Varicella Disciform Stromal Keratitis
Kirk R. Wilhelmus, M.D., M . Bowes H a m i l l , M . D . , and Dan B. Jones, M . D .
We t r e a t e d five p a t i e n t s , a g e d 2 6 , 4 , 6 , 1 3 , a n d 7 years, who developed disciform stromal ker atitis one, four, four, eight, a n d ten weeks, respectively, after t h e onset of the acute vesic ular exanthema. Serologic testing confirmed recent varicella and excluded other infectious c a u s e s in t w o c a s e s . A f t e r i n i t i a l i m p r o v e m e n t with a topical corticosteroid, three patients developed recurrent corneal inflammation re sembling zoster keratitis. These cases and previous reports indicate that varicella-zoster v i r u s is a c a u s e o f d i s c i f o r m s t r o m a l k e r a t i t i s that may occur and recur several weeks or m o n t h s after t h e p r i m a r y skin rash has r e solved.
C H I C K E N P O X is a diffuse v e s i c u l a r skin r a s h , m a i n l y affecting c h i l d r e n , c a u s e d b y p r i m a r y infection with varicella-zoster virus.' The re s e m b l a n c e o f the c u t a n e o u s l e s i o n s to c h i c k p e a s p r o b a b l y gave r i s e to t h e t e r m c h i c k e n p o x t o e m p h a s i z e its m i l d n e s s a n d s i m i l a r i t y to smallpox, and its synonym varicella originated as a d i m i n u t i v e form o f v a r i o l a . T h e e y e m a y b e affected d u r i n g , after, or r a r e l y b e f o r e t h e e x a n thema. Among the possible ocular complica t i o n s of c h i c k e n p o x a r e k e r a t o c o n j u n c t i v i t i s , uveitis, and n e u r o - o p h t h a l m i c changes.^^ Few s t u d i e s h a v e d e t e r m i n e d t h e f r e q u e n c y or i n c i d e n c e o f v a r i o u s o c u l a r findings in patients with chickenpox. Over a o n e - y e a r in t e r v a l . Griffin a n d S e a r l e " f o u n d five of 1 2 5 children ( 4 % ) with varicella w h o had c o n j u n c tivitis, o n e w i t h a l i m b a l l e s i o n . In a t w o - y e a r period, Kachmer, A n n a b l e , and D i M a r c o ' iden tified 3 3 o f 8 2 c h i l d r e n ( 4 0 % ) w i t h c h i c k e n p o x w h o h a d o c u l a r or e y e l i d i n v o l v e m e n t , i n c l u d ing six ( 7 % ) w i t h e y e l i d l e s i o n s , t e n ( 1 2 % ) w i t h p u n c t a t e k e r a t o p a t h y , a n d 21 ( 2 6 % ) w i t h i r i t i s .
Accepted for publication Feb. 6, 1991. From the Department of Ophthalmology, Gullen Eye Institute, Baylor College of Medicine, Houston, Texas. Reprint requests to Kirk R. Wilhelmus, M.D., One Baylor Plaza, Houston, TX 77030.
Of 24 children referred because of ocular symp toms, Jordan, Noel, and Clarke'reported eyelid p o c k s a n d c o n j u n c t i v i t i s as t h e m o s t c o m m o n findings, followed by uveitis and keratitis. We t r e a t e d five p a t i e n t s w i t h d i s c i f o r m s t r o m a l k e r a t i t i s after c h i c k e n p o x .
Case Reports Case 1 A 2 6 - y e a r - o l d w o m a n w a s e x a m i n e d for d e c r e a s e d v i s i o n a n d r e d n e s s o f t h e left e y e . W i t h o u t k n o w n contact with a rash illness, she had developed fever seven days previously, f o l l o w e d t w o days l a t e r b y v e s i c u l a r d e r m a t i t i s b e g i n n i n g in t h e n e c k r e g i o n w i t h s u b s e q u e n t spread to the face, trunk, arms, and legs with out localized i n v o l v e m e n t . Initial ocular signs a n d s y m p t o m s i n c l u d e d left u p p e r e y e l i d e d e ma, photophobia, and decreased vision. Slitl a m p b i o m i c r o s c o p y d i s c l o s e d faint, p a t c h y anterior stromal opacities with central disci form s t r o m a l e d e m a , fine c e l l u l a r i n f i l t r a t i o n , and pseudo cornea guttata. T h e anterior c h a m b e r c o n t a i n e d t r a c e flare a n d r a r e c e l l s . Treatment was begun with prednisolone ace tate 1% five t i m e s d a i l y a n d s c o p o l a m i n e h y drochloride 0 . 5 % three times daily. Improve m e n t occurred within two days, and a tapering dose of topical corticosteroid was continued. Within ten days, visual acuity improved to 2 0 / 2 0 with resolution of the stromal keratitis, w h i c h left a faint r e s i d u a l a n t e r i o r s t r o m a l haze. Case 2 A 4 - y e a r - o l d girl w a s r e f e r r e d for s t r o m a l k e r a t i t i s f o u r w e e k s after c h i c k e n p o x . M i l d c o n junctival hyperemia with p s e u d o b l e p h a r o p t o sis o f t h e left e y e h a d d e v e l o p e d o v e r t h e preceding ten days and had not responded to topical erythromycin ointment. Visual acuity was R . E . : 2 0 / 2 0 and L.E.: 2 0 / 4 0 0 . Slit-lamp examination showed a well-demarcated disci form stromal keratitis with localized e d e m a , pseudo cornea guttata, and mild iritis. S e r o l o g -
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ic t e s t i n g c o n f i r m e d r e c e n t v a r i c e l l a a n d e x c l u d ed o t h e r c a u s e s o f s t r o m a l k e r a t i t i s . F o u r w e e k s after o n s e t o f the skin rash, v a r i c e l l a - z o s t e r virus IgG was 1:16, h e r p e s s i m p l e x I g M a n d I g G were not detectable ( < 1:10), and Epstein-Barr viral c a p s i d a n d n u c l e a r I g G s w e r e n o t d e t e c t a b l e . S i x w e e k s later, the h e r p e s s i m p l e x a n t i b o d i e s w e r e still n o t d e t e c t a b l e . T h e m i c r o h e m a g g l u t i n a t i o n a s s a y for Treponema pallidum was nonreactive. Topical p r e d n i s o l o n e a c e t a t e 1% was b e g u n four t i m e s d a i l y . T h e p a t i e n t i m p r o v e d o v e r t h e n e x t ten days with r e d u c e d s t r o m a l e d e m a a n d infiltration, a n d v i s u a l a c u i t y i m p r o v e d to 2 0 / 30. The topical corticosteroid was gradually t a p e r e d over the s u b s e q u e n t four w e e k s , but i n c r e a s e d c o r n e a l i n f l a m m a t i o n w i t h iritis o c c u r r e d w h e n it w a s b e i n g a d m i n i s t e r e d o n c e daily. As the t o p i c a l c o r t i c o s t e r o i d d o s a g e w a s subsequently reduced, increased central disci form e d e m a a g a i n r e c u r r e d . P e r i p h e r a l superfi cial s t r o m a l v a s c u l a r i z a t i o n a n d c e n t r a l s c a r ring e n s u e d a n d l i m i t e d s p e c t a c l e - c o r r e c t e d v i s u a l acuity to 2 0 / 6 0 , w h i c h i m p r o v e d to 2 0 / 20 with contact lens correction. Chronic corticosteroid-dependent stromal keratouveitis re s u l t e d in p r o l o n g e d use o f d a i l y p r e d n i s o l o n e a c e t a t e 0 . 1 2 % o v e r the n e x t four y e a r s . Case 3 A 6 - y e a r - o l d girl d e v e l o p e d s o r e t h r o a t , l o w g r a d e fever, a n d diffuse c u t a n e o u s l e s i o n s o v e r h e r e n t i r e b o d y i n c l u d i n g h e r face a n d p e r i o c u lar r e g i o n . H e r 4 - y e a r - o l d sister h a d r e c e n t l y had a similar skin rash during a c h i c k e n p o x o u t b r e a k at the day c a r e c e n t e r . O c u l a r s y m p toms of photophobia and blurred vision began o n e m o n t h after the c u t a n e o u s l e s i o n s . V i s u a l acuity was 2 0 / 4 0 in the affected eye b e c a u s e o f c e n t r a l e d e m a , diffuse s t r o m a l infiltration, a n d dendritic epithelial keratitis. T r e a t m e n t was b e g u n w i t h trifluridine 1% a n d t o b r a m y c i n 0 . 3 % . B e c a u s e of i n c r e a s i n g s t r o m a l e d e m a with visual a c u i t y o f 2 0 / 6 0 , w e c h a n g e d t r e a t m e n t to d e x a m e t h a s o n e 0 . 1 % . Despite initial improvement, recurrent stromal keratitis o c c u r r e d d u r i n g the s u b s e q u e n t y e a r w h e n e v e r the t o p i c a l c o r t i c o s t e r o i d w a s ta pered. Residual corneal scarring limited visual a c u i t y to 2 0 / 3 0 . Case 4 A 1 3 - y e a r - o l d girl d e v e l o p e d c h i c k e n p o x ; two n e i g h b o r h o o d c h i l d r e n a l s o d e v e l o p e d c h i c k e n p o x , o n e i m m e d i a t e l y p r e c e d i n g the p a t i e n t a n d o n e s i m u l t a n e o u s l y . E i g h t w e e k s lat-
May, 1991
Figure (Wilhelmus, Hamill, and Jones). Case 4. Central disciform stromal keratitis occurring in a 13-year-old girl eight weeks after varicella. er, w e l l after all skin l e s i o n s h a d h e a l e d , t h e p a t i e n t d e v e l o p e d a red left e y e . I n i t i a l treat ment by her pediatrician with neomycin-poly myxin B-bacitracin ointment did not help. O c u lar e x a m i n a t i o n s h o w e d c e n t r a l n o n n e c r o t i z i n g disciform stromal keratitis with keratic precipi t a t e s a n d m i l d iritis ( F i g u r e ) . S e r o l o g i c t e s t i n g confirmed recent varicella and excluded other possible causes of stromal keratitis. Varicellaz o s t e r virus a n t i b o d y t i t e r s w e r e t e s t e d 11 w e e k s after o n s e t o f t h e s k i n r a s h ; I g M w a s 1:40, a n d I g G w a s 1 : 2 , 5 6 0 . S e v e n w e e k s later, IgM was not detectable ( < 1:20), and IgG was 1 : 6 4 0 . O t h e r s e r o l o g i c t e s t s p e r f o r m e d at e i g h t or 11 w e e k s after t h e skin r a s h w e r e as f o l l o w s : herpes simplex IgM not detectable ( < 1:10); h e r p e s s i m p l e x I g G n o t d e t e c t a b l e ( < 1:8); E p s t e i n - B a r r viral c a p s i d I g G n o t d e t e c t a b l e ( < 1 : 1 0 ) ; E p s t e i n - B a r r viral n u c l e a r I g G n o t d e t e c t a b l e ( < 1:4); a d e n o v i r u s I g G n o t d e t e c t a b l e ( < 1:8); m u m p s I g M n o t d e t e c t a b l e ; m u m p s I g G w e a k l y p o s i t i v e ( i n d e x = 1:3); m u m p s S a n t i b o d y n o t d e t e c t a b l e ( < 1:8); m u m p s V a n t i b o d y n o t d e t e c t a b l e ( < 1:8); r u b e o l a I g G n o t d e t e c t able; rubella IgM not detectable; rubella IgG p o s i t i v e ( i n d e x = 1:4); r a p i d p l a s m a r e a g i n n o n r e a c t i v e ; m i c r o h e m a g g l u t i n a t i o n a s s a y for T. pallidum nonreactive; Lyme disease IgM not detectable; and Lyme disease IgG not detect able. T o p i c a l p r e d n i s o l o n e p h o s p h a t e 1% w a s b e gun e v e r y t w o h o u r s w i t h i n i t i a l i m p r o v e m e n t in v i s u a l a c u i t y from 2 0 / 1 0 0 to 2 0 / 2 5 . T h e patient subsequently developed corneal anes t h e s i a with d e n d r i f o r m m u c o u s p l a q u e s . Topi cal c o r t i c o s t e r o i d s w e r e g r a d u a l l y t a p e r e d , but s h e c o n t i n u e d to d e v e l o p r e c u r r e n t s t r o m a l ker a t i t i s d u r i n g the n e x t y e a r , w h i c h r e q u i r e d p r o -
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loriged c o r t i c o s t e r o i d t h e r a p y . V i s u a l a c u i t y r e m a i n e d l i m i t e d to 2 0 / 4 0 b e c a u s e o f r e s i d u a l stromal opacification and neurotrophic epithe lial c h a n g e s . Case 5 A 7 - y e a r - o l d girl d e v e l o p e d a r e d left e y e t e n w e e k s after c h i c k e n p o x . C e n t r a l d i s c i f o r m s t r o mal keratitis was noted, and initial treatment included p r e d n i s o l o n e acetate 1% every two h o u r s a n d c y c l o p e n t o l a t e h y d r o c h l o r i d e 1% t w i c e d a i l y . V i s u a l a c u i t y w o r s e n e d to 2 0 / 2 0 0 in t h e left eye b e c a u s e o f a w e l l - d e m a r c a t e d area o f d e n s e s t r o m a l e d e m a w i t h e n d o t h e l i a l pseudo cornea guttata. Laboratory testing three m o n t h s after t h e s k i n r a s h s h o w e d a n o n d e t e c t able herpes simplex virus type 1 IgG ( < 1:10) and a varicella-zoster virus IgG titer of 1:16. After steroid proved residual
a four-week course of topical cortico therapy, visual acuity gradually im to 2 0 / 2 5 in t h e left e y e w i t h a faint opacity.
Discussion Viremia and the typical m u c o c u t a n e o u s exan thema o f varicella begin approximately two w e e k s after c o n t a c t w i t h a n i n f e c t e d p e r s o n . S e l f - l i m i t i n g p a p u l e s m a y a p p e a r in t h e m o u t h , pharynx, larynx, trachea, and gastrointestinal t r a c t . C o m m o n o c u l a r findings a r e e y e l i d v e s i c l e s or m a r g i n a l e r o s i o n s , a c u t e c o n j u n c t i v i t i s , and lesions resembling phlyctenules of the bulbar conjunctiva and semilunar fold. H u m o r al a n d c e l l u l a r i m m u n i t y c o n t r o l viral r e p l i c a tion with spontaneous resolution o f the skin and mucous m e m b r a n e rash. Corneal changes are infrequent but can occur d u r i n g t h e first w e e k or t w o after t h e o n s e t o f chickenpox. Punctate epithelial keratitis has been described infrequently.' More commonly n o t e d is a n a c u t e , p u s t u l a r s u b e p i t h e l i a l infil trate at t h e c o r n e o s c l e r a l l i m b u s . " E p i t h e l i al e r o s i o n a n d u l c e r a t i o n c o n t r i b u t e to t h e p a i n ful s y m p t o m s . A r e s i d u a l p a t c h o f p e r i p h e r a l corneal scarring with vascularization can re main. Besides these focal, usually unilateral limbal infiltrates, a c e n t r a l s u p e r f i c i a l infiltrate w i t h e p i t h e l i a l e r o s i o n c a n a l s o occur.''-2" F a i n t s u b e p i t h e l i a l o p a c i f i c a t i o n o c c u r s after s p o n t a n e ous healing, although extensive corneal scar r i n g in e a r l y c h i l d h o o d h a s l e d t o d e p r i v a t i o n a m b l y o p i a . " IParely, p r o g r e s s i v e n e c r o t i z i n g i n
577
f l a m m a t i o n a n d i r i d o c y c l i t i s h a v e p r o g r e s s e d to c o r n e a l p e r f o r a t i o n a n d p h t h i s i s bulbi.^* Nonnecrotizing, disciform stromal keratitis is a n u n u s u a l c o m p l i c a t i o n o f varicella.^ * C l i n i cal f e a t u r e s i n c l u d e i n t e r s t i t i a l h a z e c a u s e d b y localized e d e m a and cellular infiltration. A dis coid pattern of n o n c o a l e s c e n t inflammatory c e l l s is o u t l i n e d b y a s l i g h t l y d e n s e r a n n u l a r border. Mild iritis, grouped keratic precipitates, and endothelial pseudo cornea guttata are a c companying features. D i s c i f o r m k e r a t i t i s after v a r i c e l l a h a s b e e n diagnosed previously with no gender predilec t i o n , m a i n l y in c h i l d r e n (Table).''^*·" A l l c a s e s have b e e n unilateral and equally distributed b e t w e e n r i g h t a n d left e y e s . T h e s e r e p o r t s e m phasize the delayed onset of disciform keratitis, t y p i c a l l y b e g i n n i n g s e v e r a l w e e k s after t h e i n i tial skin r a s h . S o m e o f the reported cases of varicella stro mal keratitis developed dendritic epithelial ker a t i t i s , c h a r a c t e r i z e d b y gray, s w o l l e n e p i t h e l i a l c e l l s in a n o n u l c e r a t e d , l i n e a r p a t t e r n s i m i l a r to varicella-zoster virus dendrites. We also identi fied d e n d r i t i c e p i t h e l i a l k e r a t i t i s in o n e p a t i e n t and dendriform mucous plaques and filaments resembling postvaricella-zoster neurotrophic k e r a t i t i s in a n o t h e r . E v e n t h o u g h v i r a l a n t i g e n and intracellular viral inclusions can be found in t h e c o r n e a l epithelium,''^'''' a n t i v i r a l t h e r a p y is n o t a p p a r e n t l y r e q u i r e d for r e s o l u t i o n . Recurrent stromal keratitis prolongs the clini cal c o u r s e for m o n t h s or e v e n y e a r s . D e s p i t e initial antiinflammatory control with topical corticosteroid therapy, some patients develop subsequent corneal inflammation during grad ual corticosteroid d o s a g e reduction. S t r o m a l keratitis with residual corneal scarring, some t i m e s l e a d i n g to c o r n e a l transplantation,^"*^ is t h e p r i n c i p a l r e a s o n for v i s u a l l o s s . O t h e r c o m p l i c a t i o n s o f v a r i c e l l a d i s c i f o r m k e r a t i t i s in c l u d e n e u r o t r o p h i c keratopathy,''^ i r i d o c y c l i t i s w i t h s e c o n d a r y g l a u c o m a , * ' a n d iris s t r o m a l atrophy.'^ B e c a u s e t h e r e a r e few d i s t i n g u i s h i n g f e a t u r e s a m o n g the various causes of disciform stromal keratitis, herpes simplex and other infectious causes must be considered. Serologic evalua tion should exclude herpes simplex before con c l u d i n g t h a t r e c e n t v a r i c e l l a is c a u s a t i v e r a t h e r than coincidental. For example, we have treated other patients with idiopathic stromal keratitis o c c u r r i n g a few w e e k s or m o n t h s after v a r i c e l l a b u t c o u l d n o t e s t a b l i s h a definite c o n n e c t i o n because of antibodies showing previous expo s u r e to h e r p e s s i m p l e x v i r u s .
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TABLE DATA ON 32 REPORTED CASES OF VARICELLA DISCIFORM STROMAL KERATITIS* C A S E NO., A G E (YHS),
ONSET AFTER
CORTICOSTEROID
SEX, EYE
SKIN RASH
USE
1, NA, NA, NA 2, NA, NA, NA 3, 10, M, R 4, NA, NA, NA 5, 4, M, R 6, 5, M, R 7, 4, F, R 8, 7, F, L 9, 30, M, R 10, 8, NA, R 11,8, F, L 12, 5, M, R 13, 7, F, NA 14, 9, M, R
NA NA 3 weeks NA 10 days 3 weeks 3 weeks NA 8 weeks NA 3 weeks 3 weeks NA 8 days
No No No No No No No No No No No No No No
NA NA None NA None NA NA NA None NA None None NA None
NA NA 20/15 NA NA NA NA NA 20/40 NA 20/80 20/40 NA 20/20
15, NA, NA, NA
NA
NA
Secondary glaucoma
NA
16, NA, NA, R 17, 8, F, L
NA 12 weeks
NA Yes
18, 11, M, R 19, 7, M, R
2 weeks 5 weeks
No Yes
20, 3, F, L
13 weeks
Yes
Meyer and Wolter"
21, 3, M, R
NA
Yes
Wilson* Uchlda"
22, 9, M, R 23, 6, F, L 24, 3, F, R 25, 7, M, L
4 weeks 10 weeks 10 weeks 5 weeks
No Yes NA NA
deFreitas and associates"
26, 6, F, NA 27, 10, M, NA 28, 26, F, L 29, 4, F, L
6 weeks 8 weeks 1 week 4 weeks
Yes Yes Yes Yes
30, 6, F,
4 weeks
Yes
31, 13, F, L
8 weeks
Yes
32, 7, F, L
10 weeks
Yes
NA Dendritic keratitis, recurrent stromal keratitis Dendritic keratitis Dendritic keratitis. recurrent stromal keratitis Dendritic keratitis, recurrent stromal keratitis Recurrent stromal keratitis, corneal graft rejection None Dendritic keratitis Dendritic keratitis Punctate epithelial keratitis Dendritic keratitis Dendritic keratitis None Recurrent stromal keratitis Dendritic keratitis, recurrent stromal keratitis Recurrent stromal keratitis, neuro trophic keratopathy None
STUDY
Grüter» Pickard* Gözctf' Lowenstein'^ Paufique, Chauviré, and Barut" and Paufique and Bonamour**' * Neame* Cavara" Frandsen^ Cavara'' Moulié and Gofanovich Baron" Thygesen, Hogan, and Kimura*^ Gaud' Nesburn and associates'^
Tessler and Krimmer" Uchlda, Kaneko, and HayashI«
Present series (Wilhelmus, Hamill, and Jones)
*NA indicates not available.
L
COMPLICATIONS
VISUAL O U T C O M E
NA 20/30
20/20 20/20
20/50
NA
20/25 NA NA NA 20/25 20/20 20/20 20/20 20/30
20/40 20/25
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Increased IgM or increasing I g G titers can a s s i s t in t h e d i a g n o s i s o f v a r i c e l l a . H e t e r o l o gous crossreactions are excluded if antiherpes simplex antibodies are not detected. O t h e r causes of nonsuppurative stromal keratitis can be investigated with specific s e r o l o g i c tests for Epstein-Barr virus, mumps, syphilis, and Lyme disease. T h e p a t h o g e n e s i s o f v a r i c e l l a k e r a t i t i s is u n clear. As opposed to the limbal infiltrates that o c c u r d u r i n g or s o o n after t h e s k i n r a s h , t h e delayed onset of disciform stromal keratitis suggests an i m m u n o l o g i c rather t h a n infective reaction.** P e r h a p s v i r a l a n t i g e n g a i n s a c c e s s t o t h e c o r n e a l s t r o m a o r e n d o t h e l i u m from p r e c e d i n g e p i t h e l i a l i n f e c t i o n or t h r o u g h l i m b a l o r a q u e o u s r o u t e s d u r i n g v i r e m i a . In a h u m a n subject, topical inoculation of chickenpox ves i c u l a r fluid to a b l i n d e y e p r o d u c e d k e r a t o u v e i t i s t e n days l a t e r , b u t n o i n f l a m m a t i o n o c c u r r e d after s u b s e q u e n t r e c h a l l e n g e . ^ H o w viral and host factors interplay to produce stromal keratitis has not b e e n determined. Because of the restraints of h u m a n experimentation, the sparse histopathologic material, and the limitations of animal models of varicella keratitis, further insights remain speculative. T h e r o l e o f t o p i c a l c o r t i c o s t e r o i d t h e r a p y for viral s t r o m a l k e r a t i t i s r e m a i n s c o n t r o v e r s i a l . We a d m i n i s t e r e d a t o p i c a l c o r t i c o s t e r o i d to o u r patients with varicella disciform stromal keratitis b e c a u s e o f p e r s i s t e n t o r p r o g r e s s i v e c o r n e a l inflammation and edema. Apparent rapid improvement was subsequently complicated by p r o l o n g e d or r e c r u d e s c e n t c o r n e a l i n f l a m m a t i o n in t h r e e o f t h e s e five c a s e s . A l t h o u g h t o p i c a l c o r t i c o s t e r o i d s c a n affect v a r i c e l l a k e r a t i t i s a n d p o s s i b l y p r e d i s p o s e to o c c u r r e n c e s , * " w e could not determine whether topical corticoster o i d s p r o l o n g e d t h e d u r a t i o n or b e n e f i t e d v i s u al o u t c o m e . S y s t e m i c c o r t i c o s t e r o i d s a r e a v o i d ed because o f possible dissemination. The value o f antiviral agents in the treatment of varicella ocular disease h a s not b e e n determ i n e d . At t h e p r e s e n t t i m e , w e d o n o t u s e topical antiviral prophylaxis during topical cort i c o s t e r o i d t h e r a p y for v a r i c e l l a s t r o m a l k e r a t i tis. A l t h o u g h oral a c y c l o v i r r e d u c e s t h e d u r a tion of viral shedding a n d fosters resolution o f skin lesions during varicella, systemic antiviral agents have not b e e n a s s e s s e d for varicella corneal disease. T h e s e cases of disciform stromal keratitis s h o w t h a t v a r i c e l l a is a c a u s e o f s t r o m a l k e r a t i tis. B e c a u s e t h e s i g n s o f v a r i c e l l a c a n b e l i m i t e d to a m i l d s k i n r a s h s e v e r a l w e e k s or m o n t h s
before corneal changes occur, diagnosis may be problematic. Clinical awareness of varicella k e r a t i t i s is n e e d e d for a p p r o p r i a t e e v a l u a t i o n o f this potentially sight-limiting disease.
ACKNOWLEDGMENT
Frank R. Keith, Jr., M . D . , Larry H. Taber, M . D . , Paul J . Azar, Jr., M . D . , G e r a l d M. Sheldon, M . D . , and Ronald A. S c h a c h a r , M.D., r e f e r r e d t h e r e s p e c t i v e p a t i e n t s for t h i s s t u d y .
References 1. Liesegang, T. J . : The varicella-zoster virus. Systemic and ocular features. J . Am. Acad. Dermatol. 11:165, 1 9 8 4 . 2. Bonamour, G.: Les manifestations oculaires des maladies infectieuses eruptives de I'enfance. J . Med. Lyon 34:557, 1 9 5 3 . 3. Gaud, P.: Les complications oculaires des maladies infectieuses eruptives de I'enfance. Arch. Ophtalmol. 18:25, 1 9 5 8 . 4. Bonamour, G., and Gaillot, J.: Les complications oculaires de la varicelle. J . Med. Lyon 4 0 : 6 6 3 , 1 9 5 9 . 5. Nataf, R., Lépine, P., and Bonamour, G.: Oeil et Virus. Viroses Oculaires Manifestations Ophtalmologiques des Maladies Genérales å Virus. Paris, Masson, 1 9 6 0 , p. 5 7 7 . 6. Griflin, W. P., and Searle, C. W. Α.: Ocular manifestations of varicella. Lancet 2:168, 1 9 5 3 . 7. Kachmer, M. L., Annable, W. L., and DiMarco, M.: Iritis in children with varicella. J. Pediatr. Oph thalmol. Strabismus 2 7 : 2 2 1 , 1 9 9 0 . 8. Jordan, D. R., Noel, L.-P., and Clarke, W. N.: Ocular involvement in varicella, Clin. Pediatr. 23:434, 1 9 8 4 . 9. Trantas, Α.: Kératite superficielle exanthématique pendant la rougeole et d'autres maladies exanthématiques. Bull. Soc. Fr. Ophtalmol. 24:592, 1907. 10. Chow, Y.: Varizellen der Bindehaut. Klin. Monatsbl. Augenheilkd. 7 4 : 4 8 4 , 1 9 2 5 . 11. Sallman, L.: Limbusknötchen bei Varizellen. Ζ. Augenheilkd. 6 2 : 1 8 5 , 1927. 12. Falls, Η. F., and Beall, J. G.: Ocular varicella. Report of a case of corneal phlyctenule. Arch. Oph thalmol. 3 4 : 4 1 1 , 1 9 4 5 . 13. Veeneklaas, G. M. H.: Recidiverende en corneo-sclerale Varicellen. Maandschr. Kindergeneesk. 17:18, 1 9 4 9 . 14. Chan, E., and Mao, W. S.: Varicella involving the eye. Chin. Med. J . 6 8 : 3 7 5 , 1 9 5 0 . 15. Capolongo, G.: Contributo all' interpretazione della cheratocongiuntivite flittenulare che si mani festo in alcune malattie infettive. Boll. Ocul. 2 9 : 4 4 3 , 1950. 16. Postic, S.: Kératite varicelleuse. Bull. S o c . Ophtalmol. 70:127, 1 9 5 7 .
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17. Cairns, J. E.: Varicella of the cornea treated with 5-iodo-2'-deoxyuridine. Br. ] . Ophthalmol. 48:288, 1964. 18. Jervey, E. D., Armstrong, G. F., and Harkins, G.: Ocular varicella with particular reference to keratoconjunctival lesions. South. Med. J. 60:696, 1967. 19. Tersen, Α.: Notes thérapeutiques et cliniques. Clin. Ophtalmol. 10:190, 1904. 20. Oppenheimer, Ε. Η.: Varicelle der Hornhaut. Dtsch. Med. Wochenschr. 31:833, 1905. 21. Wyler, J. S.: Corneal ulcer produced by varicel la. JAMA 68:1476, 1917. 22. Rosenbaum, Η. D.: Varicella and the cornea. A case report. Am. J . Ophthalmol. 2 6 : 5 3 , 1 9 4 3 . 23. Billo, O. E.: Varicella of the cornea. With re port of a case. U.S. Navy Med. Bull. 4 6 : 1 9 0 1 , 1 9 4 6 . 24. deAlmeida Reboufas, J.: Ceratite ulcerosa varicelica. Rev. Bras. Oftalmol. 5:105, 1946. 25. Goncalves, D.: Ulcera de córnea na varicela. Rev. Bras. Oftalmol. 6:33, 1947. 26. Pillat, Α.: Über die Mitbeteiligung der Horn haut bei Varizellen. Oest. Ophthalmol. Ges. 5:32, 1960. 27. Hugonnier, R., Magnard, P., and Paufique, L.: Kératite varicellique avec amblyopie traitée par kératoplastie lamellaire et reeducation visuelle. Bull. Soc. Ophtalmol. Fr. 69:795, 1956. 28. Ellenberger, C : A case of phthisis bulbi due to chickenpox. Arch. Ophthalmol. 47:352, 1 9 5 2 . 29. Grüter, W.: Die Ätiologie der Keratitis disciformis. Ber. Zussamm. Dtsch. Ophthalmol. Ges. 48:209, 1930. 30. Pickard, R.: Varicella of the cornea. Br. J. Oph thalmol. 20:15, 1 9 3 6 . 3 1 . Gózcü, N. I.: Three cases of disciform keratitis. Turk. Oftalh. Gas. 2:477, 1 9 3 8 . 32. Loewenstein, Α.: Specific inflammation of the cornea in chickenpox. Br. J. Ophthalmol. 2 4 : 3 9 1 , 1940. 33. Paufique, L., Chauviré, Ε., and Barut, C : La kératite varicellique. J. Ophtalmol. 3:133, 1944. 34. Paufique, L., and Bonamour, G. Α.: Un nouveau cas de kératite varicellique. J. Ophtalmol. 3:255, 1944.
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35. Paufique, L., and Bonamour, G.: La kératite varicellique. J. Med. Lyon 27:499, 1946. 36. Neame, H.: Virus diseases of the eye. Trans. Ophthalmol. Soc. U.K. 64:85, 1944. 37. Cavara, V.: Le manifestazioni oculari dell'infezione erpetica. Boll. Ocul. 2 5 : 1 , 1 9 4 6 . 38. Frandsen, Ε.: Chickenpox in the cornea. Acta Ophthalmol. 2 8 : 1 1 3 , 1 9 5 0 . 39. Cavara, V.: The role of viruses in the etiology of uveitis. Acta XVII Concil. Ophthalmol. 2:1232, 1955. 40. Moulié, Η. Β., and Gofanovich Baron, H,: Her pes corneano posterior (herpes de Schnyder). Arch. Oftalmol. Buenos Aires 25:43, 1 9 5 0 . 4 1 . Thygeson, P., Hogan, Μ. J . , and Kimura, S. ] . : Observations on uveitis associated with viral disease. Trans. Am. Ophthalmol. Soc. 55:333, 1957. 42. Nesburn, A. B., Borit, Α., Pentelei-Molnar, ] . , and Lázaro, R.: Varicella dendritic keratitis. Invest. Ophthalmol. 13:764, 1974. 43. Tessler, H. H., and Krimmer, Β. Μ.: Disciform keratitis induced by varicella virus. Eye Ear Nose Throat Mon. 5 4 : 3 1 1 , 1975. 44. Uchida, Y., Kaneko, M., and Hayashi, K.: Vari cella dendritic keratitis. Am. J. Ophthalmol. 89:259, 1980. 45. Meyer, R. F., and Wolter, J. R.: Granulomatous inflammatory reaction to degenerating Descemet's membrane. Ann. Ophthalmol. 13:1113, 1 9 8 1 . 46. Wilson, F. M., II: Varicella and herpes zoster ophthalmicus. In Tabbara, K. F., and Hyndiuk, R. A. (eds.): Infections of the Eye. Boston, Little, Brown and Company, 1986, pp. 3 6 9 - 3 8 6 . 47. Uchida, Y.: Varicella dendritic keratitis. In Darrell, R. W. (ed.): Viral Diseases of the Eye. Phila delphia, Lea & Febiger, 1 9 8 5 , pp. 7 3 - 7 7 . 48. deFreitas, D., Kelly, L. D., Pavan-Langston, D., Sato, E. H., and Kenyon, K. R.: Delayed onset varicel la keratitis. Ophthalmology 97:137, 1990. 49. Collier, M.: Formes cliniques tardives de la kératite varicellique. Bull. Soc. Ophtalmol. Fr. 65:397, 1952. 50. Tessler, H. H., and Krimmer, Β. Μ.: Corticoste roids and varicella disciform keratitis. Am. J. Oph thalmol. 9 0 : 1 1 5 , 1980.
Kirk R. Wilhelmus, M.D., M . Bowes H a m i l l , M . D . , and Dan B. Jones, M . D .
We t r e a t e d five p a t i e n t s , a g e d 2 6 , 4 , 6 , 1 3 , a n d 7 years, who developed disciform stromal ker atitis one, four, four, eight, a n d ten weeks, respectively, after t h e onset of the acute vesic ular exanthema. Serologic testing confirmed recent varicella and excluded other infectious c a u s e s in t w o c a s e s . A f t e r i n i t i a l i m p r o v e m e n t with a topical corticosteroid, three patients developed recurrent corneal inflammation re sembling zoster keratitis. These cases and previous reports indicate that varicella-zoster v i r u s is a c a u s e o f d i s c i f o r m s t r o m a l k e r a t i t i s that may occur and recur several weeks or m o n t h s after t h e p r i m a r y skin rash has r e solved.
C H I C K E N P O X is a diffuse v e s i c u l a r skin r a s h , m a i n l y affecting c h i l d r e n , c a u s e d b y p r i m a r y infection with varicella-zoster virus.' The re s e m b l a n c e o f the c u t a n e o u s l e s i o n s to c h i c k p e a s p r o b a b l y gave r i s e to t h e t e r m c h i c k e n p o x t o e m p h a s i z e its m i l d n e s s a n d s i m i l a r i t y to smallpox, and its synonym varicella originated as a d i m i n u t i v e form o f v a r i o l a . T h e e y e m a y b e affected d u r i n g , after, or r a r e l y b e f o r e t h e e x a n thema. Among the possible ocular complica t i o n s of c h i c k e n p o x a r e k e r a t o c o n j u n c t i v i t i s , uveitis, and n e u r o - o p h t h a l m i c changes.^^ Few s t u d i e s h a v e d e t e r m i n e d t h e f r e q u e n c y or i n c i d e n c e o f v a r i o u s o c u l a r findings in patients with chickenpox. Over a o n e - y e a r in t e r v a l . Griffin a n d S e a r l e " f o u n d five of 1 2 5 children ( 4 % ) with varicella w h o had c o n j u n c tivitis, o n e w i t h a l i m b a l l e s i o n . In a t w o - y e a r period, Kachmer, A n n a b l e , and D i M a r c o ' iden tified 3 3 o f 8 2 c h i l d r e n ( 4 0 % ) w i t h c h i c k e n p o x w h o h a d o c u l a r or e y e l i d i n v o l v e m e n t , i n c l u d ing six ( 7 % ) w i t h e y e l i d l e s i o n s , t e n ( 1 2 % ) w i t h p u n c t a t e k e r a t o p a t h y , a n d 21 ( 2 6 % ) w i t h i r i t i s .
Accepted for publication Feb. 6, 1991. From the Department of Ophthalmology, Gullen Eye Institute, Baylor College of Medicine, Houston, Texas. Reprint requests to Kirk R. Wilhelmus, M.D., One Baylor Plaza, Houston, TX 77030.
Of 24 children referred because of ocular symp toms, Jordan, Noel, and Clarke'reported eyelid p o c k s a n d c o n j u n c t i v i t i s as t h e m o s t c o m m o n findings, followed by uveitis and keratitis. We t r e a t e d five p a t i e n t s w i t h d i s c i f o r m s t r o m a l k e r a t i t i s after c h i c k e n p o x .
Case Reports Case 1 A 2 6 - y e a r - o l d w o m a n w a s e x a m i n e d for d e c r e a s e d v i s i o n a n d r e d n e s s o f t h e left e y e . W i t h o u t k n o w n contact with a rash illness, she had developed fever seven days previously, f o l l o w e d t w o days l a t e r b y v e s i c u l a r d e r m a t i t i s b e g i n n i n g in t h e n e c k r e g i o n w i t h s u b s e q u e n t spread to the face, trunk, arms, and legs with out localized i n v o l v e m e n t . Initial ocular signs a n d s y m p t o m s i n c l u d e d left u p p e r e y e l i d e d e ma, photophobia, and decreased vision. Slitl a m p b i o m i c r o s c o p y d i s c l o s e d faint, p a t c h y anterior stromal opacities with central disci form s t r o m a l e d e m a , fine c e l l u l a r i n f i l t r a t i o n , and pseudo cornea guttata. T h e anterior c h a m b e r c o n t a i n e d t r a c e flare a n d r a r e c e l l s . Treatment was begun with prednisolone ace tate 1% five t i m e s d a i l y a n d s c o p o l a m i n e h y drochloride 0 . 5 % three times daily. Improve m e n t occurred within two days, and a tapering dose of topical corticosteroid was continued. Within ten days, visual acuity improved to 2 0 / 2 0 with resolution of the stromal keratitis, w h i c h left a faint r e s i d u a l a n t e r i o r s t r o m a l haze. Case 2 A 4 - y e a r - o l d girl w a s r e f e r r e d for s t r o m a l k e r a t i t i s f o u r w e e k s after c h i c k e n p o x . M i l d c o n junctival hyperemia with p s e u d o b l e p h a r o p t o sis o f t h e left e y e h a d d e v e l o p e d o v e r t h e preceding ten days and had not responded to topical erythromycin ointment. Visual acuity was R . E . : 2 0 / 2 0 and L.E.: 2 0 / 4 0 0 . Slit-lamp examination showed a well-demarcated disci form stromal keratitis with localized e d e m a , pseudo cornea guttata, and mild iritis. S e r o l o g -
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ic t e s t i n g c o n f i r m e d r e c e n t v a r i c e l l a a n d e x c l u d ed o t h e r c a u s e s o f s t r o m a l k e r a t i t i s . F o u r w e e k s after o n s e t o f the skin rash, v a r i c e l l a - z o s t e r virus IgG was 1:16, h e r p e s s i m p l e x I g M a n d I g G were not detectable ( < 1:10), and Epstein-Barr viral c a p s i d a n d n u c l e a r I g G s w e r e n o t d e t e c t a b l e . S i x w e e k s later, the h e r p e s s i m p l e x a n t i b o d i e s w e r e still n o t d e t e c t a b l e . T h e m i c r o h e m a g g l u t i n a t i o n a s s a y for Treponema pallidum was nonreactive. Topical p r e d n i s o l o n e a c e t a t e 1% was b e g u n four t i m e s d a i l y . T h e p a t i e n t i m p r o v e d o v e r t h e n e x t ten days with r e d u c e d s t r o m a l e d e m a a n d infiltration, a n d v i s u a l a c u i t y i m p r o v e d to 2 0 / 30. The topical corticosteroid was gradually t a p e r e d over the s u b s e q u e n t four w e e k s , but i n c r e a s e d c o r n e a l i n f l a m m a t i o n w i t h iritis o c c u r r e d w h e n it w a s b e i n g a d m i n i s t e r e d o n c e daily. As the t o p i c a l c o r t i c o s t e r o i d d o s a g e w a s subsequently reduced, increased central disci form e d e m a a g a i n r e c u r r e d . P e r i p h e r a l superfi cial s t r o m a l v a s c u l a r i z a t i o n a n d c e n t r a l s c a r ring e n s u e d a n d l i m i t e d s p e c t a c l e - c o r r e c t e d v i s u a l acuity to 2 0 / 6 0 , w h i c h i m p r o v e d to 2 0 / 20 with contact lens correction. Chronic corticosteroid-dependent stromal keratouveitis re s u l t e d in p r o l o n g e d use o f d a i l y p r e d n i s o l o n e a c e t a t e 0 . 1 2 % o v e r the n e x t four y e a r s . Case 3 A 6 - y e a r - o l d girl d e v e l o p e d s o r e t h r o a t , l o w g r a d e fever, a n d diffuse c u t a n e o u s l e s i o n s o v e r h e r e n t i r e b o d y i n c l u d i n g h e r face a n d p e r i o c u lar r e g i o n . H e r 4 - y e a r - o l d sister h a d r e c e n t l y had a similar skin rash during a c h i c k e n p o x o u t b r e a k at the day c a r e c e n t e r . O c u l a r s y m p toms of photophobia and blurred vision began o n e m o n t h after the c u t a n e o u s l e s i o n s . V i s u a l acuity was 2 0 / 4 0 in the affected eye b e c a u s e o f c e n t r a l e d e m a , diffuse s t r o m a l infiltration, a n d dendritic epithelial keratitis. T r e a t m e n t was b e g u n w i t h trifluridine 1% a n d t o b r a m y c i n 0 . 3 % . B e c a u s e of i n c r e a s i n g s t r o m a l e d e m a with visual a c u i t y o f 2 0 / 6 0 , w e c h a n g e d t r e a t m e n t to d e x a m e t h a s o n e 0 . 1 % . Despite initial improvement, recurrent stromal keratitis o c c u r r e d d u r i n g the s u b s e q u e n t y e a r w h e n e v e r the t o p i c a l c o r t i c o s t e r o i d w a s ta pered. Residual corneal scarring limited visual a c u i t y to 2 0 / 3 0 . Case 4 A 1 3 - y e a r - o l d girl d e v e l o p e d c h i c k e n p o x ; two n e i g h b o r h o o d c h i l d r e n a l s o d e v e l o p e d c h i c k e n p o x , o n e i m m e d i a t e l y p r e c e d i n g the p a t i e n t a n d o n e s i m u l t a n e o u s l y . E i g h t w e e k s lat-
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Figure (Wilhelmus, Hamill, and Jones). Case 4. Central disciform stromal keratitis occurring in a 13-year-old girl eight weeks after varicella. er, w e l l after all skin l e s i o n s h a d h e a l e d , t h e p a t i e n t d e v e l o p e d a red left e y e . I n i t i a l treat ment by her pediatrician with neomycin-poly myxin B-bacitracin ointment did not help. O c u lar e x a m i n a t i o n s h o w e d c e n t r a l n o n n e c r o t i z i n g disciform stromal keratitis with keratic precipi t a t e s a n d m i l d iritis ( F i g u r e ) . S e r o l o g i c t e s t i n g confirmed recent varicella and excluded other possible causes of stromal keratitis. Varicellaz o s t e r virus a n t i b o d y t i t e r s w e r e t e s t e d 11 w e e k s after o n s e t o f t h e s k i n r a s h ; I g M w a s 1:40, a n d I g G w a s 1 : 2 , 5 6 0 . S e v e n w e e k s later, IgM was not detectable ( < 1:20), and IgG was 1 : 6 4 0 . O t h e r s e r o l o g i c t e s t s p e r f o r m e d at e i g h t or 11 w e e k s after t h e skin r a s h w e r e as f o l l o w s : herpes simplex IgM not detectable ( < 1:10); h e r p e s s i m p l e x I g G n o t d e t e c t a b l e ( < 1:8); E p s t e i n - B a r r viral c a p s i d I g G n o t d e t e c t a b l e ( < 1 : 1 0 ) ; E p s t e i n - B a r r viral n u c l e a r I g G n o t d e t e c t a b l e ( < 1:4); a d e n o v i r u s I g G n o t d e t e c t a b l e ( < 1:8); m u m p s I g M n o t d e t e c t a b l e ; m u m p s I g G w e a k l y p o s i t i v e ( i n d e x = 1:3); m u m p s S a n t i b o d y n o t d e t e c t a b l e ( < 1:8); m u m p s V a n t i b o d y n o t d e t e c t a b l e ( < 1:8); r u b e o l a I g G n o t d e t e c t able; rubella IgM not detectable; rubella IgG p o s i t i v e ( i n d e x = 1:4); r a p i d p l a s m a r e a g i n n o n r e a c t i v e ; m i c r o h e m a g g l u t i n a t i o n a s s a y for T. pallidum nonreactive; Lyme disease IgM not detectable; and Lyme disease IgG not detect able. T o p i c a l p r e d n i s o l o n e p h o s p h a t e 1% w a s b e gun e v e r y t w o h o u r s w i t h i n i t i a l i m p r o v e m e n t in v i s u a l a c u i t y from 2 0 / 1 0 0 to 2 0 / 2 5 . T h e patient subsequently developed corneal anes t h e s i a with d e n d r i f o r m m u c o u s p l a q u e s . Topi cal c o r t i c o s t e r o i d s w e r e g r a d u a l l y t a p e r e d , but s h e c o n t i n u e d to d e v e l o p r e c u r r e n t s t r o m a l ker a t i t i s d u r i n g the n e x t y e a r , w h i c h r e q u i r e d p r o -
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Varicella Disciform Keratitis
loriged c o r t i c o s t e r o i d t h e r a p y . V i s u a l a c u i t y r e m a i n e d l i m i t e d to 2 0 / 4 0 b e c a u s e o f r e s i d u a l stromal opacification and neurotrophic epithe lial c h a n g e s . Case 5 A 7 - y e a r - o l d girl d e v e l o p e d a r e d left e y e t e n w e e k s after c h i c k e n p o x . C e n t r a l d i s c i f o r m s t r o mal keratitis was noted, and initial treatment included p r e d n i s o l o n e acetate 1% every two h o u r s a n d c y c l o p e n t o l a t e h y d r o c h l o r i d e 1% t w i c e d a i l y . V i s u a l a c u i t y w o r s e n e d to 2 0 / 2 0 0 in t h e left eye b e c a u s e o f a w e l l - d e m a r c a t e d area o f d e n s e s t r o m a l e d e m a w i t h e n d o t h e l i a l pseudo cornea guttata. Laboratory testing three m o n t h s after t h e s k i n r a s h s h o w e d a n o n d e t e c t able herpes simplex virus type 1 IgG ( < 1:10) and a varicella-zoster virus IgG titer of 1:16. After steroid proved residual
a four-week course of topical cortico therapy, visual acuity gradually im to 2 0 / 2 5 in t h e left e y e w i t h a faint opacity.
Discussion Viremia and the typical m u c o c u t a n e o u s exan thema o f varicella begin approximately two w e e k s after c o n t a c t w i t h a n i n f e c t e d p e r s o n . S e l f - l i m i t i n g p a p u l e s m a y a p p e a r in t h e m o u t h , pharynx, larynx, trachea, and gastrointestinal t r a c t . C o m m o n o c u l a r findings a r e e y e l i d v e s i c l e s or m a r g i n a l e r o s i o n s , a c u t e c o n j u n c t i v i t i s , and lesions resembling phlyctenules of the bulbar conjunctiva and semilunar fold. H u m o r al a n d c e l l u l a r i m m u n i t y c o n t r o l viral r e p l i c a tion with spontaneous resolution o f the skin and mucous m e m b r a n e rash. Corneal changes are infrequent but can occur d u r i n g t h e first w e e k or t w o after t h e o n s e t o f chickenpox. Punctate epithelial keratitis has been described infrequently.' More commonly n o t e d is a n a c u t e , p u s t u l a r s u b e p i t h e l i a l infil trate at t h e c o r n e o s c l e r a l l i m b u s . " E p i t h e l i al e r o s i o n a n d u l c e r a t i o n c o n t r i b u t e to t h e p a i n ful s y m p t o m s . A r e s i d u a l p a t c h o f p e r i p h e r a l corneal scarring with vascularization can re main. Besides these focal, usually unilateral limbal infiltrates, a c e n t r a l s u p e r f i c i a l infiltrate w i t h e p i t h e l i a l e r o s i o n c a n a l s o occur.''-2" F a i n t s u b e p i t h e l i a l o p a c i f i c a t i o n o c c u r s after s p o n t a n e ous healing, although extensive corneal scar r i n g in e a r l y c h i l d h o o d h a s l e d t o d e p r i v a t i o n a m b l y o p i a . " IParely, p r o g r e s s i v e n e c r o t i z i n g i n
577
f l a m m a t i o n a n d i r i d o c y c l i t i s h a v e p r o g r e s s e d to c o r n e a l p e r f o r a t i o n a n d p h t h i s i s bulbi.^* Nonnecrotizing, disciform stromal keratitis is a n u n u s u a l c o m p l i c a t i o n o f varicella.^ * C l i n i cal f e a t u r e s i n c l u d e i n t e r s t i t i a l h a z e c a u s e d b y localized e d e m a and cellular infiltration. A dis coid pattern of n o n c o a l e s c e n t inflammatory c e l l s is o u t l i n e d b y a s l i g h t l y d e n s e r a n n u l a r border. Mild iritis, grouped keratic precipitates, and endothelial pseudo cornea guttata are a c companying features. D i s c i f o r m k e r a t i t i s after v a r i c e l l a h a s b e e n diagnosed previously with no gender predilec t i o n , m a i n l y in c h i l d r e n (Table).''^*·" A l l c a s e s have b e e n unilateral and equally distributed b e t w e e n r i g h t a n d left e y e s . T h e s e r e p o r t s e m phasize the delayed onset of disciform keratitis, t y p i c a l l y b e g i n n i n g s e v e r a l w e e k s after t h e i n i tial skin r a s h . S o m e o f the reported cases of varicella stro mal keratitis developed dendritic epithelial ker a t i t i s , c h a r a c t e r i z e d b y gray, s w o l l e n e p i t h e l i a l c e l l s in a n o n u l c e r a t e d , l i n e a r p a t t e r n s i m i l a r to varicella-zoster virus dendrites. We also identi fied d e n d r i t i c e p i t h e l i a l k e r a t i t i s in o n e p a t i e n t and dendriform mucous plaques and filaments resembling postvaricella-zoster neurotrophic k e r a t i t i s in a n o t h e r . E v e n t h o u g h v i r a l a n t i g e n and intracellular viral inclusions can be found in t h e c o r n e a l epithelium,''^'''' a n t i v i r a l t h e r a p y is n o t a p p a r e n t l y r e q u i r e d for r e s o l u t i o n . Recurrent stromal keratitis prolongs the clini cal c o u r s e for m o n t h s or e v e n y e a r s . D e s p i t e initial antiinflammatory control with topical corticosteroid therapy, some patients develop subsequent corneal inflammation during grad ual corticosteroid d o s a g e reduction. S t r o m a l keratitis with residual corneal scarring, some t i m e s l e a d i n g to c o r n e a l transplantation,^"*^ is t h e p r i n c i p a l r e a s o n for v i s u a l l o s s . O t h e r c o m p l i c a t i o n s o f v a r i c e l l a d i s c i f o r m k e r a t i t i s in c l u d e n e u r o t r o p h i c keratopathy,''^ i r i d o c y c l i t i s w i t h s e c o n d a r y g l a u c o m a , * ' a n d iris s t r o m a l atrophy.'^ B e c a u s e t h e r e a r e few d i s t i n g u i s h i n g f e a t u r e s a m o n g the various causes of disciform stromal keratitis, herpes simplex and other infectious causes must be considered. Serologic evalua tion should exclude herpes simplex before con c l u d i n g t h a t r e c e n t v a r i c e l l a is c a u s a t i v e r a t h e r than coincidental. For example, we have treated other patients with idiopathic stromal keratitis o c c u r r i n g a few w e e k s or m o n t h s after v a r i c e l l a b u t c o u l d n o t e s t a b l i s h a definite c o n n e c t i o n because of antibodies showing previous expo s u r e to h e r p e s s i m p l e x v i r u s .
578
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TABLE DATA ON 32 REPORTED CASES OF VARICELLA DISCIFORM STROMAL KERATITIS* C A S E NO., A G E (YHS),
ONSET AFTER
CORTICOSTEROID
SEX, EYE
SKIN RASH
USE
1, NA, NA, NA 2, NA, NA, NA 3, 10, M, R 4, NA, NA, NA 5, 4, M, R 6, 5, M, R 7, 4, F, R 8, 7, F, L 9, 30, M, R 10, 8, NA, R 11,8, F, L 12, 5, M, R 13, 7, F, NA 14, 9, M, R
NA NA 3 weeks NA 10 days 3 weeks 3 weeks NA 8 weeks NA 3 weeks 3 weeks NA 8 days
No No No No No No No No No No No No No No
NA NA None NA None NA NA NA None NA None None NA None
NA NA 20/15 NA NA NA NA NA 20/40 NA 20/80 20/40 NA 20/20
15, NA, NA, NA
NA
NA
Secondary glaucoma
NA
16, NA, NA, R 17, 8, F, L
NA 12 weeks
NA Yes
18, 11, M, R 19, 7, M, R
2 weeks 5 weeks
No Yes
20, 3, F, L
13 weeks
Yes
Meyer and Wolter"
21, 3, M, R
NA
Yes
Wilson* Uchlda"
22, 9, M, R 23, 6, F, L 24, 3, F, R 25, 7, M, L
4 weeks 10 weeks 10 weeks 5 weeks
No Yes NA NA
deFreitas and associates"
26, 6, F, NA 27, 10, M, NA 28, 26, F, L 29, 4, F, L
6 weeks 8 weeks 1 week 4 weeks
Yes Yes Yes Yes
30, 6, F,
4 weeks
Yes
31, 13, F, L
8 weeks
Yes
32, 7, F, L
10 weeks
Yes
NA Dendritic keratitis, recurrent stromal keratitis Dendritic keratitis Dendritic keratitis. recurrent stromal keratitis Dendritic keratitis, recurrent stromal keratitis Recurrent stromal keratitis, corneal graft rejection None Dendritic keratitis Dendritic keratitis Punctate epithelial keratitis Dendritic keratitis Dendritic keratitis None Recurrent stromal keratitis Dendritic keratitis, recurrent stromal keratitis Recurrent stromal keratitis, neuro trophic keratopathy None
STUDY
Grüter» Pickard* Gözctf' Lowenstein'^ Paufique, Chauviré, and Barut" and Paufique and Bonamour**' * Neame* Cavara" Frandsen^ Cavara'' Moulié and Gofanovich Baron" Thygesen, Hogan, and Kimura*^ Gaud' Nesburn and associates'^
Tessler and Krimmer" Uchlda, Kaneko, and HayashI«
Present series (Wilhelmus, Hamill, and Jones)
*NA indicates not available.
L
COMPLICATIONS
VISUAL O U T C O M E
NA 20/30
20/20 20/20
20/50
NA
20/25 NA NA NA 20/25 20/20 20/20 20/20 20/30
20/40 20/25
Vol. I l l , No. 5
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Varicella Disciform Keratitis
Increased IgM or increasing I g G titers can a s s i s t in t h e d i a g n o s i s o f v a r i c e l l a . H e t e r o l o gous crossreactions are excluded if antiherpes simplex antibodies are not detected. O t h e r causes of nonsuppurative stromal keratitis can be investigated with specific s e r o l o g i c tests for Epstein-Barr virus, mumps, syphilis, and Lyme disease. T h e p a t h o g e n e s i s o f v a r i c e l l a k e r a t i t i s is u n clear. As opposed to the limbal infiltrates that o c c u r d u r i n g or s o o n after t h e s k i n r a s h , t h e delayed onset of disciform stromal keratitis suggests an i m m u n o l o g i c rather t h a n infective reaction.** P e r h a p s v i r a l a n t i g e n g a i n s a c c e s s t o t h e c o r n e a l s t r o m a o r e n d o t h e l i u m from p r e c e d i n g e p i t h e l i a l i n f e c t i o n or t h r o u g h l i m b a l o r a q u e o u s r o u t e s d u r i n g v i r e m i a . In a h u m a n subject, topical inoculation of chickenpox ves i c u l a r fluid to a b l i n d e y e p r o d u c e d k e r a t o u v e i t i s t e n days l a t e r , b u t n o i n f l a m m a t i o n o c c u r r e d after s u b s e q u e n t r e c h a l l e n g e . ^ H o w viral and host factors interplay to produce stromal keratitis has not b e e n determined. Because of the restraints of h u m a n experimentation, the sparse histopathologic material, and the limitations of animal models of varicella keratitis, further insights remain speculative. T h e r o l e o f t o p i c a l c o r t i c o s t e r o i d t h e r a p y for viral s t r o m a l k e r a t i t i s r e m a i n s c o n t r o v e r s i a l . We a d m i n i s t e r e d a t o p i c a l c o r t i c o s t e r o i d to o u r patients with varicella disciform stromal keratitis b e c a u s e o f p e r s i s t e n t o r p r o g r e s s i v e c o r n e a l inflammation and edema. Apparent rapid improvement was subsequently complicated by p r o l o n g e d or r e c r u d e s c e n t c o r n e a l i n f l a m m a t i o n in t h r e e o f t h e s e five c a s e s . A l t h o u g h t o p i c a l c o r t i c o s t e r o i d s c a n affect v a r i c e l l a k e r a t i t i s a n d p o s s i b l y p r e d i s p o s e to o c c u r r e n c e s , * " w e could not determine whether topical corticoster o i d s p r o l o n g e d t h e d u r a t i o n or b e n e f i t e d v i s u al o u t c o m e . S y s t e m i c c o r t i c o s t e r o i d s a r e a v o i d ed because o f possible dissemination. The value o f antiviral agents in the treatment of varicella ocular disease h a s not b e e n determ i n e d . At t h e p r e s e n t t i m e , w e d o n o t u s e topical antiviral prophylaxis during topical cort i c o s t e r o i d t h e r a p y for v a r i c e l l a s t r o m a l k e r a t i tis. A l t h o u g h oral a c y c l o v i r r e d u c e s t h e d u r a tion of viral shedding a n d fosters resolution o f skin lesions during varicella, systemic antiviral agents have not b e e n a s s e s s e d for varicella corneal disease. T h e s e cases of disciform stromal keratitis s h o w t h a t v a r i c e l l a is a c a u s e o f s t r o m a l k e r a t i tis. B e c a u s e t h e s i g n s o f v a r i c e l l a c a n b e l i m i t e d to a m i l d s k i n r a s h s e v e r a l w e e k s or m o n t h s
before corneal changes occur, diagnosis may be problematic. Clinical awareness of varicella k e r a t i t i s is n e e d e d for a p p r o p r i a t e e v a l u a t i o n o f this potentially sight-limiting disease.
ACKNOWLEDGMENT
Frank R. Keith, Jr., M . D . , Larry H. Taber, M . D . , Paul J . Azar, Jr., M . D . , G e r a l d M. Sheldon, M . D . , and Ronald A. S c h a c h a r , M.D., r e f e r r e d t h e r e s p e c t i v e p a t i e n t s for t h i s s t u d y .
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