Lipid keratopathy (LK) is a degenerative disease in which lipids such as cholesterol, phospholipids, and triglycerides deposit in the corneal stroma, causing corneal opacity. It was first reported by Cogan and Kuwabara in 1958.
LK is broadly divided into two types: primary and secondary.
Primary lipid keratopathy is extremely rare. Lipids deposit spontaneously without corneal neovascularization, inflammation, or trauma. It is usually bilateral and not directly associated with elevated serum lipid levels. Excessive lipid production or metabolic disorder is suspected as the cause, but the detailed mechanism is unknown.
Secondary lipid keratopathy is the more common form. It is characterized by the presence of corneal neovascularization, occurring after past ocular trauma, infection, or inflammation 1). Leakage of lipids from new vessels is the main cause of deposition 2).
As for lipid deposition in the corneal stroma, arcus senilis associated with aging is well known. Arcus senilis is deposition of cholesterol and phospholipids in the peripheral cornea, but it does not cause visual impairment and is distinguished from lipid keratopathy.
Primary lipid keratopathy involves spontaneous lipid deposition without neovascularization and is extremely rare. It is usually bilateral and characterized by no underlying disease found. Secondary lipid keratopathy involves lipid deposition associated with corneal neovascularization, with a history of herpetic keratitis or trauma. Clinically, secondary cases account for the majority.
Progressive visual loss is the main complaint. When corneal opacity involves the pupillary area, visual impairment becomes significant. If opacity remains in the periphery, it may be asymptomatic.
Findings in Primary LK
Bilateral corneal opacity: observed in the periphery, center, or diffusely
Cholesterol crystals: may be seen in the central cornea and can significantly reduce vision
Absence of neovascularization: a characteristic feature of primary LK is the lack of corneal neovascularization
Findings in Secondary LK
Yellow-white dense infiltrates: characteristic findings adjacent to corneal neovascularization1)
Fan-shaped lipid deposits: in active LK, they present a fan-shaped pattern along the neovascularization1)
Corneal neovascularization: the neovascular pedicle serves as the source of lipid deposition2)
Anterior segment optical coherence tomography (AS-OCT) findings: lipid deposits appear as hyperreflective areas. Corneal thinning may also be present2)
Secondary LK is associated with diseases or conditions that cause corneal neovascularization.
Systemic lipid metabolism disorders may be present.
If a young person has arcus-like peripheral corneal lipid deposition, systemic lipid metabolism disorders such as familial hypercholesterolemia should be considered.
It is rare but has been reported. Several cases of bilateral lipid keratopathy after long-term use of brimonidine tartrate (BT) have been reported. It is thought to be related to allergic reactions to components in BT or reactions to preservatives. Discontinuation of BT and steroid eye drops improve neovascularization and conjunctivitis, but once deposited, corneal opacity often persists.
The diagnosis of LK is based on clinical findings.
Diagnostic criteria for primary LK: Lipid deposits in the cornea without a history of corneal neovascularization, inflammation, or trauma. It is necessary to rule out any history of trauma, family history, neovascularization, and lipid metabolism abnormalities.
Diagnosis of secondary LK: Diagnosed by the presence of characteristic yellowish-white deposits adjacent to corneal neovascularization and an underlying disease.
Useful confirmatory tests:
Differential diagnosis:
| Differential disease | Key differentiating points |
|---|---|
| Arcus senilis | Limited to the periphery, normal vision |
| Schnyder corneal dystrophy | Hereditary, crystalline opacities |
| Infectious crystalline keratopathy | Crystalline deposits associated with infection |
Differential diagnoses include drug-induced corneal deposits (gold, chlorpromazine, chloroquine, etc.) and systemic lipid storage diseases (cystinosis, multiple myeloma, etc.). For drug-related LK, after excluding other etiologies, the association with the drug used should be considered 1).
Arcus senilis is a deposition of cholesterol and phospholipids in the peripheral cornea associated with aging, observed in almost all individuals over 80 years old. The central cornea is not affected, and visual acuity is not impaired. In contrast, lipid keratopathy involves deposits extending to the central cornea, causing visual loss. Secondary LK is characterized by the presence of neovascularization. If arcus-like findings are observed in individuals under 40 years old, it is recommended to perform a systemic workup for lipid metabolism abnormalities as juvenile arcus.
The mainstays of LK treatment are removal of the cause and occlusion of corneal neovascularization.
Addressing the Cause
Treatment of underlying disease: Provide appropriate treatment for the causative disease such as herpetic keratitis.
Discontinuation of causative drugs: If involvement of brimonidine or other drugs is suspected, consider discontinuation 1). A switch to an alternative drug may be necessary.
Topical steroids: Used for anti-inflammatory purposes. Effective for inflammatory neovascularization, but the effect on absorption of lipid deposits is limited 2).
Occlusion Treatment of Neovascularization
Argon laser photocoagulation: Coagulates the feeding vessels. Effective for superficial vessels but has limitations for deep neovascularization 2).
High-frequency diathermy: Uses a small bipolar diathermy to thermally coagulate the neovascular stalk. Reported as a safe and effective method 2).
Fine-needle diathermy (FND): A method in which a suture needle is inserted into the vascular lumen and an electric current is passed through 1).
Anti-VEGF therapy: Subconjunctival or intrastromal injection of bevacizumab is effective for regression of corneal neovascularization 1).
Photodynamic therapy (PDT): Photodynamic therapy using verteporfin has been reported for occlusion of neovascularization.
Surgical treatment:
By occluding new blood vessels, some lipid deposits may be absorbed, and corneal clarity may improve 2). There is a report that lipid keratopathy occurring within radial keratotomy incisions regressed almost completely after high-frequency diathermy 2).
Treatment to occlude new blood vessels may lead to partial absorption of lipid deposits and improvement in corneal clarity. However, once deposited, lipids may not completely disappear. Early treatment intervention is important; if left untreated, it progresses slowly. In severe cases, corneal transplantation may be necessary.
The essence of secondary LK is lipid leakage and deposition from corneal neovascularization 2).
Occluding the feeder vessels of new blood vessels blocks the continuous supply of lipids and promotes lipid absorption 2). In addition, the circulation of leukocytes is reduced, suppressing the persistence of the inflammatory response 2).
The mechanism of primary LK is unknown. It is speculated to involve excessive lipid production or impaired lipid metabolism. Systemic lipid metabolism disorders (such as Tangier disease, LCAT deficiency, etc.) can lead to lipid deposition in the corneal stroma.
The mechanism of lipid keratopathy caused by brimonidine tartrate (BT) has not been fully elucidated 1). It is speculated to involve an allergic reaction to some antigen in BT or a reaction to preservatives such as benzalkonium chloride 1). It is thought that BT-associated follicular conjunctivitis and conjunctival hyperemia induce new blood vessel formation, secondarily leading to lipid deposition 1).
Treatment with high-frequency diathermy: A small bipolar high-frequency diathermy using the Klöti device has been reported to be effective in occluding corneal neovascularization and inducing regression of lipid keratopathy 2). This method was applied to lipid keratopathy that developed within the incision of radial keratotomy, and almost complete regression was achieved 11 months postoperatively 2). It can be performed under local anesthesia, and its safety and efficacy have been evaluated 2).
Substance P targeted therapy: Substance P, a member of the tachykinin family, has been shown to be involved in corneal neovascularization in animal models. Tac-1 gene knockout mice have been reported to have reduced corneal neovascularization, attracting attention as a new therapeutic target.
Mitomycin C intra-vascular chemoembolization (MICE): A method of chemically embolizing new blood vessels by administering mitomycin C into them has been reported 1). It is said that partial absorption of lipid deposits can be achieved by vascular occlusion and suppression of new blood vessel formation.
Increased recognition of drug-induced LK: Lipid keratopathy caused not only by brimonidine tartrate but also by various glaucoma eye drops has been increasingly reported 1). The importance of regular corneal evaluation in patients on long-term use is recognized.
- Moshirfar M, Ziari M, Payne CJ, et al. Bilateral Lipid Keratopathy in the Setting of Brimonidine Tartrate Use. Case Rep Ophthalmol Med. 2023;2023:8115622.
- Batis V, Häller C, Hashemi KK. Radiofrequency diathermy as a treatment of lipid keratopathy in a radial keratotomy incision. Am J Ophthalmol Case Rep. 2022;27:101629.
