British Joumal of Ophthalmology 1995; 79: 453-456

Florid xanthelasmata (yellow lids) in orbitalWegener's granulomatosis

Andrew B Tullo, Paul Durrington, Elizabeth Graham, Lennox P Holt, David L Easty,Richard Bonshek, Joan L Noble

AbstractAims-A new sign of florid xanthelasmatais described in four male patients withorbital manifestations of Wegener'sgranulomatosis.Methods-The case notes of four patientswith Wegener's granulomatosis, withorbital involvement accompanied byyellow lid lesions, are reviewed.Results-All the patients had activeWegener's granulomatosis at the timethe lid lesions were most florid. Thelesions gradually resolved as the inflam-matory disease was controlled withimmunosuppressive agents. The lesionsdisplayed marked asymmetry and pre-dominantly involved the side with themost severe inflammation. Abnor-malities of lipid metabolism were notidentified and it is believed that thelesions developed in a susceptibleanatomical region affected by a vasculiticprocess.Conclusion-A 'yellow lid' associatedwith orbital inflammation and is a strongpointer to the clinical diagnosis ofWegener's granulomatosis.(Br_J Ophthalmol 1995; 79: 453-456)

University Departmentof Ophthalmology,Royal Eye Hospital,Manchester M13 9WHA B TulloR BonshekJ L Noble

University ofManchester,Department ofMedicine, ManchesterRoyal Infirmary,ManchesterP DurringtonL P Holt

Medical Eye Unit, StThomas's Hospital,London SE1 7EHE Graham

University Departmentof Ophthalmology,Bristol BS8 2LXD L Easty

University ofManchester,Department ofPathological Sciences,Manchester M13 9PTR Bonshek

Correspondence to:Mr A B Tullo.Accepted for publication9 December 1994

Wegener's granulomatosis (WG) involvesthe eye or the orbit in 50% of cases. 1-5Ophthalmological features include proptosis,lid oedema, peripheral ulcerative keratitis(PUK) scleritis, and compressive opticneuropathy, all of which may be presentingsigns of the condition. We describe anapparently new sign in WG which, after beingobserved in the first two cases, proved helpfulin the recognition of WG in two otherpatients.

Figure 1 Large waxy yellow lesion of the right upper andlower lid in case 1 in 1978.

Patients

CASE 1A 57-year-old man presented in 1973 to theBristol Eye Hospital with bilateral asym-metrical PUK. He also complained of a bloodstained nasal discharge. An x ray of the rightmaxillary antrum showed mucosal thickening.A chest x ray revealed a well defined roundedopacity in the right upper lobe which wasbiopsied and found to be 'granulomatous'. Asecond opacity was present in the right lowerlobe. The right hilum was enlarged and a smallleft pleural effusion was present. In 1978 hedeveloped proptosis of the right eye associatedwith a palpable mass above the globe andophthalmoplegia. One year later masses werepalpable above and below the globe being con-tinuous on the nasal side and overlaid by awaxy yellow discoloration. (Fig 1). Biopsies ofthe orbit and sinus revealed granulomatoustissue, but no evidence of vasculitis.He was treated with systemic steroids and

cyclophosphamide with good effect. When lastseen in 1992 his vision was 6/9 in each eye andthe inflammatory process was controlled with amaintenance dose of prednisolone 2 mg daily.Over the 14 year period of treatment sincetheir appearance the yellow lid lesions havegradually faded are now only visible on closeexamination.

In August 1989 anti-neutrophil cytoplasmicantibodies (ANCA) were detected at a titre of1:80. ANCA were negative when retested inOctober 1990 at which time C-reactive proteinwas present at 0 033 g/l. Recent fasting serumtriglyceride concentration was 1 38 mmol/l,serum cholesterol 6-47 mmol/l, low densitylipoprotein cholesterol (LDL) 4-20 mmol/l, andhigh density lipoprotein cholesterol (HDL) 1 69mmoIIl. Apoliprotein E phenotype was 3/3.-~~~~~~~~~~~~~~~~~~~~ .i: ... U

Figure 2 Raisedyellow banana-shaped lesion of rightlower lid and much smaller lesion on nasal aspect of leftlower lid in case 2 1987.

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Tullo, Durrington, Graham, Holt, Easty, Bonshek, Noble

Figure 3 Barely visible lid lesion in case 2 in 1992 aftersystemic treatmentfor Wegener's granulomatosis.

CASE 2A 29-year-old man presented in 1985 with red-ness ofboth eyes due to bilateral sclerokeratitisassociated with extensive peripheral cornealmelting. One year previously he had beeninvestigated for macroscopic haematuria andpolyarthritis. He was treated successfully withtopical steroids, but 18 months later developedswelling on both right and left lower eyelidsassociated with some proptosis and diplopia.Investigations revealed an erythrocyte sedi-mentation rate of 90 mm/h, hypergammaglob-ulinaemia, positive rheumatoid factor, positiveantinuclear, gastric parietal and antimitochon-drial antibodies. A biopsy of orbital tissueshowed an acute vasculitis with polymorphsinfiltrating the vessel wall and a chronic inflam-matory cell infiltrate around the vessel consis-tent with a diagnosis of WG. Treatmentwith systemic steroids was commenced with agood response initially, but in June 1987 hedeveloped gaze evoked amaurosis in the righteye on dextroversion. At this point he wastransferred to St Thomas's Hospital, London.There was proptosis (4 mm) of the right eye

with an extensive xanthelasma in the rightlower lid (Fig 2). Movements of the right eyewere limited in all directions, but were normalin the left eye. Visual acuity could be correctedto 6/9 in each eye with intact colour vision.Visual fields were full, but for an enlarged rightblind spot. Slit-lamp examination revealedbilateral sclerokeratitis with extensive PUK.The right optic disc was markedly swollen withchoroidal folds stretching between the opticdisc and the macula. A computed tomographyscan showed a diffuse opacification of the rightorbit consistent with a diagnosis of WG.

Figure 4 Lesion of the right lid in case 3 on presentationin 1978, also showing ptosis and marked lower lid swelling.

Figure S Lid biopsy from case 3five years aftercommencement of treatment. There are large numbers oflargefoamy macrophages within the diffusexanthelasmatous dermis. Also present are numbers oflymphocytes and macrophages. (Haematoxylin and eosinstain, X 75 magnification.)

Cyclophosphamide was added to oral steroidtherapy and the proptosis and disc oedemapartially resolved. However, his gaze evokedamaurosis persisted and consequently heunderwent right orbital decompression in 1988with resolution of this symptom. The systemictreatment has been slowly reduced and wasstopped in early 1992. He is currently asymp-tomatic and the xanthelasmata have practicallydisappeared. (Fig 3).ANCA were first tested for in 1990 and

were detected at a titre of 1 in 80. Additionalinvestigations revealed normal renal and liverfunction, cholesterol 7p0 mmol/ triglycerides2p3 mmol/l.

CASE 3A 73-year-old man presented in March 1985with a 5 month history of redness and prop-tosis of the right eye accompanied by recurrentnose bleeds. Orbital ultrasonography sug-gested features of an orbital pseudotumour. Atherapeutic trial of 40 mg of prednisolone wasstarted which produced some slight improve-ment. He was referred to the ManchesterRoyal Eye Hospital where gross right proptosiswas noted, the globe being displaced down-wards and outwards with complete ophthal-moplegia. There was marked lid swelling onthis side and a discrete raised yellowish patchon the superonasal aspect of the right upper lidwas noted (Fig 4). No tendon xanthomatawere present, nor were other types of xantho-mata present elsewhere. Visual acuities were

Figure 6 The relatively small raisedyellowbanana-shaped lesion of the right upper lid in case 4 onpresentation in 1987.

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Florid xanthelasmata (yellow lids) in orbital Wegener's granulomatosis

'counting fingers' in the right eye and 6/9 in theleft eye with a right afferent pupil defect.Biomicroscopic examination revealed PUKaffecting 3600 of the right eye with twonecrotic areas of scleritis. The right fundusshowed marked retinal venous congestion andcotton wool spots around the optic disc.Computed tomography scan showed a masssituated in the medial aspect of the right orbitwhich appeared to be surrounding the medialrectus muscle and showed slight enhancementon the post contrast films. There was amucosal thickening of the right maxillaryantrum on plain x ray.

Chest x ray revealed several cavitatinglesions in the right middle lobe. Other investi-gations included erythrocyte sedimentationrate, 65 mm in 1 hour, haemoglobin 12-2 g/dl,a normal differential white cell and plateletcount, but a raised mean cell volume. Ureaand electrolytes, C-reactive protein andimmunoglobulins, and electrophoresis wereall normal.A diagnosis ofWG was made and treatment

with cyclophosphamide 50 mg twice daily wasadded to his oral steroids. All his ocular signsbecame stable and visual acuity recovered to6/12 in the right eye. Cyclophosphamide wasstopped after 2 years. Eight years after theonset of his condition he remains well onenteric coated prednisolone 10 mg daily. In1990 he underwent cataract extraction in theleft eye for steroid related opacities, at whichtime a right upper lid biopsy (Fig 5) was takenfrom a now barely discernible lid lesion.ANCA were absent in February 1990 andagain in March 1991. Investigation of hisserum lipoproteins in 1991 gave the followingresults: serum cholesterol was 8-3 mmol/l,low density lipoprotein cholesterol (LDL)6-3 mmol/l (245 mg/dl), high density lipo-protein cholesterol 1-4 mmol/, and fastingserum triglycerides 1 2 mmoIl. Thus his totalserum cholesterol was elevated as a result of anincrease in LDL indicating type IIa hyper-lipoproteinaemia. His apolipoprotein E pheno-type was 4/4.

CASE 4A 33-year-old man was referred to theManchester Royal Eye Hospital in November1987 with a 4 year history of recurrent photo-phobia, supraorbital pain, proptosis, andswelling of the right eye. There was a 9 yearhistory ofbloody purulent nasal discharge withanosmia. Treatment with systemic steroids atanother hospital 6 months previously hadproduced an incomplete response. On exami-nation there was lid swelling, chemosis, andproptosis ofthe right eye. Two palpable masseswere present, one at the superonasal aspect ofthe left upper lid and one at the inferotemporalmargin of the right lower lid. A slightly raised,banana-shaped patch was noted in the supero-nasal aspect of the right upper lid (Fig 6). Notendon xanthelasmata were present, nor wereother types of xanthelasmata present else-where. Visual acuity was 6/6 in the right eyeand 6/18 in the left, this eye being amblyopic.

A computed tomography scan showed exten-sive soft tissue masses in both orbits. Plainx ray revealed poorly developed antra suggest-ing longstanding inflammatory changes andthe right ethmoidal sinus was opaque. Otherinvestigations included: normal full bloodcount, erythrocyte sedimentation rate, andchest x ray. A nasal biopsy showed fibroustissue with chronic inflammatory cell infiltra-tion and an orbital biopsy revealed sclerosingangiitis with marked fibrosis. ANCA werestrongly positive with a titre of 1:300, C-reac-tive protein was 0 03 g/l, serum cholesterol was5 8 mmol/l, LDL cholesterol 3-5 mmoUl, HDLcholesterol 1-6 mmoVl, and the fasting serumtriglyceride concentration was 1 2 mmol/l.Azathioprine 100 mg daily was added to hispre-existing treatment of prednisolone 25 mgdaily and the orbital signs slowly resolved overthe ensuing 18 months. The yellowish dis-coloration of the skin in upper and lower eyelids gradually resolved over the same period.In 1990 he suffered a recurrence of orbitalinflammation associated with visual loss due tooptic nerve compression. Pulsed intravenousmethylprednisolone and cyclosphosphamidebrought about an improvement, and herequired a maintenance dose of azathioprine50 mg twice daily and prednisolone 50 mg tocontrol inflammation. He died suddenly inMarch 1992 as a result of deep vein thrombo-sis and pulmonary embolism. A postmortemexamination was not performed.

DiscussionXanthelasmata were the first manifestation ofhyperlipidaemia to be described.6 It is, how-ever, recognised that they also occur in in-dividuals whose serum lipids are not clearlyelevated, and may have a dominant pattern ofinheritance even in the absence of hyper-lipidaemia.7 This argues for local anatomicalfactors also being important in the genesis ofxanthelasmata. Blood flow may also be impor-tant in the pathogenesis and is thought to be afactor in unilateral corneal arcus associatedwith carotid occlusion, where the cholesteroldeposition occurs only in the contralateraleye.8 In our experience, however, it is exceed-ingly unusual for a xanthelasma of any size tooccur unilaterally.The lipid deposits in xanthelasmata are

present at least initially in foam cells9 whichprobably represent monocyte/macrophageswhich have entered the subcutaneous tissuesfrom the blood circulation and have engulfedlipoproteins as is believed to occur in athero-genesis.'0 The lipid laden macrophages losetheir ability to migrate out of the tissues whichthus become engorged with lipid. This wholeprocess would be expected to increase as theresult of heightened vascular permeability andchemotactic factors associated with inflam-mation. An example of this is the developmentof Achilles tendon xanthomata in familialhypercholesterolaemia, which are frequentlyassociated with episodes of tendonitis, andwhere xanthomata progress more rapidly whenthe tendonitis is recurrent. I I Certainly the

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Tullo, Dumington, Graham, Holt, Easty, Bonshek, Noble

presence of structurally abnormal vessels - forexample, in the normally avascular cornea,may also lead to similar lipid deposition. Thiscan be seen in chronic herpes zoster keratitis,even without hyperlipidaemia.12 It seems

therefore, that factors potentially involved inthe pathogenesis of macroscopic lipid contain-ing lesions include hyperlipidaemia, but that a

susceptible anatomical site, and abnormalpermeability of vessels are also important.Our patients were all diagnosed as having

WG based on clinical grounds with supportfrom x ray and biopsy, and satisfied thecriteria13 which distinguish WG from otherforms of vasculitis. When the test for ANCAbecame available it proved to be unequivocallypositive only in patient 3. Both patients 1 and2 had weakly positive or negative tests forANCA after 12 and 6 years of treatmentrespectively which is, however, still consistentwith the diagnosis of WG.14 15A rare cause of lipid deposition in the lids

which should be considered in such cases isnecrobiotic xanthogranulomal6-18 in which thelesions are indurated and may ulcerate. Theymay be associated with paraproteinaemia,myeloma, or leukaemia and can present withskin lesions elsewhere. This may also occur inthe absence of hyperlipoproteinaemia or even

when hypolipoproteinaemia is present.10Another rare diagnosis deserving of inclu-

sion in the differential diagnoses is Erdheim-Chester disease in which orbital involvement isitself most unusual. 19 The condition is charac-terised by a fibrosing xanthogranulomatousprocess distinct from the histiocytosis group, inwhich the lungs, pericardium, and long tubularbones are principally targeted. Of the two

known cases with ophthalmic involvementboth had bilateral proptosis, severe optic nerve

compression, and in one case bilateral lower lidxanthelasmata and lid thinning developed.'9

In all our patients the yellow lid lesionsbecame apparent within 1 year of the onset oforbital involvement though often several years

after the onset of other clinical features ofWG.Once appropriate treatment was started therewas gradual resolution, not only in bulk of thelesions to palpation, but also in their visibilitysuch that all lesions eventually became barelyvisible. We believe that in our patients theinflammatory process itself was the cause ofxanthomatosis in a susceptible anatomicalregion despite the presence of relatively normalserum lipids in at least two out of four patients.Of the other two the serum cholesterol levelswere 7-0 mmoIl. These were thus at approxi-mately the 75th percentile and above the 95thpercentile for the British male population ofsimilar age.20 The patient with clearly elevatedcholesterol level did not have features offamilial hypercholesterolaemia such as tendonxanthomata and his apolipoprotein E pheno-type was 4/4 excluding type III hyperlipopro-teinaemia, another primary hyperlipidaemia

frequently associated with xanthomata. Histype IIa hyperlipoproteinanaemia was mostlikely, therefore, to be polygenic and of thetype not usually associated with florid xantho-matosis. It is thus unlikely that any of our seriesof patients would have developed florid orunilateral xanthelasmata in the absence ofWG.The advent of ANCA assay is a helpful

development and orbital biopsy has somevalue in WG.21 Clinical signs in orbital inflam-matory disease are of great importance thoughinvolvement of the lids is very rare.22 Wetherefore wish to draw attention to a 'yellowlid' as an additional clinical sign suggestive ofWG, and which should fade after appropriatetreatment.

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14 Nolle B, Specks U, Ludemann H, Rohrbach MS, DeRemeera, Gross WL. Anticytoplasmic autoantibodies:their immunodiagnostic value in Wegener's granulo-matosis. Ann Intern Med 1989; 111: 28-40.

15 Soukiasian SH, Foster CS, Niles JL, Raizman MB.Diagnostic value of antineutrophil cytoplasmic antibodiesin scleritis associated with Wegener's granulomatosis.Ophthalmology 1992; 99: 125-32.

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22 Jordan DR, Addison DJ. Wegener's granulomatosis.Eyelid and conjunctival manifestations as the presentingfeature in two individuals. Ophthalmology 1994; 101:602-7.

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Wegener's granulomatosis.Florid xanthelasmata (yellow lids) in orbital

L NobleA B Tullo, P Durrington, E Graham, L P Holt, D L Easty, R Bonshek and J

doi: 10.1136/bjo.79.5.4531995 79: 453-456 Br J Ophthalmol

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