Corneal dystrophy

• Summary
• Background
• Epithelial dystrophies
• Cogan (epithelial basement membrane) dystrophy
• Meesmann (epithelial) corneal dystrophy
• Bowman layer/anterior stromal dystrophies
• Reis-Bücklers corneal dystrophy
• Thiel-Behnke corneal dystrophy
• Stromal dystrophies
• Macular corneal dystrophy
• Granular corneal dystrophy type 1 (classic)
• Granular corneal dystrophy type II
• Lattice corneal dystrophy, TGFB1 type
• Meretoja syndrome
• Schnyder (crystalline) corneal dystrophy
• Other Bowman layer/anterior stromal dystrophies for interest
• Descemet membrane and endothelial dystrophies
• Fuch’s endothelial corneal dystrophy
• Summary table
• Radiology in Focus
• Optical Coherence Tomography (OCT)
• References
• Author(s)

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

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

The many corneal dystrophies share several traits:

• They are usually hereditary
• They can occur in otherwise healthy people
• Disease is bilateral
• Most progress gradually
• 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

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.

Epithelial dystrophies

Cogan (epithelial basement membrane) dystrophy

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

• Histology: thickening of the basement membrane, deposition of fibrillary protein between the basement membrane and Bowman layer
• Presentation: onset typically during teenage years; 〜1/10 patients develop corneal erosions in their 20s; the remainder remain asymptomatic
• 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.

Meesmann (epithelial) corneal dystrophy

• Rare, non-progressive abnormality of corneal epithelial metabolism
• Inheritance: AD, involving a KRT3 or KRT12 gene mutation
• Histology: intraepithelial cysts of uniform size, irregular thickening of the epithelial basement membrane
• Presentation: asymptomatic; or recurrent corneal erosions + blurring of vision (usually mild)
• Treatment: lubrication

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

• Subepithelial mutinous corneal dystrophy
• Lisch epithelial corneal dystrophy
• Gelatinous drop-like corneal dystrophy

Bowman layer/anterior stromal dystrophies

Reis-Bücklers corneal dystrophy

• An anterior variant of granular stromal dystrophy (GCD type 3), also known as ‘corneal basement dystrophy type 1 (CBD1)
• Inheritance: AD, TGFB1 gene defect
• Histology: replacement of the Bowman’s layer by connective tissue bands
• Presentation: severe recurrent corneal erosions in childhood ± visual impairment
• Signs: grey-white subepithelial opacities, most dense centrally, forming a reticular pattern with increasing age
• Treatment: excimer laser phototherapeutic keratectomy (PTK), to treat the recurrent erosions, achieves satisfactory control in some

Thiel-Behnke corneal dystrophy

• Also known as ‘honeycomb-shaped corneal dystrophy’ or ‘corneal basement dystrophy type II’ (CBD2)
• Less severe than Reis-Bücklers
• Inheritance: AD, TGFB1 defect
• Histology: Bowman’s layer “curly fibres” on electron microscopy
• Presentation: recurrent erosions in childhood
• Signs: subepithelial opacities in a ‘honeycomb-like’ arrangement (these opacities are less defined than the lesions in Reis-Bücklers dystrophy)

Stromal dystrophies

Macular corneal dystrophy

• Inheritance: autosomal recessive (AR), CHST6 gene
• Histology: aggregations of glycosaminoglycans intra- and extracellularly that stain with Alcian blue and colloidal iron
• Presentation: early visual deterioration (by the end of the first decade) + recurrent erosions are very common
• 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
• Treatment: penetrating keratoplasty. Recurrence is common

Granular corneal dystrophy type 1 (classic)

• Inheritance: AD, TGFB1 gene. Homozygous disease is more severe
• Histology: amorphous hyaline deposits staining bright red with Masson trichrome
• Presentation: glare, photophobia, blurring (as progression occurs). Recurrent erosions are rare
• Signs: discrete white central anterior stromal deposits resembling ‘sugar granules’. Gradual confluence and diffuse haze result in visual impairment
• Treatment: penetrating/deep lamellar keratoplasty is usually required by the 5th decade

Granular corneal dystrophy type II

• Also known as ‘Avellino’ or ‘combined granular-lattice dystrophy’
• Inheritance: AD, TGFB1 gene
• Histology: hyaline and amyloid
• Presentation: mild recurrent erosions, later visual impairment
• Signs: fine superficial opacities later become stellate/annular lesions. These are usually present by the end of the first decade in heterozygotes
• Refractive surgery is contraindicated, as corneal trauma accelerates progression of the dystrophy

Lattice corneal dystrophy, TGFB1 type

• This is the classic form of lattice dystrophy
• Inheritance: AD, TGFB1 gene
• Histology: amyloid with Congo red staining, which exhibits ‘apple-green’ birefringence with a polarising filter
• Presentation: recurrent erosions in childhood
• Signs: anterior stromal dots, coalescing into a fine filamentous lattice that gradually spreads across the cornea, but spares the periphery
• Treatment: penetrating or deep lamellar keratoplasty often required

Meretoja syndrome

• Also known as ‘lattice corneal dystrophy, gelsolin type’
• Can look like lattice dystrophy but is a systemic condition with associated neuropathies (of peripheral and cranial nerves), autonomic features and ‘mask-like facies’
• Inheritance: AD, GSN gene
• Histology: amyloid deposits in the corneal stroma that stain with Congo red
• Signs: stromal lattice lines starting in the periphery and spreading centrally

Schnyder (crystalline) corneal dystrophy

• Disorder of corneal lipid metabolism sometimes associated with systemic dyslipidaemia
• Inheritance: AD, UBIAD1 gene
• Histology: phospholipid and cholesterol deposits
• Presentation: visual impairment + glare
• Signs: early central haze, progressing to full-thickness involvement over time. In 〜1/2, subepithelial crystalline opacities. Prominent corneal arcus
• Treatment: excimer keratectomy or corneal transplantation

Other Bowman layer/anterior stromal dystrophies for interest

• François central cloudy dystrophy
• Congenital stromal corneal dystrophy
• Fleck corneal dystrophy
• Posterior amorphous corneal dystrophy
• Pre-Descemet corneal dystrophy

Descemet membrane and endothelial dystrophies

Fuch’s endothelial corneal dystrophy

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

Epidemiology

• More common in females (typically with a middle-age to late-age of onset)
• Associated with an increased risk of open-angle glaucoma

Presentation:

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

Signs

• Cornea guttata: irregular warts on Descemet membrane
• On specular microscopy: dark spots (due to endothelial cell loss) which progress to a “beaten metal” appearance
• 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

Management

• Conservative: topical sodium chloride 5% drops, reduction of IOP + use of a hairdryer to rehydrate the cornea
• For ruptured bullae: bandage contact lenses, cycloplegics, antibiotic ointment + lubricants
• 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

Other Descemet membrane and endothelial dystrophies:

• Posterior polymorphous corneal dystrophy
• Congenital hereditary endothelial dystrophy

Summary table

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.

Radiology in Focus

Corneal dystrophies are a group of inherited disorders characterised by the accumulation of abnormal material in the cornea, leading to visual impairment. While clinical examination is essential for diagnosis, various imaging techniques can provide valuable insights into the extent of corneal involvement, the specific type of dystrophy, and any associated complications.

Optical Coherence Tomography (OCT)

OCT provides high-resolution cross-sectional images of the cornea, allowing for detailed assessment of the corneal layers. It can help visualise the depth and extent of opacities, assess corneal thickness, and identify any associated changes in the anterior segment.

This 30-year-old Chinese female presented for evaluation of granular corneal dystrophy. She had a strong family history of cornea problems suggesting an autosomal dominant inheritance which supported the diagnosis of BIGH3 (Transforming Growth Factor Beta 1 gene, TGFβ1) related disease. Vision was 20/20 in both eyes. Her OCT is shown below:

References

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

Author(s)

Jessica Mendall

Jessica is a final year medical student studying in London. She previously studied preclinical medicine in Oxford, intercalating in Systems Neuroscience and Molecular Pathology. She is particularly interested in Ophthalmology, medical education and clinical research.

Dr Abhiyan Bhandari

Abhiyan is the Co-Founder and Radiology & Imaging Lead of Ophtnotes. He is a doctor who graduated from UCL Medical School in London. He scored in the top 10% of candidates who sat the Duke Elder examination and runs ophthalmology and Duke Elder revision sessions aimed at medical students. He also runs a YouTube channel aimed at medical students, covering topics ranging from study tips, productivity and vlogs of his journey through medical school.