BritishgJournal ofOphthalmology 1993; 77: 248-250

CASE REPORTS

Primary lipid keratopathy: a morphological andbiochemical assessment

Antonio Silva-Arautjo, Maria Amelia Tavares, Maria Manuela Lemos, Maria Isabel Soares,Jose Castro-Correia, Jose Salgado-Borges

Department ofOphthalmology, MedicalSchool of Porto/HospitalSio Joio, Porto, PortugalA C Silva-AraujoJ Castro-CorreiaJ Salgado-Borges

Institute ofAnatomy,Medical School of Porto,Porto, PortugalM A Tavares

Institute of GeneticsJacinto de Magalhies,Porto, PortugalMM LemosM I SoaresCorrespondence to:Dr Ant6nio Silva-Arauijo,Department ofOphthalmology, MedicalSchool of Porto/Hospital SioJoao, Alameda HernaniMonteiro, 4200 Porto,Portugal.Accepted for publication27 November 1992

Lipid keratopathy is a term applied to conditionswhere lipid degeneration of the cornea occurs.`-5There are only a few cases of primary lipidkeratopathy published to date,'-5 and all of themreport the morphological evaluation of a cornealbutton by different methods; in some of thesecases identification of the lipids was tentativelymade histochemically.'4 To our knowledge,however, no quantitative biochemical determi-nation of lipids has been reported in thiscondition. We present a case of primary lipidkeratopathy diagnosed by biochemical and ultra-structural analysis of a corneal button allied tothe quantitative determiination of neutral lipidsin the aqueous humour, cultured skin fibro-blasts, leucocytes, and blood plasma.

Case reportA 57-year-old woman exhibited a progressivegolden yellow infiltrate in the temporal cornea ofboth eyes over a 12 year period. This infiltrateproceeded from the perilimbic areas and occu-pied the entire thickness of the stroma, beingmore dense in its posterior half and extendingaxially to cover the pupil (Fig la, b). At the endof the 12 year period, a few deep blood vessels,not present in the initial stage of the disease,reached the lesion from the clear adjacentcorneoscleral limbus. Its central marginsglistened, with many crystals present only in theposterior stroma; the overlying epithelium wasintact and did not stain with fluorescein. In its

initial stage (in 1980) the visual acuity was 20/20in both eyes and worsened progressively until atthe end stage of the disease VA was 20/200 (left)and 20/80 (right); the-lens, the ocular fundi, andintraocular pressure were normal. There was noprevious history of ocular disease or trauma andfamily history was irrelevant.

Determination of serum lipids revealed noalterations to chylomicrons, (, pre-(3 and alipoproteins, throughout the 12 year period.A penetrating keratoplasty was performed on

the left eye. Postoperative recovery was normalwith no evidence of recurrence at the 2 yearfollow up and VA recovered to 20/30.The corneal button was sectioned into three

parts to be used for electron microscopy, histo-chemical stainings, and analysis of lipids byhigh performance thin layer chromatography(HPTLC).

Ultra-thin sections demonstrated the presenceof multiple needle-like cholesterol clefts dis-persed throughout the corneal stroma. Lipiddroplets were seen as grey, black, or clearvacuoles present in fibroblasts and histiocytes(Fig 2). Histochemical staining (oil red 0 andSudan black B) indicated deposits of neutralfats and phospholipids. Lipids of the cornea,aqueous humour, cultured skin fibroblasts,leucocytes, and blood plasma from the patientand from controls (corneas and aqueous humourfrom donors at S Joao Hospital Eye Bank) wereanalysed.6 Lipid separation was achieved byHPTLC; identification of the lipid spots was

Figure I (a) Right corneawith temporal lipidinfiltration extending into thevisual axis. (b) Left corneashowing symmetrical lipidinfiltrates (12yearfollowup).

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Primary lipid keratopathy: a morphological and biochemical assessment

Figure 2 Electronmicrograph ofthe cornealstroma showing histiocytes(H) with lipid vacuoles(arrows); extracellular g z-I _ tcholesterol clefts(arrowhead) can be seen.

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done by comparison with appropriate standardsand the lipid concentration was determined bydensitometry.The most striking biochemical finding was the

increase of cholesterol and sphingomyelin con-centrations in the cornea of the patient, being6-11 times and six times respectively higher thanin controls (Table 1). Only 12% ofthe cholesterolfrom the patient cornea was esterified in contrastto 52-68% found in controls. Since the concen-

tration of the cholesteryl esters was similar in thecornea of the patient and the controls this gives a

decrease in the cholesteryl esters/cholesterolratio (8-16 times) in the cornea of the patient. Inthe aqueous humour no significant differenceswere found in the levels of cholesterol andcholesteryl esters between the patient and con-

trols (Table 2). The concentration of neutral

Table I Quantitative distribution ofneutral lipids in the cornea, cultured skinfibroblasts, andleucocytes

Cornea Fibroblasts Leucocytes

Patient Control Control Patient Control Patient Control

pglOO mg fresh weightCE 64 92 83 8a 7b 18 13

(12%)b (68%)b (52%)b (30%)b (28%)b (51%)b (54%)bC 487 44 78 Iga 18" 17a 11PE 31 28 18 35a 36 19 8LacCer nd nd nd nd nd 32 18PC 89 48 24 33a 15 8 22Sph 108 19 18 13a 10 8 11Sph/C 0-22 0-43 0-23 0-68 0-56 0-47 1-00CE/C 0-13 2-09 1-06 0-42 0-39 1-06 1-18

aMea value (n=2).bPercent of esterified cholesterol.nd=not detected. CE=cholesteryl esters; C=cholesterol; PE=phosphatidyletbanolamineLacCer=lactosylceramide; PC=phosphatidylcholine; Sph=sphingomyelin.

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Table 2 Quantitative distribution ofthe neutral lipids in theaqueous humour and blood plasma

Aqueous hunour Plasma

Patient Control Patient Control Control

mg/100 mlCE 4-2 3-8 71 67 51

(63%)S (57%)8 (70%)8 (68%)8 (57%)8C 2-5 3-0 30 32 38GluCer nd nd 1-7 1-2 3-0PE nd nd 3-6 3-3 8-1PC nd nd 12 10 16Sph nd nd 9-0 10 9-6Sph/C 0-30 0-31 0-25CE/C 1-68 1-27 2-37 2-09 1-34

'Percent of esterified cholesterol.nd=not detected. GluCer=glucosylceramide.

lipids in cultured skin fibroblasts and leucocytes(Table 1) and in the blood plasma (Table 2) werealso determined. The activity of sphingo-myelinase was also determined in cultured skinfibroblasts from the patient (108 nmollhlmgprotein; reference values: 82-216 nmolM/mgprotein, n=3).

CommentThe patient reported herein had a bilateral andsymmetrical lipid keratopathy unrelated to pre-vious vascularisation, inflammatory alterationsor systemic lipid or lipoprotein disorders, andnormal serum values which allowed the diagno-sis of primary lipid keratopathy. Besides thehistopathological features seen in this case,which are similar to previous reports,'- thebiochemical determinations performed in thecornea, aqueous humour, cultured skin fibro-blasts, and leucocytes provided for the first timea more complete characterisation of the lipidinfiltrates involved in this disorder.

Allowing for the fact that the accumulation oflipids in the cornea in the absence of vascularisa-tion has been suggested to originate from theaqueous humour,7 the comparison of bloodplasma lipids and those present in the aqueoushumour is important for the differential diagno-sis of a local versus a systemic disorder. In thiscase, however, the cholesterol content of theaqueous humour was similar to the controlvalues thus excluding this hypothesis. Thecornea of our patient showed an increasedaccumulation of cholesterol (6-11 times) andsphingomyelin (six times) compared with thecontrols; however, similar increases in thereticuloendothelial system of the spleen, lymphnodes, and bone marrow are also a prominentfinding in Niemann-Pick group of diseases.8 Thedifferential diagnosis was settled by quantifica-tion of the activity of sphingomyelinase in thecultured skin fibroblasts of the patient whichshowed values within the range of controls.The overall observations support a disturb-

ance in cholesterol and/or sphingomyelin meta-bolism restricted to the cornea. We suggest thatthe accumulation of cholesterol in the cornea ofthe patient might have been caused by anincrease in lipid synthesis or by a decrease inesterification of cholesterol. Further studies onthe cholesterol esterification process will be animportant step for a better understanding of this

. condition.

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1 Baum JL. Cholesterol keratopathy. AmJ Ophthalmol 1969; 67:372-5.

2 Fine BS, Townsend WM, Zimmerman LE, Lashkai MH.Primary lipoidal degeneration of the cornea. Am JOphthalmol 1974; 78: 12-23.

3 Friedlander MH, Cavanagh HD, Sullivan WR, Gallager MJ,Dickersin GR. Bilateral central lipid infiltrates of the cornea.AmJ Ophthalmol 1977; 84: 781-7.

4 Alfonso E, Arellanes L, Boruchoff SA, Ormerod LD, AlbertDM. Idiopathic bilateral lipid keratopathy. BrJ Ophthalmol1988; 72: 338-43.

5 Duran JA, Rodriguez-Ares MT. Idiopathic lipid cornealdegeneration. Cornea 1991; 10: 166-9.

6 Kyrklund T. Two procedures to remove polar contaminantsfrom a crude brain lipid extract by using prepacked reversed-phase columns. Lipids 1987; 22: 274-7.

7 Shapiro LA, Farkas TG. Lipid keratopathy following corneahydrops. Arch Ophthabnol 1977; 95:456-8.

8 Spence MW, Callahn JW. Sphingomyelin-cholesterollipidosis: the Niemann-Pick group of diseases. In: ScriverCR, Beaudet AL, SlyWS, Valle D, eds. The metabolic basis ofinherited diseases. New York: MacGraw-Hill, 1989; Vol 11:1665-76.

British Journal ofOphthalmology 1993; 77: 250-251

Serious corneal complication of 5-fluorouracil

Marie Hickey-Dwyer, P K Wishart

The success of filtering surgery in eyes with apoor prognosis can be improved by5-fluorouracil (5-FU).'-5 5-FU is known to bepotentially toxic to corneal epithelium andepithelial defects have been reported.26 It hasbeen suggested that the doses of 5-FU originallyrecommended were excessive and that with lowerdoses corneal problems may be less common.7

St Paul's Eye Unit, RoyalLiverpool UniversityHospital, LiverpoolM Hickey-DwyerP K WishartCorrespondence to:Mr P KWishart, FRCS,FCOphth, St Paul's Eye Unit,Royal Liverpool UniversityHospital, Prescot Street,Liverpool L7 8XP.Accepted for publication10 December 1992

Figure I Bandkeratopathy in right eye ofpatient. The bandkeratopathy in the kft eyeundergoing trabecuketomywith 5-FU was identical tothe appearance ofthe righteye preoperatively.

Case reportThis case reports an adverse effect of 5-FUoccurring in the left eye of an 81-year-old manwho underwent a fornix based trabeculectomy tolower raised intraocular pressure uncontrolledby medical treatment. The patient had a 15 yearhistory of open angle glaucoma, and the left eyehad previously undergone an extracapsularcataract extraction (corneal section) withimplantation of a posterior chamber lens. Beforesurgery both eyes had mild idiopathic bandkeratopathy (Fig 1) for several years, with intactoverlying epithelium. The patient was diabeticand preoperatively he was receiving topicaltimolol and pilocarpine in the left eye. At surgery0-2 ml (5 mg) of undiluted 5-FU was injectedsubconjunctivally in the inferior fornix with afurther 5 mg of undiluted 5-FU the followingday. At his first outpatient review 9 days follow-ing surgery a central corneal epithelial defect wasnoted and no further 5-FU was given (Fig 2).

Figure 2 Corneal epithelial defect noted at 9 daysfollowingsurgery in left eye.

The epithelial defect failed to heal despitetopical treatment associated with padding.Because of discomfort due to the epithelialdefect, a bandage contact lens was inserted intothe eye 4 months later. This made the eyecomfortable but no healing of the ulcer occurred.He subsequently presented with reduced visualacuity in the eye, associated with intense pain.Examination revealed the presence of a deepulcer with a corneal abscess and hypopyon(Fig 3).On intensive treatment with topical

cefuroxime and gentamicin the infection was

Figure3 Corneal abscess in the kft eye at 4 monthspostoperatively.

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