REVIEW

Lipid Keratopathy: A Review of Pathophysiology,Differential Diagnosis, and Management

MacGregor N. Hall . Majid Moshirfar . Armaan Amin-Javaheri .

Dean P. Ouano . Yasmyne Ronquillo . Phillip C. Hoopes

Received: August 19, 2020 /Accepted: September 28, 2020 / Published online: October 15, 2020� The Author(s) 2020

ABSTRACT

Lipid keratopathy is a disease in which fatdeposits accumulate in the cornea, leading toopacification and decrease of visual acuity. Thiscondition can be idiopathic without signs ofprevious corneal disease or secondary to ocularor systemic diseases. Lipid keratopathy is usu-ally associated with abnormal vascularization ofthe cornea, and the lipid classically depositsadjacent to these vessels. Treatment of thiscondition usually aims to eliminate or prevent

abnormal vessel formation, and several modal-ities have been described. In this review wesummarize the etiology, pathophysiology, andclinical presentation of lipid keratopathy anddescribe current and emerging treatmentregimens.

Keywords: Angiogenesis; Corneal neovascu-larization; Lipid deposition; Lipid keratopathy;VEGF

Key Summary Points

Lipid keratopathy (LK) is a diseasecharacterized by lipid deposition in thecornea, most commonly secondary tocorneal neovascularization.

Corneal neovascularization is the growthof new blood vessels and lymphaticvessels into previously avascular areas ofthe cornea and can result from oculartrauma, inflammation, or infection.

Lipid keratopathy can be distinguishedfrom other causes of ocular lipiddeposition by the presence ofneovascularization and characteristicpathologic findings.

M. N. HallMcGovern Medical School, The University of TexasHealth Science Center at Houston, Houston, TX,USA

M. Moshirfar (&) � Y. Ronquillo � P. C. HoopesHoopes Vision Research Center, Hoopes Vision,Draper, UT, USAe-mail: cornea2020@me.com

M. MoshirfarDepartment of Ophthalmology and Visual Sciences,John A. Moran Eye Center, University of UtahSchool of Medicine, Salt Lake City, UT, USA

M. MoshirfarUtah Lions Eye Bank, Murray, UT, USA

A. Amin-JavaheriUniversity of South Carolina School of Medicine,Columbia, SC, USA

D. P. OuanoCoastal Eye Clinic, New Bern, NC, USA

Ophthalmol Ther (2020) 9:833–852

https://doi.org/10.1007/s40123-020-00309-y

http://orcid.org/0000-0003-1024-6250http://crossmark.crossref.org/dialog/?doi=10.1007/s40123-020-00309-y&domain=pdfhttps://doi.org/10.1007/s40123-020-00309-y

Secondary LK typically presentsunilaterally with cream-coloredopacification adjacent toneovascularization, while idiopathic LK isusually bilateral.

Various pharmacologic and surgicalmethods have been described in thetreatment of LK; however, high costs, riskof recurrence, and treatmentcomplications limit the clinical utility ofmany of the current regimens.

DIGITAL FEATURES

This article is published with digital features,including a summary slide, to facilitate under-standing of the article. To view digital featuresfor this article go to https://doi.org/10.6084/m9.figshare.12988532.

INTRODUCTION

Lipid keratopathy (LK) is characterized by theopacification of the cornea due to lipid deposi-tion. LK may be idiopathic, with no evidence ofsystemic or local disease, or secondary due toocular infection, inflammation, or trauma. Mostcommonly, LK occurs in regions of cornealneovascularization (NV) and scarring [1]. Theselesions can be progressive and threaten thevisual axis. Treatment modalities for LK varywidely in terms of approach and effectivity. Thepurpose of this paper is to review the literatureand analyze the etiology, pathophysiology,clinical manifestations, differential diagnosis,and treatment of LK.

METHODS

A literature search using various databases,including PubMed, Scopus, and ScienceDirect,was conducted for studies published in English.No restrictions were set for the date of publica-tions, which ranged from 1876 to 2019. Keysearch terms included ‘‘lipid keratopathy,’’ lipid

degeneration,’’ ‘‘lipid deposition,’’ ‘‘fat deposi-tion,’’ ‘‘corneal neovascularization,’’ ‘‘angiogen-esis,’’ ‘‘lymphangiogenesis,’’ and a combinationof these terms. Inclusion criteria for publica-tions included those that discussed the etiolo-gies, pathogenesis, clinical manifestations,differential diagnosis, and management of cor-neal NV or LK. References were also acquiredfrom citations in publications found in theoriginal search. Non-English articles were usedif abstract information was available in Englishor a translation was possible.

This article is based on previously conductedstudies and does not contain any studies withhuman participants or animals performed byany of the authors.

HISTORICAL OVERVIEW

Findings consistent with LK may have beenreported as early as 1876 by Baumgarten [2],who described ‘‘fatty degeneration’’ in a patientwith sclerosing keratitis. Cogan and Kuwabara[3] were the first to coin the term lipid ker-atopathy in 1958, which they described as alipid exudation adjacent to vascularization dueto inflammation or trauma. In their review,they note several alternative terms that havebeen used to describe what is now known aslipid keratopathy, including fatty dystrophy,adiposis of the eye, dystrophia adiposa corneae,lipidosis corneae, xanthomatosis, secondarysteatosis, and lipid interstitial keratitis. In theyears following the 1958 article, there havebeen many studies on the biochemical,histopathologic, and pathophysiologic aspectsof the disease.

ETIOLOGY

Idiopathic LK is characterized by neutral fat,glycoproteins, cholesterol, and lipid deposits inthe stromal layer of the cornea and the adjacentlimbus [1, 4, 5]. Idiopathic LK may occur with-out prior vascularization and inflammation,and when serum levels of chylomicrons, very-low-density lipoprotein (VLDL) low-densitylipoprotein (LDL), and high-density lipoprotein

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https://doi.org/10.6084/m9.figshare.12988532https://doi.org/10.6084/m9.figshare.12988532

(HDL) are in the expected ranges. Idiopathic LKusually occurs bilaterally. Lipid deposition inidiopathic LK may be due to excess lipid pro-duction or a failure to metabolize fat [6], possi-bly due to a similar mechanism that causesarcus senilis [7]. Some researchers havehypothesized that these lipids originate fromthe aqueous humor [8], while others suggestthat lipid can be deposited due to incompetentlimbal vessels [9]. Another proposed mecha-nism involves intrinsic metabolic derangementswithin keratocytes, leading to lipid-rich cellsand inflammatory foci with the presence ofcholesterol clefts [10]. Undetected low-gradeinflammation and subsequent NV may alsocause idiopathic LK [1]. The exact mechanism isunclear, however, and understanding of thecondition is complicated by the fact that a pri-mary disorder leading to leakage of lipid couldthen cause secondary inflammation and cornealNV. Table 1 outlines key distinguishing featuresbetween idiopathic and secondary LK.

Secondary LK almost always occurs due tothe deposition of lipids into a neovascularizedarea of the cornea; consequently virtually anycause of corneal NV can lead to LK. These eti-ologies can be inflammatory, traumatic, iatro-genic, or degenerative. Trachoma, an infectioncaused by the bacteria Chlamydia trachomatis, isthe world’s leading cause of blindness, andrecurrent episodes can lead to eyelash-inducedcorneal abrasions, ulcerations, and NV [11].Onchocerciasis, also called river blindness, is aparasitic infection caused by Onchocerca volvulusand is another common cause of blindnessworldwide. Microfilariae produced by adultworms travel to the cornea and cause inflam-mation and NV [12]. Herpetic corneal infec-tions, which can arise from either herpessimplex virus 1 (HSV-1) or herpes zoster, are alsotightly linked to NV and LK [13]. Recurrentinfection of HSV-1 causes herpes simplex ker-atitis, which is characterized by inflammationof the cornea, leading to NV, ulceration, scar-ring, and lipid deposition [14]. Reactivation ofthe varicella-zoster virus (shingles) can causeherpes zoster ophthalmicus, which can alsocause secondary LK. LK has also been reportedas a result of other forms of bacterial keratitis[15] but, in theory, could occur from any

infection of the cornea, including fungal orparasitic infections.

Ocular trauma, when severe, can also inducecorneal NV. Chemical burns, particularly alkaliburns and thermal burns, are known to causerapid and severe inflammation that promotesNV [16]. Contact lens use has been associatedwith corneal NV in up to 11–23% of individuals[17], which can also lead to LK [18]. This may bedue to hypoxia, mechanical injury, or limbalstem cell deficiency [19, 20]. Corneal

Table 1 Features of idiopathic and secondary lipidkeratopathy

Features Idiopathic LK Secondary LK

Mechanism Unknown Usually secondary

to corneal

neovascularization

Previous

ocular/

systemic

disease

Absent Present

Serum lipids Normal Sometimes

abnormal

Laterality Usually bilateral Usually unilateral

Morphology Often ring-shaped Often fan-like or

disc-shaped

surrounding

vessels

Confocal

microscopy

findings

Hyper-reflective

needle-like

crystals, no

evidence of

inflammation

Hyper-reflective

needle-like

crystals,

amorphous or

granular deposits

Management

approaches

Observation,

topical steroids,

often requires

keratoplasty

Topical steroids,

PDT, FND,

argon laser, anti-

VEGF,

keratoplasty

FND Fine needle diathermy, LK lipid keratopathy, PDTphotodynamic therapy, VEGF vascular endothelial growthfactor

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transplantation, the most common solid tissuetransplantation procedure, can cause cornealNV and subsequent LK via suture-inducedinflammation and alloimmune responses[21, 22]. Corneal NV can reduce graft survivalafter corneal transplant [23]. Intracorneal ringsegments were previously used for low to mod-erate myopia correction and now are used tomanage keratoconus, pellucid marginal degen-eration, and iatrogenic corneal ectasia [24].Implantation of these devices may cause deepstromal NV and subsequent lipid depositioninto the potential spaces between lamellarchannels and the surface of the implant[25, 26]. Indeed, any ocular foreign body couldlead to NV and lipid deposition.

Systemic dyslipoproteinemias, includingfamilial lecithin-cholesterol acyltransferase(LCAT) deficiency (FLD), Fish-eye disease (FED),and Tangier disease (TD) may also lead to lipiddeposition. All three conditions manifest withlow plasma HDL levels and corneal clouding.LCAT plays a key role in removing cholesterolfrom peripheral cells and transporting it to theliver in the form of cholesterol esters on HDL.FLD is a rare disease characterized by completeLCAT deficiency and the accumulation ofunesterified cholesterol and lecithin in theplasma. Ocular manifestations include bilateralcorneal opacities comprised of granular dotsthat are limited to the corneal stroma [27]. It isthought that the dots are composed of choles-terol or other lipid materials due to the systemicaccumulation of unesterified cholesterol [28].The corneal opacities classically appear only inhomozygotes and present before other systemicmanifestations, which include hypertension,hypertriglyceridemia, hemolytic normochromicnormocytic anemia, and proteinuria whichoften progresses to end-stage renal disease [29].Kidney biopsy will reveal lipoprotein-X deposi-tion in the glomeruli [29]. FED is another raredisease characterized by partial LCAT defi-ciency. Unlike in true LCAT deficiency, cornealopacities are the only clinical manifestation ofFED. They appear as dot-like opacities in alllayers of the cornea except the epithelium.Histopathologic studies show vacuoles fillingBowman’s layer and the corneal stromabetween collagen fibrils; these vacuoles are

believed to contain lipid [27]. Diagnosis of FLDand FED is supported by clinical findings andlaboratory tests and confirmed by gene analysis;therefore complete blood count, urinalysis, andlipid panels may be indicated in these patients ifthese diseases are suspected [29]. Lastly, TD is adisorder characterized by a deficiency of HDL inthe plasma leading to cholesterol ester accu-mulation throughout the body. This conditionpresents with corneal clouding, neuropathy,hepatosplenomegaly, large yellow-orange ton-sils, and cardiovascular disease. Corneal opaci-ties in this condition appear as a dot-like hazeon slit-lamp examination and is limited to thestroma on confocal microscopy [30, 31]. Bio-chemical and histopathologic analyses haveproven that the corneal opacities are due toesterified cholesterol and lipid deposition [32].Diagnosis can be confirmed by moleculargenetic testing [33].

Terrien marginal degeneration (TMD) is anuncommon condition that leads to slowly pro-gressive, non-inflammatory thinning of theperipheral cornea. This condition is character-ized by furrowing of the cornea that typicallybegins superiorly, followed by superficial vas-cularization and lipid deposition at the leadingedge of the pannus [34]. TMD will initiallyappear as white-yellow punctate opacificationsthat may resemble arcus senilis, but over timewill develop into a solid line at the anterioredge. LK has also been described in a patientusing nasal continuous positive airway pressurefor obstructive sleep apnea where air leakage,lagophthalmos and diminished Bell’s phe-nomenon led to chronic irritation and lipiddeposition [35]. Other etiologies of LK reportedin the literature include anterior scleritis [36],corneal hydrops [8], mustard gas exposure[37, 38] and interstitial keratitis [39]. A sum-mary of the proposed etiologies of LK is given inTable 2.

PATHOPHYSIOLOGYAND PATHOLOGY

Angiogenesis is defined as the formation of newvessels from pre-existing ones and plays animportant role in most blinding ocular

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conditions [40]. This process is regulated bygrowth factors, cytokines, and antiangiogenicmolecules. The optical quality of the cornearelies on its transparency and avascularity, twoproperties that are often tightly associated. Assuch, the cornea has developed several mecha-nisms to maintain avascularity by balancingthese pro-angiogenic factors with antiangio-genic factors. This dynamic process is termed‘‘angiogenic privilege’’ [41]. This balance can bedisturbed by tissue injury from infection,inflammation, or trauma. When this occurs,angiogenic factors become upregulated, whileantiangiogenic factors are downregulated,

leading to invasion of new blood vessels (he-mangiogenesis) and lymphatic vessels (lym-phangiogenesis) into previously avascular areasof the cornea. This is termed corneal NV.

Among the most important factors leadingto corneal NV are members of the vascularendothelial growth factor (VEGF) family,including VEGF-A, VEGF-B, VEGF-C, VEGF-D,and placental growth factor. VEGF-A is consid-ered to be the main factor for normal andpathologic blood vessel growth, while VEGF-Cand VEGF-D are mostly implicated in lym-phangiogenesis [14]. VEGF-A, when bound tothe receptor tyrosine kinase VEGF receptor 2(VEGFR-2), promotes the migration and prolif-eration of vascular endothelial cells and alsoincreases vascular permeability [14, 42]. Basicfibroblast growth factor (bFGF) includes FGF-1,which is expressed in the normal cornealepithelium, and FGF-2, which is upregulatedafter injury [43]. bFGF also leads to the migra-tion of endothelial cells as well as matrixremodeling and VEGF overexpression [44].Together, the bFGF and VEGF signaling path-ways may interact to potentiate angiogenesisand recruit monocytes, macrophages, and neu-trophils to sites of inflammation [45]. Otherimportant pro-angiogenic factors include pla-telet-derived growth factor [46], angiopoietins[47], and various inflammatory mediators[14, 48]. The proposed mechanism of LK isillustrated in Fig. 1.

The cornea, however, possesses multiplemechanisms to maintain avascularity. Some ofthese antiangiogenic factors come from thecorneal epithelium. One such example is the‘‘decoy’’ VEGF receptors that bind these mole-cules, a process which serves a critical role inpreventing angiogenesis [49, 50]. These recep-tors include soluble VEGFR-1, which preventshemangiogenesis by binding VEGF-A [49], andnon-vascular VEGFR-3, which prevents lym-phangiogenesis by binding VEGF-C and VEGF-D [51]. Membrane-type 1 metalloproteinase(MT1-MMP) appears to be another importantantiangiogenic factor expressed in the cornealbasal epithelium. MT1-MMP produces otherantiangiogenic factors, such as angiostatin andneostatin, via proteolytic activity [43]. Thelimbal stem cells also play an important role in

Table 2 Proposed etiologies of lipid keratopathy

Category Cause

Idiopathic Unknown

Infectious Bacterial

Viral

Parasitic

Fungal

Inflammatory Anterior scleritis

Interstitial keratitis

Traumatic Chemical burns

Thermal burns

Mustard gas exposure

Ocular foreign bodies

Iatrogenic Contact lens use

Corneal transplantation

Intracorneal ring segments

CPAP machine

Genetic LCAT deficiency

Fish-eye disease

Tangier disease

Ectatic disorders Corneal hydrops

Terrien marginal degeneration

CPAP Continuous positive airway pressure, LCATlecithin–cholesterol acyltransferase

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corneal epithelium renewal, and the limbusitself may prevent corneal NV, as evidenced bythe increase in corneal NV with limbal stem celldeficiency and improvement with limbal stemcell transplantation [52]. The mechanism iscontroversial, but the limbus may act as a

physical and physiologic barrier to angiogenesis[53].

Several steps must occur for blood vessels todevelop in the cornea. This likely occurs due toa process called sprouting [54]. Upon initialinjury due to infection, inflammation, ortrauma, damaged corneal epithelial cells release

Fig. 1 Proposed mechanism of lipid keratopathy. FGF fibroblast growth factor, IFN interferon, IL Interleukin, NK naturalkiller, PDGF platelet-derived growth factor, TNF tumor necrosis factor, VEGF vascular endothelial growth factor

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growth factors and interleukin (IL)-a. Thesemolecules recruit innate immune cells, includ-ing monocytes, macrophages, neutrophils, andnatural killer (NK) cells, which in turn releasecytokines such as IL-1, IL-6, and tumor necrosisfactor, which activate other immune cells.Macrophages act as another source of pro-an-giogenic factors such as VEGF and can beenhanced by NK cells secreting interferon-gamma [45, 55]. When bound to their receptorson nearby vessels, these pro-angiogenic growthfactors stimulate vascular endothelial cell pro-liferation and ‘‘activation’’ [43]. This stimula-tion leads to the alteration of endothelial celladhesion molecules and the expression of pro-teolytic enzymes, allowing the endothelial cellsto degrade their basement membrane andmigrate from post-capillary venules towardsthese angiogenic stimuli. Eventually, a lumenwill form along with the development of bran-ches, leading to the formation of a loop con-necting the tip of one lumen to another [48].These loops have afferent and efferent limbsand appear to be a basic process in corneal NV[56]. Newly formed endothelial loops are rela-tively fragile and can lead to small intracornealhemorrhages. The clearance of blood recruitsmore macrophages, which secrete VEGF, furthersupporting the vascularization process [56].Vascularization most commonly occurs in thesuperior and middle third of the anterior stroma[57].

Corneal NV can lead to lipid deposition andsubsequent LK in several ways. As blood vesselsare formed, larger quantities of lipoproteins canreach these areas, especially if accompanied byhigh levels of serum lipoproteins [58]. Coganand Kuwabara [3] proposed that most patientswith LK have associated elevations in circulat-ing cholesterol levels. These newly formed vas-cular tissues are unusually permeable due to alack of pericyte coverage, fewer basementmembrane layers, and fewer tight junctions,allowing leakage of lipid and cholesterol[59, 60]. This cholesterol-rich lipid is endocy-tosed by fibroblasts, transferred to lysosomes,and then hydrolyzed into free cholesterol. Oncere-esterified in the Golgi complex, cholesterol isthen stored as droplets in the cytoplasm or usedin membrane metabolism. Membranous

lamellae form, possibly to trap this excesscholesterol in a soluble, non-crystalline form[58]. However, these fibroblasts eventuallybecome overloaded with lipid, leading tonecrosis and deposition of these membranouslamellae along with crystalline material in thecorneal stroma [58]. Necrosis initiates aninflammatory response, exacerbating the pro-cess of NV and furthering lipid deposition.

The presence of lipid droplets is characteris-tic of LK pathology. Cogan and Kuwabara [3]described two types of fatty plaques in the set-ting of LK: globular and granular lipids. Theglobular lipids exist intracellularly and appearas bright-red droplets 10–20 lm wide on histo-chemical staining with oil red-O. The granularlipids are derived from these globular lipidswithin cells that have necrosed and appear assmaller granules. Jack and Luse [5] observedirregular spaces containing membrane rem-nants in the corneal stroma on electron micro-scopy, along with degenerative changes inkeratocytes. They also noted an abundance ofmacrophages near pathologic blood vessels,which may play a role in lipid removal andregression of LK [58]. Silva-Araujo et. al [61]performed biochemical analysis on a patientwith bilateral idiopathic LK, which revealedlevels of cholesterol and sphingomyelin thatwere 6- to 11-fold higher in the affectedpatient’s cornea than in controls.

Interestingly, while NV is almost always arequirement for LK, not all NV leads to lipiddeposition. This is particularly apparent inconditions leading to ‘‘conjunctivalization’’ ofthe cornea, such as in limbal stem cell defi-ciency (LSCD). LSCD, which is a failure of stemcells to regenerate corneal epithelium, canoccur from acquired injuries, such as chemicalor thermal ocular burns and Stevens–Johnsonsyndrome and from inherited conditions suchas aniridia and ectodermal dysplasia [62–64].These stem cells are typically located in thebasal epithelial layer at the corneal limbus andcan be congenitally absent or damaged by ocu-lar injury. When the ability to renew cornealepithelium is lost, the corneal surface willbecome covered by conjunctival epitheliuminstead, referred to as ‘‘conjunctivalization.’’[65] This may lead to persistent inflammation

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and superficial corneal NV, but it may not leadto lipid deposition [66]. The mechanism of thisphenomenon is unknown. We speculate that itcould be related to the maturation of newlyformed vessels or pericyte recruitment. Whenvascular tissue is newly formed, high levels ofangiogenic factors and decreased numbers ofpericytes, tight junctions, and basement mem-brane layers may lead to increased vessel per-meability and lipid deposition. Therefore, thereverse of these circumstances may preventlipid deposition from occurring. It is thoughtthat corneal pericytes originate from bonemarrow-derived cells and pre-existing limbalcapillaries [67]. Perhaps conjunctivalization ofthe cornea leads to faster or greater quantities oflimbal pericyte recruitment. It may also beconceivable that VEGF-induced vascular per-meability is downregulated sooner in these tis-sues. Further studies must be pursued toelucidate a mechanism for this phenomenon.

CLINICAL MANIFESTATIONSAND DIFFERENTIAL DIAGNOSIS

Idiopathic LK typically presents bilaterallywithout previous corneal NV or serum lipidabnormalities. The lens, ocular fundi, andintraocular pressure are normal. Secondary LKwill present with findings related to the primarypathology, such as keratitis and dendritic ulcersin herpes simplex infection. The associated NVcan appear in three forms, namely, superficialstromal NV, deep stromal vascularization, andvascular pannus, each of which is often associ-ated with a certain etiology. Superficial vascu-larization occurs when vessels develop from thesuperficial marginal arcade into the subepithe-lium as a result of trauma, inflammation, orinfection [68]. Deep stromal vascularizationoccurs anywhere between Bowman’s layer andDescemet’s membrane due to anterior segmentinjury, scleritis, tuberculosis, and syphilis.Lastly, vascular pannus presents with collagenand vessel growth from the limbus to theperipheral cornea. Pannus usually occurs fromocular surface disease [69]. Common to allforms of NV is a resulting decrease in visualacuity. This can be due to opacity caused by the

blood cells themselves, corneal irregularity dueto pannus, high-order aberrations from irregularvascular walls, or leakage from vessels [41]. Thisleakage can be edematous or lipidic, the latterbeing the case of LK. Lipid deposition near thepupil will cause a marked decrease in visualacuity, but isolated peripheral corneal NV rarelyhas a substantial effect on visual acuity [41].

On examination, cream-colored opacifica-tion or fan-like cholesterol crystals on the cor-neal stroma may be observed surrounding bloodvessels (Figs. 2, 3, 4, 5, 6). A fan-shaped plaque iscommon in the setting of active keratitis [3]. Adisc-shaped distribution may be seen in anotherwise normal eye years after keratitis. In thesetting of diffuse corneal NV, correspondingdiffuse lipid deposition will be observed insteadof a localized plaque. As the disease progresses,lipid deposition can cause NV, which subse-quently leads to more lipid deposition, furtherdecreasing visual acuity. Ring-shaped depositsmay be present in idiopathic LK [9, 70]. In vivoconfocal microscopy (IVCM) can also help incharacterizing lipid deposits in LK. IVCM oftenreveals crystalline structures in the stroma inboth idiopathic and secondary LK[9, 13, 18, 26, 31, 38, 71]. Deposits in secondaryLK have also been described as amorphous orgranular [18, 26, 31]. Animal models haveshown several patterns of lipid deposition thatcan appear in both the peripheral and centralcornea either adjacent or non-adjacent to cor-neal NV and anywhere from the basal epithelial

Fig. 2 Yellow-white central corneal opacification repre-senting lipid keratopathy likely due to interstitial keratitisfrom the herpes virus (Courtesy of Majid Moshirfar)

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layer to the deep stromal layer [18]. A key dif-ferentiating feature is that idiopathic LK willtypically show no evidence of inflammation[71].

Corneal lipid deposition has been describedin other conditions, including Schnyder’s crys-talline dystrophy and corneal arcus. Cornealarcus is the most common form of ocular lipiddeposition and is characterized by the deposi-tion of cholesterol and phospholipid into theperipheral cornea [58]. Although the mecha-nism of corneal arcus is unclear, it is thought tobe part of the normal aging process and mostoften appears bilaterally in patients over 50years of age [27]. Corneal arcus is more commonin men than women and can be associated withunderlying lipid disorders, such as hyperc-holesterolemia or familial hyperlipidemia [27].Corneal arcus first develops at the superior andinferior periphery of the cornea, likely due tothe greater perfusion and warmer temperaturesin these areas leading to increased capillarypermeability and lipoprotein deposition [27].When the lipid is delivered beyond the reach ofthe peripheral vascular supply, it cannot becleared, leading to arcus formation [72]. Thisdeposition begins in the deep layers of thestroma and will eventually involve the entirethickness of the stroma, including Bowman’slayer and Descemet’s membrane [73].

In contrast to LK, lipid deposition in cornealarcus occurs in the absence of inflammation or

Fig. 3 Lipid deposition at the ends of neovascular vesselsencroaching on the central cornea (Courtesy of Dean P.Ouano)

Fig. 4 Lipid keratopathy in a fan-like pattern surroundingcorneal neovascularization (Courtesy of Dean P. Ouano)

Fig. 5 Lipid deposition secondary to neovascularizationfrom intracorneal ring segments that has coalesced into awhite-colored central corneal opacification (Courtesy ofDean P. Ouano)

Fig. 6 Lipid deposition surrounding multiple cornealneovascular vessels (Courtesy of Gerald B. Rosen)

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cellular damage and is primarily extracellular.Corneal arcus will appear as gray peripherallesions that first develop at the superior andinferior periphery of the cornea and eventuallyextend around the entire circumference. Thearcus is separated from the limbus by an area0.3–1.0 mm in size (lucid interval of Vogt) [27].Corneal arcus typically occurs bilaterally, butunilateral arcus may be seen in carotid arterystenosis, possibly due to decreased ocular bloodflow to the ipsilateral eye providing protectionfrom arcus formation [74]. Because it is limitedto the periphery of the cornea, this lipid depo-sition does not cause diminished visual acuity[1].

Schnyder corneal dystrophy or crystallinestromal dystrophy is an uncommon conditionassociated with cholesterol and phospholipiddeposition in the cornea and vision loss. Thispresents typically during the first few decades oflife with central corneal haze that progressesperipherally, with the development of cornealarcus at an earlier age than in the general pop-ulation [75]. These opacities can appear crys-talline or diffuse and occur primarily in theanterior stroma into Bowman’s layer [27]. Lipidaccumulation within fibroblasts with subse-quent necrosis and lipid deposition is found inSchnyder corneal dystrophy, similar to LK [58].Again, however, there will be no associatedinflammation or corneal NV.

TREATMENT

There are multiple avenues of treatment for LK,most of which are used to eliminate corneal NV.Standard therapy for corneal NV typicallybegins with corticosteroids due to their abilityto suppress the activity of inflammatory cellsand mediators that release pro-angiogenicgrowth factors [76]. Steroids can be useful if theprimary etiology of NV is inflammatory, butthese agents do not inhibit angiogenesisdirectly, and NV can form in the absence ofinflammation. Prolonged steroid use can alsolead to well-known side effects, including cat-aract and glaucoma. Therefore, multiple steroid-sparing modalities for the treatment of cornealNV and LK have been proposed, including

photodynamic therapy (PDT), anti-VEGF anti-bodies, argon laser treatment, needlepoint cau-tery, and penetrating keratoplasty.

PDT is used to eliminate cancer cells andhas also proven useful in the field of ophthal-mology. A vascular-selective light-sensitivesubstance, such as verteporfin or dihemato-porhyrin, is injected into the cornea, followedby irradiation of the area with a low-power laserdirected towards the area of interest. The inter-action of light, oxygen, and photosensitizerscreates reactive oxygen species, leading toendothelial damage, microvascular thrombosis,and the occlusion of blood vessels in the desiredarea with little effect on surrounding tissues. Inthe setting of LK, this method can counteractNV and the deposition of cholesterol andglycoproteins in the cornea, restoring visualacuity [77].

Multiple studies have reported improvedvisual acuity after treatment with PDT for LKdue to herpes simplex keratitis [78], contact lenskeratitis [79], and corneal transplantation [80].In one prospective study, Yoon et al. [78]describe an approach using PDT to treat 18 eyeswith corneal vascularization, of which eighteyes were noted to have LK due to herpetickeratitis or trauma. Lipid-formulated verte-porfin prepared at a dose of 6 mg/m2 based onbody surface area was diluted with 5% dextrosein water to a volume of 30 mL and thenadministered intravenously over 10 min. A689-nm non-thermal laser light was delivered ata power intensity of 600 mW/cm2 over severalspots ranging in size from 3 to 5 mm, deliveringa total light dose of 150 J/cm2. After 1 year,corneal NV was reduced in 77.8% of eyes, withcomplete vascular occlusion achieved in 50% ofeyes. Visual acuity improved in 44.4% of eyes[78]. Goh et al. [13] reported a similar approachin a patient with a history of herpes zosterophthalmicus. IVCM after treatment demon-strated a marked reduction in the density of LK.Advantages of PDT are that it is minimallyinvasive and can be repeated if lesions arerecurrent. A major limitation to the use of ver-teporfin is its high cost. A less expensive optionis dihematoporphyrin; however, it is associatedwith significant side effects, such as iritis, tran-sient angioedema requiring treatment, delayed

842 Ophthalmol Ther (2020) 9:833–852

phototoxic reaction, and delayed cutaneousreaction [13].

Other treatment methods involve topical,subconjunctival, and intracorneal administra-tion of anti-VEGF monoclonal antibodies, suchas bevacizumab and ranibizumab. Bevacizumabis currently the only medication approved bythe US Food and Drug Administration forintravenous administration for the treatment ofseveral neoplastic conditions, but it is oftenused off-label to treat age-related maculardegeneration associated with choroidal NV [81],diabetic retinopathy [82], neovascular glau-coma [83], and central retinal vein occlusion[84]. VEGF plays a crucial role in angiogenesis;thus, the ability of these antibodies to blockVEGF-mediated vessel formation underlies theirclinical utility in treating neovascular condi-tions of the eye. VEGF also increases vesselpermeability, possibly contributing to lipidleakage from NV and the development of LK.Therefore, anti-VEGF therapy is a potentialtherapeutic strategy for LK. Indeed, severalstudies have shown beneficial results fromtreating corneal NV with lipid deposition,which are outlined in Table 3 [85–90]. Beva-cizumab has been shown to decrease the neo-vascularized corneal area and improve visualacuity [91]. Subconjunctival injection caninduce involution of new vessels and restorecorneal function [92]. Because bevacizumab is afull-length immunoglobulin with a molecularweight of 149 kDa, it is thought that its sizecould prevent topical formulations from pene-trating the corneal epithelium, limiting effi-cacy. However, NV can lead to a damagedepithelial barrier, allowing entry of topicalbevacizumab [93]. Indeed, topical bevacizumabappears to have comparable efficacy with sub-conjunctival injection [91].

Combining subconjunctival injection ofbevacizumab with intrastromal injection mayallow for increased drug concentrations in dee-per corneal layers. Oh et al. [85] describe anapproach to treating three eyes of three patientswith extensive superficial and deep corneal NVand consequent LK. A single subconjunctivalinjection of bevacizumab at a concentration of1.25 mg/0.05 mL was performed at the limbusadjacent to the pathologic vessels. Another

injection was performed in the stroma at thesite of NV. These injections were repeated at1-month intervals until their condition stabi-lized or vessels became occluded. Each patienthad a reduction in NV of the cornea, and onehad a reduction in lipid deposition. There wereno adverse effects, except one patient had aminor intracorneal hemorrhage, which rapidlyresolved and cleared.

Ranibizumab is another anti-VEGF antibodythat has been proposed as a treatment for cor-neal NV. This medication offers several poten-tial advantages over bevacizumab: it is one-third of the size of bevacizumab, which couldallow better corneal penetration, and it has ahigher affinity for VEGF-A [14]. Some studiesshow no difference between the two whenadministered as a subconjunctival injection,while others suggest that bevacizumab may leadto less inflammation and NV as well asdecreased length of blood vessels [69]. Admin-istration of 1.0% topical ranibizumab 4 timesdaily for 3 weeks was shown to be superior to1.0% topical bevacizumab administered withthe same treatment regimen in reducing neo-vascular area and vessel caliber, especially ifadministered earlier in the treatment course[14]. However, the differences between thegroups were not statistically significant, andmore head-to-head trials are needed.

If bevacizumab passes into the systemic cir-culation, it may remain there longer thanranibizumab due to its larger size, leading tolocal and systemic overdosage [91]. Systemicside effects may be related to inhibition ofVEGF-mediated physiologic wound healing andangiogenesis and can lead to hypertension,proteinuria, and cardiovascular events [94, 95].Subconjunctival bevacizumab has rarely beenassociated with corneal epitheliopathy [96].Topical treatment is generally safe and well-tolerated but it can inhibit corneal woundhealing and nerve regeneration [91]. Care mustbe taken in patients with neurotrophic ker-atopathy or epithelial defects.

Although studies have shown beneficialeffects of anti-VEGF treatment, it appears thatthe efficacy of bevacizumab is not alwayspromising. This lack of efficacy could be relatedto the maturity of corneal NV; it is thought that

Ophthalmol Ther (2020) 9:833–852 843

Table3

Studiesusinganti-vascular

endothelialgrow

thfactor

antibodies

forthetreatm

entof

lipid

keratopathy

Stud

yNum

ber

ofeyes

Etiology

ofLK

Treatment(s)

Rou

teof

administration

Dosage

Frequencyof

treatm

ent

Anatomic

respon

seFu

nction

alrespon

seDurationof

follo

w-upperiod

Recurrence%

andaverage

timeto

recurrence

Ohet

al.

2009

[85]

3Second

ary

Bevacizum

abSubconjunctival,

intrastrom

al1.25

mg/0.05

mL

(both

subconjunctival

andintrastrom

al)

1injection

monthly

Decreasein

cornealNV

extent,d

ensity,and

activity

Decreasein

lipid

deposition

Improvem

ent

ofVA:

33.3%

Nochange

inVA:66.6%

9.6±

1.2(range

9–11)months

N/A

Chu

etal.

2011

[86]

18Second

ary

Bevacizum

abSubconjunctival

\6clockhours:

1.25

mg/0.05

mL

C6clockhours:

2.5mg/0.1mL

1injection

monthly

Decreasein

cornealNV

extent,centricity,and

PICS

Decreasein

lipid

infiltratedensityand

PICS

Improvem

ent

ofBCVA:

33.3%

Nochange

inBCVA:

66.7%

Decreasein

BCVA:0%

8.2±

3.1(range

5–13)months

N/A

Chu

etal.

2013

[87]

a

20Second

ary

Bevacizum

abSubconjunctival

\6clockhours:

1.25

mg/0.05

mL

C6clockhours:

2.5mg/0.1mL

1injection

monthly

N/A

N/A

21.9±

4.0(range

14-27)

months

35%

10.0

±2.2

(range

6–12)months

Castro

etal.

2011

[88]

1Idiopathic

Bevacizum

abTopical

25mg/mL

4times/day/

2monthsin

adescending

regimen

Partialregression

ofcornealNV

Improvem

ent

ofVA

8months

N/A

Elbaz

etal.

2015

[89]

9(5

with

pre-

existing

LK)

Second

ary

Bevacizum

abandFN

DSubconjunctival,

intrastrom

alUpto

2.5mg/

0.1mLpereach

cornealquadrant

involved

Once

Com

pleteresolution

ofcornealNVin

8of

9eyes

Com

pleteclearanceof

lipid

deposition

in3of

5eyes

Com

plete

18.7

±12.2

(range

5–35)months

N/A

Hussain

and

Savant

2016

[90]

5Second

ary

Bevacizum

abandFN

DSubconjunctival

0.25

mL

Once

Cessation

ofprogression

orsomedegree

ofregression

oflipid

deposition

Allmaintained

preoperative

VA

6–12

months

N/A

Durationof

follow-upperiod

presentedas

amean±

standard

deviation

BCVABest-correctedvisualacuity,N

/Anotavailable,NVneovascularization,P

ICSpercentage

ofinvolved

cornealsurface,VAvisualacuity

aThisstudyisafollow-upof

Chu

etal.’s

2011

study[86]

withtwomorepatientsandafocuson

patientswithrecurrentLK

844 Ophthalmol Ther (2020) 9:833–852

bevacizumab may play a more important role inacute NV than in chronic NV [97, 98], possiblydue to the downregulation of angiogenic factorsas newly formed vessels mature; maintenance ofchronic NV appears to be less dependent onVEGF. The subsequent recruitment of pericytesmay act as a physical barrier, which typicallyoccurs within 2 weeks [60, 86]. Both of thesemechanisms can potentially decrease the effi-cacy of anti-VEGF antibodies in treating chronicNV [99]. While there appears to be no strictdefinition of chronic corneal NV, a time frameof 3–6 months has been used in the literature[60, 86, 87, 100]. Another major disadvantage ofbevacizumab is the risk of recurrence and theneed for repeated treatments to maintaineffects. Proposed mechanisms include residualsubclinical inflammation and rebound releaseof VEGF after cessation of treatment [87].Additionally, while VEGF plays a major role inangiogenesis, other factors are involved. There-fore, inhibiting VEGF alone may be insufficientfor permanently reducing corneal NV and LK[87, 101]. Combining anti-VEGF antibodieswith other procedures may be superior in effi-cacy compared to using either alone [102–104].Newer anti-VEGF therapeutics include VEGFtraps (aflibercept), VEGFR tyrosine kinase inhi-bitors, and RNA aptamers (pegaptanib)[69, 105, 106]. However, more long-term studiesmust be performed to evaluate the effectivenessand safety of anti-VEGF therapy for the treat-ment of LK before providers can fully integratethis strategy into their clinical practice.

Another potential pharmacologic target issubstance P (SP), which is a neuropeptidesecreted from nerve endings and immune cellsduring inflammation [107]. When bound to theneurokinin-1 receptor (NK-1R), SP promoteswound healing by stimulating epithelial cells toproliferate and migrate, but also leads to therelease of inflammatory mediators that can ini-tiate and maintain corneal NV [108]. Higherlevels of SP in tears of patients affected by cor-neal NV have been associated with more severevascularization [108]. NK-1R antagonists such asfosaprepitant have been shown to reduce cor-neal NV, corneal opacity, and inflammation inanimal models [109].

Argon laser treatment causes heat-inducedvessel occlusion by directing a beam of lightonto the pathologic vessels, which can beassisted by digital fluorescein angiography (FA)[14, 110, 111]. Marsh [110, 112] has authoredseveral reports of argon laser treatment for LKusing an aperture of 50 lm with 0.1-s exposureand 0.2- to 0.8-W power. This treatment led to areduction in the extent and density of LK in 62and 49% of eyes, respectively. Laser-inducedtissue destruction, however, can worsen NV bycausing inflammation and the release of angio-genic factors and can cause corneal hemor-rhage, corneal thinning, and iris atrophy [14].

Fine needle diathermy (FND) was firstdeveloped in 2000 by Pillai et al. [113]. Thistreatment involves attaching a stainless steel3/8 single-armed needle to a 10-0 monofilamentblack nylon suture held by a microsurgicalneedle holder. After the needle is inserted nearthe limbus adjacent to a pathologic vessel, agrounding electrode is strapped to the foot ofthe patient. A diathermy probe in coagulatingmode at its lowest setting (0.5–1.0 mA) is thenbrought into contact with the needle. This leadsto cauterization and elimination of the abnor-mal vessel, typically in under 1 s. In the originalstudy, 100% occlusion of vessels was achievedin two of two eyes with LK. In a more recentcase series, 82.3% of eyes with LK treated withFND showed reduced corneal lipid deposition[114]. Complications include transient whiten-ing of the cornea and intrastromal hemorrhage.The procedure may also need to be repeated dueto recanalization or collateral vessel develop-ment [113].

A more recent adaptation to the FND tech-nique uses an electrolysis needle (electrolysis-needle cauterization [ENC]). ENC involvesdirect thermal cautery instead of electrical cur-rents as in FND [115]. The electrolysis needle isalso finer and more flexible than the diathermyneedle (0.125 vs. 0.15 mm), possibly posing anadvantage for treating fine vessels. Vesselocclusion was accomplished in all three eyestreated for LK with a subtle decrease in lipid[115]. Two eyes required repeat ENC, with onerequiring a penetrating keratoplasty.

Lastly, a penetrating keratoplasty, com-monly referred to as a corneal transplant, can be

Ophthalmol Ther (2020) 9:833–852 845

effective in severe cases of LK. Complicationswith the surgery include corneal thinning,hypoesthesia, sustained vascularization, andgraft rejection [116]. In idiopathic LK, thetreatments mentioned earlier in this articleshould be implemented before consideringsurgery. If there is no resolution, then surgery isa good option. For secondary LK, the underly-ing condition should be initially treated. Ifthere is no resolution or the effects of the LKcannot be reversed with treatment of the pri-mary disease, then the treatments, as men-tioned earlier, including surgery, should beexplored to provide relief for the patient. How-ever, outcomes of keratoplasty may be worsewhen used to treat secondary LK compared tothe idiopathic form, as corneal NV has beenshown to lead to a worse prognosis after ker-atoplasty [23, 76].

The future for the management of LK is ofgreat interest, as recurrence, cost, and compli-cations limit the clinical utility of many currenttreatment regimens. The ideal treatment shoulddestroy existing abnormal corneal vessels andprevent further vascularization. Newer treat-ment modalities may include mitomycinintravascular chemoembolization, or ‘‘MICE,’’as pioneered by Dean Ouano of Coastal EyeClinic in New Bern, North Carolina (USA) (inpreliminary stages of research). Transcatheterarterial chemoembolization (TACE) has beenused for years in hepatocellular carcinoma as amethod to reduce tumor size by preventing itsblood supply [117]. This procedure combines anintra-arterial infusion of a chemotherapeuticagent with an artificial embolus that leads tovessel occlusion. A common antineoplasticagent used is mitomycin-C, a DNA cross-linkingagent that also inhibits protein and RNA syn-thesis. In theory, this method could be used toocclude pathologic vessels in corneal NV, pre-venting or halting the development of LK.Challenges include accurately identifying affer-ent and efferent blood vessels for intravascularcannulation. Afferent vessels should be targetedif possible, as chemoablation of efferent vesselsalone may lead to worsened lipid exudation.Previous studies have shown that the combi-nation of FA and indocyanine green angiogra-phy (ICGA) can better delineate vessels

compared with biomicroscopy [118]. However,this process is invasive, time-consuming, andcarries a small risk of severe anaphylaxis [119].Recently, anterior segment optical coherencetomography angiography (OCTA) has demon-strated the potential for identifying small ves-sels, especially in the setting of corneal opacitiesthat limit visualization by slit-lamp [120].Another challenge is employing a needle that isthin enough to cannulate these newly formedvessels. Presently, 33-gauge needles are readilyavailable; however, newer options include36-gauge and even 41-gauge subretinal injec-tion needles. One may even consider micro-pipettes for the delivery of intravascularchemoembolization. Further studies should bepursued to identify the safety, efficacy, andproper technique of corneal intravascularchemoembolization as a treatment for LK sec-ondary to corneal NV.

CONCLUSION

Lipid keratopathy is a disease of the eye that isclassically characterized by NV of the cornea,cholesterol deposits, opacification, and decreaseof visual acuity. The disease progresses slowlyand causes a steady decline in vision. The causeof idiopathic LK is unkown, and this formoccurs bilaterally. Secondary LK occurs sec-ondary to a disease or trauma to the eye and istypically unilateral. Although many treatmentoptions are available, further studies must beperformed to identify more robust, reliable, andprecise treatment methods that are accessibleand affordable to patients.

ACKNOWLEDGEMENTS

Funding. This review was funded by anunrestricted grant from Research to PreventBlindness (RPB), 360 Lexington Avenue, 22ndFloor New York, NY 10017 (USA). No supportwas received for the publication of this article.

Editorial Assistance. Assistance in thepreparation of this article was provided by

846 Ophthalmol Ther (2020) 9:833–852

Gerald B. Rosen of Horizon Eye Care, Charlotte,NC (USA).

Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship for thisarticle, take responsibility for the integrity ofthe work as a whole, and have given theirapproval for this version to be published.

Disclosures. MacGregor N Hall,Majid Moshirfar, Armaan Amin-Javaheri, DeanP Ouano, Gerald B Rosen, Yasmyne Ronquillo,and Phillip C Hoopes declare that they have noconflict of interest.

Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not contain any studies with humanparticipants or animals performed by any of theauthors.

Data Availability. Data sharing is notapplicable to this article as no datasets weregenerated or analyzed during the current study.

Open Access. This article is licensed under aCreative Commons Attribution-NonCommer-cial 4.0 International License, which permitsany non-commercial use, sharing, adaptation,distribution and reproduction in any mediumor format, as long as you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons licence, andindicate if changes were made. The images orother third party material in this article areincluded in the article’s Creative Commonslicence, unless indicated otherwise in a creditline to the material. If material is not includedin the article’s Creative Commons licence andyour intended use is not permitted by statutoryregulation or exceeds the permitted use, youwill need to obtain permission directly from thecopyright holder. To view a copy of this licence,visit http://creativecommons.org/licenses/by-nc/4.0/.

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Lipid Keratopathy: A Review of Pathophysiology, Differential Diagnosis, and ManagementAbstractDigital FeaturesIntroductionMethodsHistorical OverviewEtiologyPathophysiology and PathologyClinical Manifestations and Differential DiagnosisTreatmentConclusionAcknowledgementsReferences