British Journal of Ophthalmology, 1988, 72, 338-343

Idiopathic bilateral lipid keratopathy*EDUARDO ALFONSO,t'-3 LOURDES ARRELLANES,5S ARTHUR BORUCHOFF,'3 L DAVID ORMEROD,'34AND DANIEL M ALBERT23

From the 'Cornea Service and 2Cogan Eye Pathology Laboratory ofthe Massachusetts Eye and Ear Infirmary,3Department of Ophthalmology, Harvard Medical School, 4Eye Research Institute, Boston Massachusetts,USA, and 'Hospitalpara la Prevencion de la Ceguera, Mexico City, Mexico

SUMMARY A 52-year-old Mexican man presented with asymptomatic, bilaterally symmetrical lipidinfiltrates of the cornea and adjacent limbus. No evidence of previous ocular disease or systemicdisorder of lipid metabolism could be detected. Penetrating keratoplasty of the right eye wasrequired. The cornea was rigid and thick, with posterior bulging into the anterior chamber. Lightmicroscopy revealed deep corneal lipid granules, foamy histiocytes, vascularisation, and chronicnon-granulomatous inflammation. Transmission electron microscopy showed extracellular lipidspaces and numerous intracytoplasmic lipid vacuoles in histiocytes, keratocytes, conjunctivalepithelium, and the endothelium of blood vessels in the corneal stroma and adjacent limbalconjunctiva. Histochemical analysis revealed the presence of neutral fats, free fatty acids,cholesterol, and phospholipids.

Opacification of the cornea due to the deposition oflipids may be primary without evidence of previouscorneal vascularisation, or secondary to either pre-existing corneal disease with vascular exudation orsystemic disturbances of lipid metabolism.`We report an unusual case of idiopathic, bilaterally

symmetrical lipid keratopathy associated with exten-sive neovascularisation, severe limbal involvement,and stromal lipid deposition.4 The patient had noprevious ocular disease or lipoprotein disorder; thissuggests the primary nature of this condition.5

Case report

A 52-year-old Mexican man had a slowly progressiveyellow infiltrate in the superior cornea of the right eyeover a five-year period and a similar lesion for three

*Part of this paper was presented by Dr Boruchoff at the CastroviejoSociety Meeting, San Francisco, California, on 29 September 1985,and by Dr Alfonso at the Eastern Ophthalmic Pathology Society,Frenchman's Reef, St Thomas, on 1 November 1985.

tPresent address: Bascom Palmer Eye Institute, University ofMiami, Miami, Florida 33101, USA.

Correspondence to Daniel M Albert, MD, David G Cogan EyePathology Laboratory, 243 Charles Street, Boston, MA 02114,USA.

years in the left eye. There were no associatedsymptoms and no history of ocular disease or trauma.The patient had been treated for hypertension with a-methyldopa (Aldomet) for two years. Laboratoryvalues for serum cholesterol (3.70 mmol/l) and tri-glycerides (1-40 mmol/l) were normal. Serum lipidelectrophoresis revealed no chylomicrons andnormal patterns for ,3, pre-p, and a lipoproteins.Other laboratory values were normal and includedthe following: glucose 5-0 mmol/l, alkaline phos-phatase 99 U/l, haemoglobin 166 g/l, haematocrit49*5%, white blood count 9-5x109/l, and a normalleucocyte differential count. The VDRL rest resultwas non-reactive. A chest x-ray and electrocardio-gram were normal.The best corrected visual acuities were hand

motions in the right eye and 6/7-5 in the left eye. Slit-lamp examination of the right cornea revealed ayellowish white mass that occupied almost three-fifths of the superior cornea, including the visual axis(Fig. 1A). The superior limbus between the 10 and2 o'clock positions was markedly elevated, andnumerous, large, superficial, and deep stromalvessels extended into the abnormal corneal mass inthis area (Fig. 1B). Clinically the entire thickness ofthe superior stroma was affected. In the left eye a

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Idiopathic bilateral lipid keratopathy

Fig. IA Fig. LC

Fig. 1 A: Right cornea with superiorlipid infiltrationextending into the visual axis. B: Thickening andvascularisation ofsuperior limbal area ofright eye. C, D:Left eye showingsimilarfindings to righteye but withoutextension oflipid infiltrate into the visual axis.

smaller lesion with similar characteristics was found(Figs. 1C, D). The other findings of the ocularexamination were normal.A central penetrating keratoplasty of the right eye

was performed. At surgery the affected part of thecornea was rigid and bulged posteriorly into theanterior chamber and apposed the superior iris. Thepostoperative period was unremarkable, and therewas no evidence of recurrence of the disorder at thesix-month follow-up appointment.

HISTOPATHOLOGYSpecimens of limbal conjunctival biopsies and the 7-5mm corneal button were obtained and trisected in theoperating room. One fragment was placed in 2%glutaraldehyde and embedded in Epon, and thinsections were used for transmission electron micro-

scopy. A second fragment was fixed in 10% bufferedformaldehyde, embedded in paraffin, sectioned, andstained with haematoxylin and eosin, periodic acid-Schiff, Congo red, and alcian blue. A third fragmentwas frozen at -70'C, sectioned, postfixed in 37%formaldehyde fumes for 15 minutes, and stained forfats.

LIGHT MICROSCOPYThe conjunctival specimen consisted of a connectivetissue fragment lined by non-keratinised squamousepithelium of normal thickness and showed mild tomoderate intracellular oedema of the basal cell layer.Moderate numbers of goblet cells were present. Thesubstantia propria contained blood vessels, rareplasma cells, and lymphocytes.The corneal specimen was thickened posteriorly

(Fig. 2A). The corneal epithelium showed moderateoedema of the basal cell layer. At the periphery afibrocellular pannus was interposed between theepithelium and the intact Bowman's layer. Thesuperficial stroma was normal. The deep stroma wasextremely thickened, especially centrally, with

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340 EduardoAlfonso, Lourdes Arrellanes, S Arthur Boruchoff, L David Ormerod, and DanielM Albert

Fig. 2A Right eye. Thickeningandposterior bulging ofcornealspecimen caused by lipid andinflammatory infiltrate(haematoxylin and eosin, x5).

Fig. 2A

moderate vascularisation and disorganisation of thecollagen fibrils (Fig. 2B). This area was heavilyinfiltrated by lipid laden histiocytes, lymphocytes,and plasma cells. Scattered epithelioid cells were alsopresent. Descemet's membrane appeared intact. The

X ..No.e,.

Fig. 2B Posterior cornea showing , hvascularisation and disorganization ^ ^ofcollagen lamellae. The infiltrate v kconsisted oflipid laden histiocytes,Alymphocytes, plasma cells, andepithelioid cells (haematoxylin andeosin, x15). ^

corneal endothelium contained focal areas of pig-ment deposition.

TRANSMISSION ELECTRON MICROSCOPYThe conjunctival epithelium contained both intra-

Fig. 2B

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Idiopathic bilateral lipid keratopathy

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Fig. 3A Fig. 3C

Fig. 3 Transmission electron microscopy ofthe right eye,showing spaces where lipids (L) had dissolved.A: Conjunctival epithelium (x6130). B: Markeddegenerative changes in keratocytes (arrow) and collagenlamellae (C) (x 7710). C: Histiocyte, containing roughendoplasmic reticulum (ER) and red blood cell (RBC)(x 9390). D: Vascular endothelium and intravascular redblood cells (RBC) (x8000).

cellular vacuoles and extracellular spaces, whichprobably contained lipids prior to fixation (Fig. 3A).

The substantia propria and vascular endotheliumalso contained 'lipid' spaces.

In the cornea there were marked degenerativechanges in the keratocytes and disruption of theposterior collagen lamellae (Fig. 3B). Histiocytesand neovascular endothelium were vacuolated exten-sively (Figs. 3C, D), and adjacent keratocytes (Fig.3D) were pyknotic.

HISTOCHEMICAL EXAMINATIONAfter sectioning and postfixing the frozen tissue in

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342 Eduardo Alfonso, Lourdes Arrellanes, S Arthur Boruchoff, L David Ormerod, and DanielM Albert

Table Histochemical data

Stain Substance testedfor Result

Congo red Amyloid NegativeMasson trichrome Collagen NegativeAlcian blue Acid mucopolysaccharide NegativePeriodic acid-Schiff - NegativeAlizarin red Calcium NegativeOil-red-O Triglycerides, neutral fats PositiveSudan black B Neutral fats, phospholipids PositiveBaker Phospholipids, galactolipids Positive

formalin fumes we noted that the area of cornealinfiltration was somewhat birefringent. No abnormalstaining was observed with alcian blue, Massontrichrome, Congo red, periodic acid-Schiff, andbacterial and fungal stains. The alizarin stain was

negative. The Baker, Sudan black B, and oil-red-Ostains were positive for both intracellular and extra-cellular fat. The material was interpreted as consist-ing of neutral fats, free fatty acids, cholesterolcrystals, and small amounts of phospholipids (Table).

Discussion

Deposition of lipids in the cornea has been describedin several pathological conditions,4 including lipidkeratopathy, lipoidal degeneration, Schnyder'scrystalline dystrophy, corneal xanthoma, cornealarcus, and corneal xanthogranuloma. Occasionallylipids may be deposited in the cornea secondaryto systemic lipoprotein disorders (reviewed bySchaefer3), including Tangier disease, lecithincholesterol acyltransferase deficiency, and familialhigh-density lipoprotein deficiencies. In lipoproteindisorders the involvement is usually bilateral, butcorneal vascularisation is absent.

Corneal arcus, a lipid infiltration of the paralimbalcornea adjacent to Bowman's layer and Descemet'smembrane, is thought to be part of the normal agingprocess in patients over 50 years old. An associationwith hyperlipoproteinaemia in patients under the ageof 40 is controversial. The lipoprotein infiltration ofcorneal arcus is primarily extracellular, with noassociated cellular degeneration or inflammation.Corneal arcus appears clinically as peripheral greyareas separated from the limbus by a lucid interval,but limbal vasculature, corneal temperature, andlocal blood flow modify the lipid deposition.6 Fineand associates have reported a case of primarylipoidal degeneration of the cornea associated witharcus senilis.'Abnormal proliferation of lipocytes can lead to

lipid deposition in the cornea in conditions such as

juvenile xanthogranuloma. Raised limbal dermoids

should also be included in the differential diagnosis.Cogan and Kuwabara coined the term lipid kerato-

pathy to describe the deposition of fatty plaques in oradjacent to areas of abnormal corneal vascularisa-tion.4 In their review of the literature they citedreports that used various terms, such as fatty dys-trophy of the cornea, dystrophia adiposa corneae,adipbsis of the eye, xanthomatosis, lipid interstitialkeratitis, lipidosis corneae, and secondary steatosis.The pathogenesis of lipid keratopathy, as describedby these authors, is related to prior vascularisation ofthe cornea due to trauma or inflammation, leading tolipid exudation in areas adjacent to the vessels.Argon laser ablation of the vascular channels mayarrest the process of lipid deposition and occasionallyaid in resolving the lipid infiltrate.8 Experimentallyinduced corneal vascularisation can also lead to fattyinfiltration of the cornea.9

Several cases of corneal lipid deposition not associ-ated with previous eye trauma, inflammation, orsystemic disorders of lipid metabolism have beenreported."'"'2 Baum"0 described a 72-year-old womanwith unilateral lipid infiltration of the cornea, associ-ated with a slight limbal conjunctival injection. A fewdeep blood vessels extended into the lesion from theadjacent corneoscleral limbus. Thin-layer and gas-liquid chromatography detected the presence ofcholesterol but no other lipids.A case of an asymptomatic 31-year-old man

reported by Barishak and Stein" had a unilateralcorneal lipid infiltration similar in clinical appearanceto that of our patient. Vascularisation was present inthe lesion as well as in the adjacent corneosclerallimbus. The plaque contained mostly cholesterol andneutral fats, with cholesterol esters and fatty acidspresent in small quantities.Our patient shares several clinical features with

other cases."'-'2 No systemic or ocular disorder waspresent to explain the lipid deposition in the cornea inany of the four patients, yet they showed severevascularisation of the cornea and adjacent corneo-scleral limbus. No symptoms of ocular inflammationhad been present prior to or at the time of initialexamination. Our case is analogous to that ofCroxatto et al.'2 in its insidious, bilaterally sym-metrical presentation and thickened, rigid corneas.

Lipid keratopathy may be associated with con-current symptoms of ocular inflammation withsystemic abnormalities of lipid metabolism. Forexample, Friedlaender and associates reported a caseof a 55-year-old woman with bilateral lipid infiltratesof the cornea,'3 who differed from our patient inhaving a mildly raised blood cholesterol level andclinical evidence of ocular inflammation, includingpain, photophobia, central corneal epithelial defects,and a diffuse erythematous rash on the face, chest,

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Idiopathic bilateral lipid keratopathy

and hands. Jack and Luse'4 described a 51-year-oldwoman with raised blood triglycerides who had anasymptomatic corneal lipid deposition in an area of apreviously excised pterygium.

In contrast most other cases of lipid keratopathydirectly complicate corneal neovascularisationfollowing trauma or keratitis and are associatedcommonly with a systemic disorder of lipid meta-bolism;'3 '4 these conditions are classified as second-ary lipid keratopathies. The absence of previousocular disease and the apparently normal premorbidcorneas in the present case and in those of Baum,'0Barishak and Stein," and Croxatto et al.'2 suggestthat these cases should be classified as primary lipidkeratopathies (idiopathic). The remarkable sym-metry and disease pattern of our case and that ofCroxatto et al.'2 also provide support for a primaryrather than a secondary cause.The nature of the process in the idiopathic cases is

unclear. Low-grade inflammation at the corneo-scleral limbus or ocular surface, which was unnoticedby the patient but caused corneal vascularisation andsubsequent lipid deposition, is one possible explana-tion. The finding in our case and others" of 'lipid'spaces in the vascular endothelium of the lesion andadjacent conjunctiva could represent a primary func-tional defect of the vascular endothelial cells withleakage of fats into the adjacent corneal tissues.This is turn could induce secondary inflammationfollowed by corneal vascularisation and further fatexudation.4 Cogan and Kuwabara"5 and Jack andLuse'4 proposed that a derangement of corneal cellsmight lead to necrosis and exposure of intracellularfatty material as the initial event leading to inflamma-tion, vascularisation, and further deposition of fatsinto the corneal stroma. This derangement might becaused by an intrinsic defect, inflammatory toxins, ortrauma.

In animal models experimentally induced cornealvascularisation sometimes progresses to lipidexudation into the adjacent corneal tissue, thoughhypercholesterolaemia in the early phases of neo-vascularisation is usually a necessary precondition ofexperimental lipid keratopathy. The beagle' andCuban tree frog (Albert DM, personal communica-tion, 1986), however, provide animal models ofnaturally occurring primary lipid keratopathy.Further laboratory investigations are required toclarify these pathophysiological questions as to thenature of lipid keratopathy in humans.

In our case histochemical analysis of the cornealbutton revealed the presence of neutral fats, free

fatty acids, cholesterol, and a small amount ofphospholipids. Barishak and Stein" foundcholesterol and neutral fats, and Baum"' onlycholesterol, in their cases. Croxatto and colleagues'2found neutral fats, cholesterol, and phospholipids. Incases of corneal lipid deposition, corneal and plasmalipids should be analysed comparatively to ascertainwhether a systemic metabolic fat abnormality is thecause.

David G Cogan, MD, and Lorenz Zimmerman, MD, reviewed thehistopathological slides. Robert R McMukin, MD, and Ian WMcLean, MD, examined the sections stained for lipids. DiegoCuevas Cancino, MD, provided clinical information. This studywas supported in part by the Heed/Knapp Fellowship (1984-6),EY05769 (NIH), and National Society for the Prevention ofBlindness (Dr Alfonso).

References

1 West C. Corneal disease. In: Peyman GA, Sanders DR,Goldberg MF, eds. Principles and practice of ophthalmology.Philadelphia: Saunders, 1980: 410-2.

2 Smolin G. Dystrophies and degenerations. In: Smolin G. ThoftRA, eds. The cornea: scientific foundations and clinical practice.Boston, Little, Brown, 1983: 333.

3 Schaefer EJ. Clinical, biochemical, and genetic features infamilial disorders of high density lipoprotein deficiency. Arterio-sclerosis 1984; 4: 303-22.

4 Cogan DG, Kuwabara T. Lipid keratopathy and atheroma.Trans Am Ophthalmol Soc 1958; 56: 109-22.

5 Roth AM, Ekins MB, Waring III GO, Gupta LM, RosenblattLS. Oval corneal opacities in beagles. III. Histochemical demon-stration of stromal lipids without hyperlipidemia. Invest Ophthal-mol Vis Sci 1981; 21: 95-106.

6 Fielder AR, Winder AF, Sheraidah GAK, Cooke ED. Problemswith corneal arcus. Trans Ophthalmol Soc UK 1981; 101: 22-6.

7 Fine BS, Townsend WM, Zimmerman LE, Lashkari MH.Primary lipoidal degeneration of the cornea. Am J Ophthalmol1974; 78: 12-23.

8 Marsh RJ, Marshall J. Treatment of lipid keratopathy with theargon laser. BrJ Ophthalmol 1982; 66: 127-35.

9 Stock EL, Mendelsohn AD, Lo GG, Ghosh S, O'Grady RB.Lipid keratopathy in rabbits: an animal model system. ArchOphthalmol 1985; 103: 726-30.

10 Baum JL. Cholesterol keratopathy. Am J Ophthalmol 1969; 67:372-5.

11 Barishak YR, Stein R. Lipid keratopathy. Ann Ophthalmol1974; 6:377-80.

12 Croxatto JO, Dodds CM, Dodds R. Bilateral and massivelipoidal infiltration of the cornea (secondary lipoidal degenera-tion). Ophthalmology 1985; 92: 1686-90.

13 Friedlaender MH, Cavanagh HD, Sullivan WR, Gallagher MJ,Dickersin GR. Bilateral central lipid infiltrates of the cornea.Am J Ophthalmol 1977; 84: 781-7.

14 Jack RL, Luse SA. Lipid keratopathy: an electron microscopicstudy. Arch Ophthalmol 1970; 83: 678-91.

15 Cogan DG, Kuwabara T. Lipogenesis by cells of cornea. ArchPathol 1955; 59: 453-6.

Acceptedforpublication S March 1987.

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