Signs, Complications, and Platelet Aggregation in Familial Exudative Vitreoretinopathy
C. Erik van Nouhuys, M.D.
Between 1979 and 1989, I examined 106 pa t i e n t s (16 p e d i g r e e s ) w i t h s i g n s of f a m i l i a l exudative vitreoretinopathy. Of these p a t i e n t s , 101 h a d f a m i l i a l e x u d a t i v e v i t r e o r e t i n o p a t h y , a n d five h a d a s p o r a d i c m a n i f e s t a tion. The complications of familial e x u d a t i v e vitreoretinopathy, deformation of the p o s t e r i or r e t i n a , v i t r e o u s h e m o r r h a g e , a m b l y o p i a , and retinal d e t a c h m e n t , caused d i m i n i s h e d visual acuity. Of 170 eyes, retinal n e o v a s c u l a r i z a t i o n w a s o b s e r v e d in 1 8 e y e s (11%), a n d r e t i n a l e x u d a t e s w e r e o b s e r v e d i n 1 6 e y e s (90/0). S e v e r a l f o r m s of r e t i n a l d e t a c h m e n t o c c u r r e d in 37 of 1 8 0 e y e s (21%), w h i c h o f t e n t o o k a n u n f a v o r a b l e c o u r s e . A f a l c i f o r m r e t i n a l fold was o b s e r v e d in 1 4 e y e s (8%). R e t i n a l s u r g e r y was p e r f o r m e d in 14 eyes; r e a t t a c h m e n t of t h e r e t i n a w a s s u c c e s s f u l in o n l y s e v e n e y e s . Platelet aggregation studies disclosed n o sig nificant d i f f e r e n c e s b e t w e e n s e v e n p a t i e n t s with familial exudative vitreoretinopathy and ten control subjects. T h e p a t h o g e n e s i s of the d i s e a s e is b a s e d on a p r e m a t u r e a r r e s t o f t h e v a s c u l a r d e v e l o p m e n t of t h e r e t i n a .
FAMILIAL EXUDATIVE VITREORETINOPATHY
(also
known as dominant exudative vitreoretinopa thy) is a h e r e d i t a r y d i s o r d e r w i t h a u t o s o m a l dominant transmission characterized by a b o u n d a r y o f the r e t i n a l v a s c u l a r n e t w o r k in t h e e q u a t o r i a l r e g i o n o f the fundus a n d a v a s c u l a r ity o f t h e p e r i p h e r a l r e t i n a , e s p e c i a l l y o n t h e t e m p o r a l s i d e . M o r e s e v e r e l y affected e y e s s h o w a v a r i e t y o f s i g n s , s u c h as d e f o r m a t i o n o f
Accepted for publication Oct. 15, 1990. From the Department of Ophthalmology, CanisiusWilhelmina Hospital, Nijmegen, The Netherlands. This study was supported in part by the Praeventiefonds, The Hague, The Netherlands. Reprint requests to C. Erik van Nouhuys, M.D., De partment of Ophthalmology, Canisius-Wilhelmina Hos pital, P.O. Box 9015, 6500 GS Nijmegen, The Nether lands.
34
the posterior retina, ectopia of the macula, retinal neovascularization and exudates, pig m e n t a r y c h a n g e s of t h e r e t i n a , r e t i n a l b r e a k s , vitreous hemorrhages and membranes, retinoschisis, retinal detachment, cataract, bandshaped keratopathy, and phthisis bulbi.'* T h e fundus a b n o r m a l i t i e s o f f a m i l i a l e x u d a tive v i t r e o r e t i n o p a t h y are s i m i l a r to t h o s e o f retinopathy of prematurity. Therefore, retinop athy o f p r e m a t u r i t y c a n b e r e g a r d e d as a p h e n o copy of familial exudative vitreoretinopathy.*'' B e c a u s e o f its f r e q u e n t l y asymptomatic c o u r s e a n d t h e d i v e r s i t y o f s i g n s , t h e d i s e a s e is often u n r e c o g n i z e d or d i a g n o s e d i n c o r r e c t l y . T h e p u r p o s e o f t h i s s t u d y w a s to d e s c r i b e a n d catalog the various signs and complications of t h e d i s e a s e as w e l l as t h e i r p r e v a l e n c e in a relatively large group of patients. Chaudhuri and associates'" reported dis t u r b e d p l a t e l e t a g g r e g a t i o n in s e v e n p a t i e n t s w i t h f a m i l i a l e x u d a t i v e v i t r e o r e t i n o p a t h y . In v i e w o f t h e s e findings, I p e r f o r m e d a c o n t r o l l e d s t u d y o f p l a t e l e t a g g r e g a t i o n in 1 7 p a t i e n t s .
Patients and IVIethods Between 1 9 7 9 and 1 9 8 9 , I examined Dutch families with familial exudative vitreoretinopa thy at t h e E y e C l i n i c o f t h e U n i v e r s i t y of N i j m e g e n a n d at t h e C a n i s i u s - W i l h e l m i n a H o s p i t a l . Generally, familial exudative vitreoretinopathy w a s d i a g n o s e d after b i o m i c r o s c o p i c o b s e r v a tion o f t h e c h a r a c t e r i s t i c e q u a t o r i a l d e m a r c a tion between vascular and avascular retina and t h e a n g i o g r a p h i c finding o f n o n p e r f u s i o n o f t h e peripheral retina. Ophthalmic examinations of 3 5 0 patients s h o w e d c h a r a c t e r i s t i c s o f f a m i l i a l e x u d a t i v e vit r e o r e t i n o p a t h y in 1 0 6 p a t i e n t s . T h e d i s e a s e w a s f a m i l i a l in 1 0 1 p a t i e n t s from 1 6 p e d i g r e e s . In 11 of t h e s e p a t i e n t s , t h e v a s c u l a r l e s i o n s o f t h e peripheral retina were so slight that the diagno sis c o u l d n o t b e c o n f i r m e d w i t h a b s o l u t e c e r -
©AMERICAN JOURNAL OF OPHTHALMOLOGY 1 1 1 : 3 4 - 4 1 , JANUARY, 1 9 9 1
Vol. I l l , No. 1
Familial Exudative Vitreoretinopathy
t a i n t y . T h e d a t a o f t h e s e 11 p a t i e n t s are n o t included. T h e remaining 9 0 patients in the 16 pedigrees showed evident signs of the disease. Five o f t h e s e p a t i e n t s , i n c l u d i n g i d e n t i c a l twins, showed unmistakable ocular lesions, al though no signs of familial exudative vitreoreti n o p a t h y c o u l d b e f o u n d in t h e i r i m m e d i a t e family. A s s u c h s p o r a d i c c a s e s m a y r e s u l t f r o m g e n e t i c h e t e r o g e n e i t y , t h e data on t h e s e p a t i e n t s are n o t i n c l u d e d . All p a t i e n t s w i t h f a m i l ial a n d s p o r a d i c e x u d a t i v e v i t r e o r e t i n o p a t h y h a d a b i r t h w e i g h t o v e r 2 , 0 0 0 g, a n d n o n e w e r e premature. Three patients h a d b e e n given s o m e s u p p l e m e n t a l o x y g e n i m m e d i a t e l y after b i r t h for o n e or two d a y s . In all p a t i e n t s , t h e o p h t h a l m i c e x a m i n a t i o n included determination of visual acuity, deter m i n a t i o n of t h e e y e p o s i t i o n a n d k a p p a a n g l e , and slit-lamp examination of the anterior seg ment. Patients were questioned regarding any previous ocular diseases and neonatal details. O p h t h a l m o s c o p y w a s a l w a y s p e r f o r m e d in full m y d r i a s i s after i n s t i l l a t i o n o f 0 . 5 % t r o p i c a m i d e , 5 % p h e n y l e p h r i n e , a n d s o m e t i m e s 1% c y c l o p e n t o l a t e e y e d r o p s . In a l l o l d e r c h i l d r e n and adults, the fundus was e x a m i n e d by biomi c r o s c o p y w i t h a t h r e e - m i r r o r c o n t a c t l e n s . For young children, ophthalmoscopy was consid e r e d sufficient. F l u o r e s c e i n a n g i o g r a p h y a n d color photography of the peripheral fundus and p o s t e r i o r p o l e w e r e p e r f o r m e d in s e l e c t e d p a t i e n t s . In a few o f t h e p a t i e n t s , k i n e t i c p e r i m e try ( G o l d m a n n ) , s c o t o p i c a n d p h o t o p i c e l e c t r o retinography, and electro-oculography were performed. H e m a t o l o g i c tests and platelet aggregation t e s t s w e r e p e r f o r m e d in s e v e n p a t i e n t s w i t h unmistakable familial exudative vitreoretinop a t h y in t h r e e p e d i g r e e s a n d in t e n a g e - m a t c h e d control subjects. For t h e p l a t e l e t a g g r e g a t i o n t e s t s , c i t r a t e d b l o o d from p a t i e n t s a n d c o n t r o l s u b j e c t s w a s u s e d to p r e p a r e p l a t e l e t - r i c h p l a s m a b y c e n t r i f u g a t i o n on a c u s h i o n for 2 0 m i n u t e s at 2 5 0 G . " A g g r e g a t i o n in p l a t e l e t - r i c h p l a s m a w a s m e a sured with a photometer. Aggregation was in d u c e d w i t h a d e n o s i n e d i p h o s p h a t e d i l u t e d to end-concentrations of 1 0 * mol/1, 4 x 1 0 " ' mol/1, and 2 x 1 0 " ' mol/1; collagen suspen s i o n s in 0 . 9 % s o d i u m c h l o r i d e (2 x 10"* 1 a n d 5 X 10"* I); a n d a r a c h i d o n i c a c i d ( e n d c o n c e n t r a t i o n s o f 5 X 10"3 m o l / 1 a n d 1.5 X 10"^ m o l / 1 ) . The b l e e d i n g t i m e w a s d e t e r m i n e d in five p a t i e n t s a n d ten c o n t r o l s u b j e c t s . T h i s w a s d o n e after p l a c i n g a s p h y g m o m a n o m e t e r cuff o n t h e u p p e r a r m a n d inflating it t o 4 0 m m H g , u s i n g a bleeding-time device.
35
Results V i s u a l a c u i t y w a s d e t e r m i n e d in 1 7 6 e y e s o f 9 0 p a t i e n t s w i t h e v i d e n t f a m i l i a l e x u d a t i v e vit r e o r e t i n o p a t h y ( t h e p a t i e n t s w i t h m i n i m a l fun dus l e s i o n s a n d n o n f a m i l i a l e x u d a t i v e v i t r e o retinopathy were excluded). Whenever visual a c u i t y w a s d e t e r m i n e d m o r e t h a n o n c e in t h e same individual, the most recent value was recorded. O f 176 eyes, visual acuity was 2 0 / 2 0 or b e t t e r in 6 5 e y e s ( 3 7 % ) ; 2 0 / 3 5 t o 2 0 / 2 5 in 4 8 e y e s ( 2 7 % ) ; 2 0 / 7 0 t o 2 0 / 4 0 in 1 4 e y e s ( 8 % ) ; 2 0 / 2 0 0 t o 2 0 / 1 0 0 in 1 2 e y e s ( 7 % ) ; c o u n t i n g fingers i n 1 7 e y e s ( 1 0 % ) ; h a n d m o t i o n s in s e v e n e y e s ( 4 % ) ; a n d n o l i g h t p e r c e p t i o n in 1 5 e y e s ( 9 % ) . Determined binocularly, visual acuity w a s 2 0 / 1 0 0 or l e s s in 1 3 o f 8 8 p a t i e n t s ( 1 5 % ) . In 1 8 0 e y e s o f 9 0 p a t i e n t s w i t h f a m i l i a l e x u dative vitreoretinopathy, the vitreous was nor m a l in 8 0 e y e s ( 4 4 % ) ; s y n e r e s i s a n d l i q u e f a c t i o n w e r e n o t e d in 4 2 e y e s ( 2 3 % ) ; d e l i c a t e w h i t e p a r t i c l e s w e r e s e e n in 2 7 e y e s ( 1 5 % ) ; p i g m e n t e d c e l l s w e r e n o t e d in n i n e e y e s ( 5 % ) ; v i t r e o u s h e m o r r h a g e o c c u r r e d i n four e y e s ( 2 % ) ; p r e r e t i n a l m e m b r a n e s a n d o p a c i t i e s w e r e s e e n in 3 0 e y e s ( 1 7 % ) ; m e m b r a n e s in v a r i o u s p a r t s o f t h e v i t r e o u s w e r e s e e n in 2 5 e y e s ( 1 4 % ) . In 1 2 e y e s , c l i n i c a l or h i s t o l o g i c e x a m i n a t i o n d i s c l o s e d e x t e n s i v e r e t r o l e n t a l o r g a n i z a t i o n s in c o m b i n a t i o n w i t h t o t a l r e t i n a l d e t a c h m e n t a n d often with secondary lesions of the anterior s e g m e n t and atrophy of the entire g l o b e (Fig. 1). A s o l i d l o c a l fibrovascular m a s s o f t i s s u e w a s o b s e r v e d in ten e y e s ( 6 % ) . W i t h o u t e x c e p t i o n t h i s m a s s w a s l o c a l i z e d in t h e t e m p o r a l or inferotemporal part of the fundus periphery and was linked to the local retina, the ciliary body, and the peripheral part of the posterior l e n s c a p s u l e . In m o s t c a s e s , a fixed f a l c i f o r m r e t i n a l f o l d h a d d e v e l o p e d in a s s o c i a t i o n w i t h this lesion. Avascularity of the peripheral retina and the typical demarcation by the border o f aberrant t e r m i n a l r a m i f i c a t i o n s o f t h e r e t i n a l v e s s e l s in the region of the temporal equator were ob s e r v e d in 1 3 5 o f 1 7 0 e y e s ( 7 9 % ) ( F i g . 2 ) . T h e c o n f i g u r a t i o n o f t h e r e t i n a l v e s s e l s c e n t r a l to t h i s m a r g i n a l z o n e w a s o f t e n a b e r r a n t . In o t h e r studies of familial exudative vitreoretinopathy, this region s h o w e d an a b n o r m a l l y large n u m b e r o f v a s c u l a r r a m i f i c a t i o n s in w h i c h t h e c o u r s e s h o w e d an a b n o r m a l l y p a r a l l e l o r i e n t a tion.^*'^ A c o n f i g u r a t i o n o f t h i s t y p e w a s s e e n in 1 0 8 o f 1 7 0 e y e s ( 6 4 % ) in t h e p r e s e n t s e r i e s . N e o v a s c u l a r i z a t i o n s w e r e f o u n d in 1 8 o f 1 7 0 eyes ( 1 1 % ) with familial exudative vitreoreti-
36
AMERICAN JOURNAL OF OPHTHALMOLOGY
Fig. 1 (van Nouliuys). Left eye of a 25-year-old man. The anterior segment shovifs a totally cataract ous lens with a highly vascularized mass of fibrous tissue visible behind it. n o p a t h y ; t h e s e u s u a l l y d e v e l o p e d from t h e most peripheral retinal vascular ramifications on t h e t e m p o r a l s i d e o f the f u n d u s . T h e a c t i v i t y of t h e s e n e o v a s c u l a r i z a t i o n s differed c o n s i d e r a b l y . In c h i l d r e n , t h e v e s s e l s s o m e t i m e s s h o w e d a vital a p p e a r a n c e w i t h a r e d c o l o r , i n c i d e n t a l l o c a l b l e e d i n g in or in front o f t h e r e t i n a w a s s e e n , or g r o w t h w a s o b s e r v e d . In older children and adults, the neovasculariza t i o n s w e r e u s u a l l y fibrotic, a l t h o u g h fluoresce in a n g i o g r a p h y d i s c l o s e d p e r f u s i o n a n d l e a k a g e o f t h e dye (Figs. 3 a n d 4 ) . E c t o p i a of the m a c u l a , r a n g i n g from h a r d l y p e r c e p t i b l e to p r o n o u n c e d , w a s o b s e r v e d in 8 3 of 1 7 0 e y e s ( 4 9 % ) . T h e m a c u l a r d i s p l a c e m e n t w a s always t e m p o r a l or i n f e r o t e m p o r a l . As o t h e r s t u d i e s ' ^ " h a v e s h o w n , e x u d a t e s w e r e fairly u n c o m m o n , o c c u r r i n g in 1 6 o f 1 7 0 eyes ( 9 % ) . T h e y w e r e u s u a l l y s m a l l i n t r a r e t i n a l e x u d a t e s in t h e r e g i o n o f the t e m p o r a l e q u a t o r , but massive subretinal exudates were inciden tally o b s e r v e d (Fig. 5 ) . O t h e r fundus c h a n g e s i n c l u d e d the f o l l o w i n g : t o r t u o u s r e t i n a l v e i n s in 5 6 e y e s ( 3 3 % ) ; d e f o r m a t i o n o f p o s t e r i o r r e t i n a in 1 0 1 e y e s ( 5 9 % ) ; d r a g g e d o p t i c disk in 16 e y e s ( 9 % ) ; r e t i n a l p i g m e n t a t i o n in 3 5 e y e s ( 2 1 % ) ; r e t i n a l h e m o r r h a g e s in two e y e s ( 1 % ) ; r e t i n a l d e f e c t s in 19 e y e s ( 1 1 % ) ; w h i t e c h a n g e s o f p e r i p h e r a l r e t i n a in 3 7 e y e s ( 2 2 % ) ; a n d a t r o p h i c c h a n g e s of c h o r o i d a n d r e t i n a l pig m e n t e p i t h e l i u m in 3 9 e y e s ( 2 3 % ) . In 3 7 o f 1 8 0 e y e s ( 2 1 % ) w i t h e v i d e n t f a m i l i a l
January, 1991
Fig. 2 (van Nouhuys). Left fundus of a 17-year-old girl. Fluorescein angiogram (venous phase) of the temporal equator region shows the typical configura tion of retinal vessels of familial exudative vitreoreti nopathy. The peripheral retina is avascular and shows a V-shaped notch between the terminal ramifi cations of the superotemporal and inferotemporal vessels (arrow). exudative vitreoretinopathy, retinal detach m e n t o c c u r r e d o n c e or s e v e r a l t i m e s or a p r e existing retinal d e t a c h m e n t was found. Eight of 180 eyes ( 4 % ) showed retinoschisis, which was a l w a y s l i m i t e d to a s e g m e n t o f t h e p e r i p h e r a l retina. Recent rhegmatogenous retinal detachment was o b s e r v e d in n i n e o f t h e 3 7 e y e s w i t h r e t i n a l d e t a c h m e n t . T h e r e t i n a l d e f e c t s in t h i s g r o u p were widely diverse, including small round holes, horseshoe-shaped tears, and even giant t e a r s (Fig. 6 ) . Ten e y e s h a d b e c o m e b l i n d b e f o r e first e x a m i n a t i o n b e c a u s e o f c h r o n i c t o t a l r e t i n a l d e t a c h m e n t . Two e y e s in t h i s g r o u p w e r e s u b j e c t e d to l i g h t m i c r o s c o p i c e x a m i n a t i o n , w h i c h d i s c l o s e d e x t e n s i v e l e s i o n s of t h e t y p e o b s e r v e d h i s t o l o g i c a l l y in t h e t e r m i n a l s t a g e o f a p r o l i f e r a t i v e r e t i n o p a t h y . T h e p a t h o l o g i c fea t u r e s of o n e s p e c i m e n w e r e p r e v i o u s l y r e p o r t ed,* a n d t h e s e f e a t u r e s c o r r e s p o n d e d w i t h t h e m i c r o s c o p i c findings o f o t h e r studies.'^"'' Fourteen eyes showed a falciform retinal fold. In all of t h e s e e y e s , a p r o m i n e n t fold e x t e n d e d from t h e o p t i c disk t h r o u g h t h e p o s t e r i o r p o l e to the t e m p o r a l or i n f e r o t e m p o r a l p e r i p h e r y of the fundus (Fig. 7 ) . I o b s e r v e d s e v e r a l o f t h e s e falciform r e t i n a l folds over a p e r i o d o f m o r e t h a n five y e a r s , w i t h o u t any c h a n g e in t h e
Vol. I l l , No. 1
Familial Exudative Vitreoretinopathy
37
Fig. 3 (van Nouhuys). Right fundus of a 5-year-old girl. The temporal equator region shows partly fibrot ic new vessels and a few minor retinal hemorrhages.
Fig. 4 (van Nouhuys). Right fundus of a 33-yearold woman. Fluorescein angiogram shows leakage of dye from an equatorial neovascularization. The new vessels were chronic and partly fibrotic.
p o s i t i o n o f t h e r e t i n a . In t h e e y e o f a y o u n g girl, however, the formation of a falciform retinal fold c o u l d b e o b s e r v e d . A n o t h e r c h i l d w i t h b i l a t e r a l falciform r e t i n a l f o l d s s h o w e d g r a d u a l progression toward a total funnel retinal de t a c h m e n t in o n e e y e . M o s t f a l c i f o r m r e t i n a l
folds d e v e l o p e d at p r e s c h o o l a g e , a n d a few w e r e o b s e r v e d w i t h i n a few m o n t h s o f b i r t h . Only one eye showed a purely exudative retinal detachment, and biomicroscopy dis c l o s e d n o r e t i n a l d e f e c t s in t h i s e y e . In a n o t h e r eye with total, mainly fractional retinal detach-
Fig. 5 (van Nouhuys). Left fundus of a 14-year-old girl. A large subretinal exudate is visible in the nasal upper quadrant. Note the preretinal membranes.
Fig. 6 (van Nouhuys). Right eye of a 14-year-old girl. Detached retina with a giant tear on the superior side.
38
January, 1991
AMERICAN JOURNAL OF OPHTHALMOLOGY
Fig. 7 (van Nouhuys). Left fundus of a 30-year-old woman. Falciform retinal fold extending from the optic disk across the posterior pole to the inferotem poral periphery.
ment, however, extensive subretinal exudates were found (Fig. 5 ) . R e t i n a l d e t a c h m e n t s u r g e r y w a s p e r f o r m e d in 14 e y e s ( 1 2 e y e s of p a t i e n t s w i t h f a m i l i a l e x u d a tive v i t r e o r e t i n o p a t h y a n d two e y e s o f a p a t i e n t with sporadic exudative vitreoretinopathy). T h e s u r g e r y w a s d o n e in different h o s p i t a l s b y different o p h t h a l m i c s u r g e o n s a n d i n c l u d e d scleral buckling operations (eight eyes), pars p l a n a v i t r e c t o m y with or w i t h o u t s c l e r a l b u c k les (six e y e s ) , pars p l a n a v i t r e c t o m y w i t h s i l i c o n e oil (six e y e s ) , r e m o v a l o f s u b r e t i n a l sili c o n e oil ( o n e e y e ) , a n d r e m o v a l of s p o n g e s ( o n e eye). A total of 22 retinal operations were performed. S u r g e r y was p e r f o r m e d in p a t i e n t s w i t h r h e g m a t o g e n o u s r e t i n a l d e t a c h m e n t w i t h or w i t h out s i g n s of p r o l i f e r a t i v e v i t r e o r e t i n o p a t h y , fractional retinal d e t a c h m e n t without visible breaks, and exudative retinal detachment. O n e eye u n d e r w e n t a v i t r e c t o m y b e c a u s e o f p r o g r e s sion o f t r a c t i o n on an a t t a c h e d r e t i n a . S e v e n o p e r a t i o n s ( t w o v i t r e c t o m i e s a n d five scleral buckling procedures) were successful ( r e a t t a c h m e n t d u r i n g at l e a s t six m o n t h s after t h e o p e r a t i o n ) ; 13 o p e r a t i o n s ( t e n v i t r e c t o m i e s and three scleral buckling procedures) were not s u c c e s s f u l ( n o n a t t a c h m e n t or r e d e t a c h m e n t w i t h i n six m o n t h s after t h e o p e r a t i o n ) . In e i g h t eyes the first o p e r a t i o n w a s n o t s u c c e s s f u l , a n d six e y e s r e q u i r e d m o r e t h a n o n e o p e r a t i o n .
R e a t t a c h m e n t o f t h e r e t i n a in o n e o r m o r e p r o c e d u r e s w a s s u c c e s s f u l in s e v e n e y e s . T h e a g e o f t h e p a t i e n t s in t h i s g r o u p at t h e t i m e of o p e r a t i o n r a n g e d from 19 to 5 6 y e a r s ( m e a n , 3 0 years). The retinas of the other seven eyes could n o t b e r e p o s i t i o n e d . T h e a g e o f t h e s e p a t i e n t s at t h e t i m e o f s u r g e r y r a n g e d from 5 to 18 y e a r s ( m e a n , 13 y e a r s ) . T h e p l a t e l e t a g g r e g a t i o n test r e s u l t s a r e l i s t e d in t h e T a b l e . For e a c h a g g r e g a t i o n i n d u c e r , t h e m e a n and the standard deviation of the n u m b e r of aggregation units determined photometrical ly in t h e p a t i e n t g r o u p a n d in t h e c o n t r o l g r o u p were compared. Using adenosine diphosphate in t h r e e different c o n c e n t r a t i o n s , n o s i g n i f i c a n t difference w a s f o u n d b e t w e e n t h e p a t i e n t g r o u p a n d t h e c o n t r o l g r o u p (P = . 2 7 , . 5 2 , a n d . 7 0 , r e s p e c t i v e l y ) . U s i n g 1.5 m m o l / 1 o f a r a c h i d o n i c a c i d , n o s i g n i f i c a n t d i f f e r e n c e w a s f o u n d (P = .22). With 5 m m o l / 1 of arachidonic acid, how ever, p l a t e l e t a g g r e g a t i o n in t h e p a t i e n t g r o u p w a s f o u n d to e x c e e d that in t h e c o n t r o l g r o u p (P = . 0 0 3 ) . W i t h 5 X 10-« 1 o f c o l l a g e n a s i n d u c e r , t h e r e w a s n o s i g n i f i c a n t d i f f e r e n c e (P = . 5 2 ) , b u t w i t h 2 X 10"*1 of c o l l a g e n , a s l i g h t l y l o w e r a g g r e g a t i o n was f o u n d in t h e p a t i e n t g r o u p ; h o w e v e r , the d i f f e r e n c e w a s n o t s i g n i f i c a n t (P = .04). The bleeding time averaged 5 3 8 seconds ( s t a n d a r d d e v i a t i o n , 6 7 s e c o n d s ) in five p a tients, compared with 5 2 2 seconds (standard d e v i a t i o n , 1 5 7 s e c o n d s ) in t e n c o n t r o l s u b j e c t s . T h e s e v a l u e s did n o t differ s i g n i f i c a n t l y .
Discussion Although familial exudative vitreoretinopa thy may l e a d to b l i n d n e s s at an e a r l y a g e , m o s t of the gene carriers showed no severe visual handicap. The course of the visual function tests during the period o f observation con firmed t h e p o s t u l a t e t h a t t h e d i s e a s e is n o t a g r a d u a l l y p r o g r e s s i v e d e g e n e r a t i o n , as s o m e researchers believe. W h e n visual acuity was d i m i n i s h e d , it w a s a r e s u l t of c o m p l i c a t i o n s . T h e f o l l o w i n g c o m p l i c a t i o n s m a y l e a d to d i m i n ished visual acuity: deformation of the macula b e c a u s e of t r a c t i o n or e d e m a , v i t r e o u s h e m o r r h a g e , r e t i n a l d e t a c h m e n t , a n d , in y o u n g c h i l d r e n , amblyopia.**'*" A m b l y o p i a as a c o m p l i c a tion of familial exudative vitreoretinopathy h a s r a r e l y b e e n r e p o r t e d , b u t p r o b a b l y is n o t u n common.* Amblyopia, usually c o m b i n e d with c o n s i d e r a b l e a n i s o m e t r o p i a , p l a y e d a r o l e in t h e d i m i n i s h e d v i s u a l a c u i t y o f 1 2 ( 1 3 % ) o f my patients.
Vol. I l l , No. 1
39
Familial Exudative Vitreoretinopathy
In 8 0 o f 1 8 0 ( 4 4 % ) e y e s , n o v i t r e o u s l e s i o n s were observed. Pronounced vitreous m e m b r a n e s w e r e a l m o s t e x c l u s i v e l y s e e n in e y e s w i t h an e x t e n s i v e r e t i n o p a t h y or in e y e s w i t h chronic retinal detachment. T h e s e findings s e e m to w a r r a n t t h e c o n c l u s i o n t h a t t h e v i t r e o u s c h a n g e s in f a m i l i a l e x u d a t i v e v i t r e o r e t i n o p a t h y r e s u l t s from t h e v a s c u l o p a t h y a n d its c o m p l i c a t i o n s , s u c h as r e t i n a l n e o v a s c u l a r i z a tions and vitreous hemorrhages. Chronic leak age of b l o o d c o n s t i t u e n t s from r e t i n a l v e s s e l s m a y a l s o i n d u c e fibrous p r o l i f e r a t i o n i n t h e p r e r e t i n a l v i t r e o u s , as M a c h e m e r ^ " s u g g e s t e d . The vascular lesions of the peripheral retina in f a m i l i a l e x u d a t i v e v i t r e o r e t i n o p a t h y h a v e b e e n f r e q u e n t l y described.^'^'^'^-^' T h e a v a s c u larity o f t h e p e r i p h e r a l r e t i n a a n d t h e t y p i c a l demarcation by the equatorial zone o f aberrant terminal ramifications of retinal vessels were o b s e r v e d b i o m i c r o s c o p i c a l l y in 1 3 5 o f 1 7 0 e y e s ( 7 9 % ) . In f a m i l i a l e x u d a t i v e v i t r e o r e t i n o p a t h y , the marginal zone of peripheral vascular branches frequently shows a V-shaped notch near the temporal horizontal meridian (Fig. 2).*·'^ M i y a k u b o , H a s h i m o t o , a n d M i y a k u b o " f o u n d this c o n f i g u r a t i o n in 1 0 8 ( 8 1 % ) o f t h e e y e s in t h e i r s e r i e s , a n d r e g a r d e d t h e a n o m a l y as o n e o f t h e p r i n c i p a l c h a r a c t e r i s t i c s o f f a m i l i a l exudative vitreoretinopathy. It is e x t r e m e l y i n t e r e s t i n g to c o m p a r e t h i s c o n f i g u r a t i o n w i t h t h e n o r m a l h u m a n fetal r e t i na d u r i n g t h e final t w o to t h r e e m o n t h s o f t h e i n t r a u t e r i n e p e r i o d . T h e flat s p e c i m e n o f t h e n o r m a l fetal r e t i n a in t h i s s t a g e s h o w s a V s h a p e d m a r g i n a l z o n e of i m m a t u r e v a s c u l a r tissue,^^ w h i c h is i d e n t i c a l w i t h t h e c o n f i g u r a t i o n o f the b o r d e r z o n e in t h e m a t u r e e y e i n familial e x u d a t i v e v i t r e o r e t i n o p a t h y . T h i s m o r phologic similarity supports the postulate that t h e p a t h o g e n e s i s o f t h i s d i s e a s e is b a s e d o n premature arrest o f the vascular development of the r e t i n a . In v i e w o f t h e s t a t e o f d e v e l o p m e n t o f t h e r e t i n a l v a s c u l a r i z a t i o n in t h e fun dus in f a m i l i a l e x u d a t i v e v i t r e o r e t i n o p a t h y , this arrest cannot have occurred before the seventh month o f the intrauterine period. The relationship b e t w e e n familial exudative v i t r e o r e t i n o p a t h y a n d f a l c i f o r m r e t i n a l fold h a s b e e n discussed.^^'^'^ F o u r t e e n c a s e s o f f a l c i f o r m r e t i n a l fold w e r e f o u n d in f a m i l i e s w i t h f a m i l i a l exudative vitreoretinopathy, which shows that familial e x u d a t i v e v i t r e o r e t i n o p a t h y is an i m p o r t a n t a n d p r o b a b l y b y far t h e m o s t f r e q u e n t c a u s e of falciform r e t i n a l fold in p a t i e n t s w h o otherwise show no general congenital a n o m a lies. T h e s e o b s e r v a t i o n s are i m p o r t a n t , n o t o n l y
TABLE
PLATELET AGGREGATION IN PATIENTS WITH FAMILIAL EXUDATIVE VITREORETINOPATHY AND CONTROL SUBJECTS CONTROL SUBJECTS
PATIENTS NO.
NO.
UNITS OF
UNITS OF AGGREGATION
AGGREGATION AGGREGATION INDUCER
MEAN
S.D.
10
130
14
17
10
119
26
99 98 92
15 17 7
9 10 7
94 115 96
28 11 14
7
76
5
8
65
6
7
23
4
10
17
11
MEAN
S.O.
7
117
26
4
111
6 7 6
AND CONCENTRATION
Adenosine diptiosphate 10-· mol/l Adenosine diptiosptiate 4 x 1 0 - ' mol/l Adenosine diptiosptiate 2 X 10-' mol/l Collagen 2 χ lO-'l Collagen 5 χ 10-· 1 Aractiidonic acid 5 mmol/l Aractiidonic acid 1.5 mmol/l
for t h e c l a s s i f i c a t i o n o f t h e c o n g e n i t a l r e t i n a l fold s y n d r o m e b u t a l s o b e c a u s e t h e y p r o v i d e information about the pathogenesis of this con dition. M a n n ^ ' p o s t u l a t e d t h a t a f a l c i f o r m r e t i n a l fold r e s u l t e d from l o c a l a c c r e t i o n b e t w e e n t h e pri mary vitreous and the inside of the optic cup. M i c h a e l s o n ^ a n d Pruett^" m a i n t a i n e d t h a t t h e a n o m a l y r e s u l t e d from p e r s i s t e n t h y p e r p l a s t i c p r i m a r y v i t r e o u s in t h e p o s t e r i o r p a r t of t h e vitreous space. These theories concerning the primary vitreous are no longer tenable because f a l c i f o r m f o l d s d e v e l o p a s a c o m p l i c a t i o n of familial exudative vitreoretinopathy, a disease not associated with disorders o f the primary vitreous development. I believe the falciform fold t h a t d e v e l o p s in f a m i l i a l e x u d a t i v e v i t r e o retinopathy has a p a t h o g e n e s i s similar to that o f t h e f o l d , w h i c h m a y d e v e l o p in r e t i n o p a t h y of prematurity. Chaudhuri and associates'" reported dis t u r b e d p l a t e l e t a g g r e g a t i o n , e s p e c i a l l y after i n duction with a low concentration o f arachidonic a c i d ( 1 . 5 m m o l / l ) . T h e y s p e c u l a t e d t h a t a d e f i c i e n c y o f t h r o m b o x a n e A 2 (a p o t e n t v a s o c o n s t r i c t o r ) m i g h t p l a y a r o l e in t h e p a t h o g e n e sis o f t h e v a s c u l a r a n o m a l i e s in f a m i l i a l e x u d a tive v i t r e o r e t i n o p a t h y . T h i s p r o m p t e d m e to r e p e a t p l a t e l e t a g g r e g a t i o n t e s t s in p a t i e n t s with familial exudative vitreoretinopathy, using the same inducers and identical concen t r a t i o n s . 1 w a s u n a b l e to d e m o n s t r a t e any sig n i f i c a n t d i f f e r e n c e in p l a t e l e t a g g r e g a t i o n b e -
40
AMERICAN JOURNAL OF OPHTHALMOLOGY
tween patients and control subjects. These results agree with those reported by Friedrich, F r a n c i s , a n d Kim.^" H o w e v e r , t h e y f o u n d an i n c r e a s e d b l e e d i n g t i m e in o n e p a t i e n t w i t h familial e x u d a t i v e v i t r e o r e t i n o p a t h y . M y h e m a t o l o g i c findings do n o t i n d i c a t e an a b n o r m a l b l e e d i n g t i m e in t h i s d i s o r d e r . The presence and growth of nonfibrotic neo v a s c u l a r i z a t i o n s w e r e o b s e r v e d in s o m e o f t h e p a t i e n t s o l d e r t h a n six y e a r s of a g e ; in r e t i n o p a thy o f p r e m a t u r i t y t h i s h a s r a r e l y b e e n d e scribed. The clinical features of the two diseas es are t h e r e f o r e n o t a l w a y s i d e n t i c a l . Vitreous hemorrhage can be a serious com p l i c a t i o n at a y o u n g a g e , as I h a v e o b s e r v e d in a few i n f a n t s . In o n e u n t r e a t e d e y e , t h e h e m o r r h a g e w a s f o l l o w e d b y a total r e t i n a l d e t a c h m e n t w i t h a c l o s e d f u n n e l w i t h i n a few w e e k s . These observations warrant regular examina t i o n s of t h e p e r i p h e r a l fundi of y o u n g c h i l d r e n a n d p r o m p t c r y o c o a g u l a t i o n or l a s e r c o a g u l a t i o n o f any n e w v e s s e l s . S m a l l n e o v a s c u l a r i z a t i o n s g e n e r a l l y s h o w e d rapid r e g r e s s i o n after t h e r a p y (Fig. 8 ) . Adult eyes s o m e t i m e s showed small, partly fibrotic n e w v e s s e l s that w e r e a s y m p t o m a t i c a n d did n o t c h a n g e d u r i n g y e a r s o f o b s e r v a t i o n . In s u c h p a t i e n t s , p e r i o d i c c h e c k u p s w o u l d s e e m to b e sufficient. R e t i n a l d e t a c h m e n t in f a m i l i a l e x u d a t i v e vit reoretinopathy shows numerous clinical varia t i o n s a n d u s u a l l y o c c u r s at an e a r l y a g e . In my p a t i e n t s , all d e t a c h m e n t s h a d o c c u r r e d b e f o r e
Fig. 8 (van Nouhuys). Left fundus of a 10-year-old girl. Fibrotic tissue (arrows) as a remnant of neovas cularization two years after cryocoagulation of the peripheral retina.
January, 1991
a g e 3 0 y e a r s , w i t h the e x c e p t i o n o f o n e r h e g m a t o g e n o u s d e t a c h m e n t s e e n in a 5 6 - y e a r - o l d man. T r a c t i o n on t h e p e r i p h e r a l r e t i n a s e e m s to b e t h e p r i n c i p a l c a u s e o f r e t i n a l d e t a c h m e n t in familial e x u d a t i v e v i t r e o r e t i n o p a t h y . In s o m e cases, this traction displaces the retina without visible breaks. The best example of a fractional d e t a c h m e n t is the f r e q u e n t l y o b s e r v e d falci form r e t i n a l fold. O f t e n , h o w e v e r , t r a c t i o n c a u s e s r e t i n a l d e f e c t s , w h i c h may vary w i d e l y in s i z e a n d s h a p e ( F i g . 6 ) . R e t i n a l d e t a c h m e n t in f a m i l i a l e x u d a t i v e vit r e o r e t i n o p a t h y p r o v e d to b e a s e r i o u s c o m p l i c a tion with a relatively unfavorable course. O f 41 e y e s ( 3 7 e y e s of p a t i e n t s w i t h f a m i l i a l e x u d a t i v e v i t r e o r e t i n o p a t h y a n d four e y e s o f p a t i e n t s with sporadic exudative vitreoretinopathy), 22 with retinal d e t a c h m e n t had not been treated with retinal surgery. G e n e r a l l y , this was b e c a u s e of the p o o r p r o g n o s i s c o n c e r n i n g v i s u a l i m p r o v e m e n t , e s p e c i a l l y in p a t i e n t s w i t h falci form r e t i n a l folds or c h r o n i c d e t a c h m e n t s a s s o ciated with severe proliferative vitreoretinopa thy. R e t i n a l s u r g e r y in f a m i l i a l e x u d a t i v e v i t r e o r e t i n o p a t h y w a s often c o m p l i c a t e d b y n o n a t t a c h m e n t or r e d e t a c h m e n t after s u r g e r y . In o n l y s e v e n e y e s t h e r e t i n a w a s r e a t t a c h e d after o n e or m o r e o p e r a t i o n s . C o m p l i c a t i o n s after operative therapy have b e e n previously report ed.''^' T h e r e s u l t s o f r e t i n a l s u r g e r y s e e m e d to b e r e l a t e d to t h e a g e o f t h e p a t i e n t s at t h e t i m e o f o p e r a t i o n . All o p e r a t i o n s on e y e s o f p a t i e n t s y o u n g e r t h a n t h e a g e o f 19 y e a r s w e r e u n s u c cessful, w h e r e a s t h e r e t i n a s o f all e y e s o f p a t i e n t s o l d e r t h a n 19 y e a r s of a g e w e r e t r e a t e d s u c c e s s f u l l y . In t h e e y e s o f p a t i e n t s o l d e r t h a n 19 y e a r s o f a g e , e x t e n s i v e p r o l i f e r a t i v e v i t r e o r e t i n o p a t h y w a s an u n u s u a l f e a t u r e , w h e r e a s t h e r e t i n a l d e t a c h m e n t s in t h e y o u n g e r p a t i e n t s w e r e m o r e p r o n e to d e v e l o p t h i s c o m p l i c a t i o n , o f t e n b e f o r e s u r g e r y . T h e r e f o r e , p a r s p l a n a vit r e c t o m y w a s the m a i n s u r g i c a l p r o c e d u r e in t h e younger patients, whereas a scleral buckling t e c h n i q u e w a s p e r f o r m e d in m o s t o f t h e o l d e r p a t i e n t s . In c h i l d r e n w i t h f a m i l i a l e x u d a t i v e vitreoretinopathy and retinal d e t a c h m e n t , the s u r g e o n faces t h e s a m e p r o b l e m s a s in t h e t r e a t m e n t o f r e t i n a l d e t a c h m e n t in p a t i e n t s w i t h r e t i n o p a t h y o f p r e m a t u r i t y . In p a t i e n t s w i t h r e t i n o p a t h y of p r e m a t u r i t y , a l s o in t h e o l d e r p a t i e n t s w i t h r e g r e s s e d r e t i n o p a t h y of p r e m a t u r i t y , t h e risk o f r e c u r r e n t r e t i n a l d e t a c h m e n t is g r e a t e r t h a n normal.^'^ V i r t u a l l y all p a t i e n t s w i t h f a m i l i a l e x u d a t i v e vitreoretinopathy showed a pedigree consistent
Vol. I l l , No. 1
Familial Exudative Vitreoretinopathy
with a u t o s o m a l d o m i n a n t t r a n s m i s s i o n o f t h e g e n e . Five p a t i e n t s , i n c l u d i n g i d e n t i c a l t w i n s , had no close relatives with perceptible a n o m a lies. S u c h s o l i t a r y c a s e s o f p a t i e n t s w i t h o c u l a r a n o m a l i e s i d e n t i c a l to t h o s e o f f a m i l i a l e x u d a tive v i t r e o r e t i n o p a t h y h a v e a l s o b e e n o b s e r v e d by o t h e r i n v e s t i g a t o r s . ' ^ W h e t h e r s u c h c a s e s involve a mutation, n o n p e n e t r a n c e of the auto s o m a l d o m i n a n t g e n e in o n e o f t h e p a r e n t s , or g e n e t i c h e t e r o g e n e i t y is u n k n o w n .
ACKNOWLEDGMENT
T h e h e m a t o l o g i c s t u d i e s w e r e p e r f o r m e d at the D e p a r t m e n t o f H e m a t o l o g y , U n i v e r s i t y o f Nijmegen, The Netherlands.
References 1. Criswick, V. G., and Schepens, C. L.: Familial exudative vitreoretinopathy. Am. J. Ophthalmol. 68:578, 1969. 2. Gow, J . , and Oliver, G. L.: Familial exudative vitreoretinopathy. Arch. Ophthalmol. 86:150, 1 9 7 1 . 3. Canny, C. L. B., and Oliver, G. L.: Fluorescein angiographic findings in familial exudative vitreoret inopathy. Arch. Ophthalmol. 9 4 : 1 1 1 4 , 1 9 7 6 . 4. Slusher, M. M., and Hutton, W. E.: Familial exu dative vitreoretinopathy. Am. J. Ophthalmol. 87:152, 1979. 5. Ober, R. R., Bird, A. C , Hamilton, A. M., and Sehmi, K.: Autosomal dominant exudative vitreoreti nopathy. Br. J. Ophthalmol. 64:112, 1980. 6. Nijhuis, F. Α., Deutman, A. F., and Aan de Kerk, A. L.: Fluorescein angiography in mild stages of dominant exudative vitreoretinopathy. Mod. Probl. Ophthalmol. 20:107, 1 9 7 9 . 7. Laqua, H.: Familial exudative vitreoretinopathy. Graefes Arch. Clin. Exp. Ophthalmol. 2 1 3 : 1 2 1 , 1 9 8 0 . 8. van Nouhuys, C. E.: Dominant exudative vitre oretinopathy and other vascular developmental dis orders of the peripheral retina. Doc. Ophthalmol. 54:1, 1982. 9. Goldschmidt, R.: Gen und Ausseneigenschaft. Z. Vererbungslehre 69:38, 1 9 3 5 . 10. Chaudhuri, P. R., Rosenthal, A. R., Goulstine, D. B., Rowlands, D., and Mitchel, V. E.: Familial exudative vitreoretinopathy associated with familial thrombocytopathy. Br. J. Ophthalmol. 67:755, 1 9 8 3 . 11. Imandt, L., Genders, T., Wessels, J., and Haanen, C : An improved method for preparing platelet-rich plasma. Thromb. Res. 11:429, 1977. 12. Miyakubo, H., Inohara, N., and Hashimoto, K.: Retinal involvement in familial exudative vitreoreti nopathy. Ophthalmologica 185:125, 1982. 13. Miyakubo, H., Hashimoto, K., and Miyakubo, S.: Retinal vascular pattern in familial exudative vitreoretinopathy. Ophthalmology 9 1 : 1 5 2 4 , 1 9 8 4 . 14. Tasman, W., Augsburger, ] . , Shields, j . Α., Ca-
41
puto, Α., and Annesley, W, H.: Familial exudative vitreoretinopathy. Trans. Am. Soc. Ophthalmol. 74:211, 1 9 8 1 . 15. Brockhurst, R. J . , Albert, D. M., and Zakov, Z. N.: Pathological findings in familial exudative vit reoretinopathy. Arch. Ophthalmol. 9 9 : 2 1 4 3 , 1 9 8 1 . 16. Boldrey, E. E., Egbert, P., Gass, ) . D. M., and Friberg, T.: The histopathology of familial exudative vitreoretinopathy. Arch. Ophthalmol. 103:238, 1 9 8 5 . 17. Nicholson, D. H., and Galvis, V.: CriswickSchepens syndrome (familial exudative vitreoreti nopathy). Study of a Colombian kindred. Arch. Oph thalmol. 102:1519, 1 9 8 4 . 18. van Nouhuys, C. E.: Juvenile retinal detach ment as a complication of familial exudative vitreo retinopathy. Fortschr. Ophthalmol. 8 6 : 2 2 1 , 1989. 19. Schulman, J . , and Merin, S.: Hereditary vitreo retinal degenerations. In Newsome, D. A. (ed.): Reti nal Dystrophies and Degenerations. New York, Ra ven Press, 1 9 8 8 , pp. 9 5 . 20. Machemer, R.: Description and pathogenesis of late stages of retinopathy of prematurity. Ophthal mology 92:1000, 1 9 8 5 . 2 1 . Feldman, Ε. L., Norris, J. L., and Cleasby, G. W.: Autosomal dominant exudative vitreoretinop athy. Arch. Ophthalmol. 101:1532, 1983. 22. Foos, R. Y., and Kopelow, S.: Development of retinal vasculature in perinatal infants. Surv, Oph thalmol. 18:117, 1 9 7 3 . 23. Dudgeon, J.: Familial exudative vitreoretinop athy. Trans. Ophthalmol. S o c . U.K. 9 9 : 4 5 , 1 9 7 9 . 24. van Nouhuys, C. E.: Congenital retinal fold as a sign of dominant exudative vitreoretinopathy. Graefes Arch. Clin. Exp. Ophthalmol. 217:55, 1 9 8 1 . 25. Nishimura, M., Yamana, T., Sugino, M., Kohno, T., Yamana, Y., Minei, M., and Sanui, H.: Falciform retinal fold as a sign of familial exudative vitreoretinopathy. Jpn. J. Ophthalmol. 27:40, 1983. 26. Spallone, Α.: Differential diagnosis of heredi tary vitreoretinopathy. Milan, Italy, Fogliazza Editore, 1989, pp. 2 3 - 3 0 . 27. Mann, I.: Congenital retinal fold. Br. J. Oph thalmol. 19:641, 1 9 3 5 . 28. Michaelson, 1. C : Intertissue vascular rela tionships in the fundus of the eye. Invest. Ophthal mol. 5:1004, 1965. 29. Pruett, R. C : The pleomorphism and compli cations of posterior hyperplastic primary vitreous. Am. J. Ophthalmol. 80:625, 1975. 30. Friedrich, C. Α., Francis, Κ. Α., and Kim, Η. C : Familial exudative vitreoretinopathy (FEVR) and platelet dysfunction. Br. J. Ophthalmol. 73:477, 1989. 3 1 . Okubo, Y., Okubo, Α., Kubono, Τ., and Shimizu, Η.: Familial exudative vitreoretinopathy, rhegmatogenous retinal detachment and postopera tive uveitis with massive subretinal exudation. Acta Soc. Ophthalmol. Jpn. 8 8 : 1 1 5 1 , 1 9 8 4 . 32. Sneed, S. R., Pulido, J. S., Blodi, C. F., Clarkson, J. G., Flynn, H. W., Jr., and Mieler, W. F.: Surgi cal management of late-onset retinal detachments associated with regressed retinopathy of prematuri ty. Ophthalmology 97:179, 1 9 9 0 .
C. Erik van Nouhuys, M.D.
Between 1979 and 1989, I examined 106 pa t i e n t s (16 p e d i g r e e s ) w i t h s i g n s of f a m i l i a l exudative vitreoretinopathy. Of these p a t i e n t s , 101 h a d f a m i l i a l e x u d a t i v e v i t r e o r e t i n o p a t h y , a n d five h a d a s p o r a d i c m a n i f e s t a tion. The complications of familial e x u d a t i v e vitreoretinopathy, deformation of the p o s t e r i or r e t i n a , v i t r e o u s h e m o r r h a g e , a m b l y o p i a , and retinal d e t a c h m e n t , caused d i m i n i s h e d visual acuity. Of 170 eyes, retinal n e o v a s c u l a r i z a t i o n w a s o b s e r v e d in 1 8 e y e s (11%), a n d r e t i n a l e x u d a t e s w e r e o b s e r v e d i n 1 6 e y e s (90/0). S e v e r a l f o r m s of r e t i n a l d e t a c h m e n t o c c u r r e d in 37 of 1 8 0 e y e s (21%), w h i c h o f t e n t o o k a n u n f a v o r a b l e c o u r s e . A f a l c i f o r m r e t i n a l fold was o b s e r v e d in 1 4 e y e s (8%). R e t i n a l s u r g e r y was p e r f o r m e d in 14 eyes; r e a t t a c h m e n t of t h e r e t i n a w a s s u c c e s s f u l in o n l y s e v e n e y e s . Platelet aggregation studies disclosed n o sig nificant d i f f e r e n c e s b e t w e e n s e v e n p a t i e n t s with familial exudative vitreoretinopathy and ten control subjects. T h e p a t h o g e n e s i s of the d i s e a s e is b a s e d on a p r e m a t u r e a r r e s t o f t h e v a s c u l a r d e v e l o p m e n t of t h e r e t i n a .
FAMILIAL EXUDATIVE VITREORETINOPATHY
(also
known as dominant exudative vitreoretinopa thy) is a h e r e d i t a r y d i s o r d e r w i t h a u t o s o m a l dominant transmission characterized by a b o u n d a r y o f the r e t i n a l v a s c u l a r n e t w o r k in t h e e q u a t o r i a l r e g i o n o f the fundus a n d a v a s c u l a r ity o f t h e p e r i p h e r a l r e t i n a , e s p e c i a l l y o n t h e t e m p o r a l s i d e . M o r e s e v e r e l y affected e y e s s h o w a v a r i e t y o f s i g n s , s u c h as d e f o r m a t i o n o f
Accepted for publication Oct. 15, 1990. From the Department of Ophthalmology, CanisiusWilhelmina Hospital, Nijmegen, The Netherlands. This study was supported in part by the Praeventiefonds, The Hague, The Netherlands. Reprint requests to C. Erik van Nouhuys, M.D., De partment of Ophthalmology, Canisius-Wilhelmina Hos pital, P.O. Box 9015, 6500 GS Nijmegen, The Nether lands.
34
the posterior retina, ectopia of the macula, retinal neovascularization and exudates, pig m e n t a r y c h a n g e s of t h e r e t i n a , r e t i n a l b r e a k s , vitreous hemorrhages and membranes, retinoschisis, retinal detachment, cataract, bandshaped keratopathy, and phthisis bulbi.'* T h e fundus a b n o r m a l i t i e s o f f a m i l i a l e x u d a tive v i t r e o r e t i n o p a t h y are s i m i l a r to t h o s e o f retinopathy of prematurity. Therefore, retinop athy o f p r e m a t u r i t y c a n b e r e g a r d e d as a p h e n o copy of familial exudative vitreoretinopathy.*'' B e c a u s e o f its f r e q u e n t l y asymptomatic c o u r s e a n d t h e d i v e r s i t y o f s i g n s , t h e d i s e a s e is often u n r e c o g n i z e d or d i a g n o s e d i n c o r r e c t l y . T h e p u r p o s e o f t h i s s t u d y w a s to d e s c r i b e a n d catalog the various signs and complications of t h e d i s e a s e as w e l l as t h e i r p r e v a l e n c e in a relatively large group of patients. Chaudhuri and associates'" reported dis t u r b e d p l a t e l e t a g g r e g a t i o n in s e v e n p a t i e n t s w i t h f a m i l i a l e x u d a t i v e v i t r e o r e t i n o p a t h y . In v i e w o f t h e s e findings, I p e r f o r m e d a c o n t r o l l e d s t u d y o f p l a t e l e t a g g r e g a t i o n in 1 7 p a t i e n t s .
Patients and IVIethods Between 1 9 7 9 and 1 9 8 9 , I examined Dutch families with familial exudative vitreoretinopa thy at t h e E y e C l i n i c o f t h e U n i v e r s i t y of N i j m e g e n a n d at t h e C a n i s i u s - W i l h e l m i n a H o s p i t a l . Generally, familial exudative vitreoretinopathy w a s d i a g n o s e d after b i o m i c r o s c o p i c o b s e r v a tion o f t h e c h a r a c t e r i s t i c e q u a t o r i a l d e m a r c a tion between vascular and avascular retina and t h e a n g i o g r a p h i c finding o f n o n p e r f u s i o n o f t h e peripheral retina. Ophthalmic examinations of 3 5 0 patients s h o w e d c h a r a c t e r i s t i c s o f f a m i l i a l e x u d a t i v e vit r e o r e t i n o p a t h y in 1 0 6 p a t i e n t s . T h e d i s e a s e w a s f a m i l i a l in 1 0 1 p a t i e n t s from 1 6 p e d i g r e e s . In 11 of t h e s e p a t i e n t s , t h e v a s c u l a r l e s i o n s o f t h e peripheral retina were so slight that the diagno sis c o u l d n o t b e c o n f i r m e d w i t h a b s o l u t e c e r -
©AMERICAN JOURNAL OF OPHTHALMOLOGY 1 1 1 : 3 4 - 4 1 , JANUARY, 1 9 9 1
Vol. I l l , No. 1
Familial Exudative Vitreoretinopathy
t a i n t y . T h e d a t a o f t h e s e 11 p a t i e n t s are n o t included. T h e remaining 9 0 patients in the 16 pedigrees showed evident signs of the disease. Five o f t h e s e p a t i e n t s , i n c l u d i n g i d e n t i c a l twins, showed unmistakable ocular lesions, al though no signs of familial exudative vitreoreti n o p a t h y c o u l d b e f o u n d in t h e i r i m m e d i a t e family. A s s u c h s p o r a d i c c a s e s m a y r e s u l t f r o m g e n e t i c h e t e r o g e n e i t y , t h e data on t h e s e p a t i e n t s are n o t i n c l u d e d . All p a t i e n t s w i t h f a m i l ial a n d s p o r a d i c e x u d a t i v e v i t r e o r e t i n o p a t h y h a d a b i r t h w e i g h t o v e r 2 , 0 0 0 g, a n d n o n e w e r e premature. Three patients h a d b e e n given s o m e s u p p l e m e n t a l o x y g e n i m m e d i a t e l y after b i r t h for o n e or two d a y s . In all p a t i e n t s , t h e o p h t h a l m i c e x a m i n a t i o n included determination of visual acuity, deter m i n a t i o n of t h e e y e p o s i t i o n a n d k a p p a a n g l e , and slit-lamp examination of the anterior seg ment. Patients were questioned regarding any previous ocular diseases and neonatal details. O p h t h a l m o s c o p y w a s a l w a y s p e r f o r m e d in full m y d r i a s i s after i n s t i l l a t i o n o f 0 . 5 % t r o p i c a m i d e , 5 % p h e n y l e p h r i n e , a n d s o m e t i m e s 1% c y c l o p e n t o l a t e e y e d r o p s . In a l l o l d e r c h i l d r e n and adults, the fundus was e x a m i n e d by biomi c r o s c o p y w i t h a t h r e e - m i r r o r c o n t a c t l e n s . For young children, ophthalmoscopy was consid e r e d sufficient. F l u o r e s c e i n a n g i o g r a p h y a n d color photography of the peripheral fundus and p o s t e r i o r p o l e w e r e p e r f o r m e d in s e l e c t e d p a t i e n t s . In a few o f t h e p a t i e n t s , k i n e t i c p e r i m e try ( G o l d m a n n ) , s c o t o p i c a n d p h o t o p i c e l e c t r o retinography, and electro-oculography were performed. H e m a t o l o g i c tests and platelet aggregation t e s t s w e r e p e r f o r m e d in s e v e n p a t i e n t s w i t h unmistakable familial exudative vitreoretinop a t h y in t h r e e p e d i g r e e s a n d in t e n a g e - m a t c h e d control subjects. For t h e p l a t e l e t a g g r e g a t i o n t e s t s , c i t r a t e d b l o o d from p a t i e n t s a n d c o n t r o l s u b j e c t s w a s u s e d to p r e p a r e p l a t e l e t - r i c h p l a s m a b y c e n t r i f u g a t i o n on a c u s h i o n for 2 0 m i n u t e s at 2 5 0 G . " A g g r e g a t i o n in p l a t e l e t - r i c h p l a s m a w a s m e a sured with a photometer. Aggregation was in d u c e d w i t h a d e n o s i n e d i p h o s p h a t e d i l u t e d to end-concentrations of 1 0 * mol/1, 4 x 1 0 " ' mol/1, and 2 x 1 0 " ' mol/1; collagen suspen s i o n s in 0 . 9 % s o d i u m c h l o r i d e (2 x 10"* 1 a n d 5 X 10"* I); a n d a r a c h i d o n i c a c i d ( e n d c o n c e n t r a t i o n s o f 5 X 10"3 m o l / 1 a n d 1.5 X 10"^ m o l / 1 ) . The b l e e d i n g t i m e w a s d e t e r m i n e d in five p a t i e n t s a n d ten c o n t r o l s u b j e c t s . T h i s w a s d o n e after p l a c i n g a s p h y g m o m a n o m e t e r cuff o n t h e u p p e r a r m a n d inflating it t o 4 0 m m H g , u s i n g a bleeding-time device.
35
Results V i s u a l a c u i t y w a s d e t e r m i n e d in 1 7 6 e y e s o f 9 0 p a t i e n t s w i t h e v i d e n t f a m i l i a l e x u d a t i v e vit r e o r e t i n o p a t h y ( t h e p a t i e n t s w i t h m i n i m a l fun dus l e s i o n s a n d n o n f a m i l i a l e x u d a t i v e v i t r e o retinopathy were excluded). Whenever visual a c u i t y w a s d e t e r m i n e d m o r e t h a n o n c e in t h e same individual, the most recent value was recorded. O f 176 eyes, visual acuity was 2 0 / 2 0 or b e t t e r in 6 5 e y e s ( 3 7 % ) ; 2 0 / 3 5 t o 2 0 / 2 5 in 4 8 e y e s ( 2 7 % ) ; 2 0 / 7 0 t o 2 0 / 4 0 in 1 4 e y e s ( 8 % ) ; 2 0 / 2 0 0 t o 2 0 / 1 0 0 in 1 2 e y e s ( 7 % ) ; c o u n t i n g fingers i n 1 7 e y e s ( 1 0 % ) ; h a n d m o t i o n s in s e v e n e y e s ( 4 % ) ; a n d n o l i g h t p e r c e p t i o n in 1 5 e y e s ( 9 % ) . Determined binocularly, visual acuity w a s 2 0 / 1 0 0 or l e s s in 1 3 o f 8 8 p a t i e n t s ( 1 5 % ) . In 1 8 0 e y e s o f 9 0 p a t i e n t s w i t h f a m i l i a l e x u dative vitreoretinopathy, the vitreous was nor m a l in 8 0 e y e s ( 4 4 % ) ; s y n e r e s i s a n d l i q u e f a c t i o n w e r e n o t e d in 4 2 e y e s ( 2 3 % ) ; d e l i c a t e w h i t e p a r t i c l e s w e r e s e e n in 2 7 e y e s ( 1 5 % ) ; p i g m e n t e d c e l l s w e r e n o t e d in n i n e e y e s ( 5 % ) ; v i t r e o u s h e m o r r h a g e o c c u r r e d i n four e y e s ( 2 % ) ; p r e r e t i n a l m e m b r a n e s a n d o p a c i t i e s w e r e s e e n in 3 0 e y e s ( 1 7 % ) ; m e m b r a n e s in v a r i o u s p a r t s o f t h e v i t r e o u s w e r e s e e n in 2 5 e y e s ( 1 4 % ) . In 1 2 e y e s , c l i n i c a l or h i s t o l o g i c e x a m i n a t i o n d i s c l o s e d e x t e n s i v e r e t r o l e n t a l o r g a n i z a t i o n s in c o m b i n a t i o n w i t h t o t a l r e t i n a l d e t a c h m e n t a n d often with secondary lesions of the anterior s e g m e n t and atrophy of the entire g l o b e (Fig. 1). A s o l i d l o c a l fibrovascular m a s s o f t i s s u e w a s o b s e r v e d in ten e y e s ( 6 % ) . W i t h o u t e x c e p t i o n t h i s m a s s w a s l o c a l i z e d in t h e t e m p o r a l or inferotemporal part of the fundus periphery and was linked to the local retina, the ciliary body, and the peripheral part of the posterior l e n s c a p s u l e . In m o s t c a s e s , a fixed f a l c i f o r m r e t i n a l f o l d h a d d e v e l o p e d in a s s o c i a t i o n w i t h this lesion. Avascularity of the peripheral retina and the typical demarcation by the border o f aberrant t e r m i n a l r a m i f i c a t i o n s o f t h e r e t i n a l v e s s e l s in the region of the temporal equator were ob s e r v e d in 1 3 5 o f 1 7 0 e y e s ( 7 9 % ) ( F i g . 2 ) . T h e c o n f i g u r a t i o n o f t h e r e t i n a l v e s s e l s c e n t r a l to t h i s m a r g i n a l z o n e w a s o f t e n a b e r r a n t . In o t h e r studies of familial exudative vitreoretinopathy, this region s h o w e d an a b n o r m a l l y large n u m b e r o f v a s c u l a r r a m i f i c a t i o n s in w h i c h t h e c o u r s e s h o w e d an a b n o r m a l l y p a r a l l e l o r i e n t a tion.^*'^ A c o n f i g u r a t i o n o f t h i s t y p e w a s s e e n in 1 0 8 o f 1 7 0 e y e s ( 6 4 % ) in t h e p r e s e n t s e r i e s . N e o v a s c u l a r i z a t i o n s w e r e f o u n d in 1 8 o f 1 7 0 eyes ( 1 1 % ) with familial exudative vitreoreti-
36
AMERICAN JOURNAL OF OPHTHALMOLOGY
Fig. 1 (van Nouliuys). Left eye of a 25-year-old man. The anterior segment shovifs a totally cataract ous lens with a highly vascularized mass of fibrous tissue visible behind it. n o p a t h y ; t h e s e u s u a l l y d e v e l o p e d from t h e most peripheral retinal vascular ramifications on t h e t e m p o r a l s i d e o f the f u n d u s . T h e a c t i v i t y of t h e s e n e o v a s c u l a r i z a t i o n s differed c o n s i d e r a b l y . In c h i l d r e n , t h e v e s s e l s s o m e t i m e s s h o w e d a vital a p p e a r a n c e w i t h a r e d c o l o r , i n c i d e n t a l l o c a l b l e e d i n g in or in front o f t h e r e t i n a w a s s e e n , or g r o w t h w a s o b s e r v e d . In older children and adults, the neovasculariza t i o n s w e r e u s u a l l y fibrotic, a l t h o u g h fluoresce in a n g i o g r a p h y d i s c l o s e d p e r f u s i o n a n d l e a k a g e o f t h e dye (Figs. 3 a n d 4 ) . E c t o p i a of the m a c u l a , r a n g i n g from h a r d l y p e r c e p t i b l e to p r o n o u n c e d , w a s o b s e r v e d in 8 3 of 1 7 0 e y e s ( 4 9 % ) . T h e m a c u l a r d i s p l a c e m e n t w a s always t e m p o r a l or i n f e r o t e m p o r a l . As o t h e r s t u d i e s ' ^ " h a v e s h o w n , e x u d a t e s w e r e fairly u n c o m m o n , o c c u r r i n g in 1 6 o f 1 7 0 eyes ( 9 % ) . T h e y w e r e u s u a l l y s m a l l i n t r a r e t i n a l e x u d a t e s in t h e r e g i o n o f the t e m p o r a l e q u a t o r , but massive subretinal exudates were inciden tally o b s e r v e d (Fig. 5 ) . O t h e r fundus c h a n g e s i n c l u d e d the f o l l o w i n g : t o r t u o u s r e t i n a l v e i n s in 5 6 e y e s ( 3 3 % ) ; d e f o r m a t i o n o f p o s t e r i o r r e t i n a in 1 0 1 e y e s ( 5 9 % ) ; d r a g g e d o p t i c disk in 16 e y e s ( 9 % ) ; r e t i n a l p i g m e n t a t i o n in 3 5 e y e s ( 2 1 % ) ; r e t i n a l h e m o r r h a g e s in two e y e s ( 1 % ) ; r e t i n a l d e f e c t s in 19 e y e s ( 1 1 % ) ; w h i t e c h a n g e s o f p e r i p h e r a l r e t i n a in 3 7 e y e s ( 2 2 % ) ; a n d a t r o p h i c c h a n g e s of c h o r o i d a n d r e t i n a l pig m e n t e p i t h e l i u m in 3 9 e y e s ( 2 3 % ) . In 3 7 o f 1 8 0 e y e s ( 2 1 % ) w i t h e v i d e n t f a m i l i a l
January, 1991
Fig. 2 (van Nouhuys). Left fundus of a 17-year-old girl. Fluorescein angiogram (venous phase) of the temporal equator region shows the typical configura tion of retinal vessels of familial exudative vitreoreti nopathy. The peripheral retina is avascular and shows a V-shaped notch between the terminal ramifi cations of the superotemporal and inferotemporal vessels (arrow). exudative vitreoretinopathy, retinal detach m e n t o c c u r r e d o n c e or s e v e r a l t i m e s or a p r e existing retinal d e t a c h m e n t was found. Eight of 180 eyes ( 4 % ) showed retinoschisis, which was a l w a y s l i m i t e d to a s e g m e n t o f t h e p e r i p h e r a l retina. Recent rhegmatogenous retinal detachment was o b s e r v e d in n i n e o f t h e 3 7 e y e s w i t h r e t i n a l d e t a c h m e n t . T h e r e t i n a l d e f e c t s in t h i s g r o u p were widely diverse, including small round holes, horseshoe-shaped tears, and even giant t e a r s (Fig. 6 ) . Ten e y e s h a d b e c o m e b l i n d b e f o r e first e x a m i n a t i o n b e c a u s e o f c h r o n i c t o t a l r e t i n a l d e t a c h m e n t . Two e y e s in t h i s g r o u p w e r e s u b j e c t e d to l i g h t m i c r o s c o p i c e x a m i n a t i o n , w h i c h d i s c l o s e d e x t e n s i v e l e s i o n s of t h e t y p e o b s e r v e d h i s t o l o g i c a l l y in t h e t e r m i n a l s t a g e o f a p r o l i f e r a t i v e r e t i n o p a t h y . T h e p a t h o l o g i c fea t u r e s of o n e s p e c i m e n w e r e p r e v i o u s l y r e p o r t ed,* a n d t h e s e f e a t u r e s c o r r e s p o n d e d w i t h t h e m i c r o s c o p i c findings o f o t h e r studies.'^"'' Fourteen eyes showed a falciform retinal fold. In all of t h e s e e y e s , a p r o m i n e n t fold e x t e n d e d from t h e o p t i c disk t h r o u g h t h e p o s t e r i o r p o l e to the t e m p o r a l or i n f e r o t e m p o r a l p e r i p h e r y of the fundus (Fig. 7 ) . I o b s e r v e d s e v e r a l o f t h e s e falciform r e t i n a l folds over a p e r i o d o f m o r e t h a n five y e a r s , w i t h o u t any c h a n g e in t h e
Vol. I l l , No. 1
Familial Exudative Vitreoretinopathy
37
Fig. 3 (van Nouhuys). Right fundus of a 5-year-old girl. The temporal equator region shows partly fibrot ic new vessels and a few minor retinal hemorrhages.
Fig. 4 (van Nouhuys). Right fundus of a 33-yearold woman. Fluorescein angiogram shows leakage of dye from an equatorial neovascularization. The new vessels were chronic and partly fibrotic.
p o s i t i o n o f t h e r e t i n a . In t h e e y e o f a y o u n g girl, however, the formation of a falciform retinal fold c o u l d b e o b s e r v e d . A n o t h e r c h i l d w i t h b i l a t e r a l falciform r e t i n a l f o l d s s h o w e d g r a d u a l progression toward a total funnel retinal de t a c h m e n t in o n e e y e . M o s t f a l c i f o r m r e t i n a l
folds d e v e l o p e d at p r e s c h o o l a g e , a n d a few w e r e o b s e r v e d w i t h i n a few m o n t h s o f b i r t h . Only one eye showed a purely exudative retinal detachment, and biomicroscopy dis c l o s e d n o r e t i n a l d e f e c t s in t h i s e y e . In a n o t h e r eye with total, mainly fractional retinal detach-
Fig. 5 (van Nouhuys). Left fundus of a 14-year-old girl. A large subretinal exudate is visible in the nasal upper quadrant. Note the preretinal membranes.
Fig. 6 (van Nouhuys). Right eye of a 14-year-old girl. Detached retina with a giant tear on the superior side.
38
January, 1991
AMERICAN JOURNAL OF OPHTHALMOLOGY
Fig. 7 (van Nouhuys). Left fundus of a 30-year-old woman. Falciform retinal fold extending from the optic disk across the posterior pole to the inferotem poral periphery.
ment, however, extensive subretinal exudates were found (Fig. 5 ) . R e t i n a l d e t a c h m e n t s u r g e r y w a s p e r f o r m e d in 14 e y e s ( 1 2 e y e s of p a t i e n t s w i t h f a m i l i a l e x u d a tive v i t r e o r e t i n o p a t h y a n d two e y e s o f a p a t i e n t with sporadic exudative vitreoretinopathy). T h e s u r g e r y w a s d o n e in different h o s p i t a l s b y different o p h t h a l m i c s u r g e o n s a n d i n c l u d e d scleral buckling operations (eight eyes), pars p l a n a v i t r e c t o m y with or w i t h o u t s c l e r a l b u c k les (six e y e s ) , pars p l a n a v i t r e c t o m y w i t h s i l i c o n e oil (six e y e s ) , r e m o v a l o f s u b r e t i n a l sili c o n e oil ( o n e e y e ) , a n d r e m o v a l of s p o n g e s ( o n e eye). A total of 22 retinal operations were performed. S u r g e r y was p e r f o r m e d in p a t i e n t s w i t h r h e g m a t o g e n o u s r e t i n a l d e t a c h m e n t w i t h or w i t h out s i g n s of p r o l i f e r a t i v e v i t r e o r e t i n o p a t h y , fractional retinal d e t a c h m e n t without visible breaks, and exudative retinal detachment. O n e eye u n d e r w e n t a v i t r e c t o m y b e c a u s e o f p r o g r e s sion o f t r a c t i o n on an a t t a c h e d r e t i n a . S e v e n o p e r a t i o n s ( t w o v i t r e c t o m i e s a n d five scleral buckling procedures) were successful ( r e a t t a c h m e n t d u r i n g at l e a s t six m o n t h s after t h e o p e r a t i o n ) ; 13 o p e r a t i o n s ( t e n v i t r e c t o m i e s and three scleral buckling procedures) were not s u c c e s s f u l ( n o n a t t a c h m e n t or r e d e t a c h m e n t w i t h i n six m o n t h s after t h e o p e r a t i o n ) . In e i g h t eyes the first o p e r a t i o n w a s n o t s u c c e s s f u l , a n d six e y e s r e q u i r e d m o r e t h a n o n e o p e r a t i o n .
R e a t t a c h m e n t o f t h e r e t i n a in o n e o r m o r e p r o c e d u r e s w a s s u c c e s s f u l in s e v e n e y e s . T h e a g e o f t h e p a t i e n t s in t h i s g r o u p at t h e t i m e of o p e r a t i o n r a n g e d from 19 to 5 6 y e a r s ( m e a n , 3 0 years). The retinas of the other seven eyes could n o t b e r e p o s i t i o n e d . T h e a g e o f t h e s e p a t i e n t s at t h e t i m e o f s u r g e r y r a n g e d from 5 to 18 y e a r s ( m e a n , 13 y e a r s ) . T h e p l a t e l e t a g g r e g a t i o n test r e s u l t s a r e l i s t e d in t h e T a b l e . For e a c h a g g r e g a t i o n i n d u c e r , t h e m e a n and the standard deviation of the n u m b e r of aggregation units determined photometrical ly in t h e p a t i e n t g r o u p a n d in t h e c o n t r o l g r o u p were compared. Using adenosine diphosphate in t h r e e different c o n c e n t r a t i o n s , n o s i g n i f i c a n t difference w a s f o u n d b e t w e e n t h e p a t i e n t g r o u p a n d t h e c o n t r o l g r o u p (P = . 2 7 , . 5 2 , a n d . 7 0 , r e s p e c t i v e l y ) . U s i n g 1.5 m m o l / 1 o f a r a c h i d o n i c a c i d , n o s i g n i f i c a n t d i f f e r e n c e w a s f o u n d (P = .22). With 5 m m o l / 1 of arachidonic acid, how ever, p l a t e l e t a g g r e g a t i o n in t h e p a t i e n t g r o u p w a s f o u n d to e x c e e d that in t h e c o n t r o l g r o u p (P = . 0 0 3 ) . W i t h 5 X 10-« 1 o f c o l l a g e n a s i n d u c e r , t h e r e w a s n o s i g n i f i c a n t d i f f e r e n c e (P = . 5 2 ) , b u t w i t h 2 X 10"*1 of c o l l a g e n , a s l i g h t l y l o w e r a g g r e g a t i o n was f o u n d in t h e p a t i e n t g r o u p ; h o w e v e r , the d i f f e r e n c e w a s n o t s i g n i f i c a n t (P = .04). The bleeding time averaged 5 3 8 seconds ( s t a n d a r d d e v i a t i o n , 6 7 s e c o n d s ) in five p a tients, compared with 5 2 2 seconds (standard d e v i a t i o n , 1 5 7 s e c o n d s ) in t e n c o n t r o l s u b j e c t s . T h e s e v a l u e s did n o t differ s i g n i f i c a n t l y .
Discussion Although familial exudative vitreoretinopa thy may l e a d to b l i n d n e s s at an e a r l y a g e , m o s t of the gene carriers showed no severe visual handicap. The course of the visual function tests during the period o f observation con firmed t h e p o s t u l a t e t h a t t h e d i s e a s e is n o t a g r a d u a l l y p r o g r e s s i v e d e g e n e r a t i o n , as s o m e researchers believe. W h e n visual acuity was d i m i n i s h e d , it w a s a r e s u l t of c o m p l i c a t i o n s . T h e f o l l o w i n g c o m p l i c a t i o n s m a y l e a d to d i m i n ished visual acuity: deformation of the macula b e c a u s e of t r a c t i o n or e d e m a , v i t r e o u s h e m o r r h a g e , r e t i n a l d e t a c h m e n t , a n d , in y o u n g c h i l d r e n , amblyopia.**'*" A m b l y o p i a as a c o m p l i c a tion of familial exudative vitreoretinopathy h a s r a r e l y b e e n r e p o r t e d , b u t p r o b a b l y is n o t u n common.* Amblyopia, usually c o m b i n e d with c o n s i d e r a b l e a n i s o m e t r o p i a , p l a y e d a r o l e in t h e d i m i n i s h e d v i s u a l a c u i t y o f 1 2 ( 1 3 % ) o f my patients.
Vol. I l l , No. 1
39
Familial Exudative Vitreoretinopathy
In 8 0 o f 1 8 0 ( 4 4 % ) e y e s , n o v i t r e o u s l e s i o n s were observed. Pronounced vitreous m e m b r a n e s w e r e a l m o s t e x c l u s i v e l y s e e n in e y e s w i t h an e x t e n s i v e r e t i n o p a t h y or in e y e s w i t h chronic retinal detachment. T h e s e findings s e e m to w a r r a n t t h e c o n c l u s i o n t h a t t h e v i t r e o u s c h a n g e s in f a m i l i a l e x u d a t i v e v i t r e o r e t i n o p a t h y r e s u l t s from t h e v a s c u l o p a t h y a n d its c o m p l i c a t i o n s , s u c h as r e t i n a l n e o v a s c u l a r i z a tions and vitreous hemorrhages. Chronic leak age of b l o o d c o n s t i t u e n t s from r e t i n a l v e s s e l s m a y a l s o i n d u c e fibrous p r o l i f e r a t i o n i n t h e p r e r e t i n a l v i t r e o u s , as M a c h e m e r ^ " s u g g e s t e d . The vascular lesions of the peripheral retina in f a m i l i a l e x u d a t i v e v i t r e o r e t i n o p a t h y h a v e b e e n f r e q u e n t l y described.^'^'^'^-^' T h e a v a s c u larity o f t h e p e r i p h e r a l r e t i n a a n d t h e t y p i c a l demarcation by the equatorial zone o f aberrant terminal ramifications of retinal vessels were o b s e r v e d b i o m i c r o s c o p i c a l l y in 1 3 5 o f 1 7 0 e y e s ( 7 9 % ) . In f a m i l i a l e x u d a t i v e v i t r e o r e t i n o p a t h y , the marginal zone of peripheral vascular branches frequently shows a V-shaped notch near the temporal horizontal meridian (Fig. 2).*·'^ M i y a k u b o , H a s h i m o t o , a n d M i y a k u b o " f o u n d this c o n f i g u r a t i o n in 1 0 8 ( 8 1 % ) o f t h e e y e s in t h e i r s e r i e s , a n d r e g a r d e d t h e a n o m a l y as o n e o f t h e p r i n c i p a l c h a r a c t e r i s t i c s o f f a m i l i a l exudative vitreoretinopathy. It is e x t r e m e l y i n t e r e s t i n g to c o m p a r e t h i s c o n f i g u r a t i o n w i t h t h e n o r m a l h u m a n fetal r e t i na d u r i n g t h e final t w o to t h r e e m o n t h s o f t h e i n t r a u t e r i n e p e r i o d . T h e flat s p e c i m e n o f t h e n o r m a l fetal r e t i n a in t h i s s t a g e s h o w s a V s h a p e d m a r g i n a l z o n e of i m m a t u r e v a s c u l a r tissue,^^ w h i c h is i d e n t i c a l w i t h t h e c o n f i g u r a t i o n o f the b o r d e r z o n e in t h e m a t u r e e y e i n familial e x u d a t i v e v i t r e o r e t i n o p a t h y . T h i s m o r phologic similarity supports the postulate that t h e p a t h o g e n e s i s o f t h i s d i s e a s e is b a s e d o n premature arrest o f the vascular development of the r e t i n a . In v i e w o f t h e s t a t e o f d e v e l o p m e n t o f t h e r e t i n a l v a s c u l a r i z a t i o n in t h e fun dus in f a m i l i a l e x u d a t i v e v i t r e o r e t i n o p a t h y , this arrest cannot have occurred before the seventh month o f the intrauterine period. The relationship b e t w e e n familial exudative v i t r e o r e t i n o p a t h y a n d f a l c i f o r m r e t i n a l fold h a s b e e n discussed.^^'^'^ F o u r t e e n c a s e s o f f a l c i f o r m r e t i n a l fold w e r e f o u n d in f a m i l i e s w i t h f a m i l i a l exudative vitreoretinopathy, which shows that familial e x u d a t i v e v i t r e o r e t i n o p a t h y is an i m p o r t a n t a n d p r o b a b l y b y far t h e m o s t f r e q u e n t c a u s e of falciform r e t i n a l fold in p a t i e n t s w h o otherwise show no general congenital a n o m a lies. T h e s e o b s e r v a t i o n s are i m p o r t a n t , n o t o n l y
TABLE
PLATELET AGGREGATION IN PATIENTS WITH FAMILIAL EXUDATIVE VITREORETINOPATHY AND CONTROL SUBJECTS CONTROL SUBJECTS
PATIENTS NO.
NO.
UNITS OF
UNITS OF AGGREGATION
AGGREGATION AGGREGATION INDUCER
MEAN
S.D.
10
130
14
17
10
119
26
99 98 92
15 17 7
9 10 7
94 115 96
28 11 14
7
76
5
8
65
6
7
23
4
10
17
11
MEAN
S.O.
7
117
26
4
111
6 7 6
AND CONCENTRATION
Adenosine diptiosphate 10-· mol/l Adenosine diptiosptiate 4 x 1 0 - ' mol/l Adenosine diptiosptiate 2 X 10-' mol/l Collagen 2 χ lO-'l Collagen 5 χ 10-· 1 Aractiidonic acid 5 mmol/l Aractiidonic acid 1.5 mmol/l
for t h e c l a s s i f i c a t i o n o f t h e c o n g e n i t a l r e t i n a l fold s y n d r o m e b u t a l s o b e c a u s e t h e y p r o v i d e information about the pathogenesis of this con dition. M a n n ^ ' p o s t u l a t e d t h a t a f a l c i f o r m r e t i n a l fold r e s u l t e d from l o c a l a c c r e t i o n b e t w e e n t h e pri mary vitreous and the inside of the optic cup. M i c h a e l s o n ^ a n d Pruett^" m a i n t a i n e d t h a t t h e a n o m a l y r e s u l t e d from p e r s i s t e n t h y p e r p l a s t i c p r i m a r y v i t r e o u s in t h e p o s t e r i o r p a r t of t h e vitreous space. These theories concerning the primary vitreous are no longer tenable because f a l c i f o r m f o l d s d e v e l o p a s a c o m p l i c a t i o n of familial exudative vitreoretinopathy, a disease not associated with disorders o f the primary vitreous development. I believe the falciform fold t h a t d e v e l o p s in f a m i l i a l e x u d a t i v e v i t r e o retinopathy has a p a t h o g e n e s i s similar to that o f t h e f o l d , w h i c h m a y d e v e l o p in r e t i n o p a t h y of prematurity. Chaudhuri and associates'" reported dis t u r b e d p l a t e l e t a g g r e g a t i o n , e s p e c i a l l y after i n duction with a low concentration o f arachidonic a c i d ( 1 . 5 m m o l / l ) . T h e y s p e c u l a t e d t h a t a d e f i c i e n c y o f t h r o m b o x a n e A 2 (a p o t e n t v a s o c o n s t r i c t o r ) m i g h t p l a y a r o l e in t h e p a t h o g e n e sis o f t h e v a s c u l a r a n o m a l i e s in f a m i l i a l e x u d a tive v i t r e o r e t i n o p a t h y . T h i s p r o m p t e d m e to r e p e a t p l a t e l e t a g g r e g a t i o n t e s t s in p a t i e n t s with familial exudative vitreoretinopathy, using the same inducers and identical concen t r a t i o n s . 1 w a s u n a b l e to d e m o n s t r a t e any sig n i f i c a n t d i f f e r e n c e in p l a t e l e t a g g r e g a t i o n b e -
40
AMERICAN JOURNAL OF OPHTHALMOLOGY
tween patients and control subjects. These results agree with those reported by Friedrich, F r a n c i s , a n d Kim.^" H o w e v e r , t h e y f o u n d an i n c r e a s e d b l e e d i n g t i m e in o n e p a t i e n t w i t h familial e x u d a t i v e v i t r e o r e t i n o p a t h y . M y h e m a t o l o g i c findings do n o t i n d i c a t e an a b n o r m a l b l e e d i n g t i m e in t h i s d i s o r d e r . The presence and growth of nonfibrotic neo v a s c u l a r i z a t i o n s w e r e o b s e r v e d in s o m e o f t h e p a t i e n t s o l d e r t h a n six y e a r s of a g e ; in r e t i n o p a thy o f p r e m a t u r i t y t h i s h a s r a r e l y b e e n d e scribed. The clinical features of the two diseas es are t h e r e f o r e n o t a l w a y s i d e n t i c a l . Vitreous hemorrhage can be a serious com p l i c a t i o n at a y o u n g a g e , as I h a v e o b s e r v e d in a few i n f a n t s . In o n e u n t r e a t e d e y e , t h e h e m o r r h a g e w a s f o l l o w e d b y a total r e t i n a l d e t a c h m e n t w i t h a c l o s e d f u n n e l w i t h i n a few w e e k s . These observations warrant regular examina t i o n s of t h e p e r i p h e r a l fundi of y o u n g c h i l d r e n a n d p r o m p t c r y o c o a g u l a t i o n or l a s e r c o a g u l a t i o n o f any n e w v e s s e l s . S m a l l n e o v a s c u l a r i z a t i o n s g e n e r a l l y s h o w e d rapid r e g r e s s i o n after t h e r a p y (Fig. 8 ) . Adult eyes s o m e t i m e s showed small, partly fibrotic n e w v e s s e l s that w e r e a s y m p t o m a t i c a n d did n o t c h a n g e d u r i n g y e a r s o f o b s e r v a t i o n . In s u c h p a t i e n t s , p e r i o d i c c h e c k u p s w o u l d s e e m to b e sufficient. R e t i n a l d e t a c h m e n t in f a m i l i a l e x u d a t i v e vit reoretinopathy shows numerous clinical varia t i o n s a n d u s u a l l y o c c u r s at an e a r l y a g e . In my p a t i e n t s , all d e t a c h m e n t s h a d o c c u r r e d b e f o r e
Fig. 8 (van Nouhuys). Left fundus of a 10-year-old girl. Fibrotic tissue (arrows) as a remnant of neovas cularization two years after cryocoagulation of the peripheral retina.
January, 1991
a g e 3 0 y e a r s , w i t h the e x c e p t i o n o f o n e r h e g m a t o g e n o u s d e t a c h m e n t s e e n in a 5 6 - y e a r - o l d man. T r a c t i o n on t h e p e r i p h e r a l r e t i n a s e e m s to b e t h e p r i n c i p a l c a u s e o f r e t i n a l d e t a c h m e n t in familial e x u d a t i v e v i t r e o r e t i n o p a t h y . In s o m e cases, this traction displaces the retina without visible breaks. The best example of a fractional d e t a c h m e n t is the f r e q u e n t l y o b s e r v e d falci form r e t i n a l fold. O f t e n , h o w e v e r , t r a c t i o n c a u s e s r e t i n a l d e f e c t s , w h i c h may vary w i d e l y in s i z e a n d s h a p e ( F i g . 6 ) . R e t i n a l d e t a c h m e n t in f a m i l i a l e x u d a t i v e vit r e o r e t i n o p a t h y p r o v e d to b e a s e r i o u s c o m p l i c a tion with a relatively unfavorable course. O f 41 e y e s ( 3 7 e y e s of p a t i e n t s w i t h f a m i l i a l e x u d a t i v e v i t r e o r e t i n o p a t h y a n d four e y e s o f p a t i e n t s with sporadic exudative vitreoretinopathy), 22 with retinal d e t a c h m e n t had not been treated with retinal surgery. G e n e r a l l y , this was b e c a u s e of the p o o r p r o g n o s i s c o n c e r n i n g v i s u a l i m p r o v e m e n t , e s p e c i a l l y in p a t i e n t s w i t h falci form r e t i n a l folds or c h r o n i c d e t a c h m e n t s a s s o ciated with severe proliferative vitreoretinopa thy. R e t i n a l s u r g e r y in f a m i l i a l e x u d a t i v e v i t r e o r e t i n o p a t h y w a s often c o m p l i c a t e d b y n o n a t t a c h m e n t or r e d e t a c h m e n t after s u r g e r y . In o n l y s e v e n e y e s t h e r e t i n a w a s r e a t t a c h e d after o n e or m o r e o p e r a t i o n s . C o m p l i c a t i o n s after operative therapy have b e e n previously report ed.''^' T h e r e s u l t s o f r e t i n a l s u r g e r y s e e m e d to b e r e l a t e d to t h e a g e o f t h e p a t i e n t s at t h e t i m e o f o p e r a t i o n . All o p e r a t i o n s on e y e s o f p a t i e n t s y o u n g e r t h a n t h e a g e o f 19 y e a r s w e r e u n s u c cessful, w h e r e a s t h e r e t i n a s o f all e y e s o f p a t i e n t s o l d e r t h a n 19 y e a r s of a g e w e r e t r e a t e d s u c c e s s f u l l y . In t h e e y e s o f p a t i e n t s o l d e r t h a n 19 y e a r s o f a g e , e x t e n s i v e p r o l i f e r a t i v e v i t r e o r e t i n o p a t h y w a s an u n u s u a l f e a t u r e , w h e r e a s t h e r e t i n a l d e t a c h m e n t s in t h e y o u n g e r p a t i e n t s w e r e m o r e p r o n e to d e v e l o p t h i s c o m p l i c a t i o n , o f t e n b e f o r e s u r g e r y . T h e r e f o r e , p a r s p l a n a vit r e c t o m y w a s the m a i n s u r g i c a l p r o c e d u r e in t h e younger patients, whereas a scleral buckling t e c h n i q u e w a s p e r f o r m e d in m o s t o f t h e o l d e r p a t i e n t s . In c h i l d r e n w i t h f a m i l i a l e x u d a t i v e vitreoretinopathy and retinal d e t a c h m e n t , the s u r g e o n faces t h e s a m e p r o b l e m s a s in t h e t r e a t m e n t o f r e t i n a l d e t a c h m e n t in p a t i e n t s w i t h r e t i n o p a t h y o f p r e m a t u r i t y . In p a t i e n t s w i t h r e t i n o p a t h y of p r e m a t u r i t y , a l s o in t h e o l d e r p a t i e n t s w i t h r e g r e s s e d r e t i n o p a t h y of p r e m a t u r i t y , t h e risk o f r e c u r r e n t r e t i n a l d e t a c h m e n t is g r e a t e r t h a n normal.^'^ V i r t u a l l y all p a t i e n t s w i t h f a m i l i a l e x u d a t i v e vitreoretinopathy showed a pedigree consistent
Vol. I l l , No. 1
Familial Exudative Vitreoretinopathy
with a u t o s o m a l d o m i n a n t t r a n s m i s s i o n o f t h e g e n e . Five p a t i e n t s , i n c l u d i n g i d e n t i c a l t w i n s , had no close relatives with perceptible a n o m a lies. S u c h s o l i t a r y c a s e s o f p a t i e n t s w i t h o c u l a r a n o m a l i e s i d e n t i c a l to t h o s e o f f a m i l i a l e x u d a tive v i t r e o r e t i n o p a t h y h a v e a l s o b e e n o b s e r v e d by o t h e r i n v e s t i g a t o r s . ' ^ W h e t h e r s u c h c a s e s involve a mutation, n o n p e n e t r a n c e of the auto s o m a l d o m i n a n t g e n e in o n e o f t h e p a r e n t s , or g e n e t i c h e t e r o g e n e i t y is u n k n o w n .
ACKNOWLEDGMENT
T h e h e m a t o l o g i c s t u d i e s w e r e p e r f o r m e d at the D e p a r t m e n t o f H e m a t o l o g y , U n i v e r s i t y o f Nijmegen, The Netherlands.
References 1. Criswick, V. G., and Schepens, C. L.: Familial exudative vitreoretinopathy. Am. J. Ophthalmol. 68:578, 1969. 2. Gow, J . , and Oliver, G. L.: Familial exudative vitreoretinopathy. Arch. Ophthalmol. 86:150, 1 9 7 1 . 3. Canny, C. L. B., and Oliver, G. L.: Fluorescein angiographic findings in familial exudative vitreoret inopathy. Arch. Ophthalmol. 9 4 : 1 1 1 4 , 1 9 7 6 . 4. Slusher, M. M., and Hutton, W. E.: Familial exu dative vitreoretinopathy. Am. J. Ophthalmol. 87:152, 1979. 5. Ober, R. R., Bird, A. C , Hamilton, A. M., and Sehmi, K.: Autosomal dominant exudative vitreoreti nopathy. Br. J. Ophthalmol. 64:112, 1980. 6. Nijhuis, F. Α., Deutman, A. F., and Aan de Kerk, A. L.: Fluorescein angiography in mild stages of dominant exudative vitreoretinopathy. Mod. Probl. Ophthalmol. 20:107, 1 9 7 9 . 7. Laqua, H.: Familial exudative vitreoretinopathy. Graefes Arch. Clin. Exp. Ophthalmol. 2 1 3 : 1 2 1 , 1 9 8 0 . 8. van Nouhuys, C. E.: Dominant exudative vitre oretinopathy and other vascular developmental dis orders of the peripheral retina. Doc. Ophthalmol. 54:1, 1982. 9. Goldschmidt, R.: Gen und Ausseneigenschaft. Z. Vererbungslehre 69:38, 1 9 3 5 . 10. Chaudhuri, P. R., Rosenthal, A. R., Goulstine, D. B., Rowlands, D., and Mitchel, V. E.: Familial exudative vitreoretinopathy associated with familial thrombocytopathy. Br. J. Ophthalmol. 67:755, 1 9 8 3 . 11. Imandt, L., Genders, T., Wessels, J., and Haanen, C : An improved method for preparing platelet-rich plasma. Thromb. Res. 11:429, 1977. 12. Miyakubo, H., Inohara, N., and Hashimoto, K.: Retinal involvement in familial exudative vitreoreti nopathy. Ophthalmologica 185:125, 1982. 13. Miyakubo, H., Hashimoto, K., and Miyakubo, S.: Retinal vascular pattern in familial exudative vitreoretinopathy. Ophthalmology 9 1 : 1 5 2 4 , 1 9 8 4 . 14. Tasman, W., Augsburger, ] . , Shields, j . Α., Ca-
41
puto, Α., and Annesley, W, H.: Familial exudative vitreoretinopathy. Trans. Am. Soc. Ophthalmol. 74:211, 1 9 8 1 . 15. Brockhurst, R. J . , Albert, D. M., and Zakov, Z. N.: Pathological findings in familial exudative vit reoretinopathy. Arch. Ophthalmol. 9 9 : 2 1 4 3 , 1 9 8 1 . 16. Boldrey, E. E., Egbert, P., Gass, ) . D. M., and Friberg, T.: The histopathology of familial exudative vitreoretinopathy. Arch. Ophthalmol. 103:238, 1 9 8 5 . 17. Nicholson, D. H., and Galvis, V.: CriswickSchepens syndrome (familial exudative vitreoreti nopathy). Study of a Colombian kindred. Arch. Oph thalmol. 102:1519, 1 9 8 4 . 18. van Nouhuys, C. E.: Juvenile retinal detach ment as a complication of familial exudative vitreo retinopathy. Fortschr. Ophthalmol. 8 6 : 2 2 1 , 1989. 19. Schulman, J . , and Merin, S.: Hereditary vitreo retinal degenerations. In Newsome, D. A. (ed.): Reti nal Dystrophies and Degenerations. New York, Ra ven Press, 1 9 8 8 , pp. 9 5 . 20. Machemer, R.: Description and pathogenesis of late stages of retinopathy of prematurity. Ophthal mology 92:1000, 1 9 8 5 . 2 1 . Feldman, Ε. L., Norris, J. L., and Cleasby, G. W.: Autosomal dominant exudative vitreoretinop athy. Arch. Ophthalmol. 101:1532, 1983. 22. Foos, R. Y., and Kopelow, S.: Development of retinal vasculature in perinatal infants. Surv, Oph thalmol. 18:117, 1 9 7 3 . 23. Dudgeon, J.: Familial exudative vitreoretinop athy. Trans. Ophthalmol. S o c . U.K. 9 9 : 4 5 , 1 9 7 9 . 24. van Nouhuys, C. E.: Congenital retinal fold as a sign of dominant exudative vitreoretinopathy. Graefes Arch. Clin. Exp. Ophthalmol. 217:55, 1 9 8 1 . 25. Nishimura, M., Yamana, T., Sugino, M., Kohno, T., Yamana, Y., Minei, M., and Sanui, H.: Falciform retinal fold as a sign of familial exudative vitreoretinopathy. Jpn. J. Ophthalmol. 27:40, 1983. 26. Spallone, Α.: Differential diagnosis of heredi tary vitreoretinopathy. Milan, Italy, Fogliazza Editore, 1989, pp. 2 3 - 3 0 . 27. Mann, I.: Congenital retinal fold. Br. J. Oph thalmol. 19:641, 1 9 3 5 . 28. Michaelson, 1. C : Intertissue vascular rela tionships in the fundus of the eye. Invest. Ophthal mol. 5:1004, 1965. 29. Pruett, R. C : The pleomorphism and compli cations of posterior hyperplastic primary vitreous. Am. J. Ophthalmol. 80:625, 1975. 30. Friedrich, C. Α., Francis, Κ. Α., and Kim, Η. C : Familial exudative vitreoretinopathy (FEVR) and platelet dysfunction. Br. J. Ophthalmol. 73:477, 1989. 3 1 . Okubo, Y., Okubo, Α., Kubono, Τ., and Shimizu, Η.: Familial exudative vitreoretinopathy, rhegmatogenous retinal detachment and postopera tive uveitis with massive subretinal exudation. Acta Soc. Ophthalmol. Jpn. 8 8 : 1 1 5 1 , 1 9 8 4 . 32. Sneed, S. R., Pulido, J. S., Blodi, C. F., Clarkson, J. G., Flynn, H. W., Jr., and Mieler, W. F.: Surgi cal management of late-onset retinal detachments associated with regressed retinopathy of prematuri ty. Ophthalmology 97:179, 1 9 9 0 .
