Slit-lamp studies of the rhesus monkey eye

Exp. Eye Res. ( ! 987) 44, 307-318

Slit-la~p Studies of the Rhesus Monkey Eye. I. S u r v e y o f t h e A n t e r i o r S e g m e n t ,JAN ~ F. K O R F T Z * ~ , AN~;E

n.

BERTASSO*.

3 I l C l l A E L W . N E I D E R +, P A U L L . I ~ A U F M A Y ; : ~ , C..IEAN !)EI1oussEAU§ A N D I, A S Z I , O Z ! ~ I T O ¶

* B i o p h y s i c s (.:ronp a ~ d D e p a r t m e n t q f Biology, Rensselaer lSglytechnic Institute. "?"roy. ~V, ) " 1~1,.0-'3.~30. 9 ~: ,..'.e $ Departme~,t ~ O p h t h a l m o l ~ y , UnD,e ity o f |I'isconsin ( T i u i I ,~cte~ee, nler. 600 Hiffhland A~e~ue. 3 1 a d ~ o n , W I 53792, § D e p a ~ m e n / o f . . Univer.s'it?/, ~o A nthropol . . N. e w )'ork e" l|'a~,erly Place, N e w )'orlc. N ] " 10003 , a n d ¶l D e p a r t m e n t %¢ Ophthalmology, College of P h y s i c i a n s and Surgeons, Columbia I ~~ i v e r s it.~..,. 6 3 0 I !T. 1 6 8 t h St re e t, ,Y e **, ) "or k N )" 1 0 0 3 2 . ~7. S . A . (Accepted in revised.form 25 A u g u s t 1986) Slit-lamp i~hot(~graphie studies ~)t" 144 cage(| rhesus monkeys, age(l 2 m o n t h s tc~ 35 year:~, show a ~ - r c l a t e d ehan s in anteri~r-chamt~er (lel)th. lens thickness, anterior and t~osterior curvatures of the tens, and Ioeaticm (Jr the t)t~sterior lens surfilce relative t~ the anterior cornea| surfil(u,. For these parameters, as well as fi~r those measured by other tecl~niques, a ditl'eret~ce in slotm mag~itu(te and (~w) sl~)l)e sign was tbtt~(l between the growth phase which lasts for ~ 6 years, at~tl tim adult l~hase (greater than .5--6 years). Age-related eha~ges in the adult rhesus eye are (lualitative|y similar in altnost al} aspects tt) those o})st.rvett it~ the h u m a n eye. in(tieating that the rhesus is a goo(t at~itnal m()(tel for the s t u d y of hultlan loss of a c c o m m o d a t i v e amplitude. Key ~twrd,u: aeeotnmotlation; |)res|)yt~l)ia; Scheimpflug p h o t o g r a p h y : crystal|ine lens: anterior eJlatll|~('r: |ells s|tal)e; ]etlts thickness: /'estitlg refraction ; animal model.

I. I n t r o d u c t i o n

Tile m e c h a n i s m s o f a e e o m t n o d a t . i o t l a n d a g e - r e l a t e d a c c o r n n l o ( t a t i v e loss in t h e tlulnatl e y e a r e still 1-tot well u n d e r s t o o d . A c c o m m o t l a t i o n i n v o l v e s a colltrc, lled c h a n g e ill lens t h i c k n e s s a n d c u r v a t u r e , a p p a r e n t l y m e d i a t e d m a i n l y t h r o u g h c o n t r a c t i o n of t h e c i l i a r y m u s c l e , w h i c h cl~anges t h e stress e x e r t e d ,.)n t h e lens b y t h e z o n u l a r a p p a r a t u s . D e s p i t e a t t e m p t s to m o d e l t h i s p r o c e s s (e.g. O ' N e i l l a n d Doyle, ! 968- C o l e m a n . ! 9 7 0 ; K o r e t z a n d H a n d e l m a n , 1982, 1983), ttle r e l a t i v e roles o f l e n s elastic r e c o v e r y , chaIlge in zotlttlar s t r e s s t)att, erlls, a n d v i t r e o u s s u p p o r t h a v e n o t been u n e q u i v o c a l l y defined. T h e c a u s e s o f t h e ( l e v e l o p t n e n t o f p r e s b y o p i a a r e e v e n less clear. , • l¢~esearcbers b a r e s u g s t e d such d i v e r s e p r o c e s s e s as h a r d e n i n g o f t h e lens, a t r o p h y o f t b e c i l i a r y muscle. a n d l i q u e f i c a t i q n of t h e v i t r e o u s ( C a r t e r . 1982). I t is elear that, to i n v e s t i g a t e possible m e c h a n i s m s of a c c o m m o d a t i o n a n d t h e d e v e l o p m e n t o f p r e s b y o p i a , r e s e a r c l l e r s m u s t find a n d c h a r a c t e r i z e all a l l i m a l tnodel wllict~ l~rovi(tes t h e p o s s i b i l i t y o f i n v a s i v e studies. I n 1982, B i t o , D e R o u s s e a u , Kaufina~-~ a n d B i t o s u g g e s t e d t h a t t,l~e r h e s u s m o n k e y m i g h t be a n a p t ) r o p r i a t e a l l i m a l too(tel. In rllesus t n o n k e y s , as in h u m a n s , t h e a m p l i t u d e o f tt!e a c c o m m o d a t i v e r a n g e d e c r e a s e s w i t h age. Allowing for di rences in lifespan a n d a c c o m m o d a t i v e a m p l i t u d e itl t h e t w o species, t h e p r o c e s s a p p e a r s to o c c u r t o a c o m p a r a b l e e x t e n t witl~ a s i m i l a r t i m e course. F u r t h e r m o r e , B i t o e t al. ' s h o w e d t h a t a c c o m m o d a t i o n in rl~esus m o n k-e 3 ,s o f all ages itl vol yes at~ increase (1,9 82) in lens t h i c k n e s s , as it d o e s in t h e h u m a n . T o t e s t f u r t h e r t h e s u i t a b i l i t y o f t h e r h e s u s $ To whom eorresl)ondence sllouhl be a(ldresse~t. 0~) 1 4 - 4 8 3 5 / 8 7 / 0 2 0 3 0 7

+ ! 2 $03.

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(~) 1987 Academic Press ! no, ( l , o n d o n ) Limited

308

J . F . K O R ~ T Z ET A L.

as a n a n i m a l m o d e l for h u m a n a c c o m m o d a t i o n , we h a v e i n i t i a t e d a n i n t e n s i v e series o f s t u d i e s o f r h e s u s colonies a t b o t h t h e U n i v e r s i t y o f W i s c o n s i n - M a d i s o n a n d C o S a n t i a g o in P u e r t o Rico. O n e such s t u d y i n v o l v e s c h a r a c t e r i z a t i o n o f t h e r h e s u s a n t e r i o r o c u l a r s e g m e n t , u s i n g s l i t - l a m p S c h e i m p f l u g p h o t o g r a p h y on a s u b s e t o f t h e W i s c o n s i n p o p u l a t i o n . T h i s s t u d y is a n a l o g o u s to B r o w n ' s c h a c t e r i z a t i o n o f a c c o m m o d a t i o n a n d p r e s b y o p i a in t h e hu a n eye (1973a, b; 1974a, b). In t h i s a n d s u b s e q u e n t p a p e r s , t h e o p t i c a l p a r a m e t e r s t h a t can be m e a s u r e d b y s l i t - l a m p p h o t o g r a p h y will be e v a l u a t e d in t e r m s of s u b j e c t age a n d p o i n t s o f si i l a r i t y to t h e h u m a n . T h i s first r e p o r t p r e s e n t s a s u r v e y o f 144 r h e s u s m o n k e y s u n d e r t a k e n t o m e a s u r e a n t e r i o r - c h a m b e r d e p t h , lens t h i c k n e s s a n d c u r v a t u r e , a n d t h e p o s i t i o n o f t h e p o s t e r i o r lens r e l a t i v e to t h e c o r n e a a t r e s t i n g r e f r a c t i o n .

2. M a t e r i a l s a n d M e t h o d s Anin~al selection and ~ t a collection One hundred and fiarty-four rhesus monkeys (Maraca m u l a t t a ) o f botll sexes and ranging in age from 2 months to 35 years were examined. All of ttle Inonkeys belonged to the Wisconsin Regional Primate Research nter or tile Primate L a b o r a t o r y of the Psych()logy p a r t m e n t of the University of Wisconsin. both in Madison, Wisconsin. The s | i t - | a m p photographic d a t a on these sul~jects were collected during the summers of 1983 or 1984, and all of the monkeys considered here were also p a r t of a l a ~ e r survey on rhesus vision and aging. T h e y t majority of eyes were surgically u n t o u c h e d ; a ~ w had undergone total ividectomy (Kaufiman and Lfitjen-DrecoIl, 1975) 3 or more m o n t h s earlier. E x c e p t for senile cataractous lens changes in the most elderly animals, all eyes appeared biomicroscopically normal. Animals were an sthetized according to the procedure of Bito et al. (1982) using i n t r a m u s c u l a r ketamine HCI (10 mg kg -I) l~llowed by i n t r a m u s c u l a r acepromazine maleate (l mg kg-~). Both pupils were then dilated by applying 50~1 of commercial ophthalmic pheny/eI)hrine HC/ (2"5-or 10%) to the corneas. D a t a were then collected in the fi~/lowing sequence" (a) Central anterior cornea| c u r v a t u r e was determined with a l~ausch & [,ornb keratometer, whose range was extended by a + 1.25 l) spherical Bausch & Lomb orthogon lens (Manning and Miller, !978). (b) Resting re orion, the lens power requi d to render the ~ e e m m e t r o p i c in the spectacle plane 15 mm anterior to the cornea, was determined with a H a r t i n g e r coincidence refractometer. It has been shown (Bito et al., 1982) t h a t this value is a b o u t 0"5 D more negative for anesthetized monkeys. (c) Slit-lamp photographs were taken using a tilted film plane camera ~imi|ar to t h a t described by Brown (i972). The camera had a conventionM 35-ram motorized Nikon body with a 55-ram f 2 - 8 lens m o u n ~ d on a 52"5-mm extension tube. Magnification was set at × !-33 and the left edge of the film plane , when viewed m behind, was tilted 43-'25 o away from the normal planes of the film and lens. The conventional viewing screen was replaced by a correspondingly tilted screen with three etched positioning lines, one bisecting the screen horizontally and two vertical lines placed 3 mm and 6 mm from the lel2~ edge. The camera was mounted on a fixed s u p p o r t with an adjustable ~ c u s i n g track a t t a c h e d to the central pivot p o s t of a Zeiss Photo-Slitlamp microscope. The angle between the camera and slit-illuminator was fixed a t 45 °, ensuring cleat" visualization of the corneal sur£~ee, as well the a n ~ r i o r and posterior lens sur~ces. Exposures were made with a 0-3-ram wide slit beam adjusted to the height of the cornea. The flash intensity was set to the m a x i m u m output,, producing images on Pius-X film p ssed in HC-! 10 dilution "A" a t an exposure speed of ISO 200. The s h u t t e r speed w 1/90th of a cond and the f-stop was set to f 4 - 0 . Vertical alignment was achieved by tilting the monkey's head until the a n ~ r i o r corneal and anterior lens Purkinje images were bisected by the horizontal positioning line. Horizontal positioning was achieved by visually centering the vertical slit bea on the center of the cornea and directing the beam through the center of the lens. Care was taken to ensure t h a t the incident light was perpendicular to the vertical

SLIT LAMPSTUI)IES

OF T H E R H E S U S M O N K E Y E Y E

309

plane of the lens. The p i v o t was then locked. The image of the corneal c u r v a t u r e was placed between the two vertical positioning lines by a d j u s t i n g the m i c r o s c o ~ forward along the axis of the slit b e a m . Once this positioning was completed, several sequential exposures were made, and the m o s t a c c u r a ~ l y aligned images s e l e e ~ d f(Jr printing. (d) U l t r a s o u n d me u r e m e n ~ of a n ~ r i o r c h a m b e r d e p t h , lens thickness, an~ globe size along the optmal axis we m a d e with a S o n o m e t r i c s D B R - 4 A-scan uit sonograph a r the application of one d r o p of 0"5 ~/o p r o p a r a c a i n e HC] to the cornea as previously described ( D e R o u s s e a u and Bito, 1981 ). Complete collection of d a t a from each a n i m a l required 10 min.

Analysis of slit-la

phot~yraphs

The slit-lamp p h o t o g r a p h s p r o v i d e d d a t a on a n t e r i o r c h a m b e r d e p t h , lens thickness, the distance from the a n t e r i o r corneal surface to the posterior of the lens, corneal c u r v a t u r e s , a n d c u r v a t u r e s of the a n t e r i o r a n d p o s ~ r i o r lens sur!:aces. Distances were m e a s u r e d directly off of the 35-mm film from the edge o f the 15-ame to the a n t e r i o r corneal surf-ace, a n t e r i o r lens surface, and posterior lens s u r ~ c e , using a M i t u t o Optical C o m p s tor with a x 10 lens and an X - Y digital r e a d o u t ; this i n s t r u m e n t is a c c u r a t e to 0- 1 m . E a c h image was enlarged x ~2 0 , eitt~er t h r o u g h back-p jeetion onto a ground-glass sc en or by p h o t o g r a p h i c printing. All visible curves were then digitized using a Science Accessories Corporation sonic digitizer interfaced to an IBM personal c o m p u t e r wlth 8087 m a t h coprocessor. For each curve, 300 to 500 coordinate |)airs were collect~ed and stored in a d a t a file. E a c h d a t a set was later analysed for goodness of fit to a polynomial (Bevington, 1969).

Correction of im~e

tortion

When images are collected on a film plane tilted relative to the incident light, there are three ways in which the image is d i s t o r t e d from the true spatial relationships within the eye (cf. Brown, 1973a, 1974a). (a) The ~nost significant source o f error is caused by tile tilt of the fi]ln plane, which coml)resses the i m ~ e in a non-linear hion r e i n e d to the location of t h e image within the G-sine. To correct this, p h o t o g r a p h s o f an evenly s p a g r a t i n g aligned parallel a n d p e r p e n d i c u l a r to the direction of film feed were t a k e n with t h e Scheimpflug camera. T h e line spacings were m e a s u r e d as a function of distance from the edge of the film frame a n d the results stored in the c o m p u t e r . T h e d i s t o r ~ d c o o r d i n a t e s y s t e m in which tile corneal and lens c u r v a t u r e s were m e a s u r e d was then c o n v e r t e d into an orthogonal, e v e n l y spaced coordinate systetn in the c o m p u t e r using the m e a s u r e m e n t s of the g r a t i n g and the location of the a n t e r i o r cornea relative to the edge of the film £rame. The magnification of the corrected image relative to the t r u e spacings within the m o n k ~ eye was d e t e r m i n e d using the radius of c u r v a t u r e of the corrected ant~erior corneal surface, then scaled to the e q u i v a l e n t , i n d e p e n d e n t value obtained ke t o m e t r y . T h e o t h e r s p a c i n ~ and c u r v a t u r we then r e c a ] c u l a ~ d . (b) A second source of error in ttle slit-lamp p h o t r a p h y ~ c h n i q u e art s ~ o m possible image distortions caused by the cornea. Brown ( 1 9 7 3 a ) h a s shown t h a t the cornea has essentially no effect on the lens image, b u t causes u n d e r e s t i m a t i o n o f a n ~ r i o r c h a m b e r d e p t h . To c o m p e n s a t e for this, a s s u m i n g an a v e r a g e m o n k e y a n t e r i o r corneal radius of c u r v a t u r e of 7"5 m m (50 l); DeRouss~au, unpubl.), all me ured values for a n t e r i o r c h a m b e r d e p t h were increased by 0'77 ram; i%r the h u m a n eye, this value, d e t e r m i n e d empirically by Brown, is 0"70 ram. (b) The final source of error arises from the possible c o n t r i b u t i o n of lens refractive power to the i m a ~ of the lens itself. T h e reflected light c a p t u r e d from points within the lens or from the posterior lens surLuce m i g h t be refracted as it passes t h r o u g h the lens m a ~ r i a l . H o w e v e r , since each light ray travels a u n i q u e and possibly a c c o m m o d a t i o n - d e p e n d e n t patio, and since the indices of ~ t ~ a c t i o n ~ r di r a n t gions within the lens a u n k n o w n , as is t h e s h a p e o f the lens in vivo, no correction factor can be applied. One can only e s t i m a t e theoretically the p o ~ n t i a l significance of this source of error on various m e a s u I ~ m e n t s . R e s u l t s pre n ~ d in this p a p e r a t resting refraction indicate t h a t the uncor cted u l t r a s o u n d and slit-lamp m e a s u r e m e n t s of lens thickness, for example, are Within 5 o~ of each o t h e r on the average, r t h e r m o r e , in an analogous s t u d y o f h u m a n a c c o m m o d a t i o n (Koretz, H a n d e l m a n and Brown, 1984), the slope o f the linear empirical relationship between lens

3t0

J.F. KORETZ

ET AL.

FIo. 1. Slit-lamp photographs of the rhesus anterior segment taken as part of the 1983-1984 survey. (a) A ~ 5 )-ears rhesus anterior segment (growth phase); (b) Age 13 years (adult phase); (c) Age 26 years (adult phase). Note that the image of tim lens tapers with increasing distance from the anterior s u ~ c e . pr~3viding less intormation about the posterior lens curvature than allterior lens curvature. Where a cataract may be developing [e.g. (e)], the posterior surfilce is often not visible in photographs. c u r v a t u r e s a n d c u r v e location for tile a n ~ r i o r a n d p o s t e r i o r h a l v e s of t h e lens r e m a i n e d u n c h a n g e d over the full a c c o m m o d a t i v e r a n ~ o f each s u b j e c t . I t t h u s s e e m s that. a n y error arising from f r a e t i v e s p a t i a l d i s t o r t i o n ~nust be arnall. ~atistical

a

lysis

G o o d n e s s o f fit o f the a n t e r i o r and p o s t e r i o r lens c u r v a t u r e s to a p o l y n o m i a l was tested using a r e d u c e d c h i - s q u a r e t e s t as described p r e v i o u s l y ( K o r e t z e t al., 1984). T h e d a t a in general were fit b e s t by a s e c o n d - o r d e r p o l y n o m i a l ( p a r a b o l a ) for t h e form y = a + b x + c x ~, where a is t h e location of t h e c e n t e r of t h e p a r a b o l a along t h e p o l a r axis a n d b is e i t h e r 0 or v e r y close to it (since t h e c u r v e is s y m m e t r i c a r o u n d t h e p o l a r axis); c, t h e coefficient of t h e x ~ ~ r m , is r e l a t e d to t h e r a d i u s o f c u r v a t u r e of the p a r a b o l a a t its ~ m m e t ~ y c e n t e r by tile expression c = 1 / ( 2 " p ) , where p is the r a d i u s of c u r v a t u r e . A l a ~ e v a l u e of c implies a small r a d i u s of c u r v a t u r e , a n d t h u s a v e r y s h a r p l y c u r v e d surface. C o r r e l a t i o n s b e t w e e n v a r i a b l e s were t e s t e d by e v a l u a t i n g t h e linear c o r r e l a t i o n coefficient r a f u n c t i o n o f t h e nun~ber o f degrees o f edo to d e ~ r m i n e P, t h e p r o b a b i l i t y t h a t an u n c o r r e l a t ~ d p o p u l a t i o n would yield a v a l u e of r g r e a t e r t h a n t h a t o b s e r v e d ( B e v i n g t o n , 1969). F o r each ~ s t , t h e d a t a set w e v a l u a t e d t h r e e times" (a) t h e e n t i r e d a t a set was

SLIT

LAMP

STUDIES

OF THE

RHESUS

MONKEY

EYE

31']

Anterior Chomber Depth vs. Age

Q

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v L

0 L

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20D 300 hge (months)

400

500

F r o . 2. S c a t t e r p l o t of r h e s u s ~ e in m o n t h s vs. a n t e ~ o r c h a m b e r d e p t h in millimeters. F o r ages < 6 y e a r s , t h e line is fit w i t h P < 0 " ~ 1 fior n = 31 a n d r - 0.678. T h e e q u i v a l e n t d a t a for a d u l t s is P < 0.£~t for n ~ 1 ~ a n d r - ~ 0-428.

considered; (b) only subjects whose ages were grea~r than x were considered; and (c) only subjee~ whose ages were less than or equal ~:~ x we considered.

3. R e s u l t s Slit-la

a

e a r a n c e cy~ the r h e s u s eye

Typical slit-lamp p h o t o g r a p h s of rhesus m o n k e y eyes treated with phenylephrine HCi to d i l a ~ the pupil are shown in Fig. 1. Both the anterior and posterior surfaces of the lens are visible at sting refraction in a ajority of the photog phs. A larger proportion of the anterior lens c u r v a t u t h a n the p o s ~ r i o r is a l w a y s : en, a characteristic of this ~ c h n i q u e due to blockage of s c a t ~ r e d ligllt from the posterior lens surface by the iris. In some cases, generally the older c a t a r a c t o u s lenses, the p o s ~ r i o r suri~ce c a n n o t be seen. A r correction fi3r s y s ~ m a t i c image distortions on the photograptlic film, the fbllowing d a t a could be obtained from ~ o s t of the subjects" anterior c h a m b e r d e p t h (as the distance m the anterior corneal surface to the anterior lens surface), lens thickne , distance from the a n ~ r i o r corneal surface to the p ~ r i o r lens su ce (the su of a n ~ r i o r c h a m b e r d e p t h and lens thickness), a n ~ r i o r c u r v a t u r e of the lens ( r e p r e s e n ~ d as the coefficient c), and posterior c u r v a t u r e of the lens. Of these five p a r a e ~ r s , three ...........anterior chamber depth, lens thickness, and distance from the anterior corneal surface to the posterior lens surface---were also obtained using ultrasound. W h e n compared one-to-one for each of the 144 subjects, the e q u i v a l e n t m e a s u r e m e n t s were generally within 5 ~/o of each other, with slit-!a p values being, on the average, slightly larger. The degree of statistical eor lation between the u l ~ a s o u n d and p h o t o g r a p h i c e u ~ m e n ~ was also excellent. F o r a n ~ r i o r c h a m b e r depth, P, the p bability t h a t the two d a t a sets a not c o r ~ l a , was less t h a n O" 1 for r ~ 0"540; ibr lens thiekn s, P was less than 0.002 for r 0"318.

312

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F. KORETZ

ET

Lens Thickness

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Age

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v

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100

200 300 Age (months)

400

500

F I o . 3. S e a t e r plot of rhesus age in m o n t h s vs. lens t h i e k n e ~ in millimeters. The data were fit £or the y o u n g m o n k . s with P < 0 . ~ 2 ~ r n = 2 8 a n d r - - - - 0 . 5 7 7 a n d , ~ r adults, with P < 0. 5 t ~ r n = 85 and r = 0"301.

Corneo to Posterior Lens vs. A9e l u " .................., , ~ - : ,..:.................................. -...............................................................

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100

200 300 Age (months)

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plot of rhesus age in m o n t h s x-s. t ~ distance from the a n ~ r i o r corneal su to the terior lens su ce along the polar axis. The correlation is not statistically significant in the growth phase, but in the adult p h ~ e P < 0 - 1 0 f o r n = 9 5 a n d r = 0"165. FIo. 4..Seater

A ~-related

usi

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E a c h o f the five ~ e a s u r e m e n t s o b t a i n a b l e by s l i t - l a m p p h o t o g r a p h y w a s p l o t ~ d as a f u n c t i o n o f and s t a t i s t i c a l l y ~ s ~ d for g o o d n e s s o f fit to a s t r a i g h t line. As c be seen m the g r a p h s ( F i g s ), there is no single s t r a i g h t line t h a t a d e q u a t e l y d e s c r i b e s the d a ~ d i s t r i b u t i o n s . T h i s is confi ed a t h e a t i c a l l y , both t h r o u g h the size o f t h e s t a n d a r d d e v i a t i o n s for s l o p e and i n ~ r c e p t , and t h r o u g h t ~ s t i n g of the linear c o . e l a t i o n coefficient r as a f u n c t i o n o f d e g es of f r e e d o m . B e c a u s e o f t h e a p p a r e n t c u r v a t u r e of t h e d a t a sets, th w e t 9 d i v i d e d into ' y o u t h ' ( y o u n g e r t h a n years) a n d ' u l t ' (older t h a n y e a ), a n d each age range c o n s i d e r e d s e p a r a t e l y . F i g u r e 2 i l l u s t r a ~ s a n ~ r i o r c h a m b e r d e p t h as a f u n c t i o n o f s u b j e c t age. For the

SLIT LAMP S T U D I E S OF THE RHESUS MONKEY EYE

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Fro. 5. Scatter plot of rhesus age in months vs. anterior lens c. The growth phase is fitted with P <: 0.0,~1 for n = 30 and r ~ -0"634; the adult phase is fitted with P < 0'~3! for n - 81 and r - 0"380. young monkeys, there is a positive correlation between the two" anterior cha ber d e p t h increases by a b o u t 0"! m m per year. For a d u l t monkeys, there is a decrease in anterior cha ber d e p t h of a b o u t ~ 0 ' 0 2 5 mln per year. Tlmse d a t a sets are fit to t h e i r lines with P < 0 " 1. Lens thickness (Fig. 3) in the y o u n g rhesus decreas with age over tile first. ,5 y e a ( P < 0"002) with a slope of a b o u t ~0-115 m m per year, and thereafter, according to slit-lamp m e a s u r e m e n t s , increases slowly by a b o u t 0-014, m m per year. The distance between the posterior lens surface and the a n t e r i o r corneal surface is only weakly correlated with age (Fig. 4,) F o r older monkeys, there is a slight decrease ill tills distance with increasing age (about ~0.01 ! m m per year); this fit is good only to P < 0.i0. In the y o u n g e r m o n k e y s , this distance, when p l o t t e d as a function of age, has a re ship t h a t precludes any,kind of linear fit. Slit-lar~p p h o t o g r a p h y with the 'Seheimpflug c a m e r a provides d a t a a b o u t lens shape, in addition to the spatial infor ation o b t a i n a b l e by ultrasound. Figures 5 a n d 6 illust te the age- lated changes in a n t e r i o r a n d posterior lens c u r v a t u r e s speetively, exp ed as c, the coefficient of the x 2 term of a parabola. Both a n t e r i o r and posterior lens values of c decrease with increasing age in the young m o n k e y s (P < 0"001 and 0"02, respectively). Since e is reciprocally related to the radius of curvature, this indicates t h a t the lens is becoming flatter on both surfaces. In the adult., the opposit~e is true, with both anterior and posterior lens values of c increasing (P < 0"001); i e. t h e lens becomes more sharply curved with increasing age in the adult.. In s u m m a r y , the age dependence of the five ocular features measu d by slit-lamp p h o t o g r a p h y de onstrages a division in slope a n d ( o r ) g o o d n e s s of fit betw n y o u n g s u b j e e ~ and a d u l t subjects. T h e changes observed occur much ~ r e pidly in the initial growth p h a s e t h a n in the adult, phase, a c c o u n t i n g the fore for the bet.~r confidence levels o b t a i n e d statistically despite the relatively smaller population o f y o u n g monkeys in this s t u d y .

314

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Correlation to other me

urements

Th e other easu ents we made on each survey subject" anterior corneal curvature by keratometry, globe size along the optical axis by ultrasonography, and resting refraction under anesthesia by refractometry. These measurements plus the five slit-la p measu ents were each t e s ~ d for possible cor lation with every other parameter in age-dependent and age-independent fashion. The results of these tests are su arized ache atically in Fig. 7. Several of the results summarized in Fig. 7 are of particular interest. Anterior and posterior lens surfa:ce curvatures appear to be strongly correlated to each other, witll P < 0"05 in y o u t h and P < 0"001 in the adult rhesus. However, each curve is correlated differently with other measured parameters. Anterior lens curvature appears to be c o r r e l a ~ d pri arily with anterior chamber depth and globe size (i.e. the p l a c e m e n t of the lens within the globe), whereas posterior lens curvature is correlated primarily witt! lens thickness and the distance from the anterior cornea to the posterior lens (i.e. the geo etry of the anterior segment). It should also be noted that, wtmre a correlation between two parameters can be shown, tills correlation is almost always di rent (e.g. positive -~s. negative) for the youthful and adult subjects.

4. D i s c u s s i o n Devel

ent o f the rhesus eye

During the 5- to 6-year growth phase of the rhesus, which is a p p r o x i m a t e l y equivalent to the first 15- to 20 years of h u m a n develop ent, almost all of tim ocular features conside d in this s t u d y are st ngly c o r r e l a ~ d with subject age (Ii g. 7) Anterior chamber depth, globe size, and resting refraction under anesthesia (refractive error) a all positively co ! a ~ d ; for the latter, which is a negative quantity in these animals, a positive correlation indicates that resting refraction under anesthesia becomes less negative. All other m e a s u r e m e n t s - - l e n s thickness, anterior and posterior values of c, and dioptric power of the a n ~ r i o r corne negatively correlated with

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F1o. 7. Matrix representation summarizing the confidence levels Gjr correlations between all of the parameters considezvd here in pairwise fashion. Eac ) cell In the matrix shows three symbols, representing overall degree of correlation, cor~lation to the subpot)ulation in the adult phase ( a ~ > 5-6 Wears). anti correlation to the young rhesus (age < ~ 6 years)reslwctively (s~ inset). ***. P < 0"{~5" **, P < 0-05" *, P < 0.! ; ~ , P > 0"I. A minus sign befor~ the ~terisks indicates a negative linear eorre|ation coemcient. age. As t h e globe d e v e l o p s a n d e n l a r g e s , t h e | e n s b e c o m e s t h i n n e r a n d tile lens s u r f a c e s b e c o m e f l a t t e r ; t h e a n t e r i o r c o r n e a l c u r v a t u r e also f l a t t e n s . T h e thinning, o f t h e lens is a l m o s t p cisely offset b y t h e r a t e o f i n c r e a s e in a n t e r i o r . c h a m b e r d e p t h , i m p l y i n g t h a t t h e l o c a t i o n o f t h e p o s t e r i o r lens s u r f a c e r e l a t i v e to t h e a n t e r i o r s u r f a c e o f t h e c o r n e a is r o u g h l y c o n s t a n t . H o w m i g l l t t h e s e c h a n g e s in t h e r h e s u s e y e d u r i n g g r o w t h affect r e f r a c t i v e p o w e r ? T h e f l a t t e n i n g of" t h e a n t e r i o r c o r n e a l su ce, a n t e r i o r lens su ce, a n d p o s t e r i o r lens s u r f a c e will d u c e t h e d i o p t r i c c o n t r i b u t i o n o f e a c h , as will tlle inc a s e d d i s t a n c e b e t w e e n t h e c o r n e a a n d t h e lens. T h e o n l y f a c t o r w o r k i n g in t h e o p p o s i t e d i r e e t i o n ~ i . e . toward greater dioptric powe is t h e t h i n n i n g o f t h e lens, which r ults in t h e t w o f r a c g i v e su ces co ing closer t o g e t h e r . T h i s is q u a l i t a t i v e l y o u t w e i g h e d , h o w e v e r , b y t h e o t h e r factors. T h e s e t r e n d s , t a k e n in c o n c e r t , i n d i c a t e a loss o f r e f r a c t i v e p o w e r b y t h o s e p o r t i o n s o f t h e e y e t h a t a r e r e s p o n s i b l e for focusing. I-Iowever, since t h e globe is also s ~ a d i l y inc ing in size a l o n g t h e o p t i c a l is, 1 s c o n v e r g i n g p o w e r is n e c e s s a r y t o o b t a i n a focused i m a g e on t h e r e t i n a . T h e d e c r e e in r e f r a c t i v e e r r o r

316

J . F . KORETZ ET AL.

during the growth phase (Bito et al., 1982; Fig. 7 herein)suggests t h a t these opposing processes are not precisely balanced. In the a d u l t rhesus eye, m a n y of these relationships are reversed. Lens thickness, a n t e r i o r and posterior of values of c, refractive power of the anterior cornea, and globe size are all positively correlated with increasing age, whereas anterior c h a m b e r d e p t h and resting re ction a negatively correlated. The strength of the correlation is, in general, weaker for the adults, primarily because of the much slower change in the various p a r a m e t e r s with age. In some cases, the strong relationship seen during the growth phase is totally a b s e n t in the a d u l t phase. However, a few relationships become stronger. These include posterior c vs. lens thickness, anterior c vs. resting refraction under anestlaesia and the relationship between the anterior- and posterior lens curvatures. I f it is again assu ed, for the purpo s of discussion, t h a t the pri ary refracting surfaces in the monkey eye are the anterior corneal surface and the two lens surfaces, then the changes in their various relationships are again qualitatively explicable In the a d u l t phase, lens thickness increases, which increases the distance between its two surfaces and due lens re ctive power. This is co pensated for in p a r t by the decrease in the radii of c u r v a t u r e of the lens surfaces and in p a r t by a lessening of distance be een the cornea and the a n ~ r i o r lens surface, all of which inc ase the overall refractive power of the optical system. These forms of compensation for inc asing g w t h a again n o t precisely balanced, so t h a t overall refractive power increases with increasing age. As a result, resting refraction under anesthesia becomes ore negative. In an earlier survey of a c c o m m o d a t i v e loss in a caged rhesus monkey population (Bito e t a I . , 1982), the a u t h o r s d e o n s t r a t e d the a g e - d e p e n d e n t loss ofacco m o d a t i v e a m p l i t u d e . They also observed t h a t i m p o r t a n t changes in ultrasonographically de~ ined ax.ial globe length and lens thickness were d e p e n d e n t on age. Specifically, the slopes of these relationships were significantly di r e n t during the growth phase (the first 6 yea ) and the a d u l t phase. Most of the featu s considered in the present s t u d y ekhibit such a discontinuity, both explicitly as a function of age and implicitly when measure ents of two features are tested for correlation (Fig. 7). In general, then, the slit-lamp d a t a exhibit the same kind of age-related behavior and relationships indicated in the earlier ultrasonographic s t u d y of Bito et al. (1982).

arison with the h u m a n visual syste A series:of studies by Brown (1973a, b, 1974a, b) conside d age-re!ated changes in lens thickness and lens shape in h u m a n s using the Sel~eimpflug slit-lamp photographic technique. In co paring the present results with Brown's survey of 100 unaeeommodaged e m m e t r o p i e h u m a n s it is r e m a r k a b l e how great the similarity is. In p tieular, he n o ~ d age-dependent shallowing of the a n ~ r i o r eha ber, an increase in lens thickness, and a very small change in the distance of the posterior lens surface from the cornea. The question of w h e t h e r these age-dependent hu an proe ses ight exhibit a discontinuity of the sort observed in the rhesus c a n n o t be directly addressed, however; Brown had only 10 subjects who were younger t h a n age 20 years, which is e q u i v a l e n t to a b o u t age 6- to 7 years for rhesus monkeys. I n a d d i t i o n to these spatial c h a r a c ~ r i s t i c s , Brown e s t i m a t e d a n ~ r i o r and posterior lens surface c u r v a t u r e s by comparison a t the poles and off-center with sets of nested circles to d e t e r ine the best fit. He found t h a t with ine asing age both surfaces of the h u m a n lens became more sharply curved for a given a c c o m m o d a t i v e state. These

,¢~LIT LAMP S T U D I E S OF T H E R H E S U S MONKEY EYE

317

results were later confiT:med in a s t u d y t h a t used a s m a l l e r d a t a set ( K o r e t z et al., 1984), leading to a ~ n t a t i v e resolution of t h i s ' lens p a r a d o x ' ( K o r e t z a n d H a n d e l an, in press). Therefore, for t h e rhesus to be a suitable a n i m a l model for the d e v e l o p e n t of p r e s b y o p i a , it m u s t e x h i b i t n o t only a g e - d e p e n d e n t a c c o m o d a t i v e loss, b u t also a g e - r e l a t e d changes in lens s h a p e like those observed by Brown. As Figs 7 indicate, t h e a d u l t rhesus ~ o n k e y lens e x h i b i t s values of a n ~ r i o r and p o s t e r i o r c t h a t increase with increasing age, indicating t h a t t h e lens c h a n g e s shape with age in the s a ~ e fashion t h a t the h u m a n lens does. B o t h a n t e r i o r a n d p o s ~ r i o r surfaces become ~ o r e s h a r p l y curved, b u t t h e posterior sur!~ce is ~ o s h a r p l y curved a t a given age t h a n the anterior. As also occu in the h u m a n , the plot of relationship to e of the a n t e r i o r surface c u r v a t u r e (Fig. 5) e x h i b i t s less s c a t t e r t h a n t h a t of the p o s t e r i o r surface (Fig 6), which B r o w n a t t r i b u ~ d to t h e fact t h a t light from the p o s t e r i o r surface h a d to pass t h r o u g h t h e lens m a ~ r i a l . H o w e v e r , as with t h e o t h e r ocul f e a t u r e s e a s u r e d b y B r o w n , the d a t a do n o t i n d i c a t e t h a t there is a d i s c o n t i n u i t y b e t w e e n the lens c u r v a t u r e s of t h e y o u n g a n d t h e a d u l t h u m a n s . H o w e v e r , B r o w n used only a small n u m b e r of s u b j e c t s who were y o u n g e r t h a n age 20, so it is u n c l e a r w h e t h e r or n o t such a t r e n d does, in fact, exist in h u m a n s . A n o t h e r possible difference b e t w e e n t.lle h u m a n a n d t h e rhesus m o n k e y is in the slope of the age-related c u r v a t u r e challges of the t w o lens surfaces. In the h u m a n d a t a set, the slope o f the a g e - d e p e n d e n t change in the a n t e r i o r surface is a l ~ o s t 10 t i m e s t h a t of change in the posterior surface. As a result, the t w o surfaces o f the hu an lens a t t a i n the sa e c u r v a t u r e b y t h e age of 75- to 80 y e a . In c o n t r a s t , t h e slope of the age d e p e n d e n c e of a n t e r i o r a n d p o s ~ r i o r c u r v a t u r e s in the rhesus is a p p r o x i m a t e l y t h e sa e. Since t h e a n t e r i o r surface is initially uch less s h a r p l y c u r v e d tllan the p o s ~ r i o r surface, this di rence is ~ a i n t a i n e d t h r o u g h o u t t h e m o n k e y ' s lifetime. Such differences are m i n o r in relation to the m a n y similarities T h e overall conclusion to be d r a w n from this co p a r i s o n is tl~at in adult, rhesus m o n k e y s , aging of ttle optical s y s ~ m proceeds in a m a n n e r t h a t is q u a l i t a t i v e l y similar to t h a t which occurs in h u m a n s . 2:hi'"s m a k e s the a d u l t rhesus a t~ighly s u i t a b l e model for study, of the o c u l a r aging process in h u m a n s . ACKNOWLEDGMENTS The authors gra~ful!y acknowledge the support of NIH grant EY04146, and the ~chnical assistance of Kattlryn Crawford, B'Ann True, Mary Sallagian, and William Becket. REFERENCES Bevington, P R. (1969). Data R e d u c t i o n a n d Error A n a l y s i s in the P.hysical ~ i e n c e s . Pp. 92-127. McGraw-Hill Book Company- New York. Bito, L. Z., DeRousseau, C. J., Kau an, P. L. and Bito, J. x,V. (1982). Age-dependent loss of accommodative amplitude in rhesus monkeys" an anitnal mode| for presbyopia. Invest. Op~halm~. . ~ i . 23, 23-31. Brown , N P. (1972). An advanced slit-lamp ca era. Br. J. O p h t h ~ m o l . 56, 6 ~04 . . . 3. ! . Brown, N. P. (1973a). Tile change in shape and in~rnal form of the lens of the eye on accommodation. Exp. Eye Res. IS, 441-59. Brown, N. P. (1973b). Lens c h a n ~ with a ~ and cataract. The m a n Le in lation to Cataract. CIBA Foundation Symposium. Pp. 5 ¢ 7 8 . Elsevier-New York Brown, N. P. (1974a)-. The change in lens curvature with age. . E y e Res. 19, ! 7 ~ 8 3 . Brown, N. P. (1974b). The shape of the lens equator. E x p . E y e Res. 20, 571-6.

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Carter, J. H. (1982). Ttle effects of~aging on selec~d visual functions" color vision, glare sensitivity, field of vision, and accommodation. In Aging and Human Visual nction (Eds Sekuler, R., Kline, D. and Dismukes, K.). Pp. 121-30. Alan R. Liss, New York. Coleman, D. J. (1970). Unified model for accommodation mechanism. A . J. Ophthalmol. 69, !063-79. DeRousseau, C. J. and Bito, L. Z. (1981). Intraocular pressure of rhesus monkeys (Macaca mulatta). II. Juvenile ocular hypertension and its apparent relationship to ocular growth. . Eye Res. 32, 407-17. K fman, P. L. and Lfitjen-Dmcoll, E. (1975). Total iridectomy in the primate in vivo. surgical technique and postoperative anatomy. Invest. Ophthalr.nol. 14, 766-7! Komtz, J. F. and Handelman, G. H. (1982). Model of the accommodative mechanism in the human eye. Vision Res. 22, 917-24. Koretz, J. F. and Handelm , G. H. (1983). A model for accommodation in the young human eye" the effects of lens elastic anisotropy on the mechanism. Vision Res. 23, 1679-86. Koretz, J. F., Handelman, G. H. and Brown, N. P. (1984). Analysis ofhuman crystalline lens curvatu a function of accommodati state and age. ion Res. 24, ! 141-51. Manning, W. and Miller, D. (1978). Increasing the range of the keratometer. Surv. Ophthalmol. 22, 413-14. O'Neill, W. D. andDoyle, J. M. (1968). A thin shell deformation analysis of the human lens. Vision Res. 23, i 9 3 - 20 6 .