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Epithelial Dystrophy of Cornea an Ocular Manifestation in Diabetes
E P I T H E L I A L D Y S T R O P H Y OF C O R N E A A N O C U L A R M A N I F E S T A T I O N IN D I A B E T E S . LLOYD B . W H I T H A M ,
M.D.
BALTIMORE, M D . Fuchs' description of this corneal lesion in 1910 has been f o l l o w e d by several papers that are here briefly reviewed. T h e pathologic histology and clinical characters are fairly under stood. But the etiology remains obscure. T w o cases seen by the author have occurred in patients suffering f r o m diabetes. T h e general clinical history of other reported cases would not oppose such an etiology. T w o cases are here reported in which diabetes was found and treated with benefit to the corneal lesions. ( R e a d before the .American Ophthalmological Society, June, 1924.)
In a rather careful s u r v e y of the literature upon the subject of corneal dystrophies, the writer has been unable t o find a single case w i t h diabetes as either the e x c i t i n g o r indirect cause, barring the instance reported b y himself in the J o h n s H o p k i n s H o s p i t a l Bulletin of M a y , 1914. In fact, those w h o have described the c o n d i t i o n , F u c h s , Paul K n a p p , R e e s e , Guist, T r o n c o s o and Uhthofli, have consistently failed to de tect any definite e t i o l o g i c factor w h a t ever. T h e y agree, h o w e v e r , in a l m o s t all of the f o l l o w i n g p o i n t s : that it o c curs m o s t frequently in m i d d l e life, usually afifects the female sex, with a predisposition for the right e y e , is fre q u e n t l y associated with slight and tran sitory rises in the intraocular tension, and, finally, that the c o u r s e of the de generation, as w e l l as the visual d i m inution, is gradually progressive, despite any k n o w n form of treatment. T h e c o n d i t i o n , as such, w a s u n k n o w n until 1910, w h e n F u c h s ' interesting m o n o g r a p h appeared, d e s c r i b i n g the 13 cases he had seen since 1900. A s he says, m a n y cases, prior t o that time, had u n d o u b t e d l y been d i a g n o s e d and treated as g l a u c o m a , o w i n g to the ele vation of intraocular tension, and the almost characteristic appearance of the corneal epithelium. Since his splendid description of the course and character of the c o n d i t i o n , h o w e v e r , several o b servers have d i a g n o s e d similar cases, and added their reports t o the litera ture u p o n the subject, a total of 19 cases. T h e s l o w and p r o g r e s s i v e c o u r s e of this c o n d i t i o n distinguishes it clinically from any of the inflammations, for the latter are marked b y a p e r i o d of p r o gression, f o l l o w e d later b y one of re gression, while anatomically the dys trophies are characterized b y d e g e n e r
ative c h a n g e s as o p p o s e d t o the cellu lar invasion of inflammatory lesions. T h e majority of d y s t r o p h i e s are the expression either of a local disturbance of nutrition, or, as R e e s e has p o i n t e d out, s o m e general malnutrition. For e x a m p l e , the deposits of m u c i n in m y x edematous subjects after thyroidec t o m y , the g r a y i s h - g r e e n d i s c o l o r a t i o n of the cornea occurring in disseminated sclerosis, and, a c c o r d i n g to W e e k s , dis ease of the Gasserian g a n g l i o n and traumatism. But, to dystrophy o f the corneal epithelium n o definite e t i o l o g i c factor has b e e n ascribed. H e n c e the writer feels s o m e hesitation in advanc i n g his o p i n i o n that diabetes w a s the direct or remote cause in the cases to b e reported, e v e n t h o the diet, in sulin and presence o r absence of sugar did so m a r k e d l y influence the ocular condition. If the m e t a b o l i c disease in question did bear s o m e definite relation to the t r o p h i c disturbances w h i c h t o o k p l a c e in the cornea, s o m e interesting c o n j e c t u r e s as to the m o d u s operandi might be made. W a s the p r o c e s s caused b y a direct t o x i c action on the t r o p h i c a p p a r a t u s ; for instance, b y a temporary flooding o f the blood or l y m p h w i t h diacetic acid o r b e t a - o x y butyric a c i d ? O r w a s the d e g e n e r a t i o n purely a nutritive o n e , caused b y a per version o f the p a b u l u m n o r m a l l y car ried to the corneal epithelium, and due to a d e g e n e r a t i o n in the walls of the small b l o o d v e s s e l s ? A g a i n , m i g h t the b u l l o u s c o n d i t i o n o f the epithelium be a n a l o g o u s to the d e s q u a m a t i v e derma titis s o c o n s t a n t l y o b s e r v e d in dia betes? Epithelial d y s t r o p h y is easily differ entiated from family n o d u l a r keratitis, from aflfections due to n o x i o u s v a p o r s , from keratitis v a s c u l o s a with herpes.
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from postoperative sclerosis, and from hyalin o r fatty degeneration o f the cornea. T h e p a t h o l o g y of dystrophia epithelialis corneae is rather v a g u e : Paul K n a p p c o n t e n d s that it is due t o a chronic e d e m a of the epithelium. F u c h s has had the o p p o r t u n i t y of m a k i n g a m i c r o s c o p i c examination of o n e case. T h e r e w a s grayish o p a c i t y and r o u g h ening o f the surface of the cornea from small v a c u o l e s in the epithelial cells, and neivly formed tissue between Bow man's membrane and the epithelium. T h i s tissue w a s h o m o g e n e o u s , and without signs o f hyalin o r mucoid de generation. T h e epithelium covering it w a s thinner than normal, but the cells w e r e not flattened o r hornified. H e thinks that in the earlier stages the epithelium is p r o b a b l y thickened and vacuolated. Uhthoff, w r i t i n g of degenerative c h a n g e s of the c o r n e a in 1916, c o n cludes that, in dystrophia epithelialis corneae. B o w m a n ' s m e m b r a n e is af fected v e r y little, if at all, and a d m o n ishes against c o n f o u n d i n g this disease w i t h the socalled dystrophia calcárea of A x e n f e l d . F o u r years later, he had the o p p o r t u n i t y of s t u d y i n g a case m o s t minutely, his results b e i n g ab stracted as f o l l o w s : T h e patient had had the disease for o v e r 10 years, afliecting first the right eye, later the left, and presenting the clinical picture accurately described b y F u c h s a d e c a d e before. In the right eye, the d y s t r o p h y finally resulted in an intense grayish-white o p a c i t y of the entire cornea, barring a n a r r o w strip at the margin with s o m e vasculariza tion. T h e surface w a s s m o o t h , b u t the diseased area w a s slightly s w o l l e n . T h e superficial layers o f a portion o f the diseased area of the cornea w e r e r e m o v e d for examination and the epi thelial layer w a s found thickened, the superficial p o r t i o n s w o l l e n in places. T h e upper epithelial cells w e r e in places d r a w n out longitudinally, s o that o c c a s i o n a l l y t h e y s e e m e d t o b e parallel fibers. T h e l o w e s t layer of the basal cells alone c o u l d be called prac tically normal, but even here s o m e of them s h o w e d p a t h o l o g i c c h a n g e s . B o w man's m e m b r a n e w a s entirely absent.
T h e superficial layers o f the c o r n e a w e r e , in places, c o m p l e t e l y degenerated and transformed into a matted tissue of fine fibers w i t h a sparse a m o u n t o f degenerated c o r n e a . In other places the corneal tissue w a s b r o k e n d o w n into b r o a d , w a v y lines, and e d e m a t o u s . T h e c h a n g e s aflfected the superficial layers of the cornea particularly, w h i l e the deeper ones s e e m e d t o b e still transparent. Case 1. T h e patient, a negro, 53 years of age, married, and a w h i t e w a s h e r b y o c c u p a t i o n , c a m e t o the clinic on June 9, 1913, complaining that, for several w e e k s p r i o r t o that date, there had been gradual diminu tion in the vision of his right e y e , un a c c o m p a n i e d b y pain. T h e r e s e e m e d to b e a " s h a d o w " before his eye, and for the past w e e k it had been slightly sore. P r e v i o u s medical history nega tive; n o malaria, n o trauma, n o s y p h ilis. G r o s s inspection revealed a w e l l nouri.shed, v i g o r o u s m a n w i t h a rather dry, coarse skin, and a coated t o n g u e , but, o n the w h o l e , presenting n o a b n o r m a l appearance. M i n u t e inspection o f the c o r n e a of the right eye, w i t h the binocular l o u p e , s h o w e d a small, central, superficial, herpetic, epithelial loss, which was clear, uninfiltrated, and stained faintly w i t h fluorescein. M i d w a y b e t w e e n the center of the c o r n e a and the l i m b u s a v e r y faint, whitish crescent w a s seen, evidently l y i n g b e t w e e n the epithelium and B o w m a n ' s m e m b r a n e , or in the anterior lamellae of the substantia p r o pria. T h e corneal epithelium, itself, s u r r o u n d i n g this area and e x t e n d i n g t o within about 3 m m . of the l i m b u s , w a s diffusely c l o u d e d and h a z y , as t h o e d e m a t o u s ; minute, distinct vesicles b e i n g present. T h e r e w a s o n l y slight c o n g e s t i o n o f the ciliary vessels and the iris w a s n o r m a l in appearance, al tho the pupillary reactions were sluggish. T h e tension o f the g l o b e w a s n o t elevated, and the anterior c h a m b e r w a s not s h a l l o w . N o v i e w of the fun d u s c o u l d b e obtained w i t h the o p h t h a l m o s c o p e , and vision w a s limited t o c o u n t i n g fingers at 40 c m . T h e o b s e r v e r ' s first t h o u g h t w a s of a rare, ring shaped keratitis, w h i c h w a s somewhat borne out by the fact that the
DYSTROPHY OP CORNEA A N D DIABETES
crescent later c o m p l e t e l y encircled the center o f the cornea. H o w e v e r , the in flammatory e v i d e n c e s , e x c l u d i n g the v a g u e , pericorneal c o n g e s t i o n , w e r e s o slight, and s o out o f p r o p o r t i o n t o the corneal disturbances, that o n e felt in clined to a b a n d o n the diagnosis of an actual keratitis and l o o k u p o n the c o n dition as a t r o p h i c o r nutritional aflfection, an epithelial d y s t r o p h y , due, per haps, to s o m e general dyscrasia, a v i e w w h i c h w a s partially substantiated b y finding diminished sensibility o f that cornea, as c o m p a r e d w i t h its fellow, b o t h b e i n g h y p o n o r m a l in that re spect. T h e patient w a s advised to enter the hospital, and the f o l l o w i n g e x a m i n a tions w e r e m a d e b y D r . G u e r i n o t : Neurologic and physical—negative. B l o o d : Pale, s l o w l y c o a g u l a b l e , little fibrin, H b . 6 8 % , R . B. C. 3,650,000; W . B. C. 6,200. Diflferential c o u n t : Small m o n o n u c l e a r s 2 4 % , large m o n o nuclears 4 % , p o l y m o r p h o n u c l e a r s 7 0 % , eosinophiles 2 % . B l o o d pressure, 148 m m . T u b e r c u lin test ( v o n P i r q u e t ) , negative. W a s sermann b l o o d test, n e g a t i v e . T h e patient w a s p l a c e d under an ap propriate local and general regimen w i t h n o appreciable c h a n g e in the c o r neal c o n d i t i o n until June 24, w h e n urinalysis s h o w e d a specific g r a v i t y o f 1,030, and 0 . 5 % sugar. A strict " s u g a r free" diet w a s at o n c e o r d e r e d ; in six d a y s there w a s c o m p l e t e restoration of the corneal epithelium, and o n J u n e 30th, the patient w a s d i s c h a r g e d and told to report at regular intervals f o r treatment in the dispensary. H e failed to d o s o , h o w e v e r , and did not c o m e b a c k until A u g u s t 18th, w h e n he returned to the clinic w i t h the hazi ness of the c o r n e a m u c h deeper, m o r e diflfusely located, and a m o u n t i n g t o a positive s t i p p l i n g — g i v i n g the epithe lium a r o u g h e n e d appearance, as of glass w h i c h had b e e n breathed u p o n . It is interesting to note, in this con nection, that o n an intervening and un r e c o r d e d o c c a s i o n , the m a n returned to the dispensary with a foreign body i m p a c t e d u p o n the diseased c o r n e a . M y c o l l e a g u e , w h o w a s in c h a r g e at the time, u p o n b r u s h i n g off the particle with a c o t t o n w o u n d spud, n o t i c e d that
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the h a z y epithelium at that situation w a s w i p e d a w a y also, l e a v i n g clear substantia propria beneath. T h i s d e m onstrates h o w superficial was the edema. U p o n his return, in addition t o an increase in the e d e m a , there w a s a large, central, b u l l o u s loss o f epithe lium, deeper than the first, and stain ing markedly with fluorescein. The whitish ring w a s m o r e p r o n o u n c e d . H e w a s p r o m p t l y readmitted, and again placed upon a rigid sugar free diet, c l o s e q u e s t i o n i n g h a v i n g revealed the fact that he had b e e n p a r t a k i n g freely and indiscriminately of starch contain ing f o o d s . T h e s a m e local and general treatment w a s ordered as o n the pre v i o u s visit. O n this o c c a s i o n a slight transitory b y p e r t o n y w a s several times n o t i c e d , altho o p h t h a l m o t o n o m e t r y w a s n o t resorted to, b e c a u s e of the epithelial disturbances. In fact, the epithelium did n o t r e s p o n d to therapeutic and dietetic measures as rapidly as b e f o r e , and c o m p l e t e restoration did n o t o c c u r for 18 days. T h i s time the patient c o m p l a i n e d , o n c e o r t w i c e , of slight local pain, w h i c h w a s p r o m p t l y re lieved b y instillations of a 1% h o l o c a i n hydrochlorid solution. O n S e p t e m b e r 8th he w a s again dis c h a r g e d f r o m the hospital with the corneal haziness m u c h less marked, w h i l e a v e r y d i m , undetailed v i e w o f the fundus c o u l d , for the first time, be . obtained with the o p h t h a l m o s c o p e . H i s v i s i o n , 4 / 1 0 0 , also s h o w e d g r e a t i m provement. U r i n a l y s i s g a v e a high specific g r a v i t y , 1031, b u t n o sugar, acetone, o r diacetic acid. In this c o n nection, let it b e n o t e d that, w h i l e the diet caused a l o s s of w e i g h t , and less healthy general appearance, the c o r neal disturbance w a s steadily a m e l i o rated thereby. H e w a s n e x t seen on O c t o b e r 10th, w h e n his vision had i m p r o v e d to 2 0 / 1 2 0 , and the e d e m a t o u s haze of the c o r n e a had cleared markedly. T h e iris w a s clearly visible, but the w h i t e ring w a s still present, w h i l e the corneal a p e x w a s m a r k e d b y a small, almost circular, o p a q u e spot, the site of the p r e v i o u s tissue loss. F o u r d a y s later, h o w e v e r , w h e n he
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b r o u g h t a 24-hour s p e c i m e n o f urine to D r . Guerinot, 2 % sugar w a s found, in c o n j u n c t i o n with a specific gravity of 1032, altho there w e r e n o d e c o m p o s i t i o n p r o d u c t s such as acetone or diacetic acid. Strict dietary instruc tions w e r e again g i v e n him, and he w a s told to instil 5% dionin c o l l y r i u m l o cally, each day, in order to stimulate the nutrition of the cornea. T h e man w a s last o b s e r v e d on O c tober 31st, w h e n the cloudiness had diminished greatly, but b e l o w the c o r neal center, and a b o v e the w h i t e ring, a small c y s t had formed, evidently c o n taining a clear liquid. T h i s was di rectly beneath the epithelium and m o v e d in any direction w h e n pressure was made against it thru the l o w e r lid. V i s i o n had fallen slightlv, b e i n g 20/160+-f, altho a 2.25 ' diopter c o n v e x sphere, tried for the first time, b r o u g h t it to 2 0 / 5 0 . Case 2. W . M . H . , white, 53 years of age, single, a theatrical manager, experienced the first intimation of o c u lar trouble on Jan. 25th, 1923, while in W h e e l i n g , W . V a . , w h e n , because of a little v a g u e a n n o y a n c e , he consulted a local oculist w h o prescribed s o m e simple r e m e d y with the immediate al leviation of the d i s c o m f o r t . O n M a r c h 6th, w h i l e in N e w Y o r k , the irritation recurred and, within t w o days, b e c a m e so a n n o y i n g that he consulted D r . G. H . Bell, w h o treated his eyes on four c o n s e c u t i v e o c c a s i o n s . A s the soreness returned severely, in a few w e e k s , he consulted D r . C. E. W i l l i a m s , also o f N e w Y o r k , on A p r i l 4th, the latter di a g n o s i n g "fibrous ulcer of the c o r n e a " and a d v o c a t i n g the removal of a molar w h i c h p r o v e d undiseased and b o r e out the previous R o e n t g e n diagnosis o f normality. O n A p r i l 18th, he left with his c o m p a n y for Trenton, b e i n g turned over, b y D r . W i l l i a m s , to D r . H o w a r d Ivins, under w h o s e care he remained from A p r i l 20th t o J u l y 4th. During this period the use of ultraviolet rays seemed to strengthen and relieve the eye. O n July 9th, he transferred to L o n g Branch, N . J., and w a s treated up t o A u g . 11th b y D r . W . K . Campbell, w h o told him that n o t h i n g could be d o n e for the eye and that absolute rest alone
c o u l d avail to relieve him. T h i s he w a s unable to realize. O n Sept. 13th, 1923, c o n s u l t e d D r . D o l a n of W o r c e s t e r , Mass., under w h o s e care he remained until O c t . 19th, 1923, w h e n he transferred t o D r . C h a p m a n o f Springfield, Mass., w h o m he deserted after o n e consultation, enucleation h a v i n g been advised. It is interesting t o note that the patient had noticed a decided lessening in pain or ache, as the m o n t h s w o r e on, but an increase in sensitiveness t o light and feeling of ocular weakness. T h e writer first saw him o n D e c . 20th, 1923, w h e n the a b o v e history w a s given, the patient c o m p l a i n i n g that the eye had been e x c e s s i v e l y p h o t o p h o b i c and w e a k for the previous w e e k , the vision unusually blurred and lacrima tion extraordinarily c o p i o u s . H e w a s questioned as to his later treatments and it w a s d i s c o v e r e d that he had re ceived no constitutional therapy, what ever, and that he had been under a local atropin regimen for months. F a m i l y ocular and p r e v i o u s ocular his t o r y negative, but patient had had dia betes for past 6 or 7 years. Present Condition: O. D . negative. Lids o f left eye swollen, palpebral and bulbar conjunctiva congested, the veins of the latter greatly distended, tremend ous circumcorneal engorgement o f ciliary vessels. Cornea steamy, grayish and lacks luster, sensitiveness impaired, epithelium d e s q u a m a t e d centrally, sur rounding cells edematous ahd underly ing layers infiltrated. Tension o f globe "stony hard" to palpating finger tips— (tonometry not resorted to o w i n g to denudation of corneal epithelium cen trally). O . D . V . 6 / 6 — . O . S. V . H a n d m o v e ments. 1^. D i s c o n t i n u e d atropin and o r d e r e d holocain and hot compresses, pilocarpin solution and 5 % solution dionin, advising medical consultation with D r . Walter Baetjer w h o has epitomized his findings as f o l l o w s : " T h e general data in the case o f M r . H . is about as f o l l o w s : H e is 53 years old. Complainer o f diabetes and eye trouble. General health in the past en tirely normal.
DYSTROPHY OP CORNEA A N D D I A B E T E S
Present Illness: H e has had diabetes for six to eight years but without any effect on his general health unless in relation to his present eye trouble. T h e trouble with his eye began six to eight months ago with obscured vision. T h e condition has been variable, but in gen eral, has been progressive since that time. T h e history is otherwise quite normal except that he has lost from 165 pounds to his present weight o f 135. General physical examination entirely normal except for the condition o f the eyes which y o u k n o w about. Laboratory Examination: Negative except that the urine shows sugar in amount o f 3.3% without evidences o f any acidosis. Blood sugar: 266 mg. per 100 c c . Blood Wassermann: Normal. O n simple diet regulation and insulin the urine b e c a m e and remained sugar free and the b l o o d sugar d r o p p e d to normal. I heard from him the last time on A p r i l 14th, at w h i c h t i m e his urine w a s still free and he w a s ap parently feeling v e r y m u c h better. I have, of course, m o r e detailed notes that I will g l a d l y send if y o u w a n t them." U n d e r insulin injections and local regimen, eserin b e i n g substituted for pilocarpin, tension w a s reduced from + 3 . to + 2 . on D e c . 28th, and normal on the 31st. Later, aspirin w a s e x hibited for the persistent s y m p t o m s of iritis and dionin increased t o 1 0 % solu tion. B y Jan. 10th, 1924, he w a s greatly i m p r o v e d , the c o r n e a clearer, the epithelium regenerated and the c i r c u m c o r n e a l c o n g e s t i o n diminished, while the sense o f w e a k n e s s w a s less noticeable. A s he had t o leave for Cleveland w i t h his c o m p a n y , he w a s referred t o
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D r . Clark of that c i t y w h o c o n t i n u e d the same local treatment w i t h the re sult that, on Jan. 24th, he w r o t e : " T h e e y e feels pretty g o o d , stronger, and I think the sight a tiny w i n y bit better." N e x t he w e n t t o N e w Y o r k , writ ing, on F e b . 14th, that the " e y e has b e e n pretty g o o d ever since I left y o u r care." H e w a s instructed, b y return mail, t o place himself in D r . J o h n W h e e l e r ' s care immediately, w h o m he c o n s u l t e d on F e b . 21st, 1924, and w h o w r o t e , under date o f F e b . 25th, 1924, as f o l l o w s : "I found the left eye d o i n g w e l l and M r . H . w a s a l m o s t free f r o m s y m p t o m s . I advised him to c o n t i n u e the treatment y o u ordered. I s h o u l d c o n sider y o u r d i a g n o s i s the p r o p e r o n e , n a m e l y , d y s t r o p h i a epithelialis c o r n e a e . T h e slit l a m p corneal m i c r o s c o p e examination reveals cysts o f the epithe lium and facets w h e r e the c y s t s have ruptured. T h e c o r n e a is nearly an esthetic n o w and there is v e r y little discomfort." O n F e b . 29th, after his s e c o n d visit to D r . W h e e l e r , patient w r o t e that he had been d i s c h a r g e d and told t o c o n tinue with the same treatment. He added that his e y e felt m u c h stronger but that his vision w a s u n i m p r o v e d . O n M a r c h 6th, patient w r o t e for the last time telling of the c o n t i n u e d o c u lar relief and stating that D r . T e n n e y , of the Fifth A v e n u e H o s p i t a l , had just reported b o t h b l o o d and urine " s u g a r free," and that the insulin injections had been r e d u c e d to o n c e daily. T h e last report, A p r i l 14th, w a s just as f a v o r a b l e : urine s u g a r free, b l o o d s u g a r n o r m a l and patient feeling c o n stitutionally and (ocularly) "very m u c h better."
M.D.
BALTIMORE, M D . Fuchs' description of this corneal lesion in 1910 has been f o l l o w e d by several papers that are here briefly reviewed. T h e pathologic histology and clinical characters are fairly under stood. But the etiology remains obscure. T w o cases seen by the author have occurred in patients suffering f r o m diabetes. T h e general clinical history of other reported cases would not oppose such an etiology. T w o cases are here reported in which diabetes was found and treated with benefit to the corneal lesions. ( R e a d before the .American Ophthalmological Society, June, 1924.)
In a rather careful s u r v e y of the literature upon the subject of corneal dystrophies, the writer has been unable t o find a single case w i t h diabetes as either the e x c i t i n g o r indirect cause, barring the instance reported b y himself in the J o h n s H o p k i n s H o s p i t a l Bulletin of M a y , 1914. In fact, those w h o have described the c o n d i t i o n , F u c h s , Paul K n a p p , R e e s e , Guist, T r o n c o s o and Uhthofli, have consistently failed to de tect any definite e t i o l o g i c factor w h a t ever. T h e y agree, h o w e v e r , in a l m o s t all of the f o l l o w i n g p o i n t s : that it o c curs m o s t frequently in m i d d l e life, usually afifects the female sex, with a predisposition for the right e y e , is fre q u e n t l y associated with slight and tran sitory rises in the intraocular tension, and, finally, that the c o u r s e of the de generation, as w e l l as the visual d i m inution, is gradually progressive, despite any k n o w n form of treatment. T h e c o n d i t i o n , as such, w a s u n k n o w n until 1910, w h e n F u c h s ' interesting m o n o g r a p h appeared, d e s c r i b i n g the 13 cases he had seen since 1900. A s he says, m a n y cases, prior t o that time, had u n d o u b t e d l y been d i a g n o s e d and treated as g l a u c o m a , o w i n g to the ele vation of intraocular tension, and the almost characteristic appearance of the corneal epithelium. Since his splendid description of the course and character of the c o n d i t i o n , h o w e v e r , several o b servers have d i a g n o s e d similar cases, and added their reports t o the litera ture u p o n the subject, a total of 19 cases. T h e s l o w and p r o g r e s s i v e c o u r s e of this c o n d i t i o n distinguishes it clinically from any of the inflammations, for the latter are marked b y a p e r i o d of p r o gression, f o l l o w e d later b y one of re gression, while anatomically the dys trophies are characterized b y d e g e n e r
ative c h a n g e s as o p p o s e d t o the cellu lar invasion of inflammatory lesions. T h e majority of d y s t r o p h i e s are the expression either of a local disturbance of nutrition, or, as R e e s e has p o i n t e d out, s o m e general malnutrition. For e x a m p l e , the deposits of m u c i n in m y x edematous subjects after thyroidec t o m y , the g r a y i s h - g r e e n d i s c o l o r a t i o n of the cornea occurring in disseminated sclerosis, and, a c c o r d i n g to W e e k s , dis ease of the Gasserian g a n g l i o n and traumatism. But, to dystrophy o f the corneal epithelium n o definite e t i o l o g i c factor has b e e n ascribed. H e n c e the writer feels s o m e hesitation in advanc i n g his o p i n i o n that diabetes w a s the direct or remote cause in the cases to b e reported, e v e n t h o the diet, in sulin and presence o r absence of sugar did so m a r k e d l y influence the ocular condition. If the m e t a b o l i c disease in question did bear s o m e definite relation to the t r o p h i c disturbances w h i c h t o o k p l a c e in the cornea, s o m e interesting c o n j e c t u r e s as to the m o d u s operandi might be made. W a s the p r o c e s s caused b y a direct t o x i c action on the t r o p h i c a p p a r a t u s ; for instance, b y a temporary flooding o f the blood or l y m p h w i t h diacetic acid o r b e t a - o x y butyric a c i d ? O r w a s the d e g e n e r a t i o n purely a nutritive o n e , caused b y a per version o f the p a b u l u m n o r m a l l y car ried to the corneal epithelium, and due to a d e g e n e r a t i o n in the walls of the small b l o o d v e s s e l s ? A g a i n , m i g h t the b u l l o u s c o n d i t i o n o f the epithelium be a n a l o g o u s to the d e s q u a m a t i v e derma titis s o c o n s t a n t l y o b s e r v e d in dia betes? Epithelial d y s t r o p h y is easily differ entiated from family n o d u l a r keratitis, from aflfections due to n o x i o u s v a p o r s , from keratitis v a s c u l o s a with herpes.
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from postoperative sclerosis, and from hyalin o r fatty degeneration o f the cornea. T h e p a t h o l o g y of dystrophia epithelialis corneae is rather v a g u e : Paul K n a p p c o n t e n d s that it is due t o a chronic e d e m a of the epithelium. F u c h s has had the o p p o r t u n i t y of m a k i n g a m i c r o s c o p i c examination of o n e case. T h e r e w a s grayish o p a c i t y and r o u g h ening o f the surface of the cornea from small v a c u o l e s in the epithelial cells, and neivly formed tissue between Bow man's membrane and the epithelium. T h i s tissue w a s h o m o g e n e o u s , and without signs o f hyalin o r mucoid de generation. T h e epithelium covering it w a s thinner than normal, but the cells w e r e not flattened o r hornified. H e thinks that in the earlier stages the epithelium is p r o b a b l y thickened and vacuolated. Uhthoff, w r i t i n g of degenerative c h a n g e s of the c o r n e a in 1916, c o n cludes that, in dystrophia epithelialis corneae. B o w m a n ' s m e m b r a n e is af fected v e r y little, if at all, and a d m o n ishes against c o n f o u n d i n g this disease w i t h the socalled dystrophia calcárea of A x e n f e l d . F o u r years later, he had the o p p o r t u n i t y of s t u d y i n g a case m o s t minutely, his results b e i n g ab stracted as f o l l o w s : T h e patient had had the disease for o v e r 10 years, afliecting first the right eye, later the left, and presenting the clinical picture accurately described b y F u c h s a d e c a d e before. In the right eye, the d y s t r o p h y finally resulted in an intense grayish-white o p a c i t y of the entire cornea, barring a n a r r o w strip at the margin with s o m e vasculariza tion. T h e surface w a s s m o o t h , b u t the diseased area w a s slightly s w o l l e n . T h e superficial layers o f a portion o f the diseased area of the cornea w e r e r e m o v e d for examination and the epi thelial layer w a s found thickened, the superficial p o r t i o n s w o l l e n in places. T h e upper epithelial cells w e r e in places d r a w n out longitudinally, s o that o c c a s i o n a l l y t h e y s e e m e d t o b e parallel fibers. T h e l o w e s t layer of the basal cells alone c o u l d be called prac tically normal, but even here s o m e of them s h o w e d p a t h o l o g i c c h a n g e s . B o w man's m e m b r a n e w a s entirely absent.
T h e superficial layers o f the c o r n e a w e r e , in places, c o m p l e t e l y degenerated and transformed into a matted tissue of fine fibers w i t h a sparse a m o u n t o f degenerated c o r n e a . In other places the corneal tissue w a s b r o k e n d o w n into b r o a d , w a v y lines, and e d e m a t o u s . T h e c h a n g e s aflfected the superficial layers of the cornea particularly, w h i l e the deeper ones s e e m e d t o b e still transparent. Case 1. T h e patient, a negro, 53 years of age, married, and a w h i t e w a s h e r b y o c c u p a t i o n , c a m e t o the clinic on June 9, 1913, complaining that, for several w e e k s p r i o r t o that date, there had been gradual diminu tion in the vision of his right e y e , un a c c o m p a n i e d b y pain. T h e r e s e e m e d to b e a " s h a d o w " before his eye, and for the past w e e k it had been slightly sore. P r e v i o u s medical history nega tive; n o malaria, n o trauma, n o s y p h ilis. G r o s s inspection revealed a w e l l nouri.shed, v i g o r o u s m a n w i t h a rather dry, coarse skin, and a coated t o n g u e , but, o n the w h o l e , presenting n o a b n o r m a l appearance. M i n u t e inspection o f the c o r n e a of the right eye, w i t h the binocular l o u p e , s h o w e d a small, central, superficial, herpetic, epithelial loss, which was clear, uninfiltrated, and stained faintly w i t h fluorescein. M i d w a y b e t w e e n the center of the c o r n e a and the l i m b u s a v e r y faint, whitish crescent w a s seen, evidently l y i n g b e t w e e n the epithelium and B o w m a n ' s m e m b r a n e , or in the anterior lamellae of the substantia p r o pria. T h e corneal epithelium, itself, s u r r o u n d i n g this area and e x t e n d i n g t o within about 3 m m . of the l i m b u s , w a s diffusely c l o u d e d and h a z y , as t h o e d e m a t o u s ; minute, distinct vesicles b e i n g present. T h e r e w a s o n l y slight c o n g e s t i o n o f the ciliary vessels and the iris w a s n o r m a l in appearance, al tho the pupillary reactions were sluggish. T h e tension o f the g l o b e w a s n o t elevated, and the anterior c h a m b e r w a s not s h a l l o w . N o v i e w of the fun d u s c o u l d b e obtained w i t h the o p h t h a l m o s c o p e , and vision w a s limited t o c o u n t i n g fingers at 40 c m . T h e o b s e r v e r ' s first t h o u g h t w a s of a rare, ring shaped keratitis, w h i c h w a s somewhat borne out by the fact that the
DYSTROPHY OP CORNEA A N D DIABETES
crescent later c o m p l e t e l y encircled the center o f the cornea. H o w e v e r , the in flammatory e v i d e n c e s , e x c l u d i n g the v a g u e , pericorneal c o n g e s t i o n , w e r e s o slight, and s o out o f p r o p o r t i o n t o the corneal disturbances, that o n e felt in clined to a b a n d o n the diagnosis of an actual keratitis and l o o k u p o n the c o n dition as a t r o p h i c o r nutritional aflfection, an epithelial d y s t r o p h y , due, per haps, to s o m e general dyscrasia, a v i e w w h i c h w a s partially substantiated b y finding diminished sensibility o f that cornea, as c o m p a r e d w i t h its fellow, b o t h b e i n g h y p o n o r m a l in that re spect. T h e patient w a s advised to enter the hospital, and the f o l l o w i n g e x a m i n a tions w e r e m a d e b y D r . G u e r i n o t : Neurologic and physical—negative. B l o o d : Pale, s l o w l y c o a g u l a b l e , little fibrin, H b . 6 8 % , R . B. C. 3,650,000; W . B. C. 6,200. Diflferential c o u n t : Small m o n o n u c l e a r s 2 4 % , large m o n o nuclears 4 % , p o l y m o r p h o n u c l e a r s 7 0 % , eosinophiles 2 % . B l o o d pressure, 148 m m . T u b e r c u lin test ( v o n P i r q u e t ) , negative. W a s sermann b l o o d test, n e g a t i v e . T h e patient w a s p l a c e d under an ap propriate local and general regimen w i t h n o appreciable c h a n g e in the c o r neal c o n d i t i o n until June 24, w h e n urinalysis s h o w e d a specific g r a v i t y o f 1,030, and 0 . 5 % sugar. A strict " s u g a r free" diet w a s at o n c e o r d e r e d ; in six d a y s there w a s c o m p l e t e restoration of the corneal epithelium, and o n J u n e 30th, the patient w a s d i s c h a r g e d and told to report at regular intervals f o r treatment in the dispensary. H e failed to d o s o , h o w e v e r , and did not c o m e b a c k until A u g u s t 18th, w h e n he returned to the clinic w i t h the hazi ness of the c o r n e a m u c h deeper, m o r e diflfusely located, and a m o u n t i n g t o a positive s t i p p l i n g — g i v i n g the epithe lium a r o u g h e n e d appearance, as of glass w h i c h had b e e n breathed u p o n . It is interesting to note, in this con nection, that o n an intervening and un r e c o r d e d o c c a s i o n , the m a n returned to the dispensary with a foreign body i m p a c t e d u p o n the diseased c o r n e a . M y c o l l e a g u e , w h o w a s in c h a r g e at the time, u p o n b r u s h i n g off the particle with a c o t t o n w o u n d spud, n o t i c e d that
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the h a z y epithelium at that situation w a s w i p e d a w a y also, l e a v i n g clear substantia propria beneath. T h i s d e m onstrates h o w superficial was the edema. U p o n his return, in addition t o an increase in the e d e m a , there w a s a large, central, b u l l o u s loss o f epithe lium, deeper than the first, and stain ing markedly with fluorescein. The whitish ring w a s m o r e p r o n o u n c e d . H e w a s p r o m p t l y readmitted, and again placed upon a rigid sugar free diet, c l o s e q u e s t i o n i n g h a v i n g revealed the fact that he had b e e n p a r t a k i n g freely and indiscriminately of starch contain ing f o o d s . T h e s a m e local and general treatment w a s ordered as o n the pre v i o u s visit. O n this o c c a s i o n a slight transitory b y p e r t o n y w a s several times n o t i c e d , altho o p h t h a l m o t o n o m e t r y w a s n o t resorted to, b e c a u s e of the epithelial disturbances. In fact, the epithelium did n o t r e s p o n d to therapeutic and dietetic measures as rapidly as b e f o r e , and c o m p l e t e restoration did n o t o c c u r for 18 days. T h i s time the patient c o m p l a i n e d , o n c e o r t w i c e , of slight local pain, w h i c h w a s p r o m p t l y re lieved b y instillations of a 1% h o l o c a i n hydrochlorid solution. O n S e p t e m b e r 8th he w a s again dis c h a r g e d f r o m the hospital with the corneal haziness m u c h less marked, w h i l e a v e r y d i m , undetailed v i e w o f the fundus c o u l d , for the first time, be . obtained with the o p h t h a l m o s c o p e . H i s v i s i o n , 4 / 1 0 0 , also s h o w e d g r e a t i m provement. U r i n a l y s i s g a v e a high specific g r a v i t y , 1031, b u t n o sugar, acetone, o r diacetic acid. In this c o n nection, let it b e n o t e d that, w h i l e the diet caused a l o s s of w e i g h t , and less healthy general appearance, the c o r neal disturbance w a s steadily a m e l i o rated thereby. H e w a s n e x t seen on O c t o b e r 10th, w h e n his vision had i m p r o v e d to 2 0 / 1 2 0 , and the e d e m a t o u s haze of the c o r n e a had cleared markedly. T h e iris w a s clearly visible, but the w h i t e ring w a s still present, w h i l e the corneal a p e x w a s m a r k e d b y a small, almost circular, o p a q u e spot, the site of the p r e v i o u s tissue loss. F o u r d a y s later, h o w e v e r , w h e n he
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b r o u g h t a 24-hour s p e c i m e n o f urine to D r . Guerinot, 2 % sugar w a s found, in c o n j u n c t i o n with a specific gravity of 1032, altho there w e r e n o d e c o m p o s i t i o n p r o d u c t s such as acetone or diacetic acid. Strict dietary instruc tions w e r e again g i v e n him, and he w a s told to instil 5% dionin c o l l y r i u m l o cally, each day, in order to stimulate the nutrition of the cornea. T h e man w a s last o b s e r v e d on O c tober 31st, w h e n the cloudiness had diminished greatly, but b e l o w the c o r neal center, and a b o v e the w h i t e ring, a small c y s t had formed, evidently c o n taining a clear liquid. T h i s was di rectly beneath the epithelium and m o v e d in any direction w h e n pressure was made against it thru the l o w e r lid. V i s i o n had fallen slightlv, b e i n g 20/160+-f, altho a 2.25 ' diopter c o n v e x sphere, tried for the first time, b r o u g h t it to 2 0 / 5 0 . Case 2. W . M . H . , white, 53 years of age, single, a theatrical manager, experienced the first intimation of o c u lar trouble on Jan. 25th, 1923, while in W h e e l i n g , W . V a . , w h e n , because of a little v a g u e a n n o y a n c e , he consulted a local oculist w h o prescribed s o m e simple r e m e d y with the immediate al leviation of the d i s c o m f o r t . O n M a r c h 6th, w h i l e in N e w Y o r k , the irritation recurred and, within t w o days, b e c a m e so a n n o y i n g that he consulted D r . G. H . Bell, w h o treated his eyes on four c o n s e c u t i v e o c c a s i o n s . A s the soreness returned severely, in a few w e e k s , he consulted D r . C. E. W i l l i a m s , also o f N e w Y o r k , on A p r i l 4th, the latter di a g n o s i n g "fibrous ulcer of the c o r n e a " and a d v o c a t i n g the removal of a molar w h i c h p r o v e d undiseased and b o r e out the previous R o e n t g e n diagnosis o f normality. O n A p r i l 18th, he left with his c o m p a n y for Trenton, b e i n g turned over, b y D r . W i l l i a m s , to D r . H o w a r d Ivins, under w h o s e care he remained from A p r i l 20th t o J u l y 4th. During this period the use of ultraviolet rays seemed to strengthen and relieve the eye. O n July 9th, he transferred to L o n g Branch, N . J., and w a s treated up t o A u g . 11th b y D r . W . K . Campbell, w h o told him that n o t h i n g could be d o n e for the eye and that absolute rest alone
c o u l d avail to relieve him. T h i s he w a s unable to realize. O n Sept. 13th, 1923, c o n s u l t e d D r . D o l a n of W o r c e s t e r , Mass., under w h o s e care he remained until O c t . 19th, 1923, w h e n he transferred t o D r . C h a p m a n o f Springfield, Mass., w h o m he deserted after o n e consultation, enucleation h a v i n g been advised. It is interesting t o note that the patient had noticed a decided lessening in pain or ache, as the m o n t h s w o r e on, but an increase in sensitiveness t o light and feeling of ocular weakness. T h e writer first saw him o n D e c . 20th, 1923, w h e n the a b o v e history w a s given, the patient c o m p l a i n i n g that the eye had been e x c e s s i v e l y p h o t o p h o b i c and w e a k for the previous w e e k , the vision unusually blurred and lacrima tion extraordinarily c o p i o u s . H e w a s questioned as to his later treatments and it w a s d i s c o v e r e d that he had re ceived no constitutional therapy, what ever, and that he had been under a local atropin regimen for months. F a m i l y ocular and p r e v i o u s ocular his t o r y negative, but patient had had dia betes for past 6 or 7 years. Present Condition: O. D . negative. Lids o f left eye swollen, palpebral and bulbar conjunctiva congested, the veins of the latter greatly distended, tremend ous circumcorneal engorgement o f ciliary vessels. Cornea steamy, grayish and lacks luster, sensitiveness impaired, epithelium d e s q u a m a t e d centrally, sur rounding cells edematous ahd underly ing layers infiltrated. Tension o f globe "stony hard" to palpating finger tips— (tonometry not resorted to o w i n g to denudation of corneal epithelium cen trally). O . D . V . 6 / 6 — . O . S. V . H a n d m o v e ments. 1^. D i s c o n t i n u e d atropin and o r d e r e d holocain and hot compresses, pilocarpin solution and 5 % solution dionin, advising medical consultation with D r . Walter Baetjer w h o has epitomized his findings as f o l l o w s : " T h e general data in the case o f M r . H . is about as f o l l o w s : H e is 53 years old. Complainer o f diabetes and eye trouble. General health in the past en tirely normal.
DYSTROPHY OP CORNEA A N D D I A B E T E S
Present Illness: H e has had diabetes for six to eight years but without any effect on his general health unless in relation to his present eye trouble. T h e trouble with his eye began six to eight months ago with obscured vision. T h e condition has been variable, but in gen eral, has been progressive since that time. T h e history is otherwise quite normal except that he has lost from 165 pounds to his present weight o f 135. General physical examination entirely normal except for the condition o f the eyes which y o u k n o w about. Laboratory Examination: Negative except that the urine shows sugar in amount o f 3.3% without evidences o f any acidosis. Blood sugar: 266 mg. per 100 c c . Blood Wassermann: Normal. O n simple diet regulation and insulin the urine b e c a m e and remained sugar free and the b l o o d sugar d r o p p e d to normal. I heard from him the last time on A p r i l 14th, at w h i c h t i m e his urine w a s still free and he w a s ap parently feeling v e r y m u c h better. I have, of course, m o r e detailed notes that I will g l a d l y send if y o u w a n t them." U n d e r insulin injections and local regimen, eserin b e i n g substituted for pilocarpin, tension w a s reduced from + 3 . to + 2 . on D e c . 28th, and normal on the 31st. Later, aspirin w a s e x hibited for the persistent s y m p t o m s of iritis and dionin increased t o 1 0 % solu tion. B y Jan. 10th, 1924, he w a s greatly i m p r o v e d , the c o r n e a clearer, the epithelium regenerated and the c i r c u m c o r n e a l c o n g e s t i o n diminished, while the sense o f w e a k n e s s w a s less noticeable. A s he had t o leave for Cleveland w i t h his c o m p a n y , he w a s referred t o
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D r . Clark of that c i t y w h o c o n t i n u e d the same local treatment w i t h the re sult that, on Jan. 24th, he w r o t e : " T h e e y e feels pretty g o o d , stronger, and I think the sight a tiny w i n y bit better." N e x t he w e n t t o N e w Y o r k , writ ing, on F e b . 14th, that the " e y e has b e e n pretty g o o d ever since I left y o u r care." H e w a s instructed, b y return mail, t o place himself in D r . J o h n W h e e l e r ' s care immediately, w h o m he c o n s u l t e d on F e b . 21st, 1924, and w h o w r o t e , under date o f F e b . 25th, 1924, as f o l l o w s : "I found the left eye d o i n g w e l l and M r . H . w a s a l m o s t free f r o m s y m p t o m s . I advised him to c o n t i n u e the treatment y o u ordered. I s h o u l d c o n sider y o u r d i a g n o s i s the p r o p e r o n e , n a m e l y , d y s t r o p h i a epithelialis c o r n e a e . T h e slit l a m p corneal m i c r o s c o p e examination reveals cysts o f the epithe lium and facets w h e r e the c y s t s have ruptured. T h e c o r n e a is nearly an esthetic n o w and there is v e r y little discomfort." O n F e b . 29th, after his s e c o n d visit to D r . W h e e l e r , patient w r o t e that he had been d i s c h a r g e d and told t o c o n tinue with the same treatment. He added that his e y e felt m u c h stronger but that his vision w a s u n i m p r o v e d . O n M a r c h 6th, patient w r o t e for the last time telling of the c o n t i n u e d o c u lar relief and stating that D r . T e n n e y , of the Fifth A v e n u e H o s p i t a l , had just reported b o t h b l o o d and urine " s u g a r free," and that the insulin injections had been r e d u c e d to o n c e daily. T h e last report, A p r i l 14th, w a s just as f a v o r a b l e : urine s u g a r free, b l o o d s u g a r n o r m a l and patient feeling c o n stitutionally and (ocularly) "very m u c h better."