Therapeutic Ultrasound for the Treatment of Glaucoma Ronald H. Silverman, Ph.D., Barbara Vogelsang, M.D., Mark J. Rondeau, and D. Jackson Coleman, M . D .
A m u l t i c e n t e i c l i n i c a l t r i a l of t h e r a p e u t i c u l t r a s o u n d for t h e t r e a t m e n t o f g l a u c o m a i n cluded 20 c e n t e r s in t h e U n i t e d S t a t e s in w h i c h 1,117 t r e a t m e n t s w e r e p e r f o r m e d o n 8 8 0 eyes. T h e study was l i m i t e d to p a t i e n t s w i t h refractory g l a u c o m a w h o had not benefited from conventional m e d i c a l a n d surgical techn i q u e s . A p p r o x i m a t e l y 7 8 2 o f 1,117 t r e a t m e n t s (70%) s h o w e d a n i n i t i a l d e c r e a s e i n i n t r a o c u lar pressure from a p r e t r e a t m e n t m e a n of 38.1 m m Hg to 2 2 m m Hg o r l e s s . B y K a p l a n - M e i e r survival analysis, the single treatment success rate (intraocular p r e s s u r e b e t w e e n 6 a n d 22 m m Hg) was 48.7% at six m o n t h s p o s t t r e a t ment. When retreatment was used subsequent to f a i l u r e , t h e o n e - y e a r m u l t i t r e a t m e n t s u c cess rate was 79.3%. T h e most c o m m o n c o m plications were an i m m e d i a t e posttreatment intraocular pressure i n c r e a s e lasting a few hours and mild iritis. Other complications i n c l u d e d s c l e r a l t h i n n i n g i n 2 8 o f 1,117 t r e a t m e n t s (2.5%) a n d p h t h i s i s b u l b i i n 1 2 of 1,117 t r e a t m e n t s (1.1%).
U N T I L R E C E N T L Y t h e t h e r a p e u t i c o p t i o n s for patients with refractory glaucoma were severely l i m i t e d . T h e m o s t c o m m o n l y p e r f o r m e d p r o c e d u r e for p a t i e n t s w h o did n o t r e s p o n d to
Accepted for publication Dec. 12, 1990. From the Department of Ophthalmology, Cornell University Medical College, h¡ew York, New York. This study was supported in part by Research to Prevent Blindness, Inc., the Dyson Foundation, and the Rudin Foundation. The multicenter clinical trial was sponsored by Sonocare, Inc. The device described in this article is licensed to Sonocare, Inc., by the Cornell Research Foundation, Ithaca, New York. Dr. Coleman has a proprietary interest in this technique. Licensing fees help support the Department of Ophthalmology, Cornell University Medical Center. Reprint requests to D, Jackson Coleman, M.D., Department of Ophthalmology, Cornell University Medical College, 1300 York Ave., New York, NY 10021.
surgical intervention was cyclocryotherapy. Alt h o u g h t h i s p r o c e d u r e is effective in d e c r e a s i n g i n t r a o c u l a r p r e s s u r e , it is a l s o a s s o c i a t e d w i t h a h i g h rate o f o c u l a r m o r b i d i t y a n d p a t i e n t d i s c o m f o r t . After o b s e r v i n g t h a t a f o c u s e d b e a m o f h i g h - i n t e n s i t y u l t r a s o u n d is c a p a b l e o f f o r m i n g s c l e r a l l e s i o n s t h r o u g h t h e r m a l effects,''^ we b e g a n to i n v e s t i g a t e t h e p o s s i b i l i t y that t h i s m o d a l i t y m i g h t b e u s e d for t r e a t m e n t o f g l a u c o ma either by decreased aqueous production t h r o u g h c i l i o d e s t r u c t i o n or b y i n c r e a s e d outflow t h r o u g h t h e u v e a or t h e t r a n s s c l e r a l r o u t e . In 1 9 8 5 , w e d e s c r i b e d t h e effects o f h i g h i n t e n s i t y f o c u s e d u l t r a s o u n d on g l a u c o m a in an a n i m a l m o d e l ' a n d in a s m a l l g r o u p o f p a t i e n t s with end-stage glaucoma." Because of the enc o u r a g i n g r e s u l t s of t h e s e p i l o t s t u d i e s , p a t i e n t s c o n t i n u e d to b e e n r o l l e d at t h e N e w York H o s pital-Cornell Medical Center, and articles on a l a r g e r c l i n i c a l s t u d y w e r e p u b l i s h e d in 1 9 8 6 . ^ " In 1 9 8 5 , C o r n e l l U n i v e r s i t y M e d i c a l C o l l e g e , through the Cornell Research Foundation, lic e n s e d t h e u l t r a s o u n d t e c h n o l o g y d e v e l o p e d in our l a b o r a t o r y to S o n o c a r e , I n c . S o n o c a r e org a n i z e d a m u l t i c e n t e r c l i n i c a l trial u n d e r F o o d and Drug Administration guidelines involving 20 centers, including Cornell University Medical C o l l e g e . O n e o f us ( D . J . C . ) a c t e d as t h e c l i n i c a l m o n i t o r o f t h i s s t u d y . In 1 9 8 8 , after c o m p l e t i o n of t h e s t u d y e n r o l l m e n t g o a l s a n d analysis of results, the procedure was approved b y t h e F o o d a n d D r u g A d m i n i s t r a t i o n as safe and efficacious. Reports have b e e n published regarding the r e s u l t s o f c e r t a i n c e n t e r s i n v o l v e d in this study.'* We provide a c o m p r e h e n s i v e s u m m a r y of t h e r e s u l t s o b t a i n e d on 1 , 1 1 7 t r e a t m e n t s o f 8 8 0 e y e s t r e a t e d at 2 0 c e n t e r s d u r i n g t h e c o u r s e of t h e s t u d y a n d e x a m i n e t h e effect o f t r e a t m e n t variables, glaucoma type, lens status, and d e m o g r a p h i c s in t e r m s o f s u c c e s s r a t e s . A d d i t i o n a l l y , we p r o v i d e c o m p r e h e n s i v e d o c u m e n tation of patient discomfort, complications, s i d e effects, a n d c h a n g e s in v i s u a l a c u i t y a n d m e d i c a t i o n l e v e l s after t r e a t m e n t .
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Patients and (Methods Description of the technique—Transducers h a v i n g an 8 0 - m m o u t e r d i a m e t e r , 9 0 - m m focal l e n g t h , a n d f r e q u e n c y o f 4 . 6 M H z w e r e u s e d in all c e n t e r s i n v o l v e d in this s t u d y . T h e t r a n s d u c ers p r o d u c e d an u l t r a s o u n d b e a m with a focal zone having a diameter of 0.4 mm and a length of 3 . 0 m m . T h e t r a n s d u c e r a s s e m b l y i n c l u d e d a d i a g n o s t i c A s c a n (for r a n g i n g ) a n d a c o a x i a l fiberoptic a i m i n g light c o n t a i n e d in a w a t e r filled p l a s t i c c o n e . A d e s c r i p t i o n o f the t h e r a p e u t i c u l t r a s o u n d d e v i c e a n d the b i o p h y s i c a l details of l e s i o n f o r m a t i o n h a s b e e n p r e v i o u s l y reported.' After giving i n f o r m e d c o n s e n t , the p a t i e n t s w e r e given r e t r o b u l b a r a n e s t h e s i a a n d t r e a t e d on an o u t p a t i e n t b a s i s . In s o m e i n s t a n c e s , c h i l dren w e r e t r e a t e d u n d e r light h a l o t h a n e a n e s thesia. T h e t r a n s d u c e r was c o u p l e d to the e y e w i t h a sterile, s a l i n e - f i l l e d w a t e r b a t h , s i m i l a r to t h a t u s e d in i m m e r s i o n u l t r a s o n o g r a p h y . T h i s w a s n e c e s s a r y b e c a u s e u l t r a s o u n d will n o t p r o p a gate t h r o u g h air. U s i n g the a i m i n g light a n d t h e cofocal A s c a n , the t r a n s d u c e r focal z o n e was d i r e c t e d o n t o the s c l e r a at a d i s t a n c e o f 2 to 3 m m from the c o r n e o s c l e r a l l i m b u s . U n d e r the study p r o t o c o l , four to six five-second a p p l i c a t i o n s w e r e to b e m a d e with a r a d i a t i o n f o r c e o f 3 g. T h e p o s i t i o n i n g o f the a p p l i c a t i o n s in c l o c k hours was recorded, though not specified, b e c a u s e this was n o t f o u n d to b e an i m p o r t a n t factor in e a r l i e r studies a n d r e t r e a t m e n t o v e r the s a m e z o n e at a later date was n o t p r e c l u d e d . Study organization—Each of the 8 8 0 patients e n r o l l e d in this study was t r e a t e d at o n e of 2 0 c e n t e r s l o c a t e d in the c o n t i n e n t a l U n i t e d S t a t e s . In a d d i t i o n to the p r i n c i p a l i n v e s t i g a t o r , most centers had additional physicians ap p r o v e d to p e r f o r m the p r o c e d u r e . P a t i e n t fol l o w - u p a n d r e c o r d i n g o f data w e r e p e r f o r m e d b y the t r e a t m e n t c e n t e r s or b y the r e f e r r i n g ophthalmologists. T h e c l i n i c a l trial was l i m i t e d to p a t i e n t s w i t h refractory g l a u c o m a w h o h a d n o t r e s p o n d e d to c o n v e n t i o n a l m a x i m a l m e d i c a l or s u r g i c a l t h e r apy. Surgical procedures included argon laser t r a b e c u l o p l a s t y , filtering p r o c e d u r e s , M o l t e n o tubes, and cryopexy. A small n u m b e r of pa t i e n t s n o t fulfilling the r e f r a c t o r y g l a u c o m a requirement were treated under individual w a i v e r s from t h e F o o d a n d D r u g A d m i n i s t r a tion.
Before treatment, demographic and clinical data w e r e r e c o r d e d for e a c h p a t i e n t , i n c l u d i n g pretreatment visual acuity, intraocular pres s u r e , t y p e a n d c a u s e of g l a u c o m a , s u r g i c a l a n d medical treatment history, and cornea, lens, a n g l e , v i t r e o u s , and r e t i n a l status. At the t i m e of t r e a t m e n t , t r e a t m e n t v a r i a b l e s ( n u m b e r o f a p p l i c a t i o n s , focal z o n e d e p t h , r a d i a t i o n f o r c e , a n d l e s i o n l o c a t i o n ) w e r e r e c o r d e d , as w e r e type of anesthesia, medications, and complica t i o n s , if a n y . S t a n d a r d i z e d r e p o r t f o r m s for the study, w h i c h i n c l u d e d i n t r a o c u l a r p r e s s u r e , v i s u a l a c u i t y , v i s u a l fields, m e d i c a t i o n , d i s c o m fort, c o m p l i c a t i o n s , a n d s t a t u s o f v a r i o u s o c u l a r s t r u c t u r e s , w e r e c o m p l e t e d at t w o to five h o u r s , o n e day, o n e w e e k , a n d o n e , t h r e e , s i x , a n d 12 m o n t h s after t r e a t m e n t . C o p i e s o f all r e p o r t s w e r e f o r w a r d e d b y t h e m a n u f a c t u r e r to the c l i n i c a l m o n i t o r i n g c e n t e r for a n a l y s i s . Statistical evaluation—Treatment efficacy was a s s e s s e d b y the e x a m i n a t i o n o f c h a n g e s in the a v e r a g e i n t r a o c u l a r p r e s s u r e o v e r t i m e a n d the u s e of K a p l a n - M e i e r l i f e t a b l e ( s u r v i v a l ) a n a l y sis, in w h i c h failure w a s defined as e i t h e r h y p o t o n y ( i n t r a o c u l a r p r e s s u r e l e s s t h a n or e q u a l to 5 m m H g ) or u n c o n t r o l l e d i n t r a o c u l a r p r e s sure. Uncontrolled intraocular pressure was a l t e r n a t e l y defined as i n t r a o c u l a r p r e s s u r e e x c e e d i n g a t h r e s h o l d of e i t h e r 2 2 or 2 5 m m Hg. E y e s s u b s e q u e n t l y t r e a t e d w i t h u l t r a s o u n d or any o t h e r form of g l a u c o m a t h e r a p y ( o t h e r t h a n drug t h e r a p y ) w e r e a l s o c l a s s i f i e d as f a i l u r e s . C h a n g e s in v i s u a l a c u i t y w e r e e x p r e s s e d in t e r m s of S n e l l e n l i n e s . C o u n t i n g fingers, h a n d motions, light perception, and no light percep tion w e r e e a c h c o u n t e d as o n e l i n e .
Results Study population—Of 8^0 patients, 4 4 6 were male and 4 2 7 were female. (The sex of seven p a t i e n t s was n o t r e c o r d e d . ) S i x h u n d r e d s e v enty-one patients were white, 152 were black, a n d 11 w e r e classified as o t h e r . ( T h e r a c e o f 4 6 p a t i e n t s w a s n o t r e c o r d e d . ) T h e e y e s of 2 9 8 patients were phakic and 5 1 4 were aphakic. ( T h e l e n s status o f 6 8 p a t i e n t s w a s n o t r e c o r d ed.) T h e t y p e s o f g l a u c o m a i n c l u d e d t h e f o l l o w ing: c o n g e n i t a l ( 7 1 p a t i e n t s ) ; p r i m a r y o p e n angle (205 patients); primary closed-angle (37 patients); secondary open-angle (88 patients); s e c o n d a r y c l o s e d - a n g l e ( 4 1 4 p a t i e n t s ) ; a n d un classified ( 6 5 p a t i e n t s ) . T h e t y p e s o f s e c o n d a r y g l a u c o m a i n c l u d e d the f o l l o w i n g : n e o v a s c u l a r
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(158 patients); uveitic (69 patients); aphakic or Pseudophakie (105 patients); traumatic (40 pa tients); and other types or unclassified ( 1 3 0 p a t i e n t s ) . P a t i e n t a g e r a n g e d from 2 t o 9 9 y e a r s (mean, 54.2 years). The mean intraocular pres sure b e f o r e t r e a t m e n t w a s 3 8 . 1 m m H g . T h e average p r e t r e a t m e n t v i s u a l a c u i t y w a s b e tween 2 0 / 2 0 0 and 2 0 / 4 0 0 . Of the 1,117 ultrasound treatments, 8 8 0 ( 7 8 . 8 % ) were initial treatments, 2 0 5 ( 1 8 . 4 % ) w e r e first r e t r e a t m e n t s , a n d 2 8 ( 2 . 5 % ) w e r e second retreatments. Three eyes were treated four t i m e s a n d o n e e y e w a s t r e a t e d five t i m e s . Treatment efficacy—The mean intraocular p r e s s u r e s b e f o r e a n d after t r e a t m e n t a r e s h o w n in F i g u r e 1. D u r i n g t h e c o u r s e o f t h e s t u d y , w e f o u n d that s o m e p a t i e n t s h a d p o s t t r e a t m e n t intraocular pressure increase. For this reason, several centers selectively reported intraocular p r e s s u r e s t a r t i n g i m m e d i a t e l y after t r e a t m e n t . T h e s e r e p o r t s s h o w e d an a v e r a g e i n c r e a s e in intraocular pressure of 2 2 . 8 m m Hg immediate ly after t r e a t m e n t .
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pressure reduction o f 10 m m Hg or more was 582 of 844 ( 6 9 % ) and 5 3 0 of 869 ( 6 1 % ) , respec t i v e l y . At o n e m o n t h o r m o r e after t r e a t m e n t , 228 of 9 9 4 reports ( 2 3 % ) showed intraocular pressure decrease o f 2 5 m m Hg or more (medi an d e c r e a s e , 1 4 m m H g ) . Treatment success rates, evaluated by survi val a n a l y s i s w i t h i n t r a o c u l a r p r e s s u r e failure t h r e s h o l d s o f 2 2 a n d 2 5 m m H g , a r e s h o w n in Figure 2 (top). Eyes with intraocular pressure above these thresholds or 5 m m Hg or less were classified as f a i l u r e s . S t a t i s t i c a l l y , f a i l u r e s t a k ing p l a c e at a n y p o i n t d u r i n g t h e s t u d y l o w e r e d the cumulative success rates for all subsequent intervals, whereas nonfailures were counted o n l y for t h e d u r a t i o n o f f o l l o w - u p . T h e r e s u l t s f o r a s i n g l e t r e a t m e n t s h o w 2 7 9 to 335 of 1,117 treatments ( 2 5 % to 3 0 % ) did n o t r e s p o n d t o t r e a t m e n t o r f a i l e d i n t h e first m o n t h after t r e a t m e n t . At s i x m o n t h s , c u m u l a t i v e s u c cess rates of 5 4 . 5 % a n d 4 8 . 7 % were observed, u s i n g t h e 2 5 - a n d 2 2 - m m H g t h r e s h o l d s . At o n e year, the success rates were 4 1 . 9 % and 3 8 . 1 % , respectively. T h e s e results indicate that o f the approxi mately 7 0 % to 7 5 % o f eyes that did show an i n i t i a l r e s p o n s e t o t r e a t m e n t , 6 0 % w e r e still s u c c e s s f u l l y c o n t r o l l e d w i t h o u t r e t r e a t m e n t af ter o n e y e a r . S i n c e e y e s t h a t failed t o r e s p o n d t o t r e a t m e n t or t h a t f a i l e d after s o m e t i m e c a n b e retreated, the success rates obtained using sin gle treatment survival analysis underestimate the t e c h n i q u e ' s potential for control o f intraoc ular pressure. T h e s u c c e s s r a t e s f o r m u l t i p l e t r e a t m e n t s , in which the duration of intraocular pressure con trol b y o n e o r m o r e t r e a t m e n t s is d e t e r m i n e d .
By two to five h o u r s after t r e a t m e n t , t h e m e a n intraocular pressure was virtually the same as the p r e t r e a t m e n t l e v e l . At t h i s t i m e , i n t r a o c u l a r pressure increase o f 5 m m Hg or more was recorded in only 8 3 o f 4 5 9 reports ( 1 8 % ) . B y o n e day p o s t t r e a t m e n t , o n l y 6 5 o f 8 0 8 r e p o r t s ( 8 % ) showed increased intraocular pressure, and b y o n e w e e k p o s t t r e a t m e n t , 2 5 o f 8 4 4 reports ( 3 % ) showed intraocular pressure in creases above pretreatment levels. By o n e day after t r e a t m e n t , 3 2 3 o f 8 0 8 r e p o r t s ( 4 0 % ) showed an intraocular pressure decrease of 1 0 m m H g o r m o r e . At o n e w e e k a n d o n e month, the number o f eyes with intraocular
Fig. 1 (Silverman and associates). Mean intraocular pressures ± 2 standard error be fore and at specified intervals after treat ment. Number of reports received at each interval, N, are indicated above each bar.
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a n a l y s i s , s u c c e s s w a s defined as m a i n t e n a n c e o f intraocular pressure between 6 and 25 m m Hg after a s i n g l e t r e a t m e n t . Effect of number of applications—Eyes were d i v i d e d i n t o t w o g r o u p s : t h o s e given s e v e n or m o r e a p p l i c a t i o n s a n d t h o s e g i v e n six or fewer applications. Eyes given more than six applica tions h a d a significantly higher success rate. T h i s is c o n s i s t e n t w i t h p r e v i o u s l y r e p o r t e d r e sults, which also indicated that seven or more treatments had a greater intraocular pressure l o w e r i n g effect b u t a h i g h e r c o m p l i c a t i o n r a t e . Effect of patient age—Patients were divided i n t o four a g e g r o u p i n g s : 1 5 y e a r s o r y o u n g e r , 1 6 to 3 5 y e a r s , 3 6 to 6 5 y e a r s , a n d o l d e r t h a n 6 5 years. T h e results showed that the success rate is l o w e s t in c h i l d r e n a n d h i g h e s t in p a t i e n t s o l d e r t h a n 6 5 y e a r s . T h e r e a p p e a r s to b e an a l m o s t direct r e l a t i o n s h i p b e t w e e n a g e a n d s u c c e s s r a t e . T h i s is s o m e w h a t different t h a n e a r l i er findings in w h i c h it a p p e a r e d t h a t c h i l d r e n h a d t h e l o w e s t s u c c e s s r a t e , b u t n o significant differences were found a m o n g the success rates in a d u l t s a s a f u n c t i o n o f age.^
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MONTHS
Fig. 2 (Silverman and associates). Cumulative suc cess rates computed with Kaplan-Meier survival analysis. Top, Survival curves for single treatment. Bottom, Survival curves in which retreated eyes are not classified as failures. (Failures not retreated at least once are excluded.) are s h o w n in F i g u r e 2 ( b o t t o m ) . S i n c e this a n a l y s i s w a s d e s i g n e d to d e t e r m i n e t h e efficacy of t h e m u l t i t r e a t m e n t r e g i m e n , e y e s t h a t failed after t h e initial t r e a t m e n t w i t h o u t at l e a s t o n e a t t e m p t at r e t r e a t m e n t w e r e n o t c o n s i d e r e d . O f the 5 5 9 that satisfied this c r i t e r i a , s i x - m o n t h s u c c e s s rates o f 8 7 . 0 % a n d 8 3 . 9 % w e r e f o u n d , using intraocular pressures of 25 and 22 m m Hg as t h e u p p e r cutoffs. T h e c o r r e s p o n d i n g o n e y e a r s u c c e s s rates w e r e 8 4 . 8 % a n d 7 9 . 3 % . Comparative analyses—To study t h e effect o f treatment and clinical variables, such as glau coma type, previous treatment history, and p r e t r e a t m e n t o c u l a r status, we e x a m i n e d t h e s u c c e s s p e r c e n t a g e at s i x m o n t h s p o s t t r e a t m e n t . A s t a t i s t i c a l ( l o g r a n k ) test for t h e p r o b a bility t h a t t h e difference in t h e c u m u l a t i v e s u c c e s s rates a m o n g t h e t e s t e d g r o u p s m i g h t have o c c u r r e d b y c h a n c e is given in T a b l e 1. In this
Response referred to pretreatment visual poten tial—Although t h e s t u d y w a s l i m i t e d to e y e s with r e f r a c t o r y g l a u c o m a , it w a s o f i n t e r e s t to d e t e r m i n e t h e efficacy o f t h e r a p e u t i c u l t r a s o u n d in eyes t h a t r e t a i n e d a h i g h d e g r e e o f visual f u n c t i o n . F o r this p u r p o s e , w e stratified the p o p u l a t i o n i n t o t w o g r o u p s : t h o s e w i t h visual acuity of 2 0 / 1 0 0 or better a n d those with visual a c u i t y w o r s e t h a n 2 0 / 1 0 0 . T h e r e s u l t s i n d i c a t e d t h a t t h e s u c c e s s rate a m o n g e y e s w i t h good visual function was significantly higher t h a n in t h o s e w i t h p o o r v i s u a l p o t e n t i a l . Response referred to glaucoma type—Analyses stratified a c c o r d i n g to t y p e o f g l a u c o m a a n d c a u s e (for s e c o n d a r y g l a u c o m a s ) i n d i c a t e d that t h e r a p e u t i c u l t r a s o u n d w a s m o s t effective in patients with primary o p e n - a n g l e glaucoma, s o m e w h a t l e s s s u c c e s s f u l for s e c o n d a r y g l a u c o mas, a n d l e a s t s u c c e s s f u l w i t h c o n g e n i t a l g l a u c o m a . T h e l o w s u c c e s s rate in c o n g e n i t a l g l a u coma may be caused by correlation with patient age. A m o n g the eyes with secondary glaucoma, the h i g h e s t s u c c e s s rate w a s f o u n d for g l a u c o m a s e c o n d a r y to u v e i t i s , c l o s e l y f o l l o w e d b y a p h a kic, P s e u d o p h a k i e , a n d t r a u m a t i c g l a u c o m a . Eyes with neovascular glaucoma h a d the lowest success rate. Other factors—Evaluation of race, sex, and l e n s status s h o w e d n o s i g n i f i c a n t c o r r e l a t i o n with treatment o u t c o m e . Retreated eyes were f o u n d to have a s o m e w h a t h i g h e r s u c c e s s r a t e
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TABLE 1 COMPARATIVE SINGLE-TREATMENT S U C C E S S RATES
SIX-MONTH VARIABLE
GROUP
NO.
SUCCESS' PERCENTAGE ρ VALUE
No. of appli cations
£ 6 >6
767 307
50.3 65.3
.0001
Treatment
Initial Retreatments
854 226
53.7 57.6
.4930
Age (years)
£ 15 16-35 36-65 > 65
71 173 442 390
44.1 50.2 53.6 59.4
.0078
Sex
Male Female
558 515
54.3 54.2
.6140
Race
Wtiite Black Otfier
828 186 18
53.1 58.2 46.9
.5735
Pretreatment visual acuity
> 20/100 < 20/100
282 700
66.3 49.4
A m u l t i c e n t e i c l i n i c a l t r i a l of t h e r a p e u t i c u l t r a s o u n d for t h e t r e a t m e n t o f g l a u c o m a i n cluded 20 c e n t e r s in t h e U n i t e d S t a t e s in w h i c h 1,117 t r e a t m e n t s w e r e p e r f o r m e d o n 8 8 0 eyes. T h e study was l i m i t e d to p a t i e n t s w i t h refractory g l a u c o m a w h o had not benefited from conventional m e d i c a l a n d surgical techn i q u e s . A p p r o x i m a t e l y 7 8 2 o f 1,117 t r e a t m e n t s (70%) s h o w e d a n i n i t i a l d e c r e a s e i n i n t r a o c u lar pressure from a p r e t r e a t m e n t m e a n of 38.1 m m Hg to 2 2 m m Hg o r l e s s . B y K a p l a n - M e i e r survival analysis, the single treatment success rate (intraocular p r e s s u r e b e t w e e n 6 a n d 22 m m Hg) was 48.7% at six m o n t h s p o s t t r e a t ment. When retreatment was used subsequent to f a i l u r e , t h e o n e - y e a r m u l t i t r e a t m e n t s u c cess rate was 79.3%. T h e most c o m m o n c o m plications were an i m m e d i a t e posttreatment intraocular pressure i n c r e a s e lasting a few hours and mild iritis. Other complications i n c l u d e d s c l e r a l t h i n n i n g i n 2 8 o f 1,117 t r e a t m e n t s (2.5%) a n d p h t h i s i s b u l b i i n 1 2 of 1,117 t r e a t m e n t s (1.1%).
U N T I L R E C E N T L Y t h e t h e r a p e u t i c o p t i o n s for patients with refractory glaucoma were severely l i m i t e d . T h e m o s t c o m m o n l y p e r f o r m e d p r o c e d u r e for p a t i e n t s w h o did n o t r e s p o n d to
Accepted for publication Dec. 12, 1990. From the Department of Ophthalmology, Cornell University Medical College, h¡ew York, New York. This study was supported in part by Research to Prevent Blindness, Inc., the Dyson Foundation, and the Rudin Foundation. The multicenter clinical trial was sponsored by Sonocare, Inc. The device described in this article is licensed to Sonocare, Inc., by the Cornell Research Foundation, Ithaca, New York. Dr. Coleman has a proprietary interest in this technique. Licensing fees help support the Department of Ophthalmology, Cornell University Medical Center. Reprint requests to D, Jackson Coleman, M.D., Department of Ophthalmology, Cornell University Medical College, 1300 York Ave., New York, NY 10021.
surgical intervention was cyclocryotherapy. Alt h o u g h t h i s p r o c e d u r e is effective in d e c r e a s i n g i n t r a o c u l a r p r e s s u r e , it is a l s o a s s o c i a t e d w i t h a h i g h rate o f o c u l a r m o r b i d i t y a n d p a t i e n t d i s c o m f o r t . After o b s e r v i n g t h a t a f o c u s e d b e a m o f h i g h - i n t e n s i t y u l t r a s o u n d is c a p a b l e o f f o r m i n g s c l e r a l l e s i o n s t h r o u g h t h e r m a l effects,''^ we b e g a n to i n v e s t i g a t e t h e p o s s i b i l i t y that t h i s m o d a l i t y m i g h t b e u s e d for t r e a t m e n t o f g l a u c o ma either by decreased aqueous production t h r o u g h c i l i o d e s t r u c t i o n or b y i n c r e a s e d outflow t h r o u g h t h e u v e a or t h e t r a n s s c l e r a l r o u t e . In 1 9 8 5 , w e d e s c r i b e d t h e effects o f h i g h i n t e n s i t y f o c u s e d u l t r a s o u n d on g l a u c o m a in an a n i m a l m o d e l ' a n d in a s m a l l g r o u p o f p a t i e n t s with end-stage glaucoma." Because of the enc o u r a g i n g r e s u l t s of t h e s e p i l o t s t u d i e s , p a t i e n t s c o n t i n u e d to b e e n r o l l e d at t h e N e w York H o s pital-Cornell Medical Center, and articles on a l a r g e r c l i n i c a l s t u d y w e r e p u b l i s h e d in 1 9 8 6 . ^ " In 1 9 8 5 , C o r n e l l U n i v e r s i t y M e d i c a l C o l l e g e , through the Cornell Research Foundation, lic e n s e d t h e u l t r a s o u n d t e c h n o l o g y d e v e l o p e d in our l a b o r a t o r y to S o n o c a r e , I n c . S o n o c a r e org a n i z e d a m u l t i c e n t e r c l i n i c a l trial u n d e r F o o d and Drug Administration guidelines involving 20 centers, including Cornell University Medical C o l l e g e . O n e o f us ( D . J . C . ) a c t e d as t h e c l i n i c a l m o n i t o r o f t h i s s t u d y . In 1 9 8 8 , after c o m p l e t i o n of t h e s t u d y e n r o l l m e n t g o a l s a n d analysis of results, the procedure was approved b y t h e F o o d a n d D r u g A d m i n i s t r a t i o n as safe and efficacious. Reports have b e e n published regarding the r e s u l t s o f c e r t a i n c e n t e r s i n v o l v e d in this study.'* We provide a c o m p r e h e n s i v e s u m m a r y of t h e r e s u l t s o b t a i n e d on 1 , 1 1 7 t r e a t m e n t s o f 8 8 0 e y e s t r e a t e d at 2 0 c e n t e r s d u r i n g t h e c o u r s e of t h e s t u d y a n d e x a m i n e t h e effect o f t r e a t m e n t variables, glaucoma type, lens status, and d e m o g r a p h i c s in t e r m s o f s u c c e s s r a t e s . A d d i t i o n a l l y , we p r o v i d e c o m p r e h e n s i v e d o c u m e n tation of patient discomfort, complications, s i d e effects, a n d c h a n g e s in v i s u a l a c u i t y a n d m e d i c a t i o n l e v e l s after t r e a t m e n t .
©AMERICAN JOURNAL OF OPHTHALMOLOGY 111:327-337, MARCH,
1991
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MarcJi, 1991
AMERICAN JOURNAL OF OPHTHALMOLOGY
Patients and (Methods Description of the technique—Transducers h a v i n g an 8 0 - m m o u t e r d i a m e t e r , 9 0 - m m focal l e n g t h , a n d f r e q u e n c y o f 4 . 6 M H z w e r e u s e d in all c e n t e r s i n v o l v e d in this s t u d y . T h e t r a n s d u c ers p r o d u c e d an u l t r a s o u n d b e a m with a focal zone having a diameter of 0.4 mm and a length of 3 . 0 m m . T h e t r a n s d u c e r a s s e m b l y i n c l u d e d a d i a g n o s t i c A s c a n (for r a n g i n g ) a n d a c o a x i a l fiberoptic a i m i n g light c o n t a i n e d in a w a t e r filled p l a s t i c c o n e . A d e s c r i p t i o n o f the t h e r a p e u t i c u l t r a s o u n d d e v i c e a n d the b i o p h y s i c a l details of l e s i o n f o r m a t i o n h a s b e e n p r e v i o u s l y reported.' After giving i n f o r m e d c o n s e n t , the p a t i e n t s w e r e given r e t r o b u l b a r a n e s t h e s i a a n d t r e a t e d on an o u t p a t i e n t b a s i s . In s o m e i n s t a n c e s , c h i l dren w e r e t r e a t e d u n d e r light h a l o t h a n e a n e s thesia. T h e t r a n s d u c e r was c o u p l e d to the e y e w i t h a sterile, s a l i n e - f i l l e d w a t e r b a t h , s i m i l a r to t h a t u s e d in i m m e r s i o n u l t r a s o n o g r a p h y . T h i s w a s n e c e s s a r y b e c a u s e u l t r a s o u n d will n o t p r o p a gate t h r o u g h air. U s i n g the a i m i n g light a n d t h e cofocal A s c a n , the t r a n s d u c e r focal z o n e was d i r e c t e d o n t o the s c l e r a at a d i s t a n c e o f 2 to 3 m m from the c o r n e o s c l e r a l l i m b u s . U n d e r the study p r o t o c o l , four to six five-second a p p l i c a t i o n s w e r e to b e m a d e with a r a d i a t i o n f o r c e o f 3 g. T h e p o s i t i o n i n g o f the a p p l i c a t i o n s in c l o c k hours was recorded, though not specified, b e c a u s e this was n o t f o u n d to b e an i m p o r t a n t factor in e a r l i e r studies a n d r e t r e a t m e n t o v e r the s a m e z o n e at a later date was n o t p r e c l u d e d . Study organization—Each of the 8 8 0 patients e n r o l l e d in this study was t r e a t e d at o n e of 2 0 c e n t e r s l o c a t e d in the c o n t i n e n t a l U n i t e d S t a t e s . In a d d i t i o n to the p r i n c i p a l i n v e s t i g a t o r , most centers had additional physicians ap p r o v e d to p e r f o r m the p r o c e d u r e . P a t i e n t fol l o w - u p a n d r e c o r d i n g o f data w e r e p e r f o r m e d b y the t r e a t m e n t c e n t e r s or b y the r e f e r r i n g ophthalmologists. T h e c l i n i c a l trial was l i m i t e d to p a t i e n t s w i t h refractory g l a u c o m a w h o h a d n o t r e s p o n d e d to c o n v e n t i o n a l m a x i m a l m e d i c a l or s u r g i c a l t h e r apy. Surgical procedures included argon laser t r a b e c u l o p l a s t y , filtering p r o c e d u r e s , M o l t e n o tubes, and cryopexy. A small n u m b e r of pa t i e n t s n o t fulfilling the r e f r a c t o r y g l a u c o m a requirement were treated under individual w a i v e r s from t h e F o o d a n d D r u g A d m i n i s t r a tion.
Before treatment, demographic and clinical data w e r e r e c o r d e d for e a c h p a t i e n t , i n c l u d i n g pretreatment visual acuity, intraocular pres s u r e , t y p e a n d c a u s e of g l a u c o m a , s u r g i c a l a n d medical treatment history, and cornea, lens, a n g l e , v i t r e o u s , and r e t i n a l status. At the t i m e of t r e a t m e n t , t r e a t m e n t v a r i a b l e s ( n u m b e r o f a p p l i c a t i o n s , focal z o n e d e p t h , r a d i a t i o n f o r c e , a n d l e s i o n l o c a t i o n ) w e r e r e c o r d e d , as w e r e type of anesthesia, medications, and complica t i o n s , if a n y . S t a n d a r d i z e d r e p o r t f o r m s for the study, w h i c h i n c l u d e d i n t r a o c u l a r p r e s s u r e , v i s u a l a c u i t y , v i s u a l fields, m e d i c a t i o n , d i s c o m fort, c o m p l i c a t i o n s , a n d s t a t u s o f v a r i o u s o c u l a r s t r u c t u r e s , w e r e c o m p l e t e d at t w o to five h o u r s , o n e day, o n e w e e k , a n d o n e , t h r e e , s i x , a n d 12 m o n t h s after t r e a t m e n t . C o p i e s o f all r e p o r t s w e r e f o r w a r d e d b y t h e m a n u f a c t u r e r to the c l i n i c a l m o n i t o r i n g c e n t e r for a n a l y s i s . Statistical evaluation—Treatment efficacy was a s s e s s e d b y the e x a m i n a t i o n o f c h a n g e s in the a v e r a g e i n t r a o c u l a r p r e s s u r e o v e r t i m e a n d the u s e of K a p l a n - M e i e r l i f e t a b l e ( s u r v i v a l ) a n a l y sis, in w h i c h failure w a s defined as e i t h e r h y p o t o n y ( i n t r a o c u l a r p r e s s u r e l e s s t h a n or e q u a l to 5 m m H g ) or u n c o n t r o l l e d i n t r a o c u l a r p r e s sure. Uncontrolled intraocular pressure was a l t e r n a t e l y defined as i n t r a o c u l a r p r e s s u r e e x c e e d i n g a t h r e s h o l d of e i t h e r 2 2 or 2 5 m m Hg. E y e s s u b s e q u e n t l y t r e a t e d w i t h u l t r a s o u n d or any o t h e r form of g l a u c o m a t h e r a p y ( o t h e r t h a n drug t h e r a p y ) w e r e a l s o c l a s s i f i e d as f a i l u r e s . C h a n g e s in v i s u a l a c u i t y w e r e e x p r e s s e d in t e r m s of S n e l l e n l i n e s . C o u n t i n g fingers, h a n d motions, light perception, and no light percep tion w e r e e a c h c o u n t e d as o n e l i n e .
Results Study population—Of 8^0 patients, 4 4 6 were male and 4 2 7 were female. (The sex of seven p a t i e n t s was n o t r e c o r d e d . ) S i x h u n d r e d s e v enty-one patients were white, 152 were black, a n d 11 w e r e classified as o t h e r . ( T h e r a c e o f 4 6 p a t i e n t s w a s n o t r e c o r d e d . ) T h e e y e s of 2 9 8 patients were phakic and 5 1 4 were aphakic. ( T h e l e n s status o f 6 8 p a t i e n t s w a s n o t r e c o r d ed.) T h e t y p e s o f g l a u c o m a i n c l u d e d t h e f o l l o w ing: c o n g e n i t a l ( 7 1 p a t i e n t s ) ; p r i m a r y o p e n angle (205 patients); primary closed-angle (37 patients); secondary open-angle (88 patients); s e c o n d a r y c l o s e d - a n g l e ( 4 1 4 p a t i e n t s ) ; a n d un classified ( 6 5 p a t i e n t s ) . T h e t y p e s o f s e c o n d a r y g l a u c o m a i n c l u d e d the f o l l o w i n g : n e o v a s c u l a r
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Therapeutic Ultrasoimd for Glaucoma Treatment
(158 patients); uveitic (69 patients); aphakic or Pseudophakie (105 patients); traumatic (40 pa tients); and other types or unclassified ( 1 3 0 p a t i e n t s ) . P a t i e n t a g e r a n g e d from 2 t o 9 9 y e a r s (mean, 54.2 years). The mean intraocular pres sure b e f o r e t r e a t m e n t w a s 3 8 . 1 m m H g . T h e average p r e t r e a t m e n t v i s u a l a c u i t y w a s b e tween 2 0 / 2 0 0 and 2 0 / 4 0 0 . Of the 1,117 ultrasound treatments, 8 8 0 ( 7 8 . 8 % ) were initial treatments, 2 0 5 ( 1 8 . 4 % ) w e r e first r e t r e a t m e n t s , a n d 2 8 ( 2 . 5 % ) w e r e second retreatments. Three eyes were treated four t i m e s a n d o n e e y e w a s t r e a t e d five t i m e s . Treatment efficacy—The mean intraocular p r e s s u r e s b e f o r e a n d after t r e a t m e n t a r e s h o w n in F i g u r e 1. D u r i n g t h e c o u r s e o f t h e s t u d y , w e f o u n d that s o m e p a t i e n t s h a d p o s t t r e a t m e n t intraocular pressure increase. For this reason, several centers selectively reported intraocular p r e s s u r e s t a r t i n g i m m e d i a t e l y after t r e a t m e n t . T h e s e r e p o r t s s h o w e d an a v e r a g e i n c r e a s e in intraocular pressure of 2 2 . 8 m m Hg immediate ly after t r e a t m e n t .
329
pressure reduction o f 10 m m Hg or more was 582 of 844 ( 6 9 % ) and 5 3 0 of 869 ( 6 1 % ) , respec t i v e l y . At o n e m o n t h o r m o r e after t r e a t m e n t , 228 of 9 9 4 reports ( 2 3 % ) showed intraocular pressure decrease o f 2 5 m m Hg or more (medi an d e c r e a s e , 1 4 m m H g ) . Treatment success rates, evaluated by survi val a n a l y s i s w i t h i n t r a o c u l a r p r e s s u r e failure t h r e s h o l d s o f 2 2 a n d 2 5 m m H g , a r e s h o w n in Figure 2 (top). Eyes with intraocular pressure above these thresholds or 5 m m Hg or less were classified as f a i l u r e s . S t a t i s t i c a l l y , f a i l u r e s t a k ing p l a c e at a n y p o i n t d u r i n g t h e s t u d y l o w e r e d the cumulative success rates for all subsequent intervals, whereas nonfailures were counted o n l y for t h e d u r a t i o n o f f o l l o w - u p . T h e r e s u l t s f o r a s i n g l e t r e a t m e n t s h o w 2 7 9 to 335 of 1,117 treatments ( 2 5 % to 3 0 % ) did n o t r e s p o n d t o t r e a t m e n t o r f a i l e d i n t h e first m o n t h after t r e a t m e n t . At s i x m o n t h s , c u m u l a t i v e s u c cess rates of 5 4 . 5 % a n d 4 8 . 7 % were observed, u s i n g t h e 2 5 - a n d 2 2 - m m H g t h r e s h o l d s . At o n e year, the success rates were 4 1 . 9 % and 3 8 . 1 % , respectively. T h e s e results indicate that o f the approxi mately 7 0 % to 7 5 % o f eyes that did show an i n i t i a l r e s p o n s e t o t r e a t m e n t , 6 0 % w e r e still s u c c e s s f u l l y c o n t r o l l e d w i t h o u t r e t r e a t m e n t af ter o n e y e a r . S i n c e e y e s t h a t failed t o r e s p o n d t o t r e a t m e n t or t h a t f a i l e d after s o m e t i m e c a n b e retreated, the success rates obtained using sin gle treatment survival analysis underestimate the t e c h n i q u e ' s potential for control o f intraoc ular pressure. T h e s u c c e s s r a t e s f o r m u l t i p l e t r e a t m e n t s , in which the duration of intraocular pressure con trol b y o n e o r m o r e t r e a t m e n t s is d e t e r m i n e d .
By two to five h o u r s after t r e a t m e n t , t h e m e a n intraocular pressure was virtually the same as the p r e t r e a t m e n t l e v e l . At t h i s t i m e , i n t r a o c u l a r pressure increase o f 5 m m Hg or more was recorded in only 8 3 o f 4 5 9 reports ( 1 8 % ) . B y o n e day p o s t t r e a t m e n t , o n l y 6 5 o f 8 0 8 r e p o r t s ( 8 % ) showed increased intraocular pressure, and b y o n e w e e k p o s t t r e a t m e n t , 2 5 o f 8 4 4 reports ( 3 % ) showed intraocular pressure in creases above pretreatment levels. By o n e day after t r e a t m e n t , 3 2 3 o f 8 0 8 r e p o r t s ( 4 0 % ) showed an intraocular pressure decrease of 1 0 m m H g o r m o r e . At o n e w e e k a n d o n e month, the number o f eyes with intraocular
Fig. 1 (Silverman and associates). Mean intraocular pressures ± 2 standard error be fore and at specified intervals after treat ment. Number of reports received at each interval, N, are indicated above each bar.
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330
AMERICAN JOURNAL OF OPHTHALMOLOGY
a n a l y s i s , s u c c e s s w a s defined as m a i n t e n a n c e o f intraocular pressure between 6 and 25 m m Hg after a s i n g l e t r e a t m e n t . Effect of number of applications—Eyes were d i v i d e d i n t o t w o g r o u p s : t h o s e given s e v e n or m o r e a p p l i c a t i o n s a n d t h o s e g i v e n six or fewer applications. Eyes given more than six applica tions h a d a significantly higher success rate. T h i s is c o n s i s t e n t w i t h p r e v i o u s l y r e p o r t e d r e sults, which also indicated that seven or more treatments had a greater intraocular pressure l o w e r i n g effect b u t a h i g h e r c o m p l i c a t i o n r a t e . Effect of patient age—Patients were divided i n t o four a g e g r o u p i n g s : 1 5 y e a r s o r y o u n g e r , 1 6 to 3 5 y e a r s , 3 6 to 6 5 y e a r s , a n d o l d e r t h a n 6 5 years. T h e results showed that the success rate is l o w e s t in c h i l d r e n a n d h i g h e s t in p a t i e n t s o l d e r t h a n 6 5 y e a r s . T h e r e a p p e a r s to b e an a l m o s t direct r e l a t i o n s h i p b e t w e e n a g e a n d s u c c e s s r a t e . T h i s is s o m e w h a t different t h a n e a r l i er findings in w h i c h it a p p e a r e d t h a t c h i l d r e n h a d t h e l o w e s t s u c c e s s r a t e , b u t n o significant differences were found a m o n g the success rates in a d u l t s a s a f u n c t i o n o f age.^
lOP-etoZSmmHf lOP-etanmmHg
MONTHS
100. 90. 80.
S ™
20l O P . β to 26 mmHg lOP - β to 22 mmHg
10.
0
3
β
9
March, 1991
12
MONTHS
Fig. 2 (Silverman and associates). Cumulative suc cess rates computed with Kaplan-Meier survival analysis. Top, Survival curves for single treatment. Bottom, Survival curves in which retreated eyes are not classified as failures. (Failures not retreated at least once are excluded.) are s h o w n in F i g u r e 2 ( b o t t o m ) . S i n c e this a n a l y s i s w a s d e s i g n e d to d e t e r m i n e t h e efficacy of t h e m u l t i t r e a t m e n t r e g i m e n , e y e s t h a t failed after t h e initial t r e a t m e n t w i t h o u t at l e a s t o n e a t t e m p t at r e t r e a t m e n t w e r e n o t c o n s i d e r e d . O f the 5 5 9 that satisfied this c r i t e r i a , s i x - m o n t h s u c c e s s rates o f 8 7 . 0 % a n d 8 3 . 9 % w e r e f o u n d , using intraocular pressures of 25 and 22 m m Hg as t h e u p p e r cutoffs. T h e c o r r e s p o n d i n g o n e y e a r s u c c e s s rates w e r e 8 4 . 8 % a n d 7 9 . 3 % . Comparative analyses—To study t h e effect o f treatment and clinical variables, such as glau coma type, previous treatment history, and p r e t r e a t m e n t o c u l a r status, we e x a m i n e d t h e s u c c e s s p e r c e n t a g e at s i x m o n t h s p o s t t r e a t m e n t . A s t a t i s t i c a l ( l o g r a n k ) test for t h e p r o b a bility t h a t t h e difference in t h e c u m u l a t i v e s u c c e s s rates a m o n g t h e t e s t e d g r o u p s m i g h t have o c c u r r e d b y c h a n c e is given in T a b l e 1. In this
Response referred to pretreatment visual poten tial—Although t h e s t u d y w a s l i m i t e d to e y e s with r e f r a c t o r y g l a u c o m a , it w a s o f i n t e r e s t to d e t e r m i n e t h e efficacy o f t h e r a p e u t i c u l t r a s o u n d in eyes t h a t r e t a i n e d a h i g h d e g r e e o f visual f u n c t i o n . F o r this p u r p o s e , w e stratified the p o p u l a t i o n i n t o t w o g r o u p s : t h o s e w i t h visual acuity of 2 0 / 1 0 0 or better a n d those with visual a c u i t y w o r s e t h a n 2 0 / 1 0 0 . T h e r e s u l t s i n d i c a t e d t h a t t h e s u c c e s s rate a m o n g e y e s w i t h good visual function was significantly higher t h a n in t h o s e w i t h p o o r v i s u a l p o t e n t i a l . Response referred to glaucoma type—Analyses stratified a c c o r d i n g to t y p e o f g l a u c o m a a n d c a u s e (for s e c o n d a r y g l a u c o m a s ) i n d i c a t e d that t h e r a p e u t i c u l t r a s o u n d w a s m o s t effective in patients with primary o p e n - a n g l e glaucoma, s o m e w h a t l e s s s u c c e s s f u l for s e c o n d a r y g l a u c o mas, a n d l e a s t s u c c e s s f u l w i t h c o n g e n i t a l g l a u c o m a . T h e l o w s u c c e s s rate in c o n g e n i t a l g l a u coma may be caused by correlation with patient age. A m o n g the eyes with secondary glaucoma, the h i g h e s t s u c c e s s rate w a s f o u n d for g l a u c o m a s e c o n d a r y to u v e i t i s , c l o s e l y f o l l o w e d b y a p h a kic, P s e u d o p h a k i e , a n d t r a u m a t i c g l a u c o m a . Eyes with neovascular glaucoma h a d the lowest success rate. Other factors—Evaluation of race, sex, and l e n s status s h o w e d n o s i g n i f i c a n t c o r r e l a t i o n with treatment o u t c o m e . Retreated eyes were f o u n d to have a s o m e w h a t h i g h e r s u c c e s s r a t e
Vol. I l l , No. 3
Therapeutic Ultrasound for Glaucoma Treatment
TABLE 1 COMPARATIVE SINGLE-TREATMENT S U C C E S S RATES
SIX-MONTH VARIABLE
GROUP
NO.
SUCCESS' PERCENTAGE ρ VALUE
No. of appli cations
£ 6 >6
767 307
50.3 65.3
.0001
Treatment
Initial Retreatments
854 226
53.7 57.6
.4930
Age (years)
£ 15 16-35 36-65 > 65
71 173 442 390
44.1 50.2 53.6 59.4
.0078
Sex
Male Female
558 515
54.3 54.2
.6140
Race
Wtiite Black Otfier
828 186 18
53.1 58.2 46.9
.5735
Pretreatment visual acuity
> 20/100 < 20/100
282 700
66.3 49.4
