stromal thickness) ± subepithelial crystals (in individuals younger than 23 years)

2.dense corneal arcus lipoides (third decade)

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

4.decreased corneal sensation

Figure 10-13 Schnyder corneal dystrophy with (A) central subepithelial crystalline deposition and (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), leading to corneal transplantation in most patients older than 50 years. The dystrophy can recur after PK. PTK has been used to treat decreased vision from subepithelial crystals, but it does not treat panstromal haze. Abnormal serum lipids are managed by diet and/or medication but do not affect the progression of the corneal dystrophy. A fasting lipid profile should be done for possible hyperlipoproteinemia (type II-a, III, or IV) or hyperlipidemia. Most patients have elevated serum cholesterol levels that often respond to dietary therapy or medication. 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.

Congenital stromal corneal dystrophy (CSCD)

Alternative names Congenital hereditary stromal dystrophy, congenital stromal dystrophy of the cornea

Inheritance Autosomal dominant

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 about 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 due to increased reflectivity.

CLINICAL FINDINGS Congenital diffuse, bilateral corneal clouding with flakelike, whitish opacities is found throughout the stroma (Fig 10-14). The corneas are thickened. The course is nonprogressive or slowly progressive, with moderate to severe vision loss.

Inheritance Autosomal dominant

PATHOLOGY Focal attenuation of 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 FINDINGS PACD presents in the first decade of life with a diffuse, gray-white, sheetlike opacity of the cornea, usually posteriorly (Fig 10-16). The condition is slowly progressive or nonprogressive. The cornea is flat (<41 D) and thin (as low as 380 μm) and there is associated hyperopia. The Descemet membrane and endothelium may be indented by opacities. Focal endothelial abnormalities have been observed, as have a prominent Schwalbe line, fine iris processes, pupillary remnant, iridocorneal adhesions, corectopia, pseudopolycoria, and anterior stromal tags. There is no associated glaucoma. Vision is only mildly affected.

Figure 10-16 Posterior amorphous corneal dystrophy: central deep stromal, pre-Descemet opacity. (Reproduced with

permission from Weiss JS, Møller H, Lisch W, et al. The IC3D classification of the corneal dystrophies. Cornea. 2008;27(10:Suppl 2):S24.)

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

Johnson AT, Folberg R, Vrabec MP, Florakis GJ, Stone EM, Krachmer JH. The pathology of posterior amorphous corneal dystrophy. Ophthalmology. 1990;97(9):104–109.

Pre-Descemet corneal dystrophy (PDCD)

Alternative names None

Inheritance No definite pattern of inheritance, although it has been described in families over 2–4 generations

PATHOLOGY Large keratocytes are seen in the posterior stroma, with vacuoles and intracytoplasmic inclusions containing lipid-like 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 FINDINGS Focal, fine, gray opacities are seen in the deep stroma anterior to the Descemet membrane (Fig 10-17). Onset is usually after age 30, but it has been reported in children as young as 3 years. The rest of the cornea is normal. Vision is normal. Similar opacities have been described in pseudoxanthoma elasticum, X-linked and recessive ichthyosis, keratoconus, PPCD, and EBMD.

Figure 10-17 Pre-Descemet corneal dystrophy: punctate opacities anterior to the Descemet membrane demonstrated with

indirect illumination (A) and slit-lamp beam (B). (Reproduced with permission from Weiss JS, Møller H, Lisch W, et al. The IC3D classification of the corneal dystrophies. Cornea. 2008;27(10:Suppl 2):S26.)