Corneal dystrophy

Summary

Corneal dystrophies are a group of progressive disorders involving abnormal, usually bilateral deposition of substances in the cornea, which can eventually opacify the cornea and obstruct vision. Underlying genetic abnormalities have been identified for most corneal dystrophies, and most are hereditary.

Background

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Over 20 corneal dystrophies exist, which affect all parts of the cornea and are categorised by anatomical location.

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The many corneal dystrophies share several traits:

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• They are usually hereditary

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• They can occur in otherwise healthy people

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• Disease is bilateral

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• Most progress gradually

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• They usually begin in one of the five layers of the cornea (epithelium, Bowman’s layer, stromal, Descemet’s membrane, endothelium), and may later spread to nearby layers

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Some corneal dystrophies cause severe visual impairment, whilst others cause mild or no visual problems, and are diagnosed incidentally during an eye examination. Common features of disease that has progressed are recurrent corneal erosions, blurring of vision and reduced corneal sensation.

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Epithelial dystrophies

Cogan (epithelial basement membrane) dystrophy

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• The commonest corneal epithelial dystrophy

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• Inheritance: usually sporadic, occurring without a family history. Rarely, it can be inherited (autosomal dominant, AD) and involve the TGFB1 gene

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Mutations in the TGFB1 gene, which encodes ‘transforming growth factor beta induced’, causes several forms of corneal dystrophies. Other than Reis-Buckler’s dystrophy, TGFB1 mutations are found in: epithelial basement membrane dystrophy; Thiel-Behnke dystrophy; granular corneal dystrophy; and lattice corneal dystrophy.

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• Histology: thickening of the basement membrane, deposition of fibrillary protein between the basement membrane and Bowman layer

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• Presentation: onset typically during teenage years; 〜1/10 patients develop corneal erosions in their 20s; the remainder remain asymptomatic

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• Lesions are best visualised by retroillumination on slit-lamp or scleral scatter. The following signs are characteristic: “fingerprint-like” subepithelial ridges; “map-like” subepithelial opacities; and “dot-like” intraepithelial cysts.

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Cogan dystrophy is also known as ‘map-dot-fingerprint dystrophy’ (MDF dystrophy) due to these characteristic signs.

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Meesmann (epithelial) corneal dystrophy

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• Rare, non-progressive abnormality of corneal epithelial metabolism

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• Inheritance: AD, involving a KRT3 or KRT12 gene mutation

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• Histology: intraepithelial cysts of uniform size, irregular thickening of the epithelial basement membrane

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• Presentation: asymptomatic; or recurrent corneal erosions + blurring of vision (usually mild)

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• Treatment: lubrication

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Other epithelial and subepithelial dystrophies for further reading (but less likely to be tested in the Duke-Elder exam) are:

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• Subepithelial mutinous corneal dystrophy

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• Lisch epithelial corneal dystrophy

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• Gelatinous drop-like corneal dystrophy

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Bowman layer/anterior stromal dystrophies

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Reis-Bücklers corneal dystrophy

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• An anterior variant of granular stromal dystrophy (GCD type 3), also known as ‘corneal basement dystrophy type 1 (CBD1)

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• Inheritance: AD, TGFB1 gene defect

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• Histology: replacement of the Bowman’s layer by connective tissue bands

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• Presentation: severe recurrent corneal erosions in childhood ± visual impairment

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• Signs: grey-white subepithelial opacities, most dense centrally, forming a reticular pattern with increasing age

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• Treatment: excimer laser phototherapeutic keratectomy (PTK), to treat the recurrent erosions, achieves satisfactory control in some.

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Thiel-Behnke corneal dystrophy

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• Also known as ‘honeycomb-shaped corneal dystrophy’ or ‘corneal basement dystrophy type II’ (CBD2)

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• Less severe than Reis-Bücklers

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• Inheritance: AD, TGFB1 defect

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• Histology: Bowman’s layer “curly fibres” on electron microscopy

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• Presentation: recurrent erosions in childhood

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• Signs: subepithelial opacities in a ‘honeycomb-like’ arrangement (these opacities are less defined than the lesions in Reis-Bücklers dystrophy)

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Stromal dystrophies

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Macular corneal dystrophy

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• Inheritance: autosomal recessive (AR), CHST6 gene

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• Histology: aggregations of glycosaminoglycans intra- and extracellularly that stain with Alcian blue and colloidal iron

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• Presentation: early visual deterioration (by the end of the first decade) + recurrent erosions are very common

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• Signs: dense, poorly delineated greyish-white spots centrally in the anterior stroma, and peripherally in the posterior stroma. Eventually, the full thickness of the stroma will be involved

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• Treatment: penetrating keratoplasty. Recurrence is common.

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Granular corneal dystrophy type 1 (classic)

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• Inheritance: AD, TGFB1 gene. Homozygous disease is more severe

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• Histology: amorphous hyaline deposits staining bright red with Masson trichrome

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• Presentation: glare, photophobia, blurring (as progression occurs). Recurrent erosions are rare

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• Signs: discrete white central anterior stromal deposits resembling ‘sugar granules’. Gradual confluence and diffuse haze result in visual impairment

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• Treatment: penetrating/deep lamellar keratoplasty is usually required by the 5th decade.

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Granular corneal dystrophy type II

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• Also known as ‘Avellino’ or ‘combined granular-lattice dystrophy’

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• Inheritance: AD, TGFB1 gene

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• Histology: hyaline and amyloid

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• Presentation: mild recurrent erosions, later visual impairment

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• Signs: fine superficial opacities later become stellate/annular lesions. These are usually present by the end of the first decade in heterozygotes

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• Refractive surgery is contraindicated, as corneal trauma accelerates progression of the dystrophy

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Lattice corneal dystrophy, TGFB1 type

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• This is the classic form of lattice dystrophy

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• Inheritance: AD, TGFB1 gene

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• Histology: amyloid with Congo red staining, which exhibits ‘apple-green’ birefringence with a polarising filter

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• Presentation: recurrent erosions in childhood

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• Signs: anterior stromal dots, coalescing into a fine filamentous lattice that gradually spreads across the cornea, but spares the periphery

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• Treatment: penetrating or deep lamellar keratoplasty often required.

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The above stromal corneal dystrophies and their associated histological findings and stains can be remembered with the following mnemonic:

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,,“Marilyn Monroe Always Gets Her Men in L.A. County”

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• ,,“Marilyn Monroe Always” = Macular dystrophy, Mucopolysaccharide, Alcian blue

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• ,,“Gets Her Men” = Granular dystrophy, Hyaline materials, Masson trichome

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• ,,“L.A. County” = Lattice dystrophy, Amyloid, Congo red

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Meretoja syndrome

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• Also known as ‘lattice corneal dystrophy, gelsolin type’

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• Can look like lattice dystrophy but is a systemic condition with associated neuropathies (of peripheral and cranial nerves), autonomic features and ‘mask-like facies’

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• Inheritance: AD, GSN gene

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• Histology: amyloid deposits in the corneal stroma that stain with Congo red

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• Signs: stromal lattice lines starting in the periphery and spreading centrally

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Schnyder (crystalline) corneal dystrophy

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• Disorder of corneal lipid metabolism, sometimes associated with systemic dyslipidaemia

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• Inheritance: AD, UBIAD1 gene

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• Histology: phospholipid and cholesterol deposits

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• Presentation: visual impairment + glare

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• Signs: early central haze, progressing to full-thickness involvement over time. In 〜1/2, subepithelial crystalline opacities. Prominent corneal arcus

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• Treatment: excimer keratectomy or corneal transplantation

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Other Bowman layer/anterior stromal dystrophies for interest:

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• François central cloudy dystrophy

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• Congenital stromal corneal dystrophy

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• Fleck corneal dystrophy

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• Posterior amorphous corneal dystrophy

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• Pre-Descemet corneal dystrophy

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Descemet membrane and endothelial dystrophies

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Fuch’s endothelial corneal dystrophy

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Fuch’s endothelial dystrophy is perhaps the most important corneal dystrophy to learn about for the Duke-Elder exam

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• The most common corneal dystrophy

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• Inheritance: AD, COL8A2 gene (in the early-onset variant), TCF4 gene (in most other cases)

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• Pathophysiology: failure of sodium-potassium pump in corneal endothelium —> fluid accumulation + bilateral accelerated endothelial cell loss. Corneal oedema can be worsened after eye surgery (e.g. cataract surgery)

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Epidemiology

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• More common in females (typically with a middle-age to late-age of onset)

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• Associated with an increased risk of open-angle glaucoma

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Presentation:

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• Blurry vision (due to corneal oedema), worse in the morning, clearing towards the end of the day

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• Blurry vision is worse in the morning because the eyes are shut overnight, and so corneal fluid evaporation is limited. The eyes are open and blinking throughout the day, enabling better clearing of the accumulated fluid

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Signs

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• Cornea guttata: irregular warts on Descemet membrane

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• On specular microscopy: dark spots (due to endothelial cell loss) which progress to a “beaten metal” appearance

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• Central stromal oedema, with epithelial oedema in more advanced cases with presence of microcysts and bullae (bullous keratopathy). Rupture of bullae exposes nerve fibres causing pain

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Management

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• Conservative: topical sodium chloride 5% drops, reduction of IOP + use of a hairdryer to rehydrate the cornea

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• For ruptured bullae: bandage contact lenses, cycloplegics, antibiotic ointment + lubricants

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• Surgical: posterior lamellar keratoplasties e.g. Descement Membrane Endothelial Keratoplasty (DMEK) and Descemet’s Stripping Automated Endothelial Keratoplasty (DSAEK), and penetrating keratoplasty, can treat severe disease

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Cataract surgery can cause persistent corneal oedema due to endothelial cell loss, particularly if the preoperative central corneal thickness is more than 630-640µm. A ‘triple procedure’ (combined cataract surgery, lens implantation + keratoplasty) can be considered in eyes with corneal oedema.

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Other Descemet membrane and endothelial dystrophies:

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• Posterior polymorphous corneal dystrophy

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• Congenital hereditary endothelial dystrophy

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Summary table

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Here we have included a summary table of the above corneal dystrophies with their associated inheritance patterns, involved genes and key signs to look out for in exam questions.

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References

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1. Salmon, John F., and Jack J. Kanski. Kanski’s Clinical Ophthalmology: A Systematic Approach. Ninth Edition, Elsevier, 2020.

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2. Klintworth, Gordon K. ‘Corneal Dystrophies’. Orphanet Journal of Rare Diseases, vol. 4, Feb. 2009, p. 7. PubMed Central, https://doi.org/10.1186/1750-1172-4-7.

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3. Szaflik, Jacek P., et al. ‘Genetics of Meesmann Corneal Dystrophy: A Novel Mutation in the Keratin 3 Gene in an Asymptomatic Family Suggests Genotype-Phenotype Correlation’. Molecular Vision, vol. 14, Sept. 2008, pp. 1713–18. PubMed Central, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2538492/.

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4. Cho, Kyong Jin, et al. ‘TGFBI Gene Mutations in a Korean Population with Corneal Dystrophy’. Molecular Vision, vol. 18, July 2012, pp. 2012–21. PubMed Central, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3413419/.

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