British Journal of Ophthalmology, 1989, 73, 669-673

Corneal subepithelial monoclonal kappa IgG depositsin essential cryoglobulinaemiaISRAEL KREMER,' PETER WRIGHT,2 SHAUL MERIN,3 JEHUDA WEISS,'A I PICK,4 AND HERBERT KAUFMAN5

From the 'Departments of Ophthalmology and 4Clinical Immunology, Beilinson Medical Center, Petah Tiqva,and Tel Aviv University Sackler School ofMedicine, Israel; the 2External Eye Diseases Clinic, Moorfields EyeHospital, London; the 3Department ofOphthalmology, Hadassah Medical Center, Jerusalem, Israel; and 5LSUEye Center, New Orleans, LA, USA

SUMMARY A 60-year-old man suffering from photophobia and visual disturbances was found tohave bilateral superficial corneal grey-white gelatinous deposits. An abnormal cold-precipitableserum component was found and characterised as homogeneous IgG-kappa immunoglobulin.Corneal immunohistochemical examination revealed subepithelial IgG-kappa deposits, focallyreplacing Bowman's layer. The patient underwent superficial keratectomy in both eyes withsatisfactory visual results.

Bilateral corneal deposits have been described inassociation with dysproteinaemia since 1934.' Toour knowledge there is only one report9 describingcorneal subepithelial immunoglobulin deposits inbenign monoclonal gammopathy, simulating theclinical non-crystalline appearance and distributionof the corneal deposits found in our patient. Suchdeposits have never been described in essentialcryoglobulinaemia. We present the results ofbilateral superficial keratectomy performed on apatient with essential IgG-kappa cryoglobulinaemia,the only manifestation of which was the superficialcorneal immunoglobulin deposits.

Case report

A 60-year-old man presented with photophobia,tearing, and gradually decreasing vision. On exami-nation his best corrected visual acuity (VA) was 6/12in both eyes. Slit-lamp examination of both corneasshowed raised gelatinous grey-white subepithelialavascular nodules, in the corneal periphery butsparing the limbus (Fig. 1). These confluent non-crystalline nodular masses extended towards thevisual axis by finger-like projections. The cornealstroma, Descemet's membrane, and endotheliumappeared normal. The anterior and posterior seg-

Correspondence to Dr I Kremer, Department of Ophthalmology,Beilinson Medical Center, Petah Tiqva, 49 100, Israel.

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ments were completely normal, as were the eyelidsand conjunctiva.The physical examination and bone x-rays showed

nothing abnormal.

Fig. 1 Slit-lamp photograph showing the confluent nodulargelatinous-like superficial corneal deposits, extendingtowards the corneal centre byfinger-like projections (arrow).

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Fig. 2 (a-d) Electrophoresis andimmunoelectrophoresis of thepatient's serum (a, b) andcryoprecipitate (c, d), revealing thepresence ofhomogeneous IgG-kappa immunoglobulin.

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Subsequently the patient's serum was examined. Acryoprecipitate was discovered and was characterisedby immunoelectrophoresis as a homogeneousIgG-kappa immunoglobulin (Fig. 2). Serum immuno-globulins were quantitated by nephelometry (Table1).

Table 1 Results ofserum cellulose acetate electrophoresis

Protein g/l Normal range gil

IgG 30 2-0-10S5IgA 1-86 0-8-2 7IgM 1-24 0-4-11

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Fig. 3 Massive accumulation ofred coloured subepithelialdeposits located between the atrophic epithelium andBowman's zone (arrow), which is focally disrupted.(Masson-trichrome stain, original magnification x250).

As a bone marrow biopsy showed normalappearances, the diagnosis of essential IgG-kappacryoglobulinaemia was established.A small lamellar biopsy was performed in the right

cornea. The histopathological examination withhaematoxylin-eosin showed eosinophilic subepithe-lial deposits, located between Bowman's layer orsuperficial stroma and basal epithelial layer.Bowman's layer was focally disrupted and replacedby the eosinophilic periodic acid Schiff positivematerial. With Masson trichrome staining red-coloured aggregates were seen beneath the elevatedatrophic epithelium (Fig. 3). Stains for amyloid werenegative. Electron microscopy revealed that thedeposits were composed of numerous rod-shapedbodies (Fig. 4). Each rod was composed of parallelfine filaments with a 9-5-10 nm periodicity (Fig. 5). Aconjunctival biopsy revealed the presence of con-junctival subepithelial aggregates of homogeneouskappa-IgG (Fig. 6).During the following years the VA decreased

gradually to 6/40, with J-7 in both eyes. It was notpossible to perform skiascopy or keratometry, as thecorneal surface was irregular.

Fig. 4 Electron microscopy of thecorneal biopsy specimen showingnumerous subepithelial rod-shapedbodies (arrows). (Originalmagnification x8200.)

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Israel Kremer, Peter Wright, Shaul Merin, Jehuda Weiss, A I Pick, and Herbert Kaufman

Fig. 5 At higher magnification(EM) the rod-shaped bodies areseen to be composed ofparallelfinefilaments (arrow) with a periodicityofapproximately 10 nm. (Originalmagnification x 42 000).

Owing to the subepithelial location of the cornealdeposits, approaching the corneal centre, it wasdecided to perform superficial keratectomy byshaving the cornea with a scalpel blade. After thisprocedure, the VA improved to 6/7 5 in the right eyeand 6/7 in the left, with J-1 in both eyes. Thekeratometry revealed bilateral regular astigmatismof O-5 D.

Immunohistochemical examination of thekeratectomised material showed that the cornealimmunoglobulin deposits were antigenicallyidentical to the homogeneous IgG-kappa (cryo-globulin) serum component.

Fourteen months after the operation the cornealsurface was completely smooth, and a peripheral

Fig. 6 Massive accumulation ofconjunctival subepithelialimmunoglobulin G deposits (anti-JgG positive).(Immunoperoxidase stain, original magnification x 400.)

band of superficial stromal scarring was notedbilaterally (Fig. 7).

Discussion

Corneal immunoglobulin deposits in association withhypergammaglobulinaemia have been describedmainly as crystals.8 10-'4 The definitive evidence thatthe latter corneal crystals are immunoglobulins wasprovided by Klintworth et al.6 using immunofluore-scent and immunoperoxidase techniques. Garner

Fig. 7 Patient's right cornea six months after superficialkeratectomy, showing confluent superficial stromalpacification covered by a completely smooth epithelium inthose areas where the deposits have been removed.

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Cornealsubepithelial monoclonal kappa IgG deposits in essential cryoglobulinaemia

and Kirkness'4 maintain that the unifying character-istic of these crystals is the 10 nm periodicity of theirbanded infrastructure.The clinical appearance and anatomical location of

these corneal deposits may be quite variable.'34 Inmost cases they are found in the stroma`57-13 and onlyrarely in the corneal epithelium proper6 or immedi-ately beneath it.9 Paraproteinaemic keratopathy inassociation with true monoclonal gammopathy ofunknown significance (MGUS) is very rare and hasbeen reported in only four cases.' '3 '5 Our patient isthe fifth recorded case with MGUS. However, as themonoclonal paraprotein found in his serum had thecharacteristics of cryoglobulin his disease may bedefined also as essential cryoglobulinaemia.As regards cryoglobulinaemia, Palm'5 was the first

author to report on superficial corneal deposits in acase of crystalcryoglobulinaemia. The nature of thesecorneal deposits differed from that of our patient inthat they had a crystalline appearance. Oglesby'6 isthe only author to report on corneal non-crystallinedeposits in a patient with cryoglobulinaemia, whichwas associated with reticulohistiocytosis. Thecorneal stromal involvement in this patient waspredominantly posterior. However, Oglesby'6presented no histological or immunohistochemicalproof for the presence of corneal immunoglobulindeposits. No surgical or medical treatment wasmentioned in these two reports.5 16

Allansmith and colleagues" 11 reported that almostall immunoglobulins can be found in normal corneasand that their concentration correlates with theserum level. They maintain that corneal immuno-globulins are derived mainly from the serum bydiffusion from perilimbal vessels.The presence of a cold precipitable immuno-

globulin in the serum of our patient may explain itsmassive preferential accumulation in the cornealsubepithelial region, as it is probably one of thecoldest areas in the human body.'9 According toWaltman and Hart'9 the difference in temperaturebetween the rabbit cornea and the iris amounts to5°C. As the cryoglobulin precipitates in a tempera-ture below 34°C2, it may undergo crystalloid changesfollowing precipitation under the corneal epithelium,the temperature of which is probably around 32°C.These corneal cryoglobulin precipitates found in

our patient were removed by superficial keratectomy,after which a smooth corneal resurfacing wasachieved. For the time being invasive surgical tech-niques, such as perforating or lamellar keratoplasty,have been postponed. Whenever the above-described corneal deposits recur outside the corneal

centre, superficial keratectomy can be repeated.However, if they appear in the central zone, kerato-plasty is indicated. It is our opinion that this pro-cedure should probably be supplemented in futureeither by plasmapheresis or by low dosage chemo-therapy2' in order to keep the corneal graft clear.References

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3 Miller KH, Green WR, Stark WJ, Wells HA, Mendelsohn G,Kanhofer H. Immunoprotein deposition in the cornea.Ophthalmology 1980; 87: 944-50.

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6 Klintworth GK, Bredehoeft SJ, Reed JW. Analysis of cornealcrystalline deposits in multiple myeloma. Am J Ophthalmol1978; 86: 303-13.

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10 Laibson PR, Damiano VV. X-ray and electron diffraction ofocular and bone marrow crystals in paraproteinemia. Science1969; 163:581-3.

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Acceptedfor publication 3 February 1989.

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