Scleritis and Wegener's Granulomatosis in Children
Robert D. Sacks, M.D., E. Lee Stock, M.D., Susan E. Crawford, M . D . , Mark J. Greenwald, M.D., and Richard B, O'Grady, M . D .
We t r e a t e d t w o c h i l d r e n w i t h s c l e r i t i s ( o n e unilateral, one bilateral), in w h o m Wegener's g r a n u l o m a t o s i s w a s d i a g n o s e d o n t h e b a s i s of p a t h o l o g i c c h a n g e s in respiratory tract m u c o sa. B o t h p a t i e n t s w e r e g i r l s , 13 a n d 1 4 y e a r s o f age, respectively. O n e patient had otitis media and a nodular scleritis. Laboratory test results demonstrated an increased erythrocyte sedi mentation rate and microscopic hematuria. A biopsy of the sinus confirmed t h e diagnosis of Wegener's granulomatosis. T h e second pa tient h a d fever, a r t h r a l g i a s , a n o n p r o d u c t i v e cough, and bilateral scleritis. Laboratory test results demonstrated an increased erythro cyte sedimentation rate, positive test results for r h e u m a t o i d f a c t o r , a n d b i l a t e r a l p u l m o nary nodules on chest x-ray. Open-lung biop sy c o n f i r m e d t h e d i a g n o s i s o f W e g e n e r ' s g r a n ulomatosis. B o t h p a t i e n t s r e s p o n d e d well to t r e a t m e n t w i t h ?i c o m b i n a t i o n o f p r e d n i s o n e and cyclophosphamide.
S C L E R I T I S o c c u r s r a r e l y in c h i l d r e n . A few p e d i a t r i c c a s e s h a v e p r e v i o u s l y b e e n r e p o r t e d , " for w h i c h n o definitive e t i o l o g i c o r i g i n w a s e s t a b lished. W e g e n e r ' s g r a n u l o m a t o s i s is a m u l t i s y s t e m disease, primarily of aduíts, which consists of upper and lower respiratory tract necrotizing granulomas and vasculitis,'yaried degrees of g e n e r a l i z e d s m a l l v e s s e l v a s c u l i t i s , a n d a focal necrotizing glomerulonephritis. A limited form of the d i s e a s e w i t h o u t r e n a l i n v o l v e m e n t h a s a
Accepted for publication Dec. 28, 1990. From tlie Department of Ophthalmology, Northwest ern University Medical School, and Lakeside Veteran's Administration, Chicago, Illinois (Drs. Sacks, Stock, and O'Grady); and Department of Pathology (Dr. Crawford) and Division of Ophthalmology (Dr. Greenwald), Chil dren's Memorial Hospital, Chicago, Illinois. This study, was supported in part by an unrestricted grant from Research to Prevent Blindness, Inc. Reprint requests to E. Lee Stock, M.D., 303 E. Chicago Ave., Department of Ophthalmology, Northwestern University Medical School, Chicago, IL 60611.
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b e t t e r p r o g n o s i s . ' ' We t r e a t e d t w o c h i l d r e n in w h o m scleritis was the initial manifestation of Wegener's granulomatosis.
Case Reports Case 1 A 1 3 - y e a r - o l d girl e n t e r e d t h e h o s p i t a l for treatment of otitis and scleritis. T h e patient h a d recurrent otitis media treated with bilateral myringotomy o n e year before admission. Five weeks earlier, she had developed arthralgias, decreased appetite with mild weight loss, and fatigability. Recurrent otitis media one week later necessitated insertion o f an ear tube and t r e a t m e n t w i t h o r a l c e f a c l o r a n t i b i o t i c . Ten days before admission, the patient developed a white spot on the right c o r n e a , which was d i a g n o s e d as b a c t e r i a l k e r a t i t i s b y a n o p h t h a l mologist and treated with topical tobramycin e y e d r o p s . T h e c o n d i t i o n a l m o s t r e s o l v e d after four days, but t h e n t h e r i g h t e y e b e c a m e r e d a n d painful. T h e o p h t h a l m o l o g i s t then prescribed gentamicin sulfate eyedrops, bacitracin oph t h a l m i c o i n t m e n t , a n d o r a l p e n i c i l l i n . F o u r days before admission, the pain increased, and pho tophobia and blurred vision developed. The patient was admitted to Children's M e m o r i a l H o s p i t a l for fever a n d l e t h a r g y in a d d i t i o n to the ocular complaints. I n i t i a l findings i n c l u d e d v i s u a l a c u i t y o f R . E . : 2 0 / 3 0 and L.E.: 2 0 / 2 0 . Results of examination of the pupils were normal, and ocular m o v e m e n t s w e r e full. T h e r e w a s m i l d r i g h t u p p e r eyelid blepharoptosis with e d e m a . Slit-lamp examination demonstrated conjunctival injec tion superiorly with prominent scleral vessels and scleral edema. A 3 x 4-mm scleral nodule was noted superiorly with adjacent small, dis crete, limbal infiltrates. T h e r e was no associat ed c o r n e a l t h i n n i n g . T h e a n t e r i o r c h a m b e r w a s clear, and intraocular pressure and results of a fundus e x a m i n a t i o n w e r e n o r m a l . T h e girl a p p e a r e d c h r o n i c a l l y i l l . Y e l l o w w h i t e d i s c h a r g e d r a i n e d from t h e r i g h t e y e , a n d
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the t y m p a n i c m e m b r a n e was i n f l a m e d . B i l a t e r a l ear t u b e s w e r e in p l a c e . R e s u l t s o f t h e r e m a i n der o f the p h y s i c a l e x a m i n a t i o n w e r e n o r m a l . Initial laboratory testing included n o r m a l re s u l t s o f a c o m p l e t e b l o o d cell c o u n t , e l e c t r o l y t e level, and creatinine level. Urinalysis d e m o n s t r a t e d m i c r o s c o p i c h e m a t u r i a (four to five r e d b l o o d c e l l s p e r h i g h - p o w e r field). W e s t e r g r e n erythrocyte sedimentation rate was 41 m m / h o u r ( n o r m a l , 0 to 2 0 m m / h o u r ) . R h e u m a t o i d factor, a n t i n u c l e a r a n t i b o d y , a n d c o m p l e m e n t levels were normal. Results of a chest x-ray were normal. Computed tomography disclosed probable right mastoiditis. Initial treatment consisted of intravenous g e n t a m i c i n sulfate a n d t o p i c a l 1% o c u l a r p r e d nisolone acetate, which produced minimal im p r o v e m e n t in b o t h t h e o c u l a r c o n d i t i o n a n d otalgia after 4 8 h o u r s . R e s u l t s o f a c u l t u r e o f the c o r n e a w e r e n e g a t i v e , b u t c u l t u r e o f fluid d r a i n ing from the right e a r g r e w Achromobacter xylosoxidans. T h e regimen was c h a n g e d to oral trimethoprim/sulfamethoxazole and predni s o n e , w h i c h r e s u l t e d in o c u l a r a n d s y s t e m i c improvement within 3 6 hours. B a s e d on c l i n i c a l findings, b i o p s y s p e c i m e n s of the m i d d l e ear, m a x i l l a r y s i n u s m u c o s a , s u b g l o t t i c m u c o s a , a n d b o n e from t h e m a x i l l a r y sinus w e r e o b t a i n e d . O n l y the m a x i l l a r y m u c o sa w a s a b n o r m a l . T h e r e vyas m a r k e d v a s c u l i t i s w i t h p o l y m o r p h o n u c l e a r a n d p l a s m a cell infil t r a t i o n in the v e s s e l w a l l s a s w e l l a s o c c a s i o n a l g r a n u l o m a a n d m u l t i n u c l e a t e d g i a n t c e l l s (Fig. 1). T h e h i s t o p a t h o l o g i c d i a g n o s i s w a s W e g ener's granulomatosis. Bacterial and fungal cul tures o f b i o p s y t i s s u e w e r e n e g a t i v e . After a t e n - d a y r e g i m e n o f s y s t e m i c p r e d n i sone, both the scleritis and systemic symptoms had greatly improved, and the patient was dis c h a r g e d from the h o s p i t a l . I n c r e a s e d m i c r o scopic hematuria, proteinuria, serum creatinine level, a n d b l o o d u r e a n i t r o g e n l e v e l d e v e l o p e d four w e e k s l a t e r . C y c l o p h o s p h a m i d e w a s a d d e d to the t r e a t m e n t r e g i m e n . For a s h o r t t i m e , azotemia continued to progress, and hyperkale mia d e v e l o p e d , w h i c h r e q u i r e d p e r i t o n e a l d i a l ysis. D u r i n g the e n s u i n g t w o m o n t h s , r e n a l function showed marked improvement. T h e scleritis resolved completely with c y c l o p h o s phamide and corticosteroid therapy. Case 2 A 1 4 - y e a r - o l d girl e n t e r e d t h e h o s p i t a l w i t h fever, a r t h r a l g i a s , n a s a l c o n g e s t i o n w i t h a m i l d nonproductive cough, decreased appetite, and fatigue o f t h r e e w e e k s ' d u r a t i o n . Two days b e
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fore a d m i s s i o n the p a t i e n t h a d d e v e l o p e d i r r i t a t i o n , t e a r i n g , r e d n e s s , a n d dull p a i n in b o t h eyes. O c u l a r e x a m i n a t i o n d i s c l o s e d v i s u a l a c u i t y of 2 0 / 2 0 in b o t h e y e s a s w e l l a s n o r m a l p u p i l s a n d ocular motility. Slit-lamp examination demon strated mild conjunctival injection and moder ate b i l a t e r a l s c l e r a l i n j e c t i o n a n d e d e m a s u p e r i orly in b o t h e y e s . B o t h a n t e r i o r c h a m b e r s w e r e deep and clear, and intraocular pressure and results of fundus examination were normal. Laboratory results included a Westergren erythrocyte s e d i m e n t a t i o n rate of 3 7 m m / h o u r , a p o s i t i v e r h e u m a t o i d f a c t o r test at 1:1>280 dilution, negative antinuclear antibody test, and normal complement levels. Urinalysis demonstrated four to eight red b l o o d cells per h i g h - p o w e r field. A c h e s t x-ray d i s c l o s e d m u l t i ple b i l a t e r a l p u l m o n a r y n o d u l e s . A t u b e r c u l i n skin test w a s n e g a t i v e . T h e p a t i e n t u n d e r w e n t an o p e n - l u n g b i o p s y , which confirmed a microscopic diagnosis of W e g e n e r ' s g r a n u l o m a t o s i s (Fig. 2 ) . T h e r e w a s evidence of marked vasculitis with destruction o f the v e s s e l w a l l s . M a n y i n f l a m m a t o r y c e l l s consisting of both polymorphonuclear leuko cytes and lymphocytes with a moderäje amount of giant cells were also noted. Batterial and fungal c u l t u r e s o f the b i o p s y s p e c i m e n w e r e negative. Treatment with oral prednisone and cyclophosphamide was initiated, with resolu t i o n o f s y s t e m i c s y m p t o m s a n d s c l e r i t i s after s e v e n days.
Discussion W e g e n e r ' s g r a n u l o m a t o s i s is a d i s e a s e m a i n l y of a d u l t s , w i t h the a v e r a g e a g e o f o n s e t in the f o u r t h t o fifth d e c a d e s o f life a n d r e l a t i v e l y rare o c c u r r e n c e in 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 16 years. The recorded frequency of ocular i n v o l v e m e n t in W e g e n e r ' s g r a n u l o m a t o s i s h a s r a n g e d from 2 9 % to 4 8 % . " T h e anterior s e g m e n t is c o m m o n l y the site o f focal ocular in v o l v e m e n t , w i t h t h e s c l e r a a n d e p i s c l e r a in v o l v e d in up to 3 8 % o f c a s e s . ' . C o f i t i g u o u s i n v o l v e m e n t o f t h e o r b i t is a l s o c o m m o n l y n o t ed.^' Scleritis associated with Wegener's granu lomatosis can be devastating, with subsequent blindness despite aggressive t h e r a p y . ' " In 1 9 8 5 , Parelhoff, C h a v i s , a n d F r i e n d l y " r e v i e w e d t h e l i t e r a t u r e a n d f o u n d ofily 2 1 w e l l documented cases of Wegener's granulomatosis in c h i l d r e n u n d e r 1 6 y e a r s o f a g e , o f w h o m
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Fig. 1 (Sacks and associates). Case 1. Maxillary mucosa biopsy specimen. Left, Subepithelial zone is thickened by perivascular chronic inflammatory cell infiltrate and an area of necrosis (hematoxylin and eosin, x 100). Right, Chronic inflammatory cells surround a central histiocytic focus containing a multinucleated giant cell (hematoxylin and eosin, x 450). e i g h t h a d o c u l a r or o r b i t a l s i g n s , b u t n o n e h a d s c l e r i t i s . A s u b s e q u e n t r e p o r t d e s c r i b e d four c h i l d r e n u n d e r a g e 14 y e a r s w i t h W e g e n e r ' s g r a n u l o m a t o s i s ; two h a d c o n j u n c t i v i t i s as t h e o n l y o c u l a r m a n i f e s t a t i o n . ' ^ In 1 9 8 6 , H a l s t e a d , K a r m o d y , a n d Wolff'^ d e s c r i b e d 5 0 p a t i e n t s with W e g e n e r ' s g r a n u l o m a t o s i s , i n c l u d i n g four p a t i e n t s y o u n g e r t h a n 1 6 y e a r s o f a g e . O n e of t h e i r p a t i e n t s h a d a c o r n e a l u l c e r as t h e i n i t i a l symptom. Mohanlal and associates'^ described an 1 1 - y e a r - o l d girl w i t h W e g e n e r ' s g r a n u l o m a t o s i s b u t w i t h o u t o c u l a r i n v o l v e m e n t . In c o n trast to p r e v i o u s r e p o r t s , b o t h o f our p a t i e n t s
h a d s c l e r i t i s as o n e o f t h e i n i t i a l m a n i f e s t a t i o n s o f the u n d e r l y i n g s y s t e m i c p r o c e s s . T h e a v e r a g e a g e o f o n s e t o f s c l e r i t i s at o n e r e f e r r a l c e n t e r w a s 4 6 . 6 years.'* W a t s o n a n d Hayreh"^ r e p o r t e d a p e a k i n c i d e n c e in t h e fourth d e c a d e in m e n a n d t w o p e a k s in w o m e n : o n e in t h e third d e c a d e a n d o n e in t h e s i x t h decade. S c l e r i t i s is t h e r e s u l t o f g r a n u l o m a t o u s c h a n g e s o f t h e s c l e r a b e l i e v e d to b e a n i m m u n e r e s p o n s e e i t h e r w i t h i n t h e s c l e r a l t i s s u e or its v a s c u l a r s u p p l y . " ' * B e c a u s e s c l e r i t i s is u s u a l l y s e c o n d a r y to a s y s t e m i c d i s e a s e a n d t h e i n f l a m -
Fig. 2 (Sacks and associates). Case 2. Lung biopsy specimen. Left, Note aggregation of acute and chronic inflammatory cells admixed with giant cells (hematoxylin and eosin, x 225). Right, Evidence of destructive vasculitis with disruption of the elastic wall in a pulmonary artery (Weigert's elastic tissue stain with Van Giesen counterstain, x 225).
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m a t o r y c e l l s r e s p o n s i b l e for it o r i g i n a t e d i s t a n t from the e y e , t r e a t m e n t w i t h s y s t e m i c c o r t i c o s t e r o i d s or n o n c o r t i c o s t e r o i d a n t i i n f l a m m a t o r y a g e n t s are often effective. P a t i e n t s u n a b l e to t o l e r a t e c o r t i c o s t e r o i d s or u n r e s p o n s i v e b e c a u s e of the i n t e n s e n a t u r e o f t h e l o c a l g r a n u l o m a t o u s r e s p o n s e m a y b e n e f i t from c y t o t o x i c a g e n t s . T h e c o n d i t i o n in our first p a t i e n t did n o t r e s p o n d to t o p i c a l m e d i c a t i o n for s c l e r i t i s but did i m p r o v e on o r a l p r e d n i s o n e . T h e s y s temic manifestations progressed, despite treat m e n t w i t h s y s t e m i c c o r t i c o s t e r o i d s , a n d finally resolved when cyclophosphamide was added. C y c l o p h o s p h a m i d e t h e r a p y is c o n s i d e r e d t h e p r e f e r r e d drug for W e g e n e r ' s g r a n u l o m a t o s i s b e c a u s e o f its p r o v e n e f f i c a c y T h e c o n d i t i o n in our s e c o n d p a t i e n t , w h o h a d b i l a t e r a l , l e s s severe scleritis, demonstrated a rapid response to i n i t i a l c o m b i n a t i o n t r e a t m e n t w i t h c o r t i c o steroids and c y c l o p h o s p h a m i d e . T h e findings in our t w o p a t i e n t s s u g g e s t t h a t s c l e r i t i s in c h i l d r e n s h o u l d p r o m p t t h o r o u g h i n v e s t i g a t i o n for an u n d e r l y i n g s y s t e m i c d i s o r der. T r e a t m e n t w i t h s y s t e m i c c o r t i c o s t e r o i d s a n d p o s s i b l y i m m u n o s u p p r e s s i v e d r u g s is l i k e ly to b e n e c e s s a r y . W i t h e a r l y i n i t i a t i o n o f a p p r o p r i a t e t h e r a p y , t h e p r o g n o s i s for s c l e r i t i s a s s o c i a t e d w i t h W e g e n e r ' s g r a n u l o m a t o s i s in c h i l d r e n a p p e a r s to b e g o o d .
References 1. Stock, E. L., Rich, K., and Bouchard, C : Scleritis in children. A report of three cases. Intern. Med. Specialist 8:104, 1987. 2. Berger, Β., and Reeser, F.: Retinal pigment epi thelial detachments in posterior scleritis. Am. J. Oph thalmol. 90:604, 1980. 3. Hayreh, S. S., and Watson, P. G.: Prednisolone21-stearoylglycolate in scleritis. Br. J. Ophthalmol. 54:394, 1 9 7 0 . 4. Carrington, C. B., and Liebow, A. Α.: Limited forms of angiitis and granulomatosis of Wegener's type. Am. J. Med. 41:497, 1 9 6 6 . 5. Straatsma, B. R.: Ocular manifestations of Weg ener's granulomatosis. Am. J. Ophthalmol. 44:789, 1957. 6. Haynes, B. F., Fishman, M. L., Fauci, A. S., and Wolff, S. M.: The ocular manifestations of Wegener's
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granulomatosis. Fifteen years' experience and review of the literature. Am. J. Med. 6 3 : 1 3 1 , 1977. 7. Bullen, C. L., Liesegang, T. J . , McDonald, T. J . , and DeRemee, R. Α.: Ocular complications of Weg ener's granulomatosis. Ophthalmology 90:279, 1983. 8. Hodges, E. J . , Turner, S., and Doud, R. B.: Re fractory scleritis due to Wegener's granulomatosis. West. J. Med. 146:361, 1987. 9. Brubaker, R., Font, R. L., and Shepherd, E. M.: Granulomatous sclerouveitis. Regression of ocular lesions with cyclophosphamide and prednisone. Arch. Ophthalmol. 86:517, 1 9 7 1 . 10. Vogiatzis, K. v.: Bilateral blindness due to nec rotizing scleritis in a case of Wegener's granulomato sis. Ann. Ophthalmol. 15:185, 1 9 8 3 . 11. Parelhoff, E. S., Chavis, R. M., and Friendly, D. S.: Wegener's granulomatosis presenting as orbit al pseudotumor in children. J. Pediatr. Ophthalmol. Strabismus 22:100, 1 9 8 5 . 12. Hall, S. L., Miller, L. C., Duggan, E., Mauer, S. Μ., Beatty, Ε. C., and Hellerstein, S.: Wegener's granulomatosis in pediatric patients. J. Pediatr. 106:739, 1985. 13. Halstead, L. Α., Karmody, C. S., and Wolff, S. M.: Presentation of Wegener's granulomatosis in young patients. Otolaryngol. Head Neck Surg. 94:368, 1986. 14. M o h a n l a l D., Meyers, K. E. C., Van Niekerk, I., and Richards, G. Α.: Wegener's granulomatosis in an 11 year old chUd. S. Afr. Med. J. 73:608, 1 9 8 8 . 15. Lachman, S. M., Hazleman, B. L., and Watson, P. G.: Scleritis and associated disease. Br. Med. J. 1:88, 1 9 7 8 . 16. Watson, P. G., and Hayreh, S. S.: Scleritis and episcleritis. Br. J. Ophthalmol. 6 0 : 1 6 3 , 1 9 8 0 . 17. Watson, P. G.: The diagnosis and management of scleritis. Ophthalmology 87:716, 1 9 8 0 . 18. Rao, N. Α., Marak, G. E., and Hidayat, A. Α.: Necrotizing scleritis. A clinicopathologic study of 41 cases. Ophthalmology 9 2 : 1 5 4 2 , 1 9 8 5 . 19. JampoL L. M., West, C., and Goldberg, M. F.: Therapy of scleritis with cytotoxic agents. Am. J. Ophthalmol. 86:266, 1 9 7 8 . 20. Foster, C. S.: Immunosuppressive therapy for external ocular inflammatory disease. Ophthalmolo gy 87:140, 1 9 8 0 . 2 1 . Fauci, A. S., and Wolfe, S. M.: Wegener's gran ulomatosis. Studies in 18 patients and a review of the literature. Medicine 5 2 : 5 3 5 , 1 9 7 3 . 22. Wolff, S. M., Fauci, A. S., and Horn, R. G.: Wegener's granulomatosis. Ann. Intern. Med. 81:513, 1974. 23. Novack, S. N., and Pearson, C. M.: Cyclophos phamide therapy in Wegener's granulomatosis. N. Engl. J. Med. 2 8 4 : 9 3 8 , 1 9 7 1 .
Robert D. Sacks, M.D., E. Lee Stock, M.D., Susan E. Crawford, M . D . , Mark J. Greenwald, M.D., and Richard B, O'Grady, M . D .
We t r e a t e d t w o c h i l d r e n w i t h s c l e r i t i s ( o n e unilateral, one bilateral), in w h o m Wegener's g r a n u l o m a t o s i s w a s d i a g n o s e d o n t h e b a s i s of p a t h o l o g i c c h a n g e s in respiratory tract m u c o sa. B o t h p a t i e n t s w e r e g i r l s , 13 a n d 1 4 y e a r s o f age, respectively. O n e patient had otitis media and a nodular scleritis. Laboratory test results demonstrated an increased erythrocyte sedi mentation rate and microscopic hematuria. A biopsy of the sinus confirmed t h e diagnosis of Wegener's granulomatosis. T h e second pa tient h a d fever, a r t h r a l g i a s , a n o n p r o d u c t i v e cough, and bilateral scleritis. Laboratory test results demonstrated an increased erythro cyte sedimentation rate, positive test results for r h e u m a t o i d f a c t o r , a n d b i l a t e r a l p u l m o nary nodules on chest x-ray. Open-lung biop sy c o n f i r m e d t h e d i a g n o s i s o f W e g e n e r ' s g r a n ulomatosis. B o t h p a t i e n t s r e s p o n d e d well to t r e a t m e n t w i t h ?i c o m b i n a t i o n o f p r e d n i s o n e and cyclophosphamide.
S C L E R I T I S o c c u r s r a r e l y in c h i l d r e n . A few p e d i a t r i c c a s e s h a v e p r e v i o u s l y b e e n r e p o r t e d , " for w h i c h n o definitive e t i o l o g i c o r i g i n w a s e s t a b lished. W e g e n e r ' s g r a n u l o m a t o s i s is a m u l t i s y s t e m disease, primarily of aduíts, which consists of upper and lower respiratory tract necrotizing granulomas and vasculitis,'yaried degrees of g e n e r a l i z e d s m a l l v e s s e l v a s c u l i t i s , a n d a focal necrotizing glomerulonephritis. A limited form of the d i s e a s e w i t h o u t r e n a l i n v o l v e m e n t h a s a
Accepted for publication Dec. 28, 1990. From tlie Department of Ophthalmology, Northwest ern University Medical School, and Lakeside Veteran's Administration, Chicago, Illinois (Drs. Sacks, Stock, and O'Grady); and Department of Pathology (Dr. Crawford) and Division of Ophthalmology (Dr. Greenwald), Chil dren's Memorial Hospital, Chicago, Illinois. This study, was supported in part by an unrestricted grant from Research to Prevent Blindness, Inc. Reprint requests to E. Lee Stock, M.D., 303 E. Chicago Ave., Department of Ophthalmology, Northwestern University Medical School, Chicago, IL 60611.
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b e t t e r p r o g n o s i s . ' ' We t r e a t e d t w o c h i l d r e n in w h o m scleritis was the initial manifestation of Wegener's granulomatosis.
Case Reports Case 1 A 1 3 - y e a r - o l d girl e n t e r e d t h e h o s p i t a l for treatment of otitis and scleritis. T h e patient h a d recurrent otitis media treated with bilateral myringotomy o n e year before admission. Five weeks earlier, she had developed arthralgias, decreased appetite with mild weight loss, and fatigability. Recurrent otitis media one week later necessitated insertion o f an ear tube and t r e a t m e n t w i t h o r a l c e f a c l o r a n t i b i o t i c . Ten days before admission, the patient developed a white spot on the right c o r n e a , which was d i a g n o s e d as b a c t e r i a l k e r a t i t i s b y a n o p h t h a l mologist and treated with topical tobramycin e y e d r o p s . T h e c o n d i t i o n a l m o s t r e s o l v e d after four days, but t h e n t h e r i g h t e y e b e c a m e r e d a n d painful. T h e o p h t h a l m o l o g i s t then prescribed gentamicin sulfate eyedrops, bacitracin oph t h a l m i c o i n t m e n t , a n d o r a l p e n i c i l l i n . F o u r days before admission, the pain increased, and pho tophobia and blurred vision developed. The patient was admitted to Children's M e m o r i a l H o s p i t a l for fever a n d l e t h a r g y in a d d i t i o n to the ocular complaints. I n i t i a l findings i n c l u d e d v i s u a l a c u i t y o f R . E . : 2 0 / 3 0 and L.E.: 2 0 / 2 0 . Results of examination of the pupils were normal, and ocular m o v e m e n t s w e r e full. T h e r e w a s m i l d r i g h t u p p e r eyelid blepharoptosis with e d e m a . Slit-lamp examination demonstrated conjunctival injec tion superiorly with prominent scleral vessels and scleral edema. A 3 x 4-mm scleral nodule was noted superiorly with adjacent small, dis crete, limbal infiltrates. T h e r e was no associat ed c o r n e a l t h i n n i n g . T h e a n t e r i o r c h a m b e r w a s clear, and intraocular pressure and results of a fundus e x a m i n a t i o n w e r e n o r m a l . T h e girl a p p e a r e d c h r o n i c a l l y i l l . Y e l l o w w h i t e d i s c h a r g e d r a i n e d from t h e r i g h t e y e , a n d
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the t y m p a n i c m e m b r a n e was i n f l a m e d . B i l a t e r a l ear t u b e s w e r e in p l a c e . R e s u l t s o f t h e r e m a i n der o f the p h y s i c a l e x a m i n a t i o n w e r e n o r m a l . Initial laboratory testing included n o r m a l re s u l t s o f a c o m p l e t e b l o o d cell c o u n t , e l e c t r o l y t e level, and creatinine level. Urinalysis d e m o n s t r a t e d m i c r o s c o p i c h e m a t u r i a (four to five r e d b l o o d c e l l s p e r h i g h - p o w e r field). W e s t e r g r e n erythrocyte sedimentation rate was 41 m m / h o u r ( n o r m a l , 0 to 2 0 m m / h o u r ) . R h e u m a t o i d factor, a n t i n u c l e a r a n t i b o d y , a n d c o m p l e m e n t levels were normal. Results of a chest x-ray were normal. Computed tomography disclosed probable right mastoiditis. Initial treatment consisted of intravenous g e n t a m i c i n sulfate a n d t o p i c a l 1% o c u l a r p r e d nisolone acetate, which produced minimal im p r o v e m e n t in b o t h t h e o c u l a r c o n d i t i o n a n d otalgia after 4 8 h o u r s . R e s u l t s o f a c u l t u r e o f the c o r n e a w e r e n e g a t i v e , b u t c u l t u r e o f fluid d r a i n ing from the right e a r g r e w Achromobacter xylosoxidans. T h e regimen was c h a n g e d to oral trimethoprim/sulfamethoxazole and predni s o n e , w h i c h r e s u l t e d in o c u l a r a n d s y s t e m i c improvement within 3 6 hours. B a s e d on c l i n i c a l findings, b i o p s y s p e c i m e n s of the m i d d l e ear, m a x i l l a r y s i n u s m u c o s a , s u b g l o t t i c m u c o s a , a n d b o n e from t h e m a x i l l a r y sinus w e r e o b t a i n e d . O n l y the m a x i l l a r y m u c o sa w a s a b n o r m a l . T h e r e vyas m a r k e d v a s c u l i t i s w i t h p o l y m o r p h o n u c l e a r a n d p l a s m a cell infil t r a t i o n in the v e s s e l w a l l s a s w e l l a s o c c a s i o n a l g r a n u l o m a a n d m u l t i n u c l e a t e d g i a n t c e l l s (Fig. 1). T h e h i s t o p a t h o l o g i c d i a g n o s i s w a s W e g ener's granulomatosis. Bacterial and fungal cul tures o f b i o p s y t i s s u e w e r e n e g a t i v e . After a t e n - d a y r e g i m e n o f s y s t e m i c p r e d n i sone, both the scleritis and systemic symptoms had greatly improved, and the patient was dis c h a r g e d from the h o s p i t a l . I n c r e a s e d m i c r o scopic hematuria, proteinuria, serum creatinine level, a n d b l o o d u r e a n i t r o g e n l e v e l d e v e l o p e d four w e e k s l a t e r . C y c l o p h o s p h a m i d e w a s a d d e d to the t r e a t m e n t r e g i m e n . For a s h o r t t i m e , azotemia continued to progress, and hyperkale mia d e v e l o p e d , w h i c h r e q u i r e d p e r i t o n e a l d i a l ysis. D u r i n g the e n s u i n g t w o m o n t h s , r e n a l function showed marked improvement. T h e scleritis resolved completely with c y c l o p h o s phamide and corticosteroid therapy. Case 2 A 1 4 - y e a r - o l d girl e n t e r e d t h e h o s p i t a l w i t h fever, a r t h r a l g i a s , n a s a l c o n g e s t i o n w i t h a m i l d nonproductive cough, decreased appetite, and fatigue o f t h r e e w e e k s ' d u r a t i o n . Two days b e
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fore a d m i s s i o n the p a t i e n t h a d d e v e l o p e d i r r i t a t i o n , t e a r i n g , r e d n e s s , a n d dull p a i n in b o t h eyes. O c u l a r e x a m i n a t i o n d i s c l o s e d v i s u a l a c u i t y of 2 0 / 2 0 in b o t h e y e s a s w e l l a s n o r m a l p u p i l s a n d ocular motility. Slit-lamp examination demon strated mild conjunctival injection and moder ate b i l a t e r a l s c l e r a l i n j e c t i o n a n d e d e m a s u p e r i orly in b o t h e y e s . B o t h a n t e r i o r c h a m b e r s w e r e deep and clear, and intraocular pressure and results of fundus examination were normal. Laboratory results included a Westergren erythrocyte s e d i m e n t a t i o n rate of 3 7 m m / h o u r , a p o s i t i v e r h e u m a t o i d f a c t o r test at 1:1>280 dilution, negative antinuclear antibody test, and normal complement levels. Urinalysis demonstrated four to eight red b l o o d cells per h i g h - p o w e r field. A c h e s t x-ray d i s c l o s e d m u l t i ple b i l a t e r a l p u l m o n a r y n o d u l e s . A t u b e r c u l i n skin test w a s n e g a t i v e . T h e p a t i e n t u n d e r w e n t an o p e n - l u n g b i o p s y , which confirmed a microscopic diagnosis of W e g e n e r ' s g r a n u l o m a t o s i s (Fig. 2 ) . T h e r e w a s evidence of marked vasculitis with destruction o f the v e s s e l w a l l s . M a n y i n f l a m m a t o r y c e l l s consisting of both polymorphonuclear leuko cytes and lymphocytes with a moderäje amount of giant cells were also noted. Batterial and fungal c u l t u r e s o f the b i o p s y s p e c i m e n w e r e negative. Treatment with oral prednisone and cyclophosphamide was initiated, with resolu t i o n o f s y s t e m i c s y m p t o m s a n d s c l e r i t i s after s e v e n days.
Discussion W e g e n e r ' s g r a n u l o m a t o s i s is a d i s e a s e m a i n l y of a d u l t s , w i t h the a v e r a g e a g e o f o n s e t in the f o u r t h t o fifth d e c a d e s o f life a n d r e l a t i v e l y rare o c c u r r e n c e in 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 16 years. The recorded frequency of ocular i n v o l v e m e n t in W e g e n e r ' s g r a n u l o m a t o s i s h a s r a n g e d from 2 9 % to 4 8 % . " T h e anterior s e g m e n t is c o m m o n l y the site o f focal ocular in v o l v e m e n t , w i t h t h e s c l e r a a n d e p i s c l e r a in v o l v e d in up to 3 8 % o f c a s e s . ' . C o f i t i g u o u s i n v o l v e m e n t o f t h e o r b i t is a l s o c o m m o n l y n o t ed.^' Scleritis associated with Wegener's granu lomatosis can be devastating, with subsequent blindness despite aggressive t h e r a p y . ' " In 1 9 8 5 , Parelhoff, C h a v i s , a n d F r i e n d l y " r e v i e w e d t h e l i t e r a t u r e a n d f o u n d ofily 2 1 w e l l documented cases of Wegener's granulomatosis in c h i l d r e n u n d e r 1 6 y e a r s o f a g e , o f w h o m
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Fig. 1 (Sacks and associates). Case 1. Maxillary mucosa biopsy specimen. Left, Subepithelial zone is thickened by perivascular chronic inflammatory cell infiltrate and an area of necrosis (hematoxylin and eosin, x 100). Right, Chronic inflammatory cells surround a central histiocytic focus containing a multinucleated giant cell (hematoxylin and eosin, x 450). e i g h t h a d o c u l a r or o r b i t a l s i g n s , b u t n o n e h a d s c l e r i t i s . A s u b s e q u e n t r e p o r t d e s c r i b e d four c h i l d r e n u n d e r a g e 14 y e a r s w i t h W e g e n e r ' s g r a n u l o m a t o s i s ; two h a d c o n j u n c t i v i t i s as t h e o n l y o c u l a r m a n i f e s t a t i o n . ' ^ In 1 9 8 6 , H a l s t e a d , K a r m o d y , a n d Wolff'^ d e s c r i b e d 5 0 p a t i e n t s with W e g e n e r ' s g r a n u l o m a t o s i s , i n c l u d i n g four p a t i e n t s y o u n g e r t h a n 1 6 y e a r s o f a g e . O n e of t h e i r p a t i e n t s h a d a c o r n e a l u l c e r as t h e i n i t i a l symptom. Mohanlal and associates'^ described an 1 1 - y e a r - o l d girl w i t h W e g e n e r ' s g r a n u l o m a t o s i s b u t w i t h o u t o c u l a r i n v o l v e m e n t . In c o n trast to p r e v i o u s r e p o r t s , b o t h o f our p a t i e n t s
h a d s c l e r i t i s as o n e o f t h e i n i t i a l m a n i f e s t a t i o n s o f the u n d e r l y i n g s y s t e m i c p r o c e s s . T h e a v e r a g e a g e o f o n s e t o f s c l e r i t i s at o n e r e f e r r a l c e n t e r w a s 4 6 . 6 years.'* W a t s o n a n d Hayreh"^ r e p o r t e d a p e a k i n c i d e n c e in t h e fourth d e c a d e in m e n a n d t w o p e a k s in w o m e n : o n e in t h e third d e c a d e a n d o n e in t h e s i x t h decade. S c l e r i t i s is t h e r e s u l t o f g r a n u l o m a t o u s c h a n g e s o f t h e s c l e r a b e l i e v e d to b e a n i m m u n e r e s p o n s e e i t h e r w i t h i n t h e s c l e r a l t i s s u e or its v a s c u l a r s u p p l y . " ' * B e c a u s e s c l e r i t i s is u s u a l l y s e c o n d a r y to a s y s t e m i c d i s e a s e a n d t h e i n f l a m -
Fig. 2 (Sacks and associates). Case 2. Lung biopsy specimen. Left, Note aggregation of acute and chronic inflammatory cells admixed with giant cells (hematoxylin and eosin, x 225). Right, Evidence of destructive vasculitis with disruption of the elastic wall in a pulmonary artery (Weigert's elastic tissue stain with Van Giesen counterstain, x 225).
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m a t o r y c e l l s r e s p o n s i b l e for it o r i g i n a t e d i s t a n t from the e y e , t r e a t m e n t w i t h s y s t e m i c c o r t i c o s t e r o i d s or n o n c o r t i c o s t e r o i d a n t i i n f l a m m a t o r y a g e n t s are often effective. P a t i e n t s u n a b l e to t o l e r a t e c o r t i c o s t e r o i d s or u n r e s p o n s i v e b e c a u s e of the i n t e n s e n a t u r e o f t h e l o c a l g r a n u l o m a t o u s r e s p o n s e m a y b e n e f i t from c y t o t o x i c a g e n t s . T h e c o n d i t i o n in our first p a t i e n t did n o t r e s p o n d to t o p i c a l m e d i c a t i o n for s c l e r i t i s but did i m p r o v e on o r a l p r e d n i s o n e . T h e s y s temic manifestations progressed, despite treat m e n t w i t h s y s t e m i c c o r t i c o s t e r o i d s , a n d finally resolved when cyclophosphamide was added. C y c l o p h o s p h a m i d e t h e r a p y is c o n s i d e r e d t h e p r e f e r r e d drug for W e g e n e r ' s g r a n u l o m a t o s i s b e c a u s e o f its p r o v e n e f f i c a c y T h e c o n d i t i o n in our s e c o n d p a t i e n t , w h o h a d b i l a t e r a l , l e s s severe scleritis, demonstrated a rapid response to i n i t i a l c o m b i n a t i o n t r e a t m e n t w i t h c o r t i c o steroids and c y c l o p h o s p h a m i d e . T h e findings in our t w o p a t i e n t s s u g g e s t t h a t s c l e r i t i s in c h i l d r e n s h o u l d p r o m p t t h o r o u g h i n v e s t i g a t i o n for an u n d e r l y i n g s y s t e m i c d i s o r der. T r e a t m e n t w i t h s y s t e m i c c o r t i c o s t e r o i d s a n d p o s s i b l y i m m u n o s u p p r e s s i v e d r u g s is l i k e ly to b e n e c e s s a r y . W i t h e a r l y i n i t i a t i o n o f a p p r o p r i a t e t h e r a p y , t h e p r o g n o s i s for s c l e r i t i s a s s o c i a t e d w i t h W e g e n e r ' s g r a n u l o m a t o s i s in c h i l d r e n a p p e a r s to b e g o o d .
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granulomatosis. Fifteen years' experience and review of the literature. Am. J. Med. 6 3 : 1 3 1 , 1977. 7. Bullen, C. L., Liesegang, T. J . , McDonald, T. J . , and DeRemee, R. Α.: Ocular complications of Weg ener's granulomatosis. Ophthalmology 90:279, 1983. 8. Hodges, E. J . , Turner, S., and Doud, R. B.: Re fractory scleritis due to Wegener's granulomatosis. West. J. Med. 146:361, 1987. 9. Brubaker, R., Font, R. L., and Shepherd, E. M.: Granulomatous sclerouveitis. Regression of ocular lesions with cyclophosphamide and prednisone. Arch. Ophthalmol. 86:517, 1 9 7 1 . 10. Vogiatzis, K. v.: Bilateral blindness due to nec rotizing scleritis in a case of Wegener's granulomato sis. Ann. Ophthalmol. 15:185, 1 9 8 3 . 11. Parelhoff, E. S., Chavis, R. M., and Friendly, D. S.: Wegener's granulomatosis presenting as orbit al pseudotumor in children. J. Pediatr. Ophthalmol. Strabismus 22:100, 1 9 8 5 . 12. Hall, S. L., Miller, L. C., Duggan, E., Mauer, S. Μ., Beatty, Ε. C., and Hellerstein, S.: Wegener's granulomatosis in pediatric patients. J. Pediatr. 106:739, 1985. 13. Halstead, L. Α., Karmody, C. S., and Wolff, S. M.: Presentation of Wegener's granulomatosis in young patients. Otolaryngol. Head Neck Surg. 94:368, 1986. 14. M o h a n l a l D., Meyers, K. E. C., Van Niekerk, I., and Richards, G. Α.: Wegener's granulomatosis in an 11 year old chUd. S. Afr. Med. J. 73:608, 1 9 8 8 . 15. Lachman, S. M., Hazleman, B. L., and Watson, P. G.: Scleritis and associated disease. Br. Med. J. 1:88, 1 9 7 8 . 16. Watson, P. G., and Hayreh, S. S.: Scleritis and episcleritis. Br. J. Ophthalmol. 6 0 : 1 6 3 , 1 9 8 0 . 17. Watson, P. G.: The diagnosis and management of scleritis. Ophthalmology 87:716, 1 9 8 0 . 18. Rao, N. Α., Marak, G. E., and Hidayat, A. Α.: Necrotizing scleritis. A clinicopathologic study of 41 cases. Ophthalmology 9 2 : 1 5 4 2 , 1 9 8 5 . 19. JampoL L. M., West, C., and Goldberg, M. F.: Therapy of scleritis with cytotoxic agents. Am. J. Ophthalmol. 86:266, 1 9 7 8 . 20. Foster, C. S.: Immunosuppressive therapy for external ocular inflammatory disease. Ophthalmolo gy 87:140, 1 9 8 0 . 2 1 . Fauci, A. S., and Wolfe, S. M.: Wegener's gran ulomatosis. Studies in 18 patients and a review of the literature. Medicine 5 2 : 5 3 5 , 1 9 7 3 . 22. Wolff, S. M., Fauci, A. S., and Horn, R. G.: Wegener's granulomatosis. Ann. Intern. Med. 81:513, 1974. 23. Novack, S. N., and Pearson, C. M.: Cyclophos phamide therapy in Wegener's granulomatosis. N. Engl. J. Med. 2 8 4 : 9 3 8 , 1 9 7 1 .
