Keratopathies

• Summary
• Neurotrophic keratopathy
• Exposure keratopathy
• Metabolic keratopathy
• Wilson’s disease
• Fabry disease
• Cystinosis
• Mucopolysaccharidoses (MPS)
• Lecithin-cholesterol-acyltransferase (LCAT) deficiency
• Immunoprotein deposition
• Tyrosinaemia type 2
• Calcific Band Keratopathy
• References
• Author(s)

Summary

Keratopathy is defined as disease of the cornea. There are many different types of keratopathy; some have local causes, whereas others have systemic causes. Here, we provide a summary of some of the important types of keratopathy to learn about for the Duke-Elder exam.

Neurotrophic keratopathy

Neurotrophic keratopathy (NK) is caused by loss of trigeminal innervation to the cornea, resulting in anaesthesia (partial or complete) and ulceration of the cornea. Loss of innervation results in intracellular oedema, exfoliation, loss of goblet cells and breakdown of the epithelium, causing persistent ulceration.

Causes:

NK may be caused by any condition that damages the trigeminal nerve.

• Stroke
• Tumour
• Surgical ablation of the trigeminal ganglia (for trigeminal neuralgia)
• Peripheral neuropathy (e.g. due to diabetes)
• Infection - herpes simplex and herpes zoster keratitis

Clinical features:

• Loss of sensation to the cornea (painless)
• Persistent epithelial defect (i.e. ulceration) which can lead to stromal oedema and stromal “melting” (where the cornea becomes very soft due to enzymatic degradation and breakdown of corneal collagen)

Management:

• Discontinue any potentially toxic drugs
• Topical lubricants - for associated dry eye/corneal exposure
• Topical/systemic anticollagenase agents e.g. tetracyclines
• Cenegermin - a topical recombinant human nerve growth factor, has been reported to be of benefit in moderate/severe ulcers (but the long-term effects are not yet known)
• Protection of the ocular surface e.g. taping the eyelids (especially at night), botulinum toxin-induced ptosis, partial/complete tarsorrhaphy (joining of the upper and lower eyelids, temporarily or permanently), therapeutic silicone contact lenses

An epithelial erosion and defect in the central cornea with conjunctival hyperaemia, secondary to lateral medullary syndrome (Wallenberg syndrome). Image courtesy of Wu et al.

Exposure keratopathy

Inability to close the eyelids (lagophthalmos) causes the cornea to be exposed to the external environment for a prolonged period. This can result in drying of the ocular surface, despite normal tear production, causing a dry and eventually ulcerated eye. Exposure keratopathy can also lead to microbial keratitis, and permanent visual loss due to scarring.

Causes:

Exposure keratopathy can be caused by any condition that impairs the ability of the eye to protect the cornea: by inability to completely close the eyelid, an inadequate blink rate or blink reflex, or decreased protective lubrication of the cornea.

• Neuroparalysis e.g. facial nerve palsy
• Reduced muscle tone in Parkinson’s disease
• Mechanical e.g. lid scarring, eczematous skin tightening, post-blepharoplasty
• Proptosis
• Medication effects - especially sedatives or neuromuscular blockers

Clinical features:

• Symptoms of dry eye syndrome - burning, stinging, tearing, itching, gritty feeling, foreign body sensation, redness, light sensitivity, frequent blinding, eye pain/headache
• Punctate epithelial changes involving the inferior 1/3 of the cornea (especially with nocturnal lagophthalmos)
• Epithelial breakdown stromal melting, occasionally resulting in perforation
• Inferior fibrovascular change
• Secondary infection

Management:

Depends on whether the lagophthalmos is expected to recover, and the severity of exposure.

• Reversible exposure: artificial tears and ointment, taping the lid at night, bandage contact lenses, temporary tarsorrhaphy
• Permanent exposure: permanent tarsorrhaphy, gold weight upper lid insertion (for facial nerve palsy)

Metabolic keratopathy

Metabolic keratopathy is caused by various diseases involving characteristic deposits in the cornea. The causes of metabolic keratopathy are summarised below.

Wilson’s disease

See our ‘Genetic disorders with ocular manifestations’ notes for more detail on Wilson’s disease.

• Wilson’s disease is a rare autosomal recessive disorder characterised by copper deposition around the body. It is caused by a deficiency of caeruloplasmin, a copper-carrying protein
• The typical presentation is neuropsychiatric or hepatic symptoms in a young person
• A fine copper dusting in Descemet’s membrane causes a brownish-yellow ring, called a Kayser-Fleischer ring
• Some patients have anterior capsular ‘sunflower’ cataracts
• Treatment is with the chelating agent penicillamine, which can reverse the Kayser-Fleischer rings

Fabry disease

• Fairy disease is an X-linked lysosomal storage disorder caused by a deficiency of the enzyme alpha-galactosidase A. This results in abnormal tissue accumulation of a glycolipid
• All males and some heterozygous females with the gene are affected

Systemic features:

• Episodic burning in the extremities (acroparaesthesia) and GI tract
• Angiokeratomas (benign cutaneous capillary lesions)
• Cardiomyopathy
• Renal disease

Ocular manifestations:

• Golden vortex keratopathy (occurs in 75%), also known as whorl keratopathy or cornea verticillata - white to golden-brown corneal opacities in a vortex pattern. This is often the first feature of Fabry disease
• Wedge- or spoke-shaped posterior cataract - known as ‘Fabry cataract’
• ‘Corkscrew vessels’ (conjunctival vascular tortuosity) and aneurysm formation
• Retinal vascular tortuosity

Ocular changes seen in patients with Fabry disease: (A) vortex keratopathy, (B) increased tortuosity of conjunctival vessels, and (C) increased tortuosity of retinal vessels. Image courtesy of Pitz et al. (D) Vortex keratopathy (cornea verticillata) in a patient with Fabry disease. Image courtesy of Burlina et al.

Cystinosis

• A rare autosomal recessive lysosomal storage disorder caused by a mutation in the CTNS gene
• Characterised by widespread deposition of cystine crystals —> renal failure in childhood and other systemic problems
• Keratopathy can occur in the first year of life: cystine crystals are deposited in the cornea and conjunctiva —> photophobia epithelial erosions and visual impairment
• Management is with cysteamine

Mucopolysaccharidoses (MPS)

• A group of lysosomal storage disorders (mainly autosomal recessive) involving defective breakdown of glycosaminoglycans. Altered metabolites accumulate intracellular
• Systemic features: coarse facial features, heart disease, skeletal abnormalities, learning difficult
• Keratopathy: diffuse stromal haze and punctate corneal opacification (occurring in all MPS apart from Hunter and Sanfilippo MPS)

Lecithin-cholesterol-acyltransferase (LCAT) deficiency

• Autosomal recessive disorder of lipoprotein metabolism, caused by a mutation in the LCAT gene
• Two forms of the disease are found: Norum disease (complete disease, with systemic manifestations) and fisheye disease (partial disease, causing only corneal opacification)
• The keratopathy involves numerous small greyish dots throughout the cornea, often concentrated in the periphery

Immunoprotein deposition

Several systemic diseases (e.g. multiple myeloma, Waldenström macroglobulinaemia, some lymphoproliferative disorders and leukaemia) result in immunoprotein deposition.

When the cornea is involved, bands of punctate flake-like opacities are seen, largely in the posterior stroma.

Management:

• Treat the underlying disease
• Corneal transplantation for severe corneal involvement

Tyrosinaemia type 2

• Very rare autosomal recessive disease caused by a mutation in the TAT gene —> elevated plasma tyrosine levels
• Systemic features: painful palmar and plantar hyperkeratotic lesions, CNS involvement
• Ocular features: bilateral pseudodendritic keratitis with crystalline edges —> photophobia, watering, redness

Calcific Band Keratopathy

Calcific Band Keratopathy (also known as Band Keratopathy) is a corneal degeneration that involves the age-related deposition of calcium salts in the Bowman layer, epithelial basement membrane and anterior stroma.

Aetiology:

• Age-related
• Ocular disease: glaucoma, anterior uveitis (especially in children after juvenile idiopathic arthritis), intraocular surgery
• Metabolic: secondary to hypercalcaemia
• Hereditary
• Idiopathic

Signs:

• A band-shaped horizontal opacity that grows from peripheral cornea towards the central cornea
• The initial deposits are grey, but the colour develops into chalky-white, and with dots in the areas of corneal nerves
• Advanced lesions can become nodular and elevated

Management:

• Indications for treatment: discomfort or threat to vision
• Chelation using a microscopy (for mild cases)
• Other options include excimer laser keratectomy, lamellar keratoplasty and diamond burr

Severe band keratopathy in the left eye of a boy with juvenile idiopathic arthritis-associated anterior uveitis. Image courtesy of Tugal-Tutkun.

Another image of band keratopathy after uveitis. Image courtesy of Nascimento et al.

References

1. Salmon, John F., and Jack J. Kanski. Kanski’s Clinical Ophthalmology: A Systematic Approach. Ninth Edition, Elsevier, 2020.
2. Singh, Prabhakar, and Koushik Tripathy. ‘Keratopathy’. StatPearls, StatPearls Publishing, 2022. PubMed, http://www.ncbi.nlm.nih.gov/books/NBK562153/.
3. Sacchetti, Marta, and Alessandro Lambiase. ‘Diagnosis and Management of Neurotrophic Keratitis’. Clinical Ophthalmology (Auckland, N.Z.), vol. 8, 2014, pp. 571–79. PubMed, https://doi.org/10.2147/OPTH.S45921.
4. Jhanji, Vishal, et al. ‘Corneal Calcific Band Keratopathy’. Current Opinion in Ophthalmology, vol. 22, no. 4, July 2011, pp. 283–89. DOI.org (Crossref), https://doi.org/10.1097/ICU.0b013e3283477d36.
5. Wu, Songdi, et al. ‘Neurotrophic Keratopathy Due to Dorsolateral Medullary Infarction (Wallenberg Syndrome): Case Report and Literature Review’. BMC Neurology, vol. 14, Dec. 2014, p. 231. PubMed Central, https://doi.org/10.1186/s12883-014-0231-y.
6. Pitz, Susanne, et al. ‘Ocular Signs Correlate Well with Disease Severity and Genotype in Fabry Disease’. PLoS ONE, vol. 10, no. 3, Mar. 2015, p. e0120814. PubMed Central, https://doi.org/10.1371/journal.pone.0120814.
7. Burlina, Alessandro P., et al. ‘Early Diagnosis of Peripheral Nervous System Involvement in Fabry Disease and Treatment of Neuropathic Pain: The Report of an Expert Panel’. BMC Neurology, vol. 11, May 2011, p. 61. PubMed Central, https://doi.org/10.1186/1471-2377-11-61.
8. Tugal-Tutkun, Ilknur. ‘Pediatric Uveitis’. Journal of Ophthalmic & Vision Research, vol. 6, no. 4, Oct. 2011, pp. 259–69. PubMed Central, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306124/.
9. Nascimento, Heloisa, et al. ‘Uveitic Band Keratopathy: Child and Adult’. Journal of Ophthalmic Inflammation and Infection, vol. 5, Nov. 2015, p. 35. PubMed Central, https://doi.org/10.1186/s12348-015-0062-z.

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.