Paraproteinemic Corneal Deposits in Plasma Cell Myeloma
Klaus-Peter Steuhl, M.D., Marcus Knorr, M.D., Jens M a r t i n Rohrbach, M.D., Walter Lisch, M.D., Edwin Kaiserling, M.D., and Hans-Jürgen T h i e l , M . D .
We t r e a t e d t w o p a t i e n t s w h o h a d I g G kappa-light chain monoclonal gammopathy with partially crystalline and partially amor phic corneal deposits. Impairment of vision m a d e k e r a t o p l a s t y n e c e s s a r y for e a c h p a t i e n t . H i s t o l o g i c e x a m i n a t i o n of t h e c o r n e a l s p e c i mens showed deposits that stained positively for M a s s o n ' s t r i c h r o m e in a l l c o r n e a l c e l l s . I m m u n o h i s t o c h e m i c a l tests identified t h e s e deposits as IgG-kappa-light chain i m m u n o globulin fragments. Electron microscopy showed intracellular, rhomboid-shaped de posits enveloped by a m e m b r a n e . T h e s a m e d e p o s i t s a p p e a r e d in t h e c o n j u n c t i v a l e p i t h e l i u m , w i t h i n s u b c o n j u n c t i v a l fibrocytes, a n d in t h e p l a s m a c e l l s of t h e b o n e m a r r o w . I m m u noelectrophoresis showed IgG-kappa-light c h a i n f r a g m e n t s in t h e b l o o d s e r u m , t h e l a c r i m a l film, a n d t h e a q u e o u s h u m o r . T h i s s u g gests that the intracellular i m m u n o g l o b u l i n fragments may have entered the corneal and c o n j u n c t i v a l e p i t h e l i u m by w a y of t h e l a c r i m a l film, t h e k e r a t o c y t e s by w a y of t h e c o r n e o scleral limbus vasculature, and the endotheli al cells from the aqueous h u m o r .
M O N O C L O N A L G A M M O P A T H Y r e s u l t s from un c o n t r o l l e d p r o l i f e r a t i o n o f a p l a s m a cell c l o n e , w h i c h p r o d u c e s an e x c e s s e i t h e r o f i m m u n o g l o b u l i n s or t h e i r h e a v y or l i g h t c h a i n frag m e n t s . D i s e a s e s a s s o c i a t e d with e x c e s s i v e s e c r e t i o n o f m o n o c l o n a l p a r a p r o t e i n s are e i t h e r b e n i g n , with l i m i t e d p l a s m a cell g r o w t h , or malignant, with uncontrolled plasma cell growth. The malignant monoclonal g a m m o -
Accepted for publication Dec. 6, 1990. From the University Eye Clinic Tübingen (Drs. Steuhl, Knorr, Rohrbach, Lisch, and Thiel), and Institute of Pathology (Dr. Kaiserling), University of Tübingen, Tubingen, Germany. This study was supported in part by a grant from Pharm-Allergan, Karlsruhe, Germany. Reprint requests to K.-P. Steuhl, University Eye Clin ic, Schleichstr. 12, D-7400 Tübingen, Germany.
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p a t h i e s ( m o r e t h a n h a l f o f t h e s e are p l a s m a c y tomas') are characterized by continuous growth of t h e p l a s m a cell c l o n e , w h i c h r e s u l t s in an exponential increase of the m o n o c l o n a l protein in t h e b l o o d . T h i s l e a d s to a n e m i a , failure o f t h e i m m u n e s y s t e m , h y p e r c a l c e m i a , soft t i s s u e a n d skin tumors, altered blood rheologic tests, and r e n a l failure,^ a n d o s t e o l y t i c b o n e l e s i o n s w h e n the tumor manifests extramedullarily. T h e an n u a l i n c i d e n c e o f p l a s m a c e l l n e o p l a s m s is e s t i m a t e d as t h r e e in a p o p u l a t i o n o f 1 0 0 , 0 0 0 . ^ ^ The circulating paraproteins are considered r e s p o n s i b l e for n o n a m y l o i d o r g a n deposits.^'' Ocular sites of paraprotein deposits are the conjunctival, corneal, and lens epithelium, k e r a t o c y t e s , e n d o t h e l i a l c e l l s , p l a s m a cell infil t r a t i o n o f the u v e a w i t h c o n c o m i t a n t u v e i t i s , c y s t s of t h e c i l i a r y b o d y , hyperviscosityderived occlusion of the retinal vessels, and retinal h e m o r r h a g e s . ' ' ' We studied partially crystalline and partially a m o r p h o u s corneal de p o s i t s in t w o p a t i e n t s w i t h p l a s m a c e l l m y e l o m a and associated monoclonal gammopathy.
Case Reports Case 1 In 1 9 7 3 , p l a s m a c y t o m a w a s d i a g n o s e d in a 5 0 - y e a r - o l d m a n on t h e b a s i s o f t y p i c a l p r o nounced increase of IgG fraction with a high paraprotein increase (IgG, 2 , 8 9 7 m g / d l ; nor m a l , 8 0 0 to 1 , 8 0 0 m g / d l ) , d e c r e a s e o f I g A a n d IgM, and the increased n u m b e r of atypical plas m a c e l l s in a s p i r a t e d s t e r n a l b o n e m a r r o w (approximately 2 5 % ; normal, 2 % ) . Immuno e l e c t r o p h o r e s i s i d e n t i f i e d t h e p a r a p r o t e i n as L - c h a i n k a p p a t y p e . L a b o r a t o r y test r e s u l t s for serum lipids, e n z y m e status, and electrolytes w e r e all n o r m a l . T h e b l o o d c e l l c o u n t s w e r e normal, with a mild a n e m i a ( h e m o g l o b i n b e tween 6.8 g / d l and 11.7 g / d l ) . T h e patient had two o s t e o l y t i c s k u l l l e s i o n s a n d a b i l a t e r a l c a r pal c a n a l s y n d r o m e as e x t r a m e d u l l a r y m a n i f e s -
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Fig. 1 (Steuhl and associates). Microscopic appearance of the superficial (left) and deeper (right) corneal tissue. Intracytoplasmic deposits within epithelial cells (arrows) and keratocytes (arrowheads). Note the endothelium filled with intracytoplasmic deposits and positive staining for Masson's trichrome (asterisk) ( x 250).
t a t i o n s o f the d i s e a s e . R e p e a t e d r e c t a l b i o p s y specimens showed no signs of amyloidosis. Bence Jones proteinuria of approximately 3 0 0 m g / d l b e g i n n i n g in t h e e a r l y 1 9 8 0 s led to irreversible tubular damage and kidney atro phy. D i a l y s i s w a s r e q u i r e d in J u n e 1 9 8 5 . R e peated treatment with 6 mg of m e l p h a l a n daily for five days a n d 4 m g of m e t h y l p r e d n i s o l o n e l o n g - t e r m r e s u l t e d in n o o v e r a l l i m p r o v e m e n t . T h e p a t i e n t d i e d in August 1 9 8 7 . A slight l o s s o f c o r n e a l t r a n s p a r e n c y w i t h o u t r e d u c t i o n in v i s i o n w a s o b s e r v e d in the e a r l y 1 9 7 0 s . W h e n e x a m i n e d at t h e U n i v e r s i t y E y e C l i n i c in T u b i n g e n in A p r i l 1 9 8 2 , t h e c o r n e a s were hazy because of dense, white, partially c r y s t a l l i n e d e p o s i t s in all c o r n e a l l a y e r s , p a r t i c ularly the deep stroma and the endothelium. A p a r t from a n u c l e a r c a t a r a c t , o t h e r o p h t h a l m i c findings w e r e u n r e m a r k a b l e ( t h e v i e w of t h e fundus w a s o b s c u r e d ) . T h e r e w e r e n o s i g n s o f a c t i v e or r e c u r r e n t u v e i t i s . P e n e t r a t i n g k e r a t o p l a s t y w a s p e r f o r m e d on t h e r i g h t e y e in J a n u ary 1 9 8 4 , a n d an e x t r a c a p s u l a r c a t a r a c t e x t r a c tion a n d p o s t e r i o r c h a m b e r i n t r a o c u l a r l e n s i m p l a n t a t i o n w a s p e r f o r m e d in S e p t e m b e r 1 9 8 4 . Best-corrected visual acuity was 2 0 / 2 0 . At that t i m e , a s l i g h t , c o r n e a l h a z e w a s o b s e r v e d in t h e graft o f t h e r i g h t e y e . T h e o p a c i ties w e r e l o c a t e d p r i m a r i l y in t h e d e e p e r l a y e r s of the p e r i p h e r y o f t h e t r a n s p l a n t . In J a n u a r y 1 9 8 5 , v i s u a l a c u i t y in t h e r i g h t e y e w a s r e d u c e d to 1 0 / 2 0 . In April 1 9 8 6 , v i s u a l a c u i t y in t h e left e y e w a s 2 / 2 0 . Simultaneous perforating keratoplasty a n d e x t r a c a p s u l a r c a t a r a c t e x t r a c t i o n with p o s terior c h a m b e r i n t r a o c u l a r l e n s i m p l a n t a t i o n w a s p e r f o r m e d on the left e y e , a n d b e s t - c o r r e c t ed visual a c u i t y w a s 8 / 2 0 . In O c t o b e r 1 9 8 6 ,
c o r n e a l o p a c i t i e s h a d r e c u r r e d in t h e left e y e , a n d t h e t r a n s p l a n t in t h e r i g h t e y e s h o w e d d e p o s i t s in all l a y e r s . V i s u a l a c u i t y w a s R . E . : 1 0 / 2 0 and L.E.: 6 / 2 0 .
Fig. 2 (Steuhl and associates). Electron microscopic aspect of the conjunctival epithelium showing intra cellular inclusions (arrows) and subepithelial tissue (ST). Note that the intracellular deposits are also visible within subepithelial fibrocytes (arrowhead) ( X 1,600).
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F i g . 3 (Steuhl and associates). Electron micrograph of the superficial (left) and basal (right) region of the corneal epithelium with numerous intracytoplasmic deposits (arrows). (M, microvilli; N, nuclei; and BL, Bowman's layer.) (Left, x 12,500; right, x 2,000.)
Case 2 In A u g u s t 1 9 8 9 , p l a s m a c y t o m a w a s d i a g n o s e d in a 7 8 - y e a r - o l d w o m a n o n t h e b a s i s of t y p i c a l findings in s e r u m e l e c t r o p h o r e s i s o f I g G level g r e a t e r t h a n 4 , 0 0 0 m g / d l , d e c r e a s e d I g A level to 4 0 m g / d l , I g M level o f 3 0 m g / d l , a n d b o n e marrow puncture with 1 8 % plasma cells. L i g h t m i c r o s c o p y s h o w e d that t h e s e p l a s m a cells had marked vacuolization with crystalline inclusions. Immunoelectrophoresis showed a p l a s m a c y t o m a of I g G - k a p p a - l i g h t c h a i n t y p e . E x c e p t for t h e o p h t h a l m i c findings, n o e x t r a m e d u l l a r y m a n i f e s t a t i o n s of t h e d i s e a s e w e r e f o u n d . L a b o r a t o r y test r e s u l t s for s e r u m l i p i d s , e n z y m e status, a n d s e r u m e l e c t r o l y t e s ( i n c l u d ing c a l c i u m a n d c o p p e r ) w e r e n o r m a l . T h e p a tient had anemia (hemoglobin, 8.7 g / d l ) , and c r e a t i n i n e a n d urea l e v e l s w e r e n o r m a l . T h e urine contained 150 m g / d l of protein (Bence J o n e s p r o t e i n u r i a of I g G - k a p p a - l i g h t c h a i n type). Biopsy specimen of the oral mucosa showed no indication of generalized amyloido sis. T h e p a t i e n t died D e c . 2 5 , 1 9 8 9 , o f p u l m o
n a r y h e a r t failure after c y t o s t a t i c t r e a t m e n t o f the disease. T h e first m y e l o m a - a s s o c i a t e d o c u l a r i n v o l v e m e n t b e g a n in t h e l a t e 1 9 7 0 s . In April 1 9 8 8 , visual acuity was R.E.: 3 / 2 0 and L.E.: 8 / 2 0 . T h e r e d u c e d v i s u a l a c u i t y w a s c a u s e d b y diffuse, b i l a t e r a l c o r n e a l h a z e . W h e n e x a m i n e d at the U n i v e r s i t y E y e C l i n i c T ü b i n g e n in S e p t e m b e r 1 9 8 9 , visual acuity was R . E . : 4 / 2 0 0 and L.E.: 6 / 2 0 . D e n s e , diffuse, p a r t i a l l y c r y s t a l l i n e c o r n e a l o p a c i t i e s i n v o l v e d all c o r n e a l l a y e r s . In October 1 9 8 9 , perforating keratoplasty and ex tracapsular cataract extraction were performed in t h e r i g h t e y e . T h e r e w e r e n o i n t r a o p e r a t i v e or postoperative complications, and best-correct ed v i s u a l a c u i t y w a s 5 / 2 0 .
Material and Methods S e m i t h i n paraffin s e c t i o n s w e r e s t a i n e d w i t h periodic acid-Schiff, C o n g o red, and M a s s o n ' s
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layer in b o t h p a t i e n t s . T h e l a m e l l a e o f the corneal stroma were loosened edematously, a n d t h e rarified e n d o t h e l i u m d i s c l o s e d v a c u o l i c d e g e n e r a t i o n . In b o t h c a s e s i n t r a c y t o p l a s m i c d e p o s i t s w e r e l o c a t e d w i t h i n all c o r n e a l c e l l s and stained positive with Masson's trichrome (Fig. 1 ) . A m y l o i d w a s e x c l u d e d s i n c e t h e y did n o t s t a i n w i t h C o n g o r e d a n d w e r e n e g a t i v e for green birefringence. No extracellular material was found. Electron micrographs showed these i n t r a c y t o p l a s m i c d e p o s i t s to b e p a r a c r y s t a l l i n e , r h o m b o i d , a n d p r e s e n t in t h e c o n j u n c t i v a l e p i thelium (Fig. 2 ) , in the epithelial layers o f the c o r n e a ( F i g . 3 ) , in k e r a t o c y t e s ( F i g . 4 ) , a n d in t h e e n d o t h e l i a l layer ( F i g . 5 ) , w h e r e t h e y l e d to pronounced degenerative changes. This intra cytoplasmic material was enveloped by a dou ble membrane and had a periodicity of approxi m a t e l y 1 6 n m (Fig. 4 ) . T h e s a m e i n t e r c e l l u l a r deposits were located within plasma cells of the iliac crest puncture by electron microscopy. As in l i g h t m i c r o s c o p y , n o e x t r a c e l l u l a r m a t e r i a l was found. Fig. 4 (Steuhl and associates). Stromal keratocyte with typical intracytoplasmic inclusions (asterisk). These deposits are enveloped by a double membrane (arrow) and show a periodicity of approximately 16 nm ( X 75,000).
trichrome. Other sections were studied with the avidin-biotin peroxidase complex technique, using polyclonal rabbit a n t i h u m a n antibodies to i d e n t i f y i m m u n o g l o b u l i n s o r t h e i r f r a g m e n t s in c o r n e a l t i s s u e . For t r a n s m i s s i o n e l e c t r o n m i c r o s c o p y , the c o r n e a l s p e c i m e n s , c o n j u n c t i v a , anterior lens capsule, and b o n e marrow of the iliac crest p u n c t u r e w e r e fixed in b u f f e r e d g l u taraldehyde solution, dehydrated, and e m b e d d e d in E p o n . S e m i t h i n s e c t i o n s w e r e p r e p a r e d w i t h an u l t r a m i c r o t o m e a n d s t a i n e d a c c o r d i n g to R i c h a r d s o n , J a r e t t , a n d F i n k e ' s m e t h o d . * For i m m u n o e l e c t r o p h o r e t i c d e t e r m i n a t i o n o f the i m m u n o g l o b u l i n s , t e a r fluid a n d a q u e o u s humor specimens were taken intraoperatively with micropipettes. After e l e c t r o p h o r e t i c split ting o f t h e p r o t e i n s , an i m m u n o f i x a t i o n b y monospecific anti-lgG and anti-kappa-light c h a i n a n t i s e r a was p e r f o r m e d . '
Results T h e c o r n e a l e p i t h e l i u m d i s c l o s e d an i n t r a c y t o p l a s m i c e d e m a p r i m a r i l y w i t h i n the b a s a l
Immunohistochemical analysis identified these corneal deposits as IgG-kappa-light chain i m m u n o g l o b u l i n f r a g m e n t s ( F i g . 6 ) . T h e y did n o t s t a i n w i t h a n t i - l g G , a n t i - I g M , a n t i - l g A , or a n t i - l a m b d a - l i g h t c h a i n a n t i b o d i e s , w h i c h in dicated that these deposits c o r r e s p o n d e d to the p a r a p r o t e i n s i d e n t i f i e d in t h e b l o o d . I g G k a p p a - l i g h t c h a i n f r a g m e n t s w e r e a l s o f o u n d in the tears and the aqueous h u m o r of one patient (Case 2 ) by I m m u n o e l e c t r o p h o r e s i s (Fig. 7 ) . T h e lens capsule and the lens epithelium had n o d e p o s i t s c o m p a r a b l e to t h o s e o f t h e c o r n e a l tissue.
Discussion P l a s m a cell n e o p l a s m s c o n s i s t o f l a r g e n u m bers of plasma cells, representing one B-lymp h o c y t e l i n e a g e . T h i s cell p o p u l a t i o n is d e s c e n d e d from t h e o r i g i n a l p l a s m a cell a n d s y n t h e s i z e s h o m o g e n e o u s i m m u n o g l o b u l i n or its f r a g m e n t s . C o r n e a l a c c u m u l a t i o n o f t h e s e c o m p o n e n t s is u n c o m m o n in p a t i e n t s w i t h m u l tiple myeloma. No corneal deposits were found in 13 p a t i e n t s w i t h m u l t i p l e m y e l o m a , a n d o n l y one patient with primary amyloidosis had crys talline corneal deposits of 1 0 0 patients with monoclonal gammopathy."" Intracellular and extracellular deposits were first d e s c r i b e d in 1 9 1 7 in m a n y o r g a n s o f a patient with multiple myeloma and amyloido-
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Fig. 5 (Steuhl and associates). Endothelial cells with intracellular inclusions (asterisks). Vacuolization of the cytoplasm (V) signals degenerative changes. (N, nucleus; and D, Descemet's membrane.) (Left, x 4,700; right, X 3,150.) sis.'^ C o r r e s p o n d i n g c o r n e a l d e p o s i t s first d r e w a t t e n t i o n in 1 9 3 4 , w h e n M e e s m a n n " s p e c u l a t e d that s u c h c r y s t a l l i n e c o r n e a l o p a c i t i e s i n v o l v e d the s a m e d e p o s i t s as t h e h o m o g e n e o u s or c r y s t a l l i n e m a s s e s f o u n d in o t h e r o r g a n s o f p a t i e n t s with myeloma. Aronson and Shaw'" postulated that the c o r n e a l d e p o s i t s w e r e lipids. C o n v e r s e ly, Frangois a n d R a b a e y ' ^ a n d P i n k e r t o n a n d R o b e r t s o n ' ^ s h a r e d M e e s m a n n ' s o p i n i o n . In 1978, Klintworth, Bredehoeft, and Reed'" dem onstrated immunohistochemically that the cor n e a l d e p o s i t s c o r r e s p o n d e d in all i n s t a n c e s to t h e m o n o c l o n a l p r o t e i n of t h e c a u s a t i v e p l a s m a cell n e o p l a s m . T h e rarity o f s u c h c o r n e a l c h a n g es in p a t i e n t s w i t h p l a s m a cell n e o p l a s m s is c a u s e d b y two f a c t o r s : a g a m m o p a t h y o f I g G k a p p a - l i g h t c h a i n type must b e p r e s e n t , a n d t h e d i s e a s e must b e c h r o n i c . C h a r a c t e r i s t i c s o f t h e p a r a p r o t e i n s , s u c h as s o l u b i l i t y , the i s o e l e c t r i c p o i n t , s u s c e p t i b i l i t y to p r o t e o l y s i s , the a b i l i t y
to i n t e r a c t s p e c i f i c a l l y w i t h c e l l u l a r a n t i g e n s a n d t i s s u e , a n d o t h e r as y e t u n k n o w n p r o p e r t i e s , " ' * a l s o play a p a r t . Paracrystalline corneal inclusions appear o n l y w h e n I g G - k a p p a - l i g h t c h a i n p r o t e i n s are synthesized by a proliferating monoclonal plas m a c e l l . " C r y s t a l l i n e c o r n e a l d e p o s i t s in I g G lambda-light chain gammopathy, however, h a v e b e e n reported.^"'^' B o t h s t u d i e s d e s c r i b e d t h e d e p o s i t s as g o l d e n - b r o w n a n d i r i d e s c e n t . L e w i s , Falls, a n d Troyer^' a t t r i b u t e d t h e c o r n e a l o p a c i t i e s to an i n c r e a s e in s e r u m c o p p e r l e v e l , with accompanying sunflower cataract. Firkin a n d associates^" did n o t m e n t i o n s e r u m c o p p e r content. Ormerod and associates'" described intracel l u l a r a n d e x t r a c e l l u l a r d e p o s i t s in all c o r n e a l layers b u t w e r e u n a b l e to verify t h i s in t h e endothelium, since no endothelial cells were d e t e c t a b l e in t h e i r p r e p a r a t i o n . All p a r a c r y s t a l -
Fig. 6 (Steuhl and associates). Paraffin section of the cornea after staining with anti-lgG-kappa-light chain antibodies. The intracytoplasmic inclusions stained positively (arrows) ( x 2 5 0 ) . (BL, Bowman's layer; and D, Descemet's membrane.)
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Fig. 7 (Steuhl and associates). Immunoelectrophoresis with clear IgG-kappa bands of the blood serum, the tear fluid, and the aqueous humor. l i n e d e p o s i t s in t h e e y e s of o u r p a t i e n t s w e r e i n t r a c e l l u l a r a n d p r e s e n t in b o t h t h e superficial corneal epithelial cells and the conjunctival epithelium (Figs. 2 and 3 ) . Barr, G e l e n d e r , a n d Font^^ a n d C h e r r y a n d associates^' also described exclusively intracel lular paraprotein deposits. Barr, G e l e n d e r , and Font^^ r e g a r d e d t h e s e as an i n d i c a t i o n t h a t t h e p r o t e i n i n c l u s i o n s d e v e l o p from t h e c o r n e a l c e l l s , b u t C h e r r y a n d a s s o c i a t e s ^ ' t h o u g h t that the m a t e r i a l w a s p h a g o c y t o s e d b y t h e c e l l s . We share the view of Cherry and associates, since the i n t r a c e l l u l a r i n c l u s i o n s o f our p a t i e n t s w e r e surrounded by a double m e m b r a n e (Fig. 4 ) . T h e p r e c i p i t a t i o n o f t h e p a r a p r o t e i n s is t h e r e f o r e probably associated with phagocytosis and the a c t i o n of l y s o s o m a l e n z y m e s . In 1 9 6 8 , Gloor^^ n o t e d that c o r n e a l c h a n g e s in d i s e a s e s that a c c o m p a n y p a r a p r o t e i n e m i a d i s play a m o r p h o l o g i c d i v e r s i t y . Different p a t t e r n s of o p a c i t y h a v e a l s o b e e n d e s c r i b e d r e g a r d i n g IgG-kappa-light chain type monoclonal gammopathy. Thus, anterior opacities may involve only the epithelium, B o w m a n ' s m e m b r a n e , and the a n t e r i o r stroma.^^'^'^ L a m e l l a r k e r a t o p l a s t y is t h e p r e f e r r e d t h e r a p y if t h e s e o p a c i t i e s r e d u c e v i s i o n m a r k e d l y . B a r r , G e l e n d e r , a n d Font^^and C h e r r y a n d a s s o c i a t e s ^ ' d e s c r i b e d t h r e e c a s e s in which partially crystalline and partially amor phous deposits involved the entire corneal stro m a w i t h n o i n v o l v e m e n t o f t h e e p i t h e l i u m or the e n d o t h e l i u m . F u r t h e r m o r e , two c a s e s h a v e b e e n r e p o r t e d in w h i c h d e p o s i t s in t h e d e e p s t r o m a left t h e c o r n e o s c l e r a l l i m b u s a r e a clear."-' The patients described by Ormerod a n d associates''* a n d M e y t h a l e r a n d Flick^* m o s t r e s e m b l e ours.
The f a c t o r s t h a t d e t e r m i n e t h e e x t e n t a n d f o r m o f the d e p o s i t s in I g G - k a p p a - l i g h t c h a i n g a m m o p a t h y have not been identified. The course, the intensity, and the duration of the disease may be important. Conversely, the lo c a t i o n a n d form o f t h e d e p o s i t s m a y b e influ enced by the m e c h a n i s m s by which parapro t e i n s are t r a n s p o r t e d to t h e c o r n e a l c e l l s , t h e a b i l i t y o f t h e c o r n e a l c e l l s to p h a g o c y t o s e , or b y the biologic properties of the paraproteins.''"*
References 1. Ameis, Α., Ko, Η. S., and Pruzanski, W.: Mcomponent. A review of 1244 cases. Can. Med. J. 114:889, 1976. 2. Bergsagel, D. Ε., and Rider, W. D.: Plasma cell neoplasms. In Devita, V. T., Hellman, S., and Rosen berg, S. A. (eds.): Cancer. Principles and Practice of Oncology. Philadelphia, J. B. Lippincott, 1985, p. 1753. 3. McMahon, B., and Clark, D. W.: Incidence of multiple myeloma. J. Chronic Dis. 4:508, 1 9 5 6 . 4. McPhedron, P., Heath, C. W., Jr., and Garcia, J . : Multiple myeloma incidence in metropolitan Atlanta, Georgia. Racial and seasonal variations. Blood 39:866, 1972. 5. Raman, S. B. K., and Van Slyck, E. J.: Nature of intracytoplasmic crystalline inclusions in myeloma cells. Am. J. Clin. Pathol. 80:244, 1 9 8 3 . 6. Ashton, N.: Ocular changes in multiple myelo matosis. Arch. Ophthalmol. 73:487, 1 9 6 5 . 7. Knapp, A. J., Gartner, S., and Henkind, P.: Mul tiple myeloma and its ocular manifestations. Surv. Ophthalmol. 31:343, 1 9 8 7 . 8. Richardson, K. C , Jarett, C , and Finke, Ε. Η.:
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Embedding in epoxy resins for uhrathin sectioning in electron microscopy. Stain Teclinol. 35:313, 1960. 9. Ritchie, R. P., and Smith, T. R.: Immunofixation. General principles and applications to agarose gel electrophoresis. Clin. Chem. 22:497, 1 9 7 6 . 10. Aronson, S. B., and Shaw, R.: Corneal crystals in multiple myeloma. Arch. Ophthalmol. 6 1 : 5 4 1 , 1959. 11. Bourne, W. M., Kyle, R. Α., Brubaker, R. F., and Greipp, P. R.: Incidence of corneal crystals in the monoclonal gammopathies. Am. J. Ophthalmol. 107:192, 1989. 12. Gaus, Α.: Über multiples Myelozytom mit eigenartigen, zum Teil kristallähnlichen Zellein lagerungen, kombiniert mit Elastolyse und aus gedehnter Amyloidose und Verkalkung. Virchows Arch. Pathol. Anat. 223:301, 1917. 13. Meesmann, Α.: Über eine eigenartige Horn hautdegeneration (Ablagerung des Bence-Jonesschen Eiweißkörpers in der Hornhaut). Ber. Dtsch. Ophthalmol. Ges. 5 0 : 3 1 1 , 1 9 3 4 . 14. Franςois, ] . , and Rabaey, M.: Corneal dystro phy and paraproteinemia. Am. J. Ophthalmol. 52:895, 1 9 6 1 . 15. Pinkerton, R. M. H., and Robertson, D. M.: Corneal and conjunctival changes in dysproteinemia. Invest. Ophthalmol. Vis. Sei. 8:3157, 1 9 6 9 . 16. Klintworth, G. Κ., Bredehoeft, S. J., and Reed, J. W.: Analysis of corneal crystalline deposits in mul tiple myeloma. Am. J. Ophthalmol. 86:303, 1 9 7 8 . 17. Merlini, G., Farhangi, Μ., and Osserman, E. F.: Monoclonal immunoglobulins with antibody activity in myeloma, macroglobulinemia and related plasma cell dyscrasias. Semin. Oncol. 13:350, 1 9 8 6 . 18. Solomon, Α.: Clinical implications of mono clonal light chains. Semin. Oncol. 13:3141, 1986.
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19. Ormerod, L. D., Collin, H. B., Dohlman, C. H., Craft, J. C , Desforges, J. F., and Albert, D. M.: Para proteinemic crystalline keratopathy. Ophthalmology 95:202, 1988. 20. Firkin, F. C , Lee, N., Ramsey, R., and Robert son, J . : Visual loss caused by corneal crystals in myeloma. Rapid improvement with plasma exchange and chemotherapy. Med. J. Aust. 29:677, 1 9 7 9 . 21. Lewis, R. Α., Falls, F., and Troyer, D. O.: Ocu lar manifestations of hypercupremia associated with multiple myeloma. Arch. Ophthalmol. 9 3 : 1 0 5 0 , 1975. 22. Barr, C. C , Gelender, Η., and Font, R. L.: Cor neal crystalline deposits associated with dyspro teinemia. Arch. Ophthalmol. 9 8 : 8 8 4 , 1 9 8 0 . 23. Cherry, P. M. H., Kraft, S., McGowan, H., Ghosh, M., and Shenken, E.: Corneal and conjuncti val deposits in monoclonal gammopathy. Can. J. Ophthalmol. 18:142, 1 9 8 3 . 24. Gloor, B.: Diffuse Hornhautdegeneration bei einem Fall von Makroglobulinämie Waldenstrom. Ophthalmologica 155:449, 1968. 25. Eiferman, R. Α., and Rodrigues, Μ. Μ.: Unusu al superficial stromal deposits in IgG kappa monoclo nal gammopathy. Arch. Ophthalmol. 98:78, 1 9 8 0 . 26. Kremer, J., Wright, P., Merin, S., Weiss, J., Pick, Α., and Kaufman, H.; Corneal subepithelial monoclonal kappa IgG deposits in essential cryoglobulinaemia. Br. J. Ophthalmol. 73:669, 1 9 8 9 . 27. Rodrigues, Μ. Μ., Krachmer, J. Η., Miller, S. D., and Newsome, D, Α.: Posterior corneal crystal line deposits in benign monoclonal gammopathy. Arch. Ophthalmol. 97:124, 1 9 7 9 . 28. Meythaler, H., and Flick, K.: Augenbeteiligung beim Plasmozytom. Klin. Monatsbl. Augenheilkd. 169:100, 1976.
Klaus-Peter Steuhl, M.D., Marcus Knorr, M.D., Jens M a r t i n Rohrbach, M.D., Walter Lisch, M.D., Edwin Kaiserling, M.D., and Hans-Jürgen T h i e l , M . D .
We t r e a t e d t w o p a t i e n t s w h o h a d I g G kappa-light chain monoclonal gammopathy with partially crystalline and partially amor phic corneal deposits. Impairment of vision m a d e k e r a t o p l a s t y n e c e s s a r y for e a c h p a t i e n t . H i s t o l o g i c e x a m i n a t i o n of t h e c o r n e a l s p e c i mens showed deposits that stained positively for M a s s o n ' s t r i c h r o m e in a l l c o r n e a l c e l l s . I m m u n o h i s t o c h e m i c a l tests identified t h e s e deposits as IgG-kappa-light chain i m m u n o globulin fragments. Electron microscopy showed intracellular, rhomboid-shaped de posits enveloped by a m e m b r a n e . T h e s a m e d e p o s i t s a p p e a r e d in t h e c o n j u n c t i v a l e p i t h e l i u m , w i t h i n s u b c o n j u n c t i v a l fibrocytes, a n d in t h e p l a s m a c e l l s of t h e b o n e m a r r o w . I m m u noelectrophoresis showed IgG-kappa-light c h a i n f r a g m e n t s in t h e b l o o d s e r u m , t h e l a c r i m a l film, a n d t h e a q u e o u s h u m o r . T h i s s u g gests that the intracellular i m m u n o g l o b u l i n fragments may have entered the corneal and c o n j u n c t i v a l e p i t h e l i u m by w a y of t h e l a c r i m a l film, t h e k e r a t o c y t e s by w a y of t h e c o r n e o scleral limbus vasculature, and the endotheli al cells from the aqueous h u m o r .
M O N O C L O N A L G A M M O P A T H Y r e s u l t s from un c o n t r o l l e d p r o l i f e r a t i o n o f a p l a s m a cell c l o n e , w h i c h p r o d u c e s an e x c e s s e i t h e r o f i m m u n o g l o b u l i n s or t h e i r h e a v y or l i g h t c h a i n frag m e n t s . D i s e a s e s a s s o c i a t e d with e x c e s s i v e s e c r e t i o n o f m o n o c l o n a l p a r a p r o t e i n s are e i t h e r b e n i g n , with l i m i t e d p l a s m a cell g r o w t h , or malignant, with uncontrolled plasma cell growth. The malignant monoclonal g a m m o -
Accepted for publication Dec. 6, 1990. From the University Eye Clinic Tübingen (Drs. Steuhl, Knorr, Rohrbach, Lisch, and Thiel), and Institute of Pathology (Dr. Kaiserling), University of Tübingen, Tubingen, Germany. This study was supported in part by a grant from Pharm-Allergan, Karlsruhe, Germany. Reprint requests to K.-P. Steuhl, University Eye Clin ic, Schleichstr. 12, D-7400 Tübingen, Germany.
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p a t h i e s ( m o r e t h a n h a l f o f t h e s e are p l a s m a c y tomas') are characterized by continuous growth of t h e p l a s m a cell c l o n e , w h i c h r e s u l t s in an exponential increase of the m o n o c l o n a l protein in t h e b l o o d . T h i s l e a d s to a n e m i a , failure o f t h e i m m u n e s y s t e m , h y p e r c a l c e m i a , soft t i s s u e a n d skin tumors, altered blood rheologic tests, and r e n a l failure,^ a n d o s t e o l y t i c b o n e l e s i o n s w h e n the tumor manifests extramedullarily. T h e an n u a l i n c i d e n c e o f p l a s m a c e l l n e o p l a s m s is e s t i m a t e d as t h r e e in a p o p u l a t i o n o f 1 0 0 , 0 0 0 . ^ ^ The circulating paraproteins are considered r e s p o n s i b l e for n o n a m y l o i d o r g a n deposits.^'' Ocular sites of paraprotein deposits are the conjunctival, corneal, and lens epithelium, k e r a t o c y t e s , e n d o t h e l i a l c e l l s , p l a s m a cell infil t r a t i o n o f the u v e a w i t h c o n c o m i t a n t u v e i t i s , c y s t s of t h e c i l i a r y b o d y , hyperviscosityderived occlusion of the retinal vessels, and retinal h e m o r r h a g e s . ' ' ' We studied partially crystalline and partially a m o r p h o u s corneal de p o s i t s in t w o p a t i e n t s w i t h p l a s m a c e l l m y e l o m a and associated monoclonal gammopathy.
Case Reports Case 1 In 1 9 7 3 , p l a s m a c y t o m a w a s d i a g n o s e d in a 5 0 - y e a r - o l d m a n on t h e b a s i s o f t y p i c a l p r o nounced increase of IgG fraction with a high paraprotein increase (IgG, 2 , 8 9 7 m g / d l ; nor m a l , 8 0 0 to 1 , 8 0 0 m g / d l ) , d e c r e a s e o f I g A a n d IgM, and the increased n u m b e r of atypical plas m a c e l l s in a s p i r a t e d s t e r n a l b o n e m a r r o w (approximately 2 5 % ; normal, 2 % ) . Immuno e l e c t r o p h o r e s i s i d e n t i f i e d t h e p a r a p r o t e i n as L - c h a i n k a p p a t y p e . L a b o r a t o r y test r e s u l t s for serum lipids, e n z y m e status, and electrolytes w e r e all n o r m a l . T h e b l o o d c e l l c o u n t s w e r e normal, with a mild a n e m i a ( h e m o g l o b i n b e tween 6.8 g / d l and 11.7 g / d l ) . T h e patient had two o s t e o l y t i c s k u l l l e s i o n s a n d a b i l a t e r a l c a r pal c a n a l s y n d r o m e as e x t r a m e d u l l a r y m a n i f e s -
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Fig. 1 (Steuhl and associates). Microscopic appearance of the superficial (left) and deeper (right) corneal tissue. Intracytoplasmic deposits within epithelial cells (arrows) and keratocytes (arrowheads). Note the endothelium filled with intracytoplasmic deposits and positive staining for Masson's trichrome (asterisk) ( x 250).
t a t i o n s o f the d i s e a s e . R e p e a t e d r e c t a l b i o p s y specimens showed no signs of amyloidosis. Bence Jones proteinuria of approximately 3 0 0 m g / d l b e g i n n i n g in t h e e a r l y 1 9 8 0 s led to irreversible tubular damage and kidney atro phy. D i a l y s i s w a s r e q u i r e d in J u n e 1 9 8 5 . R e peated treatment with 6 mg of m e l p h a l a n daily for five days a n d 4 m g of m e t h y l p r e d n i s o l o n e l o n g - t e r m r e s u l t e d in n o o v e r a l l i m p r o v e m e n t . T h e p a t i e n t d i e d in August 1 9 8 7 . A slight l o s s o f c o r n e a l t r a n s p a r e n c y w i t h o u t r e d u c t i o n in v i s i o n w a s o b s e r v e d in the e a r l y 1 9 7 0 s . W h e n e x a m i n e d at t h e U n i v e r s i t y E y e C l i n i c in T u b i n g e n in A p r i l 1 9 8 2 , t h e c o r n e a s were hazy because of dense, white, partially c r y s t a l l i n e d e p o s i t s in all c o r n e a l l a y e r s , p a r t i c ularly the deep stroma and the endothelium. A p a r t from a n u c l e a r c a t a r a c t , o t h e r o p h t h a l m i c findings w e r e u n r e m a r k a b l e ( t h e v i e w of t h e fundus w a s o b s c u r e d ) . T h e r e w e r e n o s i g n s o f a c t i v e or r e c u r r e n t u v e i t i s . P e n e t r a t i n g k e r a t o p l a s t y w a s p e r f o r m e d on t h e r i g h t e y e in J a n u ary 1 9 8 4 , a n d an e x t r a c a p s u l a r c a t a r a c t e x t r a c tion a n d p o s t e r i o r c h a m b e r i n t r a o c u l a r l e n s i m p l a n t a t i o n w a s p e r f o r m e d in S e p t e m b e r 1 9 8 4 . Best-corrected visual acuity was 2 0 / 2 0 . At that t i m e , a s l i g h t , c o r n e a l h a z e w a s o b s e r v e d in t h e graft o f t h e r i g h t e y e . T h e o p a c i ties w e r e l o c a t e d p r i m a r i l y in t h e d e e p e r l a y e r s of the p e r i p h e r y o f t h e t r a n s p l a n t . In J a n u a r y 1 9 8 5 , v i s u a l a c u i t y in t h e r i g h t e y e w a s r e d u c e d to 1 0 / 2 0 . In April 1 9 8 6 , v i s u a l a c u i t y in t h e left e y e w a s 2 / 2 0 . Simultaneous perforating keratoplasty a n d e x t r a c a p s u l a r c a t a r a c t e x t r a c t i o n with p o s terior c h a m b e r i n t r a o c u l a r l e n s i m p l a n t a t i o n w a s p e r f o r m e d on the left e y e , a n d b e s t - c o r r e c t ed visual a c u i t y w a s 8 / 2 0 . In O c t o b e r 1 9 8 6 ,
c o r n e a l o p a c i t i e s h a d r e c u r r e d in t h e left e y e , a n d t h e t r a n s p l a n t in t h e r i g h t e y e s h o w e d d e p o s i t s in all l a y e r s . V i s u a l a c u i t y w a s R . E . : 1 0 / 2 0 and L.E.: 6 / 2 0 .
Fig. 2 (Steuhl and associates). Electron microscopic aspect of the conjunctival epithelium showing intra cellular inclusions (arrows) and subepithelial tissue (ST). Note that the intracellular deposits are also visible within subepithelial fibrocytes (arrowhead) ( X 1,600).
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F i g . 3 (Steuhl and associates). Electron micrograph of the superficial (left) and basal (right) region of the corneal epithelium with numerous intracytoplasmic deposits (arrows). (M, microvilli; N, nuclei; and BL, Bowman's layer.) (Left, x 12,500; right, x 2,000.)
Case 2 In A u g u s t 1 9 8 9 , p l a s m a c y t o m a w a s d i a g n o s e d in a 7 8 - y e a r - o l d w o m a n o n t h e b a s i s of t y p i c a l findings in s e r u m e l e c t r o p h o r e s i s o f I g G level g r e a t e r t h a n 4 , 0 0 0 m g / d l , d e c r e a s e d I g A level to 4 0 m g / d l , I g M level o f 3 0 m g / d l , a n d b o n e marrow puncture with 1 8 % plasma cells. L i g h t m i c r o s c o p y s h o w e d that t h e s e p l a s m a cells had marked vacuolization with crystalline inclusions. Immunoelectrophoresis showed a p l a s m a c y t o m a of I g G - k a p p a - l i g h t c h a i n t y p e . E x c e p t for t h e o p h t h a l m i c findings, n o e x t r a m e d u l l a r y m a n i f e s t a t i o n s of t h e d i s e a s e w e r e f o u n d . L a b o r a t o r y test r e s u l t s for s e r u m l i p i d s , e n z y m e status, a n d s e r u m e l e c t r o l y t e s ( i n c l u d ing c a l c i u m a n d c o p p e r ) w e r e n o r m a l . T h e p a tient had anemia (hemoglobin, 8.7 g / d l ) , and c r e a t i n i n e a n d urea l e v e l s w e r e n o r m a l . T h e urine contained 150 m g / d l of protein (Bence J o n e s p r o t e i n u r i a of I g G - k a p p a - l i g h t c h a i n type). Biopsy specimen of the oral mucosa showed no indication of generalized amyloido sis. T h e p a t i e n t died D e c . 2 5 , 1 9 8 9 , o f p u l m o
n a r y h e a r t failure after c y t o s t a t i c t r e a t m e n t o f the disease. T h e first m y e l o m a - a s s o c i a t e d o c u l a r i n v o l v e m e n t b e g a n in t h e l a t e 1 9 7 0 s . In April 1 9 8 8 , visual acuity was R.E.: 3 / 2 0 and L.E.: 8 / 2 0 . T h e r e d u c e d v i s u a l a c u i t y w a s c a u s e d b y diffuse, b i l a t e r a l c o r n e a l h a z e . W h e n e x a m i n e d at the U n i v e r s i t y E y e C l i n i c T ü b i n g e n in S e p t e m b e r 1 9 8 9 , visual acuity was R . E . : 4 / 2 0 0 and L.E.: 6 / 2 0 . D e n s e , diffuse, p a r t i a l l y c r y s t a l l i n e c o r n e a l o p a c i t i e s i n v o l v e d all c o r n e a l l a y e r s . In October 1 9 8 9 , perforating keratoplasty and ex tracapsular cataract extraction were performed in t h e r i g h t e y e . T h e r e w e r e n o i n t r a o p e r a t i v e or postoperative complications, and best-correct ed v i s u a l a c u i t y w a s 5 / 2 0 .
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layer in b o t h p a t i e n t s . T h e l a m e l l a e o f the corneal stroma were loosened edematously, a n d t h e rarified e n d o t h e l i u m d i s c l o s e d v a c u o l i c d e g e n e r a t i o n . In b o t h c a s e s i n t r a c y t o p l a s m i c d e p o s i t s w e r e l o c a t e d w i t h i n all c o r n e a l c e l l s and stained positive with Masson's trichrome (Fig. 1 ) . A m y l o i d w a s e x c l u d e d s i n c e t h e y did n o t s t a i n w i t h C o n g o r e d a n d w e r e n e g a t i v e for green birefringence. No extracellular material was found. Electron micrographs showed these i n t r a c y t o p l a s m i c d e p o s i t s to b e p a r a c r y s t a l l i n e , r h o m b o i d , a n d p r e s e n t in t h e c o n j u n c t i v a l e p i thelium (Fig. 2 ) , in the epithelial layers o f the c o r n e a ( F i g . 3 ) , in k e r a t o c y t e s ( F i g . 4 ) , a n d in t h e e n d o t h e l i a l layer ( F i g . 5 ) , w h e r e t h e y l e d to pronounced degenerative changes. This intra cytoplasmic material was enveloped by a dou ble membrane and had a periodicity of approxi m a t e l y 1 6 n m (Fig. 4 ) . T h e s a m e i n t e r c e l l u l a r deposits were located within plasma cells of the iliac crest puncture by electron microscopy. As in l i g h t m i c r o s c o p y , n o e x t r a c e l l u l a r m a t e r i a l was found. Fig. 4 (Steuhl and associates). Stromal keratocyte with typical intracytoplasmic inclusions (asterisk). These deposits are enveloped by a double membrane (arrow) and show a periodicity of approximately 16 nm ( X 75,000).
trichrome. Other sections were studied with the avidin-biotin peroxidase complex technique, using polyclonal rabbit a n t i h u m a n antibodies to i d e n t i f y i m m u n o g l o b u l i n s o r t h e i r f r a g m e n t s in c o r n e a l t i s s u e . For t r a n s m i s s i o n e l e c t r o n m i c r o s c o p y , the c o r n e a l s p e c i m e n s , c o n j u n c t i v a , anterior lens capsule, and b o n e marrow of the iliac crest p u n c t u r e w e r e fixed in b u f f e r e d g l u taraldehyde solution, dehydrated, and e m b e d d e d in E p o n . S e m i t h i n s e c t i o n s w e r e p r e p a r e d w i t h an u l t r a m i c r o t o m e a n d s t a i n e d a c c o r d i n g to R i c h a r d s o n , J a r e t t , a n d F i n k e ' s m e t h o d . * For i m m u n o e l e c t r o p h o r e t i c d e t e r m i n a t i o n o f the i m m u n o g l o b u l i n s , t e a r fluid a n d a q u e o u s humor specimens were taken intraoperatively with micropipettes. After e l e c t r o p h o r e t i c split ting o f t h e p r o t e i n s , an i m m u n o f i x a t i o n b y monospecific anti-lgG and anti-kappa-light c h a i n a n t i s e r a was p e r f o r m e d . '
Results T h e c o r n e a l e p i t h e l i u m d i s c l o s e d an i n t r a c y t o p l a s m i c e d e m a p r i m a r i l y w i t h i n the b a s a l
Immunohistochemical analysis identified these corneal deposits as IgG-kappa-light chain i m m u n o g l o b u l i n f r a g m e n t s ( F i g . 6 ) . T h e y did n o t s t a i n w i t h a n t i - l g G , a n t i - I g M , a n t i - l g A , or a n t i - l a m b d a - l i g h t c h a i n a n t i b o d i e s , w h i c h in dicated that these deposits c o r r e s p o n d e d to the p a r a p r o t e i n s i d e n t i f i e d in t h e b l o o d . I g G k a p p a - l i g h t c h a i n f r a g m e n t s w e r e a l s o f o u n d in the tears and the aqueous h u m o r of one patient (Case 2 ) by I m m u n o e l e c t r o p h o r e s i s (Fig. 7 ) . T h e lens capsule and the lens epithelium had n o d e p o s i t s c o m p a r a b l e to t h o s e o f t h e c o r n e a l tissue.
Discussion P l a s m a cell n e o p l a s m s c o n s i s t o f l a r g e n u m bers of plasma cells, representing one B-lymp h o c y t e l i n e a g e . T h i s cell p o p u l a t i o n is d e s c e n d e d from t h e o r i g i n a l p l a s m a cell a n d s y n t h e s i z e s h o m o g e n e o u s i m m u n o g l o b u l i n or its f r a g m e n t s . C o r n e a l a c c u m u l a t i o n o f t h e s e c o m p o n e n t s is u n c o m m o n in p a t i e n t s w i t h m u l tiple myeloma. No corneal deposits were found in 13 p a t i e n t s w i t h m u l t i p l e m y e l o m a , a n d o n l y one patient with primary amyloidosis had crys talline corneal deposits of 1 0 0 patients with monoclonal gammopathy."" Intracellular and extracellular deposits were first d e s c r i b e d in 1 9 1 7 in m a n y o r g a n s o f a patient with multiple myeloma and amyloido-
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Fig. 5 (Steuhl and associates). Endothelial cells with intracellular inclusions (asterisks). Vacuolization of the cytoplasm (V) signals degenerative changes. (N, nucleus; and D, Descemet's membrane.) (Left, x 4,700; right, X 3,150.) sis.'^ C o r r e s p o n d i n g c o r n e a l d e p o s i t s first d r e w a t t e n t i o n in 1 9 3 4 , w h e n M e e s m a n n " s p e c u l a t e d that s u c h c r y s t a l l i n e c o r n e a l o p a c i t i e s i n v o l v e d the s a m e d e p o s i t s as t h e h o m o g e n e o u s or c r y s t a l l i n e m a s s e s f o u n d in o t h e r o r g a n s o f p a t i e n t s with myeloma. Aronson and Shaw'" postulated that the c o r n e a l d e p o s i t s w e r e lipids. C o n v e r s e ly, Frangois a n d R a b a e y ' ^ a n d P i n k e r t o n a n d R o b e r t s o n ' ^ s h a r e d M e e s m a n n ' s o p i n i o n . In 1978, Klintworth, Bredehoeft, and Reed'" dem onstrated immunohistochemically that the cor n e a l d e p o s i t s c o r r e s p o n d e d in all i n s t a n c e s to t h e m o n o c l o n a l p r o t e i n of t h e c a u s a t i v e p l a s m a cell n e o p l a s m . T h e rarity o f s u c h c o r n e a l c h a n g es in p a t i e n t s w i t h p l a s m a cell n e o p l a s m s is c a u s e d b y two f a c t o r s : a g a m m o p a t h y o f I g G k a p p a - l i g h t c h a i n type must b e p r e s e n t , a n d t h e d i s e a s e must b e c h r o n i c . C h a r a c t e r i s t i c s o f t h e p a r a p r o t e i n s , s u c h as s o l u b i l i t y , the i s o e l e c t r i c p o i n t , s u s c e p t i b i l i t y to p r o t e o l y s i s , the a b i l i t y
to i n t e r a c t s p e c i f i c a l l y w i t h c e l l u l a r a n t i g e n s a n d t i s s u e , a n d o t h e r as y e t u n k n o w n p r o p e r t i e s , " ' * a l s o play a p a r t . Paracrystalline corneal inclusions appear o n l y w h e n I g G - k a p p a - l i g h t c h a i n p r o t e i n s are synthesized by a proliferating monoclonal plas m a c e l l . " C r y s t a l l i n e c o r n e a l d e p o s i t s in I g G lambda-light chain gammopathy, however, h a v e b e e n reported.^"'^' B o t h s t u d i e s d e s c r i b e d t h e d e p o s i t s as g o l d e n - b r o w n a n d i r i d e s c e n t . L e w i s , Falls, a n d Troyer^' a t t r i b u t e d t h e c o r n e a l o p a c i t i e s to an i n c r e a s e in s e r u m c o p p e r l e v e l , with accompanying sunflower cataract. Firkin a n d associates^" did n o t m e n t i o n s e r u m c o p p e r content. Ormerod and associates'" described intracel l u l a r a n d e x t r a c e l l u l a r d e p o s i t s in all c o r n e a l layers b u t w e r e u n a b l e to verify t h i s in t h e endothelium, since no endothelial cells were d e t e c t a b l e in t h e i r p r e p a r a t i o n . All p a r a c r y s t a l -
Fig. 6 (Steuhl and associates). Paraffin section of the cornea after staining with anti-lgG-kappa-light chain antibodies. The intracytoplasmic inclusions stained positively (arrows) ( x 2 5 0 ) . (BL, Bowman's layer; and D, Descemet's membrane.)
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Fig. 7 (Steuhl and associates). Immunoelectrophoresis with clear IgG-kappa bands of the blood serum, the tear fluid, and the aqueous humor. l i n e d e p o s i t s in t h e e y e s of o u r p a t i e n t s w e r e i n t r a c e l l u l a r a n d p r e s e n t in b o t h t h e superficial corneal epithelial cells and the conjunctival epithelium (Figs. 2 and 3 ) . Barr, G e l e n d e r , a n d Font^^ a n d C h e r r y a n d associates^' also described exclusively intracel lular paraprotein deposits. Barr, G e l e n d e r , and Font^^ r e g a r d e d t h e s e as an i n d i c a t i o n t h a t t h e p r o t e i n i n c l u s i o n s d e v e l o p from t h e c o r n e a l c e l l s , b u t C h e r r y a n d a s s o c i a t e s ^ ' t h o u g h t that the m a t e r i a l w a s p h a g o c y t o s e d b y t h e c e l l s . We share the view of Cherry and associates, since the i n t r a c e l l u l a r i n c l u s i o n s o f our p a t i e n t s w e r e surrounded by a double m e m b r a n e (Fig. 4 ) . T h e p r e c i p i t a t i o n o f t h e p a r a p r o t e i n s is t h e r e f o r e probably associated with phagocytosis and the a c t i o n of l y s o s o m a l e n z y m e s . In 1 9 6 8 , Gloor^^ n o t e d that c o r n e a l c h a n g e s in d i s e a s e s that a c c o m p a n y p a r a p r o t e i n e m i a d i s play a m o r p h o l o g i c d i v e r s i t y . Different p a t t e r n s of o p a c i t y h a v e a l s o b e e n d e s c r i b e d r e g a r d i n g IgG-kappa-light chain type monoclonal gammopathy. Thus, anterior opacities may involve only the epithelium, B o w m a n ' s m e m b r a n e , and the a n t e r i o r stroma.^^'^'^ L a m e l l a r k e r a t o p l a s t y is t h e p r e f e r r e d t h e r a p y if t h e s e o p a c i t i e s r e d u c e v i s i o n m a r k e d l y . B a r r , G e l e n d e r , a n d Font^^and C h e r r y a n d a s s o c i a t e s ^ ' d e s c r i b e d t h r e e c a s e s in which partially crystalline and partially amor phous deposits involved the entire corneal stro m a w i t h n o i n v o l v e m e n t o f t h e e p i t h e l i u m or the e n d o t h e l i u m . F u r t h e r m o r e , two c a s e s h a v e b e e n r e p o r t e d in w h i c h d e p o s i t s in t h e d e e p s t r o m a left t h e c o r n e o s c l e r a l l i m b u s a r e a clear."-' The patients described by Ormerod a n d associates''* a n d M e y t h a l e r a n d Flick^* m o s t r e s e m b l e ours.
The f a c t o r s t h a t d e t e r m i n e t h e e x t e n t a n d f o r m o f the d e p o s i t s in I g G - k a p p a - l i g h t c h a i n g a m m o p a t h y have not been identified. The course, the intensity, and the duration of the disease may be important. Conversely, the lo c a t i o n a n d form o f t h e d e p o s i t s m a y b e influ enced by the m e c h a n i s m s by which parapro t e i n s are t r a n s p o r t e d to t h e c o r n e a l c e l l s , t h e a b i l i t y o f t h e c o r n e a l c e l l s to p h a g o c y t o s e , or b y the biologic properties of the paraproteins.''"*
References 1. Ameis, Α., Ko, Η. S., and Pruzanski, W.: Mcomponent. A review of 1244 cases. Can. Med. J. 114:889, 1976. 2. Bergsagel, D. Ε., and Rider, W. D.: Plasma cell neoplasms. In Devita, V. T., Hellman, S., and Rosen berg, S. A. (eds.): Cancer. Principles and Practice of Oncology. Philadelphia, J. B. Lippincott, 1985, p. 1753. 3. McMahon, B., and Clark, D. W.: Incidence of multiple myeloma. J. Chronic Dis. 4:508, 1 9 5 6 . 4. McPhedron, P., Heath, C. W., Jr., and Garcia, J . : Multiple myeloma incidence in metropolitan Atlanta, Georgia. Racial and seasonal variations. Blood 39:866, 1972. 5. Raman, S. B. K., and Van Slyck, E. J.: Nature of intracytoplasmic crystalline inclusions in myeloma cells. Am. J. Clin. Pathol. 80:244, 1 9 8 3 . 6. Ashton, N.: Ocular changes in multiple myelo matosis. Arch. Ophthalmol. 73:487, 1 9 6 5 . 7. Knapp, A. J., Gartner, S., and Henkind, P.: Mul tiple myeloma and its ocular manifestations. Surv. Ophthalmol. 31:343, 1 9 8 7 . 8. Richardson, K. C , Jarett, C , and Finke, Ε. Η.:
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Embedding in epoxy resins for uhrathin sectioning in electron microscopy. Stain Teclinol. 35:313, 1960. 9. Ritchie, R. P., and Smith, T. R.: Immunofixation. General principles and applications to agarose gel electrophoresis. Clin. Chem. 22:497, 1 9 7 6 . 10. Aronson, S. B., and Shaw, R.: Corneal crystals in multiple myeloma. Arch. Ophthalmol. 6 1 : 5 4 1 , 1959. 11. Bourne, W. M., Kyle, R. Α., Brubaker, R. F., and Greipp, P. R.: Incidence of corneal crystals in the monoclonal gammopathies. Am. J. Ophthalmol. 107:192, 1989. 12. Gaus, Α.: Über multiples Myelozytom mit eigenartigen, zum Teil kristallähnlichen Zellein lagerungen, kombiniert mit Elastolyse und aus gedehnter Amyloidose und Verkalkung. Virchows Arch. Pathol. Anat. 223:301, 1917. 13. Meesmann, Α.: Über eine eigenartige Horn hautdegeneration (Ablagerung des Bence-Jonesschen Eiweißkörpers in der Hornhaut). Ber. Dtsch. Ophthalmol. Ges. 5 0 : 3 1 1 , 1 9 3 4 . 14. Franςois, ] . , and Rabaey, M.: Corneal dystro phy and paraproteinemia. Am. J. Ophthalmol. 52:895, 1 9 6 1 . 15. Pinkerton, R. M. H., and Robertson, D. M.: Corneal and conjunctival changes in dysproteinemia. Invest. Ophthalmol. Vis. Sei. 8:3157, 1 9 6 9 . 16. Klintworth, G. Κ., Bredehoeft, S. J., and Reed, J. W.: Analysis of corneal crystalline deposits in mul tiple myeloma. Am. J. Ophthalmol. 86:303, 1 9 7 8 . 17. Merlini, G., Farhangi, Μ., and Osserman, E. F.: Monoclonal immunoglobulins with antibody activity in myeloma, macroglobulinemia and related plasma cell dyscrasias. Semin. Oncol. 13:350, 1 9 8 6 . 18. Solomon, Α.: Clinical implications of mono clonal light chains. Semin. Oncol. 13:3141, 1986.
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19. Ormerod, L. D., Collin, H. B., Dohlman, C. H., Craft, J. C , Desforges, J. F., and Albert, D. M.: Para proteinemic crystalline keratopathy. Ophthalmology 95:202, 1988. 20. Firkin, F. C , Lee, N., Ramsey, R., and Robert son, J . : Visual loss caused by corneal crystals in myeloma. Rapid improvement with plasma exchange and chemotherapy. Med. J. Aust. 29:677, 1 9 7 9 . 21. Lewis, R. Α., Falls, F., and Troyer, D. O.: Ocu lar manifestations of hypercupremia associated with multiple myeloma. Arch. Ophthalmol. 9 3 : 1 0 5 0 , 1975. 22. Barr, C. C , Gelender, Η., and Font, R. L.: Cor neal crystalline deposits associated with dyspro teinemia. Arch. Ophthalmol. 9 8 : 8 8 4 , 1 9 8 0 . 23. Cherry, P. M. H., Kraft, S., McGowan, H., Ghosh, M., and Shenken, E.: Corneal and conjuncti val deposits in monoclonal gammopathy. Can. J. Ophthalmol. 18:142, 1 9 8 3 . 24. Gloor, B.: Diffuse Hornhautdegeneration bei einem Fall von Makroglobulinämie Waldenstrom. Ophthalmologica 155:449, 1968. 25. Eiferman, R. Α., and Rodrigues, Μ. Μ.: Unusu al superficial stromal deposits in IgG kappa monoclo nal gammopathy. Arch. Ophthalmol. 98:78, 1 9 8 0 . 26. Kremer, J., Wright, P., Merin, S., Weiss, J., Pick, Α., and Kaufman, H.; Corneal subepithelial monoclonal kappa IgG deposits in essential cryoglobulinaemia. Br. J. Ophthalmol. 73:669, 1 9 8 9 . 27. Rodrigues, Μ. Μ., Krachmer, J. Η., Miller, S. D., and Newsome, D, Α.: Posterior corneal crystal line deposits in benign monoclonal gammopathy. Arch. Ophthalmol. 97:124, 1 9 7 9 . 28. Meythaler, H., and Flick, K.: Augenbeteiligung beim Plasmozytom. Klin. Monatsbl. Augenheilkd. 169:100, 1976.
