Current Practices in the Management of Ocular Toxoplasmosis

Robert E. Engstrom, Jr., M.D., Gary N . Holland, M . D . , Robert B. Nussenblatt, M.D., and Douglas A. Jabs, M . D .

To d e t e r m i n e c u r r e n t p r a c t i c e s i n t h e m a n ­ a g e m e n t of o c u l a r t o x o p l a s m o s i s , 7 2 of 8 5 u v e i t i s s p e c i a l i s t s (85%) i n t h e A m e r i c a n U v e ­ itis Society c o m p l e t e d a detailed q u e s t i o n ­ n a i r e . Q u e s t i o n s i n v o l v e d t h e i n d i c a t i o n s for beginning t r e a t m e n t , c h o i c e of a n t i p a r a s i t i c / antimicrobial agents, and experience with t r e a t m e n t o f o c u l a r t o x o p l a s m o s i s in s p e c i a l situations including pregnancy, neonatal in­ fections, and i m m u n o c o m p r o m i s e d patients. M o s t of t h e r e s p o n d e n t s t r e a t p a t i e n t s w h o s e v i s u a l acuity h a d d e c r e a s e d to w o r s e t h a n 2 0 / 2 0 0 , l e s i o n s l o c a t e d in t h e p e r i p a p i l ­ lary, perifoveal, or maculopapillary bundle regions, and lesions associated with severe vitreous inflammation. Most would not treat patients w h o r e t a i n e d visual a c u i t y of 2 0 / 2 0 , l e s i o n s l o c a t e d in t h e f a r p e r i p h e r a l r e t i n a , o r lesions associated with only trace to mild vitreous inflammation. Treatment of other c o m b i n a t i o n s of f a c t o r s r e m a i n s c o n t r o v e r ­ sial. E i g h t different a n t i m i c r o b i a l d r u g s a r e u s e d in v a r i o u s c o m b i n a t i o n s for l e s i o n s t h r e a t e n ­ ing t h e m a c u l a o r o p t i c n e r v e h e a d . S y s t e m i c corticosteroids are used by 59 of 62 r e s p o n ­ d e n t s (95%) a s p a r t o f t h e i r i n i t i a l t r e a t m e n t regimen. The most commonly used regimens

Accepted for publication Jan. 3 0 , 1 9 9 1 . From the UCLA Ocular Inflammatory Disease Center, Jules Stein Eye Institute, and Department of Ophthal­ mology, UCLA School of Medicine, Los Angeles, Cali­ fornia (Drs. Engstrom and Holland); National Eye Insti­ tute, National Institutes of Health, Bethesda, Maryland (Dr. Nussenblatt); and Wilmer Ophthalmological Insti­ tute, Johns Hopkins University and Hospital, Baltimore, Maryland (Dr. Jabs). This study was a project of the Education and Research Committee, American Uveitis Society. This study was supported in part by Research to Prevent Blindness, Inc. (Dr. Holland). Reprint requests to Gary N. Holland, M.D., Jules Stein Eye Institute, 1 0 0 Stein Plaza, UCLA, Los Angeles, CA 90024-7003.

are p y r i m e t h a m i n e / s u l f a d i a z i n e / c o r t i c o s t e ­ r o i d s (20 o f 62 [32%]) a n d p y r i m e t h a m i n e / s u l f a d i a z i n e / c l i n d a m y c i n / c o r t i c o s t e r o i d s (17 of 62 [ 2 7 % ] ) . A d j u n c t i v e t h e r a p i e s ( p h o t o c o a g ­ ulation, cryotherapy, or vitrectomy) have been used by 20 of 60 r e s p o n d e n t s (33%). Most alter t r e a t m e n t d u r i n g p r e g n a n c y , in n e w b o r n p a ­ tients, and in patients with the acquired im­ munodeficiency syndrome.

T O X O P L A S M A G O N D I I is t h e m o s t c o m m o n c a u s e of i n f e c t i o u s r e t i n o c h o r o i d i t i s in o t h e r w i s e healthy individuals.' A l t h o u g h the c o m b i n a ­ tion of p y r i m e t h a m i n e and sulfadiazine has b e e n r e c o m m e n d e d for m a n y y e a r s a s a t r e a t ­ m e n t for o c u l a r t o x o p l a s m o s i s , ^ ' ' t h e few p r o ­ spective, randomized clinical studies designed to a s s e s s t h e e f f e c t i v e n e s s o f this c o m b i n a t i o n h a v e p r o v i d e d c o n f l i c t i n g results.** A n u m b e r o f o t h e r d r u g s h a v e d e m o n s t r a t e d in v i t r o a n d in vivo efficacy a g a i n s t T. gondii, b u t t h e i r r o l e in t h e t r e a t m e n t o f h u m a n o c u l a r t o x o p l a s m o s i s r e m a i n s u n c e r t a i n . T h e b e s t t r e a t m e n t for p a ­ t i e n t s w i t h o c u l a r t o x o p l a s m o s i s in s p e c i a l cir­ c u m s t a n c e s , s u c h as t h e i m m u n o c o m p r o m i s e d p a t i e n t or t h e p r e g n a n t p a t i e n t , r e m a i n s e v e n l e s s c l e a r l y defined. N o n m e d i c a l t h e r a p i e s , in­ cluding laser photocoagulation,'* cryotherapy,' or v i t r e c t o m y , ' " h a v e a l s o b e e n r e c o m m e n d e d b y s o m e for t h e t r e a t m e n t o f a c u t e l e s i o n s . To g a i n a b e t t e r u n d e r s t a n d i n g o f c u r r e n t t r e a t m e n t p r a c t i c e s for o c u l a r t o x o p l a s m o s i s , a d e t a i l e d q u e s t i o n n a i r e w a s s e n t to p h y s i c i a n members of the American Uveitis Society. The Society comprises physicians and other vision s c i e n t i s t s w i t h a s p e c i a l i n t e r e s t in o c u l a r in­ flammation. For m e m b e r s h i p in t h e A m e r i c a n Uveitis Society, ophthalmologists must have h a d f e l l o w s h i p t r a i n i n g in u v e i t i s or h a v e b e e n in p r a c t i c e for at l e a s t t h r e e y e a r s after r e s i d e n ­ cy training, with 2 5 % of their patient-care time s p e n t in t h e t r e a t m e n t o f p a t i e n t s w i t h i n t r a o c ­ ular inflammation.

©AMERICAN JOURNAL OF OPHTFIALMOLOGY 1 1 1 : 6 0 1 - 6 1 0 , MAY, 1 9 9 1

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The questionnaire addressed three major cat­ egories of toxoplasmosis management: indica­ t i o n s for b e g i n n i n g t r e a t m e n t ; m a n a g e m e n t p r a c t i c e s for t y p i c a l p a t i e n t s ( t h a t is, i m m u n o ­ c o m p e t e n t a d u l t m a l e or n o n p r e g n a n t f e m a l e p a t i e n t s with a r e c u r r e n t , v i s i o n - t h r e a t e n i n g m a c u l a r l e s i o n a n d a d e c r e a s e in v i s i o n b u t w i t h o u t foveal d e s t r u c t i o n a n d t h e r e f o r e g o o d p o t e n t i a l for full v i s u a l r e c o v e r y w i t h s u c c e s s ­ ful t h e r a p y ) ; a n d m a n a g e m e n t o f a c t i v e d i s e a s e in p r e g n a n t , n e w b o r n , or i m m u n o c o m p r o m i s e d patients.

Material and Methods M e m b e r s w e r e a s k e d to e s t i m a t e t h e n u m b e r of patients with active ocular toxoplasmosis w h o m they e x a m i n e each year. If the n u m b e r of p a t i e n t s s e e n w a s p r o v i d e d as a r a n g e , t h e m e a n o f t h e u p p e r a n d l o w e r v a l u e s w a s u s e d to estimate the number of patients seen each year b y that r e s p o n d e n t . O n l y t h o s e m e m b e r s w h o have treated patients with ocular toxoplasmosis w e r e a s k e d to c o m p l e t e t h e q u e s t i o n n a i r e . M e m b e r s w e r e a s k e d w h e t h e r t h e y t r e a t e d all c a s e s o f t y p i c a l o c u l a r t o x o p l a s m o s i s as d e f i n e d r e g a r d l e s s o f t h e o c u l a r findings. I f m e m b e r s did n o t treat e v e r y c a s e , t h e y w e r e a s k e d to i d e n t i f y factors t h a t m i g h t i n f l u e n c e t h e i r d e c i ­ s i o n to treat in five c a t e g o r i e s : c h a n g e s in v i s u a l acuity; lesion location; lesion size; the type of lesion; and the amount of associated vitreous inflammatory reaction. They were then asked w h e t h e r that factor w a s an a b s o l u t e i n d i c a t i o n ( w o u l d always treat w h e n t h e f a c t o r w a s p r e s ­ ent), a relative indication (would be more likely t o t r e a t w h e n t h e factor w a s p r e s e n t b u t w o u l d n o t treat b a s e d o n the f a c t o r a l o n e ) , a r e l a t i v e c o n t r a i n d i c a t i o n ( w o u l d b e l e s s l i k e l y to treat w h e n t h e factor w a s p r e s e n t b u t w o u l d n o t p r e v e n t b e g i n n i n g t r e a t m e n t in e v e r y c a s e ) , an a b s o l u t e c o n t r a i n d i c a t i o n ( w o u l d n e v e r treat w h e n the factor was present), or an irrelevant factor ( p r e s e n c e of f a c t o r w o u l d h a v e n o r o l e on d e c i s i o n to t r e a t ) . Specific factors w e r e p r o v i d e d for e a c h c a t e ­ g o r y c o n s i d e r e d . C h a n g e s in v i s u a l a c u i t y w e r e divided into the following: retention of 2 0 / 2 0 visual a c u i t y ; d e c r e a s e in v i s u a l a c u i t y to 2 0 / 4 0 ; a n d d e c r e a s e in v i s u a l a c u i t y to w o r s e t h a n 2 0 / 2 0 0 . L e s i o n l o c a t i o n w a s identified b y r e t i ­ nal z o n e s p r e v i o u s l y d e s c r i b e d in a s t u d y o f necrotizing retinal infections." Retinal zones and subdivisions included the following: Z o n e

May, 1991

1, c o n s i d e r e d to b e t h a t p o r t i o n o f t h e r e t i n a w h e r e i n f e c t i o n is i m m e d i a t e l y s i g h t - t h r e a t e n ­ ing a n d c o r r e s p o n d i n g to an a r e a e x t e n d i n g 3 , 0 0 0 μ m (2 disk d i a m e t e r s ) from t h e f o v e a (approximately that area e n c l o s e d by the major t e m p o r a l v a s c u l a r a r c a d e s ) or 1 , 5 0 0 μ m from the margins of the optic nerve head; Z o n e 2, e x t e n d i n g a n t e r i o r from Z o n e 1 to t h e c l i n i c a l equator of the eye, identified by the anterior b o r d e r s o f the a m p u l l a e o f t h e v o r t e x v e i n s ( t h e farthest anterior extent o f the retina that can be photographed easily); and Zone 3, extending a n t e r i o r from Z o n e 2 to t h e ora s e r r a t a . Z o n e 1 w a s further d i v i d e d i n t o p e r i p a p i l l a r y , m a c u l o papillary bundle, and perifoveal areas. Lesion s i z e w a s d i v i d e d i n t o a r e a s l e s s t h a n or e q u a l to 1 disk d i a m e t e r or g r e a t e r t h a n 1 disk d i a m e t e r . P o t e n t i a l l y i m p o r t a n t l e s i o n c h a r a c t e r i s t i c s list­ ed on the questionnaire included the following: single, recurrent satellite; multifocal; punctate outer retinal toxoplasmosis; acquired lesions; a n d l e s i o n s p e r s i s t i n g for m o r e t h a n o n e m o n t h r e g a r d l e s s o f s i z e or l o c a t i o n . V i t r e o u s r e a c t i o n w a s s c o r e d o n a s c a l e o f s e v e r i t y from t r a c e through mild, moderate, marked, and severe, b a s e d on t h e s c a l e d e s c r i b e d b y N u s s e n b l a t t and associates.'^ (These descriptive terms corre­ s p o n d to t h e i r n u m e r i c s c a l e as f o l l o w s : m i l d , l+; moderate, 2 + ; marked, 3 + ; and severe, 4-t-.) T h e m o t i v a t i o n o f r e s p o n d e n t s for c h o o s ­ ing v a r i o u s i n d i c a t i o n s w a s n o t s o l i c i t e d in t h e questionnaire. Questions regarding treatment addressed the f o l l o w i n g : p r e f e r r e d a n t i m i c r o b i a l t h e r a p y for a typical case; management of drug-related toxic­ ity; u s e o f c o r t i c o s t e r o i d s ( i n c l u d i n g t o p i c a l , periocular, and oral routes of administration); experience with investigational agents; and use of a d j u n c t i v e t h e r a p i e s , s u c h as l a s e r p h o t o c o ­ a g u l a t i o n , c r y o t h e r a p y , or v i t r e c t o m y . M e m ­ b e r s w e r e a l s o a s k e d to d e s c r i b e l e s i o n - a s s o ­ c i a t e d f a c t o r s for w h i c h t h e y w o u l d m o d i f y their standard therapeutic regimen. To d e t e r m i n e w h e t h e r m e m b e r s a l t e r t h e i r m a n a g e m e n t in s p e c i a l s i t u a t i o n s , t h e y w e r e a s k e d to d e s c r i b e h o w t h e y t r e a t p r e g n a n t p a ­ tients, neonatal patients, and immunosuppres­ sed patients with ocular toxoplamosis. With r e g a r d to p r e g n a n t p a t i e n t s , t h e y w e r e a s k e d about indications and drug therapy, whether t h e y treat a c q u i r e d m a t e r n a l d i s e a s e s p e c i f i c a l ­ ly to p r o t e c t t h e fetus, a n d if t h e y t r e a t r e c u r ­ r e n t o c u l a r d i s e a s e in t h e w o m a n to p r e s e r v e v i s i o n . M e m b e r s w e r e a s k e d to d e s c r i b e t h e ways in w h i c h t h e i r t r e a t m e n t o f n e w b o r n s w i t h a c t i v e t o x o p l a s m o s i s differed, i f at all, from t h a t

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of adult p a t i e n t s . Q u e s t i o n s p e r t a i n i n g to t h e t r e a t m e n t o f the i m m u n o c o m p r o m i s e d p a t i e n t dealt with w h e t h e r their i n d i c a t i o n s for t r e a t ­ m e n t , the d r u g s u s e d , a n d p a t i e n t f o l l o w - u p differed from t h a t for an i m m u n o c o m p e t e n t patient. For e a c h q u e s t i o n in w h i c h v a r i o u s f a c t o r s w e r e listed as r e s p o n s e s in a m u l t i p l e - c h o i c e f o r m a t (for e x a m p l e , i n d i c a t i o n s for t r e a t m e n t ) , m e m b e r s w e r e a l s o a l l o w e d to a n s w e r w i t h information other than those factors already listed.

Results Completed questionnaires were returned by 72 o f the 8 5 p h y s i c i a n m e m b e r s ( 8 5 % ) o f t h e A m e r i c a n U v e i t i s S o c i e t y . O f the r e s p o n d e n t s , ten ( 1 4 % ) s t a t e d that t h e y e i t h e r do n o t e x a m i n e p a t i e n t s or have n o t h a d p a t i e n t s with a c t i v e o c u l a r t o x o p l a s m o s i s in t h e i r p r a c t i c e s . T h e remaining 62 respondents ( 8 6 % ) reported ex­ a m i n i n g a m e d i a n o f te n p a t i e n t s w i t h o c u l a r t o x o p l a s m o s i s ( r a n g e , two to 7 5 p a t i e n t s ) p e r y e a r . T h e r e s u l t s are b a s e d o n the r e s p o n s e s o f these 62 respondents. S o m e r e s p o n d e n t s did n o t a n s w e r e v e r y q u e s ­ t i o n . N u m e r i c d a t a reflect t h e a c t u a l n u m b e r o f respondents answering any individual question a n d are r e p o r t e d as t h e n u m b e r o f r e s p o n d e n t s a n s w e r i n g y e s to a q u e s t i o n o r c h o o s i n g a g i v e n r e s p o n s e in a m u l t i p l e - c h o i c e q u e s t i o n a n d t h e total n u m b e r a n s w e r i n g that q u e s t i o n , f o l l o w e d by the c o r r e s p o n d i n g p e r c e n t a g e . Indications for treatment—Of the 62 physi­ cians who reported having patients with active o c u l a r t o x o p l a s m o s i s in t h e i r p r a c t i c e , four ( 6 % ) treat all a c t i v e c a s e s r e g a r d l e s s o f t h e o c u l a r findings. For t h e r e m a i n i n g r e s p o n d e n t s , disease-associated factors that are considered to b e a b s o l u t e or r e l a t i v e i n d i c a t i o n s for t h e r a ­ py b y at least 2 0 % a r e l i s t e d in T a b l e 1. F a c t o r s c o n s i d e r e d to b e a b s o l u t e or r e l a t i v e c o n t r a i n ­ d i c a t i o n s for t h e r a p y by at l e a s t 2 0 % are l i s t e d in T a b l e 2. Visual acuity—Any d e c r e a s e in v i s i o n f r o m b a s e l i n e is c o n s i d e r e d an i n d i c a t i o n for t r e a t ­ ment by 38 of 5 2 ( 7 5 % ) respondents. The per­ c e n t a g e w h o c o n s i d e r d e c r e a s e d v i s i o n an a b s o ­ lute i n d i c a t i o n , r e g a r d l e s s o f o t h e r findings, increases with the severity of visual loss, with 34 of 5 6 ( 6 1 % ) considering visual acuity worse t h a n 2 0 / 2 0 0 as an a b s o l u t e i n d i c a t i o n for treat­ m e n t . In c o n t r a s t , 3 2 o f 5 3 ( 6 0 % ) b e l i e v e that

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r e t e n t i o n o f 2 0 / 2 0 v i s u a l a c u i t y is a r e l a t i v e c o n t r a i n d i c a t i o n to t r e a t m e n t . Lesion location and size—Of 58 respondents, m o s t treat l e s i o n s l o c a t e d a n y w h e r e w i t h i n Z o n e 1, r e g a r d l e s s o f o t h e r f a c t o r s : 4 5 ( 7 8 % ) for p e r i p a p i l l a r y l e s i o n s ; 5 4 ( 9 3 % ) for m a c u l o p a p ­ i l l a r y b u n d l e l e s i o n s ; a n d 5 7 ( 9 8 % ) for p e r i ­ foveal l e s i o n s . T h e r e w a s n o c o n s e n s u s r e g a r d ­ ing t r e a t m e n t o f Z o n e 2 l e s i o n s ; this l o c a t i o n is considered a relative indication by 2 6 of 53 ( 4 9 % ) , a r e l a t i v e c o n t r a i n d i c a t i o n b y 19 o f 5 3 ( 3 6 % ) , a n d an i r r e l e v a n t factor b y e i g h t o f 5 3 ( 1 5 % ) . L o c a t i o n in Z o n e 3 , h o w e v e r , is b e l i e v e d b y 3 3 o f 5 2 ( 6 3 % ) to b e a r e l a t i v e c o n t r a i n d i c a ­ t i o n to t r e a t m e n t . Of 5 6 respondents, 34 ( 6 3 % ) consider lesion s i z e l a r g e r t h a n 1 disk d i a m e t e r an i n d i c a t i o n for t r e a t m e n t ; s e v e n ( 1 3 % ) c o n s i d e r it an a b s o ­ lute i n d i c a t i o n for t r e a t m e n t . T w e n t y - s e v e n o f 5 3 ( 5 1 % ) c o n s i d e r l e s i o n s i z e l e s s t h a n 1 disk d i a m e t e r an i r r e l e v a n t f a c t o r in t h e i r d e c i s i o n to treat. N i n e o f 5 3 ( 1 7 % ) c o n s i d e r s m a l l l e s i o n s a r e l a t i v e c o n t r a i n d i c a t i o n to t r e a t m e n t . Other lesion characteristics—Most (30 of 5 5 , 5 5 % ) consider the presence of active retinal l e s i o n s in a c q u i r e d d i s e a s e (as o p p o s e d to r e ­ c u r r e n t o c u l a r t o x o p l a s m o s i s ) to b e an i n d i c a ­ t i o n for t r e a t m e n t , b u t o n l y 1 1 o f 5 5 ( 2 0 % ) c o n s i d e r it an a b s o l u t e i n d i c a t i o n . T h e p r e s e n c e of multiple active lesions are believed by 29 of 5 6 ( 5 2 % ) to b e a n i n d i c a t i o n for t r e a t m e n t ; n i n e of 5 6 ( 1 6 % ) c o n s i d e r m u l t i f o c a l d i s e a s e an absolute indication. A c o n s e n s u s did n o t e x i s t r e g a r d i n g treat­ m e n t o f p u n c t a t e o u t e r r e t i n a l t o x o p l a s m o s i s . It was considered a relative indication by 23 of 51 ( 4 5 % ) , an i r r e l e v a n t f a c t o r b y 1 7 o f 5 1 ( 3 3 % ) , and a relative contraindication by nine of 51 (18%). P e r s i s t e n c e o f d i s e a s e a c t i v i t y for m o r e t h a n one month, regardless of other lesion charac­ t e r i s t i c s , is c o n s i d e r e d an i n d i c a t i o n for i n i t i a ­ tion of treatment by most respondents (43 of 5 8 , 7 4 % ) , w i t h 1 2 % c o n s i d e r i n g it an a b s o l u t e indication (seven of 5 8 , 1 2 % ) . Vitreous inflammation—Vitreous inflammato­ ry r e a c t i o n is c o n s i d e r e d a n i n d i c a t i o n for treat­ m e n t b y m o s t o f the r e s p o n d e n t s o n l y w h e n it is g r e a t e r t h a n m o d e r a t e in s e v e r i t y . F i f t y - s i x o f 5 7 ( 9 8 % ) c o n s i d e r s e v e r e v i t r e o u s r e a c t i o n an i n d i c a t i o n for t r e a t m e n t ; 3 6 o f 5 7 ( 6 3 % ) c o n s i d ­ er this l e v e l o f r e a c t i o n an a b s o l u t e i n d i c a t i o n . Antimicrobial agents—Eight different a n t i m i ­ crobial agents (pyrimethamine, sulfadiazine, clindamycin, sulfisoxazole, sulfadiazine/sulfamerazine/sulfamethazine, trimethoprim/sul-

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TABLE 1 FACTORS SUGGESTING THAT OCULAR TOXOPLASMOSIS SHOULD BE TREATED

FACTOR*

Visual acuity Any decrease in visual acuity Visual acuity below 20/40 Visual acuity below 20/200 Lesion location Zone 1, peripapillary Zone 1, maculopapillary bundle Zone 1, perlfoveal Lesion size £ 1 disk diameter > 1 disk diameter Vitreous reaction Trace Mild Moderate Marked Severe Type of active lesion Single, recurrent satellite Multifocal infection Punctate outer retinal lesions Acquired infection Persistence > 1 month

NO. OF RESPONDENTS WHO NO. OF CONSIDER FACTOR RESPONDENTS IN AN ABSOLUTE AGREEMENT/ INDICATION/TOTAL TOTAL NO. OF NO. OF RESPONDENTS (%) RESPONDENTS (%)

38/52 (75)

1/52 (02)

49/57 (86)

12/57(21)

55/56 (98)

34/56 (61)

58/58 (100)

45/58 (80)

58/58 (100) 58/58(100)

54/58 (93) 57/58 (98)

17/53 (32) 34/57 (60)

2/53 (04) 7/57 (12)

12/57 (21) 15/57(26) 34/56(61) 49/57 (86) 56/57 (98)

0/57 (00) 2/57 (04) 6/56 (11) 23/57 (40) 36/57 (63)

23/55 (42) 38/56 (68)

1/55(02) 9/56 (16)

25/51 (49) 30/55 (55) 43/58 (74)

2/51 (04) 11/55 (20) 7/58(12)

•Factors identified by at least 20% of respondents as an absolute or relative indication for treatment.

famethoxazole, minocycline, and tetracycline) both with and without corticosteroids are c o m ­ b i n e d in 1 5 different r e g i m e n s a s t h e t r e a t m e n t of c h o i c e for o c u l a r t o x o p l a s m o s i s ( T a b l e 3 ) . S u l f o n a m i d e s are u s e d b y 5 6 o f t h e 6 2 r e ­ s p o n d e n t s ( 9 0 % ) . S u l f a d i a z i n e is t h e m o s t c o m ­ monly used agent (51 of 6 2 , 8 2 % ) . A sulfona­ m i d e is u s e d w i t h p y r i m e t h a m i n e b y 4 3 o f 6 2 ( 6 9 % ) in v a r i o u s r e g i m e n s . C l i n d a m y c i n is u s e d b y 3 4 of 6 2 ( 5 5 % ) r e s p o n d e n t s . The combination of pyrimethamine, sulfadia­ z i n e , a n d c o r t i c o s t e r o i d s is u s e d b y 2 0 o f 6 2

May, 1991

( 3 2 % ) . C l i n d a m y c i n is u s e d w i t h t h e s e t h r e e a g e n t s ( q u a d r u p l e t h e r a p y ) as t r e a t m e n t o f choice by 17 of 6 2 ( 2 7 % ) . A c o m b i n e d regimen of s u l f a d i a z i n e , c l i n d a m y c i n , a n d c o r t i c o s t e ­ r o i d s is u s e d b y t e n o f 6 2 ( 1 6 % ) . C l i n d a m y c i n a n d c o r t i c o s t e r o i d s are u s e d b y four o f 6 2 ( 6 % ) ( T a b l e 4 ) . All o t h e r c o m b i n a t i o n s are u s e d b y only one respondent each. Of those respondents who use pyrimeth­ amine, 37 of 42 ( 8 8 % ) administer a loading d o s e , r a n g i n g from 5 0 m g g i v e n o n c e to 1 0 0 to 2 0 0 m g g i v e n for o n e or t w o days. T h e m o s t f r e q u e n t l y u s e d l o a d i n g d o s e is 7 5 to 1 0 0 m g g i v e n in o n e day a n d d i v i d e d i n t o t h r e e o r four d o s e s ( 2 3 o f 3 7 , 6 2 % ) . S u b s e q u e n t t r e a t m e n t is a d m i n i s t e r e d as e i t h e r 2 5 m g d a i l y ( 1 9 o f 4 1 , 4 7 % ) or 5 0 m g d a i l y ( 1 9 o f 4 1 , 4 7 % ) . D u r a t i o n of p y r i m e t h a m i n e t h e r a p y is u s u a l l y four to six w e e k s ( r a n g e , o n e to e i g h t w e e k s ) . M o s t a d j u s t the duration of therapy b a s e d on the clinical response. N e a r l y all r e s p o n d e n t s w h o u s e p y r i m e t h ­ a m i n e a l s o a d m i n i s t e r f o l i n i c a c i d to p r e v e n t hematologic toxicity (51 of 5 2 , 9 8 % ) . The tablet form o f f o l i n i c a c i d is u s e d b y 3 1 o f 5 2 ( 6 0 % ) , with 5 mg given three times a week being the most commonly used dose. The remainder (21 of 5 2 , 4 0 % ) a d m i n i s t e r t h e i n t r a v e n o u s p r e p a ­ r a t i o n o f f o l i n i c a c i d o r a l l y as o n e v i a l (3 m g ) e i t h e r t w o or t h r e e t i m e s p e r w e e k . L a b o r a t o r y t e s t i n g is p e r f o r m e d r o u t i n e l y b y n e a r l y all r e s p o n d e n t s t o m o n i t o r for d e v e l o p ­ ment of leukopenia and thrombocytopenia. Most check laboratory variables weekly and d i s c o n t i n u e t h e r a p y for a w h i t e b l o o d cell c o u n t l e s s t h a n 4 , 0 0 0 c e l l s / m m ' or a p l a t e l e t count less than 1 0 0 , 0 0 0 / m m ' . O f r e s p o n d e n t s w h o u s e p y r i m e t h a m i n e as a d r u g o f first c h o i c e a n d e n c o u n t e r a d v e r s e r e a c ­ t i o n s r e s t r i c t i n g its u s e , 2 9 o f 3 8 ( 7 6 % ) s u b s t i ­ tute clindamycin while continuing other a g e n t s . Two o f 3 8 ( 5 % ) u s e s p i r a m y c i n , o n e o f 38 ( 3 % ) tetracycline, and one of 38 ( 3 % ) mino­ cycline. Six of 38 ( 1 6 % ) discontinue pyrimeth­ amine without adding a replacement agent. S u l f a d i a z i n e is a d m i n i s t e r e d a s a 1-g d o s e given four t i m e s d a i l y for four t o six w e e k s b y 3 8 o f 4 3 ( 8 8 % ) . A n i n i t i a l l o a d i n g d o s e o f 2 to 4 g in o n e a d m i n i s t r a t i o n is g i v e n b y 2 3 o f 3 7 r e s p o n d e n t s ( 6 2 % ) . W h e n t o x i c i t y to s u l f a d i a ­ z i n e is e n c o u n t e r e d , 3 0 o f 4 6 ( 6 5 % ) s u b s t i t u t e clindamycin while continuing other agents. Other less frequently used alternative agents i n c l u d e m i n o c y c l i n e (five o f 4 6 , 11 % ) a n d t e t r a ­ c y c l i n e (four o f 4 6 , 9 % ) . S e v e n o f 4 6 ( 1 5 % )

Vol. I l l , No. 5

Management of Ocular Toxoplasmosis

TABLE 2 FACTORS SUGGESTING THAT OCULAR TOXOPLASMOSIS DOES NOT NEED TREATMENT

FACTOR* Visual acuity 20/20 Lesion location Zone 2 Zone 3 Vitreous inflammatory reaction Trace Mild

NO. OF RESPONDENTS WHO NO. OF CONSIDER FACTOR RESPONDENTS IN AN ABSOLUTE AGREEMENT/TOTAL CONTRAINDICATION/ NO. OF TOTAL NO. OF RESPONDENTS (%) RESPONDENTS (%) 36/58 (68)

4/58(7)

19/53 (36) 34/52 (65)

0/53 (0) 1/52(2)

24/56 (43) 23/57 (40)

0/56 (0) 1/57 (2)

•Factors identified by at least 20% of respondents as a relative or absolute contraindication for treatment.

discontinue sulfadiazine without adding a re­ placement agent. C l i n d a m y c i n is a d m i n i s t e r e d in a 3 0 0 - m g d o s e g i v e n four t i m e s d a i l y for t h r e e to s i x weeks by 31 of 34 respondents ( 9 1 % ) . Spiramycin has been used by only three of 62 r e s p o n d e n t s ( 5 % ) . Two o f t h e t h r e e r e s p o n ­ d e n t s u s e s p i r a m y c i n for s l o w l y h e a l i n g l e s i o n s o n l y after p a t i e n t s h a v e r e c e i v e d s e q u e n t i a l six-week courses of combination pyrimeth­ amine/sulfadiazine therapy and clindamycin t h e r a p y . S p i r a m y c i n is t h e n a d m i n i s t e r e d for u p to two y e a r s after t h e a c u t e e p i s o d e . T h e o t h e r r e s p o n d e n t h a s u s e d s p i r a m y c i n as a s u l f o n a ­ m i d e a l t e r n a t i v e in a p a t i e n t w i t h k n o w n s u l ­ fonamide allergy. Corticosteroids—Only 16 of 5 9 respondents use t o p i c a l c o r t i c o s t e r o i d s t o t r e a t a n y a n t e r i o r chamber inflammatory reaction associated with toxoplasmic retinochoroiditis. T h e rest b a s e their u s e o f t o p i c a l c o r t i c o s t e r o i d s o n t h e s e v e r ­ ity o f t h e r e a c t i o n a n d its a s s o c i a t e d c o m p l i ­ cations and symptoms. All respondents use t o p i c a l c o r t i c o s t e r o i d s for a n t e r i o r c h a m b e r inflammation if synechiae have formed, and m o s t t r e a t for r e d n e s s a n d d i s c o m f o r t ( 4 8 o f 5 9 , 81%). Periocular corticosteroids have been used by 1 6 of 6 1 ( 2 6 % ) r e s p o n d e n t s , b u t 1 5 o f t h e s e 1 6 ( 9 4 % ) have done so only with concurrent anti­ p a r a s i t i c t h e r a p y . C o m m o n i n d i c a t i o n s are i n ­

605

t o l e r a n c e or c o n t r a i n d i c a t i o n s to o r a l c o r t i c o ­ s t e r o i d u s e ( s i x o f 1 6 , 3 8 % ) or s e v e r e v i t r e o u s i n f l a m m a t i o n (four o f 1 6 , 2 5 % ) . O t h e r i n d i c a ­ tions include macular or peripapillary lesions, presence of hypopyon, or patient n o n c o m p l i ­ ance to oral therapy. Eight of 16 ( 5 0 % ) use 4 0 m g o f t r i a m c i n o l o n e a c e t o n i d e , a n d five o f 1 6 ( 3 1 % ) use 4 0 mg of m e t h y l p r e d n i s o l o n e given o n c e or t w i c e , w i t h f a v o r a b l e o u t c o m e s r e p o r t ­ ed b y n i n e o f 1 2 r e s p o n d e n t s ( 7 5 % ) . O f t h e 1 2 respondents providing outcomes of therapy, only one reported worsening of disease. Oral corticosteroids are used b y 5 6 of 5 7 r e s p o n d e n t s ( 9 8 % ) for a c t i v e l e s i o n s t h r e a t e n ­ i n g t h e m a c u l a or o p t i c n e r v e h e a d . T h i r t y eight o f 53 ( 7 2 % ) also use oral corticosteroids for l e s i o n s c a u s i n g a d e c r e a s e in v i s i o n , w h e r e ­ a s o n l y s e v e n o f 5 4 ( 1 3 % ) give o r a l c o r t i c o s t e ­ roids based only on the presence of a vitreitis. Oral corticosteroids as single therapy have b e e n used b y four of 5 6 ( 7 % ) . Indications cited for u s e o f c o r t i c o s t e r o i d s a s t h e o n l y a g e n t i n c l u d e d t h e n e e d t o t r e a t p a t i e n t s i n t o l e r a n t to both pyrimethamine and sulfadiazine. N o ad­ verse reactions were reported by the respon­ dents. Corticosteroids are begun simultaneously with antiparasitic agents by 29 of 5 8 ( 5 0 % ) , whereas the remaining 29 initiate corticoster­ o i d t h e r a p y o n l y after 2 4 t o 4 8 h o u r s o f a n t i p a r ­ asitic therapy. Thirty-seven of 4 6 ( 8 0 % ) discon­ tinue corticosteroids on the basis o f clinical response, whereas the remaining nine ( 2 0 % ) o n l y a d m i n i s t e r c o r t i c o s t e r o i d s d u r i n g t h e first o n e to three w e e k s of therapy. Adjunctive therapies—Laser photocoagula­ tion, cryotherapy, or vitrectomy have b e e n used for a c t i v e o c u l a r t o x o p l a s m o s i s b y o n e t h i r d o f the respondents ( 2 0 o f 6 0 , 3 3 % ) with seven of 60 ( 1 2 % ) having used more than one modality. Laser photocoagulation has been used by eight o f 6 0 ( 1 3 % ) r e s p o n d e n t s e i t h e r for s i g h t - t h r e a t ­ e n i n g l e s i o n s , i n t o l e r a n c e to o r a l m e d i c a t i o n s , p e r s i s t e n c e o f l e s i o n s for l o n g e r t h a n o n e y e a r , or during pregnancy. Treatment o u t c o m e s were d e s c r i b e d as g e n e r a l l y f a v o r a b l e . C r y o t h e r a p y has been used by six of 60 ( 1 0 % ) respondents p r i m a r i l y for p a t i e n t s w i t h c h r o n i c , p e r i p h e r a l l e s i o n s a n d c o n t r a i n d i c a t i o n s to a n t i p a r a s i t i c d r u g s . R a p i d r e s o l u t i o n after c r y o t h e r a p y w a s reported by three respondents, whereas slow resolution was reported by two respondents. V i t r e c t o m y h a s b e e n u s e d b y five o f 6 0 ( 8 % ) for treating active inflammation. O f the three re­ spondents providing outcomes, two reported

606

AMERICAN JOURNAL OF OPHTHALMOLOGY

May, 1991

TABLE 3 AGENTS USED IN THE TREATMENT OF OCULAR TOXOPLASMOSIS

AGENTDlhydrofolate reductase inhibitors Pyrimethamine Trimethoprim/sulfamethoxazole Sulfonamides Sulfadiazine Sulfadtazine/sulfamerazine/sulfamethazine Sulfisoxazole

USUAL DOSAGE' 75-100 mg loading dose given over 24 hours, followed by 25-50 mg daily for 4-6 weeks One tablet given twice daily for 4-6 weeks 2.0-4.0 g loading dose initially, followed by 1.0 g given four times daily for 4-6 weeks 2.0-4.0 g loading dose initially, followed by 1.0 g given four times daily for 4-6 weeks 2.0 g loading dose initially, followed by 1.0 g given four times daily for 4-6 weeks

Tetracyclines Tetracycline Minocycline Other antimicrobial agents Clindamycin Other drugs Folinic acid Prednisone

2.0 g load over 24 hours, then 250 mg given four times daily for 4-6 weeks 100 mg given once or twice daily for 4-6 weeks 300 mg given four times daily for 3-6 weeks 5.0 mg tablet or 3 mg intravenous preparation given orally, two to three times weekly for duration of pyrimethamine therapy 40-60 mg daily for 2-6 weeks depending on clinical response; taper off before discontinuing antimicrobial therapy

•Drug used by at least one respondent as part of initial therapy for typical toxoplasmic lesions. 'Most frequently cited dosage by those using each drug as part of their initial therapy for typical toxoplasmic lesions.

excellent results with the other reporting de­ creased visual acuity, marked retinal traction, a n d s u b r e t i n a l fluid c o l l e c t i o n . Special situations—Pregnancy: Active ocular t o x o p l a s m o s i s in p r e g n a n t w o m e n h a s b e e n treated by 22 o f 5 7 respondents ( 3 9 % ) . O f t h e s e , o n l y six ( 2 7 % ) h a v e t r e a t e d t h e w o m a n w i t h t h e g o a l o f p r o t e c t i n g t h e fetus from i n f e c ­ t i o n , w h e r e a s all will t r e a t t h e w o m a n to p r e ­ serve vision. Eighteen of 22 ( 8 2 % ) have the s a m e i n d i c a t i o n s for b e g i n n i n g t r e a t m e n t a s for the nonpregnant patient, whereas three ( 1 4 % ) will o n l y treat w h e n l e s i o n s a r e l o c a t e d in Z o n e 1. S i x t e e n o f 21 ( 7 6 % ) a l t e r t h e r a p y d u r i n g p r e g n a n c y . S u l f a d i a z i n e is t h e m o s t c o m m o n l y u s e d drug (ten o f 1 6 , 6 3 % ) , e i t h e r as s i n g l e t h e r a p y ( t h r e e o f 1 6 , 1 9 % ) or in c o m b i n a t i o n with c o r t i c o s t e r o i d s ( t h r e e o f 1 6 , 1 9 % ) , w i t h c l i n d a m y c i n ( t h r e e o f 1 6 , 1 9 % ) , or w i t h p y r i ­ methamine (one of 16, 6 % ) . Pyrimethamine, e i t h e r a l o n e or in c o m b i n a t i o n w i t h o t h e r a g e n t s , is u s e d b y four o f 2 1 ( 1 9 % ) d u r i n g pregnancy. Spiramycin has been used by two of 1 6 ( 1 3 % ) r e s p o n d e n t s for t r e a t m e n t o f t h e p r e g ­ nant patient. Neonatal disease: O n l y four o f 5 7 respon­

dents ( 7 % ) have treated neonatal patients with a c t i v e o c u l a r d i s e a s e . All four r e s p o n d e n t s t r e a t e v e r y p a t i e n t r e g a r d l e s s o f findings. Two u s e a combination of pyrimethamine and sulfadia­ z i n e for s i x w e e k s , f o l l o w e d b y s p i r a m y c i n t h e r ­ a p y for e i g h t w e e k s ; t h i s c y c l e i s r e p e a t e d t h r e e times with two-month intervals of no therapy b e t w e e n c y c l e s . T h e r e m a i n i n g two r e s p o n ­ d e n t s a d m i n i s t e r t h e s a m e d r u g s as t h o s e u s e d for a d u l t s b u t w i t h a d j u s t e d d o s e s . Immunocompromised patients: Active ocular t o x o p l a s m o s i s h a s b e e n t r e a t e d in p a t i e n t s w h o are i m m u n o c o m p r o m i s e d b y 3 8 o f 5 6 r e s p o n ­ d e n t s ( 6 8 % ) . O f t h e c o n d i t i o n s r e s p o n s i b l e for immunosuppression, human immunodeficien­ cy v i r u s - a s s o c i a t e d d i s e a s e is t h e m o s t c o m ­ mon, with other causes including organ trans­ plantation and autoimmune disorders. Twenty of 3 5 ( 5 7 % ) h a v e t h e s a m e i n d i c a t i o n s for b e ­ g i n n i n g t r e a t m e n t as in i m m u n o c o m p e t e n t p a ­ t i e n t s . O f t h o s e m o d i f y i n g t h e i r i n d i c a t i o n s for t r e a t m e n t , 11 o f 15 ( 7 3 % ) t r e a t all l e s i o n s in t h e s e p a t i e n t s . D r u g t h e r a p y is a l t e r e d b y five o f 38 ( 1 3 % ) , most frequently by excluding both pyrimethamine and corticosteroids. Continued administration of drugs (maintenance therapy)

Vol. I l l , No. 5

Management of Ocular Toxoplasmosis

TABLE 4 PREFERRED THERAPEUTIC REGIMENS FOR TYPICAL CASES OF OCULAR TOXOPLASMOSIS* RESPONDENTS REGIMEN'

NO. (%)

Pyrimethamine/folinic acid, sulfadiazine, prednisone Pyrimethamlne/folJnlc acid. sulfadiazine, clindamycin. prednisone* Sulfadiazine, clindamycin. prednisone Clindamycin, prednisone

20 (32) 17 (27) 10(16) 4(06)

*A typical case was defined as an immunocompetent male or nonpregnant female patient witti a lesion ttireatening the macu­ la or optic nerve head, who has decreased vision but potential for full recovery of central vision. 'All drug combinations cited by more than one respondent. •Referred to by some investigators as quadruple therapy.

for t h e d u r a t i o n o f t h e i m m u n o c o m p r o m i s e d state is p r o v i d e d b y 2 4 o f 3 8 ( 6 3 % ) , wrhereas t h e r e m a i n d e r treat o n l y w h i l e l e s i o n s a r e a c t i v e . M o n i t o r i n g o f t h e s e p a t i e n t s is p e r f o r m e d dif­ f e r e n t l y b y 2 0 o f 3 8 ( 5 3 % ) , u s u a l l y in t h e f o r m of m o r e f r e q u e n t f o l l o w - u p .

Discussion Toxoplasma gondii h a s b e e n r e c o g n i z e d a s a h u m a n o c u l a r p a t h o g e n for n e a r l y 5 0 y e a r s , b u t t h e b e s t t r e a t m e n t for t h i s i n f e c t i o n r e m a i n s a subject of controversy. The synergistic combi­ nation of pyrimethamine and sulfadiazine was first r e c o m m e n d e d b y E y l e s a n d C o l e m a n ^ " in 1 9 5 3 . In t h e e n s u i n g y e a r s , o t h e r r e p o r t s h a v e provided conflicting data and r e c o m m e n d a ­ tions regarding the m a n a g e m e n t of ocular toxo­ plasmosis. Consequently, a variety of therapeu­ tic r e g i m e n s a r e u s e d . I n t h i s s t u d y w e a t t e m p t e d to i d e n t i f y v a r i a t i o n s in t h e m a n a g e ­ ment of ocular toxoplasmosis as currently prac­ ticed by uveitis specialists. Few treat e v e r y c a s e o f a c t i v e o c u l a r t o x o p l a s ­ mosis regardless of lesion characteristics. Most m o d i f y t h e i r t h e r a p y for t h e i n d i v i d u a l p a t i e n t . V i s u a l i m p a i r m e n t a n d t h e p o t e n t i a l for v i s u a l l o s s are c o n s i d e r e d to b e t h e m o s t i m p o r t a n t factors i n d e t e r m i n i n g w h e t h e r t o b e g i n t r e a t ­ m e n t . T r e a t m e n t is u s u a l l y b e g u n w h e n l e s i o n s

607

c a u s e a s u d d e n d e c r e a s e in v i s i o n . T h e p r o p o r ­ tion w h o treat, b a s e d on vision alone, increases with increasing severity of visual loss. Most also begin treatment if the lesion, by virtue of i t s l o c a t i o n in r e l a t i o n t o t h e f o v e a or o p t i c n e r v e h e a d , h a s t h e p o t e n t i a l for c a u s i n g p e r ­ m a n e n t v i s u a l i m p a i r m e n t . L e s i o n s l e s s liicely to affect v i s i o n ( t h o s e l o c a t e d p e r i p h e r a l l y a n d those associated with minimal vitreous reac­ tion) are usually observed without treatment. Lesion size alone is considered less important in m a n a g e m e n t d e c i s i o n s , p r e s u m a b l y b e c a u s e s i z e is l e s s i m p o r t a n t t h a n l o c a t i o n for v i s u a l i m p a i r m e n t . A l a r g e p e r i p h e r a l l e s i o n , for e x ­ a m p l e , w i l l affect v i s i o n l e s s t h a n a s m a l l p e r i ­ foveal lesion. Nevertheless, 3 4 o f 5 7 respon­ d e n t s ( 6 0 % ) still c o n s i d e r l e s i o n s g r e a t e r t h a n 1 disk d i a m e t e r to b e at l e a s t a r e l a t i v e i n d i c a t i o n for t r e a t m e n t . The natural course of solitary lesions occur­ r i n g at t h e m a r g i n o f a h e a l e d s c a r or s i n g l e s a t e l l i t e l e s i o n s t h a t a r e r e m o v e d from a r e t i n o c h o r o i d a l s c a r is g e n e r a l l y a c c e p t e d as s e l f limited. When considering lesion characteris­ tics alone, most r e s p o n d e n t s are less likely to treat single, recurrent lesions. Only half of the respondents consider punc­ tate outer retinal t o x o p l a s m o s i s lesions a rela­ tive i n d i c a t i o n for t r e a t m e n t , p e r h a p s b e c a u s e these lesions are not typically associated with vitreous inflammation."'* Despite the absence of inflammation with these lesions, their natu­ ral c o u r s e a n d t h e i r p o t e n t i a l for r e t i n a l d e ­ struction appear to be similar to more typical ocular toxoplasmosis lesions. Other atypical l e s i o n s w h o s e n a t u r a l c o u r s e is p e r h a p s l e s s u n d e r s t o o d or t h a t m a y i n d i c a t e a m o r e s e v e r e i n f e c t i o n , s u c h as m u l t i f o c a l l e s i o n s , a c q u i r e d l e s i o n s , a n d l e s i o n s p e r s i s t i n g for m o r e t h a n o n e month, are generally considered an indica­ t i o n for t r e a t m e n t . A number of antimicrobial/antiparasitic a g e n t s h a v e d e m o n s t r a t e d e i t h e r in v i t r o o r in v i v o efficacy a g a i n s t T. gondii, including pyri­ methamine,'" various sulfonamides (sulfadia­ z i n e , " sulfamerazine," sulfamethazine," and sulfapyrizine'*), c l i n d a m y c i n , " a n d tetracy­ clines.^" E i g h t different a n t i m i c r o b i a l a g e n t s a r e u s e d w i t h or w i t h o u t c o r t i c o s t e r o i d s in 15 dif­ f e r e n t r e g i m e n s as i n i t i a l t h e r a p y for o c u l a r toxoplasmosis. Of these, 51 of 62 respondents ( 8 2 % ) u s e o n e o f o n l y four different r e g i m e n s . Regimens consisting of multiple drugs were cited by most, with 5 3 of 62 respondents ( 8 5 % ) u s i n g e i t h e r t h r e e or four a g e n t s . T h i s p r a c t i c e

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may reflect a p e r c e p t i o n t h a t l e s i o n s r e s p o n d i n c o m p l e t e l y to any g i v e n a g e n t . T h e r e is less e v i d e n c e in p u b l i s h e d r e p o r t s t h a t c l i n d a m y c i n is as effective for t r e a t m e n t o f o c u l a r t o x o p l a s m o s i s as p y r i m e t h a m i n e or s u l ­ f a d i a z i n e , b u t it is u s e d b y m o r e t h a n h a l f o f t h e r e s p o n d e n t s as p a r t o f their i n i t i a l t h e r a p y . C l i n d a m y c i n is a l s o the m o s t f r e q u e n t c h o i c e for a l t e r n a t i v e t h e r a p y w h e n t o x i c i t y to e i t h e r p y r i m e t h a m i n e or s u l f a d i a z i n e is e n c o u n t e r e d . I n t e r e s t a m o n g o p h t h a l m o l o g i s t s in t h e u s e o f c l i n d a m y c i n is p r o b a b l y b e c a u s e the d r u g a p ­ p e a r s to b e c o n c e n t r a t e d in o c u l a r t i s s u e a n d c a n p e n e t r a t e c y s t walls.^' A n i m a l e x p e r i m e n t s have s h o w n t h a t c l i n d a m y c i n t r e a t m e n t r e d u c e s the n u m b e r of, a l t h o u g h it d o e s n o t e l i m i n a t e , t i s s u e cysts,^^ b u t t h e r e is n o g o o d c l i n i c a l e v i d e n c e to s u p p o r t t h e c o n c e p t t h a t c l i n d a m y ­ cin p r e v e n t s r e c u r r e n c e s . ^ R e t i n a l n e c r o s i s c a u s e d b y T. gondii i n f e c t i o n is b e l i e v e d to r e s u l t d i r e c t l y from cell lysis b y the parasite.^"" I n f l a m m a t o r y r e a c t i o n s c a u s e secondary problems, including cystoid macular edema, vitreitis, anterior c h a m b e r inflamma­ t i o n , a n d r e t i n a l vasculitis.^'' C o r t i c o s t e r o i d s , which decrease these inflammation-associated p r o b l e m s , are t h e r e f o r e given w i t h a n t i m i c r o b i ­ al a g e n t s . 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 u s e d b y n e a r l y all r e s p o n d e n t s for t r e a t i n g l e s i o n s t h r e a t e n i n g the m a c u l a or o p t i c n e r v e h e a d . O n l y rarely did r e s p o n d e n t s state t h a t t h e y have t r e a t e d p a t i e n t s w i t h c o r t i c o s t e r o i d s a s single therapy. Without concurrent antipara­ sitic therapy, the suppression of i m m u n e de­ fense m e c h a n i s m s by corticosteroids can lead to f u l m i n a n t T. gondii i n f e c t i o n , b u t w h e n g i v e n concurrently with antimicrobial agents, the use of c o r t i c o s t e r o i d s h a s n e v e r b e e n s h o w n to worsen the underlying infection." Further con­ t r o v e r s y e x i s t s as to h o w l o n g , if at a l l , a n t i m i ­ c r o b i a l t h e r a p y must b e g i v e n b e f o r e i n i t i a t i n g c o r t i c o s t e r o i d t h e r a p y . T h e start o f c o r t i c o s t e r ­ oid a d m i n i s t r a t i o n is s o m e t i m e s d e l a y e d to a l ­ l o w a d e q u a t e b l o o d l e v e l s o f the a n t i m i c r o b i a l s to b e reached.^' W h e t h e r this delay is c l i n i c a l l y n e c e s s a r y is u n k n o w n . R e s p o n d e n t s a r e e v e n l y divided among those beginning corticosteroids concurrently with antimicrobial agents and t h o s e w a i t i n g 2 4 to 4 8 h o u r s . Topical c o r t i c o s t e r o i d s are u s e d for a n t e r i o r s e g m e n t i n f l a m m a t i o n b y n e a r l y all r e s p o n ­ d e n t s . T h e r e is little c o n t r o v e r s y s u r r o u n d i n g t h e i r u s e , p r o b a b l y b e c a u s e T. gondii h a s n e v e r b e e n i s o l a t e d from a n t e r i o r s e g m e n t s t r u c t u r e s e x c e p t in an i m m u n o c o m p r o m i s e d p a t i e n t . "

May, 1991

Experience with periocular corticosteroid in­ j e c t i o n s a m o n g r e s p o n d e n t s is l i m i t e d . Its u s e h a s b e e n d i s c o u r a g e d b e c a u s e o f e x p e r i e n c e s in w h i c h it h a s b e e n a s s o c i a t e d w i t h u n c o n t r o l l a ­ ble spread of infection, presumably because of intense suppression of host protective mecha­ nisms.^* A d j u n c t i v e t h e r a p y for a c t i v e o c u l a r t o x o ­ plasmosis, including laser photocoagulation, c r y o t h e r a p y , or v i t r e c t o m y , h a s b e e n u s e d b y n e a r l y o n e third o f the r e s p o n d e n t s . A c o n ­ trolled study evaluating the role of these ad­ j u n c t i v e t h e r a p i e s in t r e a t i n g a c t i v e t o x o p l a s ­ m i c i n f e c t i o n s h a s yet t o b e c o n d u c t e d . L a s e r p h o t o c o a g u l a t i o n w a s the m o s t f r e q u e n t l y u s e d modality, with the presumed goal of encircling an a c t i v e l e s i o n w i t h a r e g i o n o f p h o t o c o a g u l a t ed retina, thereby limiting cell-to-cell spread of i n f e c t i o n . L a s e r p h o t o c o a g u l a t i o n will n o t p r e ­ v e n t r e c u r r e n c e s from d i s t a n t s a t e l l i t e foci a n d c a n n o t b e a d m i n i s t e r e d in t h e p r e s e n c e o f m o d ­ e r a t e to s e v e r e v i t r e o u s i n f l a m m a t i o n . C r y o ­ t h e r a p y h a s b e e n u s e d for p e r i p h e r a l l e s i o n s in p a t i e n t s h a v i n g c o n t r a i n d i c a t i o n s to m e d i c a l t h e r a p y . V i t r e c t o m y h a s b e e n u s e d for s e v e r e or p e r s i s t e n t v i t r e o u s i n f l a m m a t i o n in p a t i e n t s w i t h a c t i v e l e s i o n s , a l t h o u g h this p r o c e d u r e is m o r e c o m m o n l y u s e d for r e m o v a l o f p e r s i s t e n t v i t r e o u s o p a c i t i e s in o t h e r w i s e q u i e t e y e s . R e ­ spondents generally reported favorable out­ c o m e s for e a c h o f t h e s e m o d a l i t i e s . O c u l a r t o x o p l a s m o s i s in t h e p r e g n a n t w o m a n is an i m p o r t a n t i s s u e s i n c e c o n v e n t i o n a l m e d i ­ cal t h e r a p y m a y b e t e r a t o g e n i c ^ ' a n d m a t e r n a l l y a c q u i r e d d i s e a s e c a n r e s u l t in fetal i n f e c t i o n . Over one third of respondents have treated patients who were pregnant with active ocular t o x o p l a s m o s i s . All s t a t e d t h a t t h e y will treat the w o m a n to p r e s e r v e h e r v i s i o n , w i t h m o s t u s i n g the s a m e o p h t h a l m i c c r i t e r i a for b e g i n n i n g t r e a t m e n t as in t h e n o n p r e g n a n t p a t i e n t . T h e teratogenicity o f dlhydrofolate reductase inhib­ itors h a s n o t b e e n c o n v i n c i n g l y d e m o n s t r a t e d in humans.'"' N e v e r t h e l e s s , o n l y t h r e e o f 2 0 r e s p o n d e n t s ( 1 5 % ) w h o treat p r e g n a n t p a t i e n t s with ocular toxoplasmosis use pyrimethamine. T h e r e m a i n d e r u s e s u l f a d i a z i n e ( a l o n e or c o n ­ c u r r e n t l y w i t h e i t h e r c l i n d a m y c i n or c o r t i c o s t e ­ r o i d s ) , s p i r a m y c i n a l o n e , or c l i n d a m y c i n a l o n e . S p i r a m y c i n is a m a c r o l i d e a n t i b i o t i c w i t h a n t i - T . gondii a c t i v i t y t h a t h a s m i n i m a l side effects a n d m a y d e c r e a s e the i n c i d e n c e o f c o n genitally infected infants." Spiramycin use among members of the American Uveitis Socie­ ty is l i m i t e d , b e c a u s e it is o n l y a v a i l a b l e in t h e

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Management of Ocular Toxoplasmosis

United States on a compassionate-use basis. A d d i t i o n a l l y , six o f 18 r e s p o n d e n t s ( 3 3 % ) stat­ e d they have t r e a t e d a c q u i r e d d i s e a s e in t h e w o m a n to p r o t e c t t h e f e t u s . T h e r e is little c o n ­ c e r n a b o u t the fetus in r e c u r r e n t d i s e a s e s i n c e p r e e x i s t i n g m a t e r n a l a n t i b o d i e s a r e b e l i e v e d to be protective. Few A m e r i c a n U v e i t i s S o c i e t y m e m b e r s (four of 5 7 , 7 % ) h a v e t r e a t e d n e w b o r n s w i t h a c t i v e ocular toxoplasmosis. They initiate treatment for any a c t i v e r e t i n a l d i s e a s e w i t h a c o u r s e o f t h e r a p y l a s t i n g until at l e a s t 1 y e a r o f a g e , independent of lesion resolution. Given the systemic nature of active congenital disease, m o s t c a s e s are u s u a l l y m a n a g e d b y p e d i a t r i ­ cians. S y s t e m i c d i s s e m i n a t i o n o f T . gondii is a fre­ quent complication of many immunodeficiency disease processes including those caused by m a l i g n a n c i e s , ' ^ c o r t i c o s t e r o i d or c y t o t o x i c t h e r ­ a p y , " and the acquired immunodeficiency syn­ drome.'* O c u l a r t o x o p l a s m o s i s in p a t i e n t s w i t h A I D S u s u a l l y r e s p o n d s favorably to a n t i p a r a ­ sitic therapy.'* M o s t r e s p o n d e n t s h a v e t r e a t e d immunocompromised patients with active ocu­ lar t o x o p l a s m o s i s , w i t h H I V - r e l a t e d i l l n e s s e s c o m p r i s i n g m o s t of t h e c a s e s s e e n . A l t h o u g h m o s t ( 2 0 o f 3 5 , 5 7 % ) u s e t h e s a m e c r i t e r i a for b e g i n n i n g t r e a t m e n t as for i m m u n o c o m p e t e n t p a t i e n t s , an i n c r e a s e d p r o p o r t i o n ( 1 1 o f 3 5 , 3 1 % ) b e g i n t r e a t m e n t in t h e p r e s e n c e of any a c t i v e l e s i o n w h e n t h e p a t i e n t is i m m u n o c o m ­ p r o m i s e d . M o s t a d m i n i s t e r the s a m e a n t i m i c r o b i a l / a n t i p a r a s i t i c a g e n t s as for i m m u n o c o m p e ­ t e n t p a t i e n t s , a l t h o u g h s o m e (four o f 3 5 , 1 1 % ) withhold pyrimethamine and corticosteroids from t h e r a p y . P y r i m e t h a m i n e u s e is s o m e t i m e s avoided b e c a u s e o f p r e e x i s t i n g b o n e m a r r o w s u p p r e s s i o n , a n d c o r t i c o s t e r o i d u s e is a v o i d e d to p r e v e n t further s u p p r e s s i o n o f h o s t i m m u n e mechanisms. Other considerations should be the h i g h i n c i d e n c e o f s u l f o n a m i d e a l l e r g i e s a m o n g p a t i e n t s w i t h A I D S a n d that z i d o v u d i n e (an a n t i r e t r o v i r a l a g e n t u s e d c o m m o n l y in p a ­ t i e n t s w i t h A I D S ) h a s b e e n s h o w n to b e a n t a g o ­ n i s t i c to p y r i m e t h a m i n e , w h i c h m a y l e a d to t r e a t m e n t failures if b o t h of t h e s e a g e n t s a r e used concurrently.'* L i k e m a n y i n f e c t i o n s in i m m u n o c o m p r o ­ m i s e d p a t i e n t s , t o x o p l a s m o s i s t e n d s to r e a c t i ­ vate if a n t i p a r a s i t i c t h e r a p y is d i s c o n t i n u e d . ' * Maintenance therapy with lower, suppressive d o s a g e s of a n t i m i c r o b i a l a g e n t s m a y p r e v e n t the r e a c t i v a t i o n o f d i s e a s e . M o s t r e s p o n d e n t s ( 2 4 of 3 8 , 6 3 % ) a d m i n i s t e r m a i n t e n a n c e a n t i m i ­

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c r o b i a l t h e r a p y for t h e d u r a t i o n of t h e i m m u n o ­ c o m p r o m i s e d state w i t h c l i n d a m y c i n b e i n g the most frequently used agent followed by sulfadi­ a z i n e given at r e d u c e d d o s a g e s . T h e r e m a i n d e r of respondents administer pyrimethamine, doxycycline, or m i n o c y c l i n e as suppressive t h e r a p y . F o l l o w - u p o f t h e s e p a t i e n t s is p e r ­ f o r m e d m o r e f r e q u e n t l y to m o n i t o r for r e a c t i v a ­ tion of ocular disease. This study provides a better understanding of c u r r e n t t r e a t m e n t p r a c t i c e s for o c u l a r t o x o p l a s ­ mosis and clearly demonstrates a diversity of o p i n i o n s a m o n g u v e i t i s s p e c i a l i s t s . T h i s finding p r o b a b l y reflects t h e l a c k o f e v i d e n c e d e m o n ­ s t r a t i n g t h e s u p e r i o r i t y o f a n y given t h e r a p e u t i c r e g i m e n a n d s u g g e s t s the n e e d for p r o s p e c t i v e i n v e s t i g a t i o n s . I n f o r m a t i o n o b t a i n e d from t h i s s t u d y c o u l d b e u s e d in the d e s i g n o f a s t u d y c o m p a r i n g different r e g i m e n s as w e l l as t h e n e e d to t r e a t different l e s i o n s b a s e d on t h e i r clinical characteristics. T h e r e s u l t s o f t h i s s t u d y a r e p r e s e n t e d as i n f o r m a t i o n o n l y a n d a r e n o t i n t e n d e d as treat­ m e n t r e c o m m e n d a t i o n s b y t h e a u t h o r s or b y the American Uveitis Society.

References 1. Henderly, D. E., Genstler, A. ] . , Smith, R. E., and Rao, N. Α.: Changing patterns of uveitis. Am. J. Ophthalmol. 1 0 3 : 1 3 1 , 1 9 8 7 . 2. Drugs for parasitic infections. Med. Lett. 32:23, 1990. 3. Eyles, D. E., and Coleman, N.: Synergistic effect of sulfadiazine and Daraprim against experimental toxoplasmosis in the mouse. Antibiot. Chemother. 3:483, 1 9 5 3 . 4. Acers, Τ. Ε.: Toxoplasmic retinochoroiditis. A double blind therapeutic study. Arch. Ophthalmol. 71:58, 1 9 6 4 . 5. Perkins, E. S., Smith, C. H., and Schofield, P. B.: Treatment of uveitis with pyrimethamine (Daraprim). Br. J. Ophthalmol. 40:577, 1956. 6. Rothova, Α., Buitenhuis, H. J . , Meenken, C , Baarsma, G. S., Boen-Tan, T. N., de Jong, P. T. V. M., Schweitzer, C , Timmerman, Z., de Vries, J., Zaal, M., and Kijlstra, Α.: Therapy in ocular toxoplasmosis. Int. Ophthalmol. 13:415, 1989. 7. Ghartey, K. N., and Brockhurst, R. J . : Photoco­ agulation of active toxoplasmic retinochoroiditis. Am. J. Ophthalmol. 89:858, 1 9 8 0 . 8. Spalter, Η. F., Campbell, C. J . , Noyori, Κ. S., Rittler, Μ. C , and Koester, C. J . : Prophylactic photo­ coagulation of recurrent toxoplasmic retinochoroidi­ tis. Arch. Ophthalmol. 7 5 : 2 1 , 1 9 6 6 .

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