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Home , Eye disease, Heterochromia iridum, Pterygium (conjunctiva)

CAUSES OF HETEROCHROMIA IRIDIS WITH SPECIAL REFER- ENCE TO PARALYSIS OF THE CERVICAL SYMPATHETIC.

F. PHINIZY CALHOUN, M. D.

ATLANTA, GA.

This abstract of a candidate's thesis presented for membership in the American Ophthal- mological Society, includes the reports of cases, a general review of the literature of the sub- ject, the results of experiments, and histologic observations on the effect of extirpation of the cervical sympathetic in the rab'bit, the conclusions reached from the investigation, and a bib- liography.

That curious condition which con- thinks that the word hetcrochromia sists in a difference in the pigmentation should apply to those cases in which of the two , is regarded by the parts of the same have different casual observer as a play or caprice of . In those cases where a cycli- nature. This phenomenon has for cen- tis accompanies the iris decoloration, turies been noted, and was called hcte- Butler8 uses the term "heterochromic roglaucus by Aristotle1. One who cyclitis," but the "Chronic Cyclitis seriously studies the subject, is at once with Decoloration of the Iris" as de- impressed with the complexity of the scribed by Fuchs" undoubtedly gives a situation, and soon learns that nature more accurate description of the dis- plays a comparatively small part in its ease, notwithstanding its long title. causation. It is however only within The commonly accepted and most uni- a comparatively recent time that the versally used term Hetcrochromia Iri- pathologic aspect has been considered, dis exactly expresses and implies the and in this discussion I especially wish picture from its derivation (irtpoa to draw attention to that part played other, xpw/xa) . Other newly by the cervical sympathetic. coined words only add disorder to an Many writers have given Hutchin- already chaotic classification of dis- son2 (1869) credit for first describing eases. a difference in the color of the irides, Dr. Willis H. Bocock, my friend and with which was associated. I former professor of Greek at the Uni- by chance discovered that Lawrence'3 versity of Georgia, has suggested the (1853) described' irregularities in the word irideterochromia. "The o (as in color of the iris and cited two cases; in iridoplegia) is not used in composition one of slowly changing color, and an- before a vowel; therefore hid in the other of changed color of the iris with word above. Hetc.ro (as in hetero- cataract. He also quoted Wilde4 who chromia) loses the /j in composition, mentioned the fact that plays therefore irideterochromia." an important part in many of these ab- While it would be advantageous to normalities. have the meaning so expressed in one word, its derivation would not be as NOMENCLATURE obvious as the term heterochromia iri- Various terms have been applied for dis, unless the reader possessed a this inequality in the color of the iri- working knowledge of Greek. des, such as heteroglaucus of the an- cients ; WeilK' uses the word heteroph- CLASSIFICATION thalmus; anisoiridochromia is men- Any exact classification of this con- tioned by Scalinci" and chromohetero- dition is almost an impossible task, and pia is suggested by Malgat7, who also mindful of its limitations I venture to 256 P. P. CALHOUN submit the following as a working ba- development of a pathologic lesion. sis of study: And one reason why more cases are Heredity. Sympathetic par- not so classified is that the observer, in- alysis. different to the causes of heredity, does Cyclitis and cata- { ract. not stress its influence, and also that Primary.. With [-Sympathetic par- too few of our patients (clinical pa- Acquired or J alysis. tients especially) know enough of their without T Cyclitis or Cala- is ract. ancestry. . Sidero- The history of cases I and II from [" sis bulbi. the same family (more fully described J Uveal — ] . under the heading of symphthetic pa- { I . ralysis) where the paralysis and lighter Strictly speaking, as Sym10 has iris were all on the same side, in a pointed out, there could be no such manner substantiates the fact that- he- thing as a congenital form of hetero- redity does play an important part. If chromia iridis, since it is about the the paralysis was the cause for the twelfth or sixteenth month that the iris decoloration it would be proper to child's iris ceases to be light and takes consider it as the disorder inherited. on color. Brown has however Galezowski'1, Bistis12 and Scalinci" been noted to appear on the iris as report cases of sympathetic paralysis, early as six months. where one or more children in a fam- I am not in accord with Sym and ily had iris decolorations which were Scalinci who maintained that we inherited. But we should bear in mind should reserve the term heterochromia Priestley Smith's13 words that "hered- iridis for the instances in which there ity is not in any real sense a cause. It has not been any obvious pathologic may account for the presence of a dis- process in the , such as glaucoma order in an individual or family, but it or iridocyclitis. The term expresses tells us nothing as to its origin. In the condition regardless of the cause. some former generation there must I have recently seen a case in which have been a first departure from the there was a decoloration of the iris in normal." an adult negro, who at first glance pre- Osborne14 as early as 1849, drew at- sented evidences of a sympathetic pa- tention to the difference in color of the ralysis, namely a smaller and a 10 irides of a person (that is they were narrower palpebral aperture than the irregularly marked), who had fifteen opposite eye. The case proved to be brothers and five sisters who all pos- the result of an received during sessed the same abnormality which childhood, and the presence of a for- was derived from the mother, whose eign body in the could be three sisters and one brother had the demonstrated. The was trau- same which were again derived from matic, the myosis was due to posterior the mother's side. Gunn15 mentions adhesions, and the iris decoloration similar cases and classifies them as was probably a bulbi, or " iris." caused from a low grade iridocyclitis. It has been stated many times that I can see no objection to classifying in congenital heterochromia iridis the this as one of heterochromia of the iris, color of one eye is inherited from the of secondary origin due to an old in- father, while the color of the other is jury (foreign body with ). derived from the mother. In many in- stances this has been true, but the re- HEREDITY verse is as often the case, and even Heredity as a cause for heterochro- eyes of an entirely different color to mia iridis, has not received the same either parent have been observed. This consideration from modern writers as contradictory observation however from those of a generation ago. I am would not refute the hereditary theory firmly convinced that there are many of transmission, bearing in mind the such congenital cases without sign of principles of Mendel's Law. HETEROCHHOMIA IRIDIS 257

The family reported by Gossage10 is facialis) heterochromia iridis as a symp- the only recorded case beyond the sec- tom. Mayou18 in 1910 was probably ond generation that I find mentioned. the first to accurately describe these A detailed description and examination changes, although Homer (quoted by of the eye unfortunately is not given, Samclsohn20) as early as 1875 did altho the author states that " in draw attention, to a case in which a this family hetcrochromia of the iris light iris occurred on the same side tended to appear when one eye, always with a ptosis of sympathetic origin. In the left, was grayish blue in color, with all only thirty-three cases have been chestnut brown patches. Of the off- reported, ten of which were compli- springs of the affected members of the cated cither with cataract or a slow family eight were affected and twenty- uveitis. two free." The following authors reported: From a genetic point of view, Przi- 17 Galezowski", 2 cases, 1 complicated; bram's work on angora is inter- Horner's case reported by Samel- esting. He found that the union of an solur"; Dethleffseir1, 5 cases, 1 compli- cated ; Lutz22, 13 cases, 3 complicated; Hutchinson2, 1 case; Alexander and I I Lander"'2, 5 cases, 2 complicated; Bis- M o :!0 18 [ tis , 2 complicated cases; Mayou , 3 A F cases and Scalinci", 1 case. i_ From my own observation I can re- F o port four cases; the first two being of the same family with positive sym- d 4 A F i 4 F A

did not perspire on the right side of his not used. normal, no corneal brow. deposits. Vision 20/20. Left, dark blue The examination showed on the iris, with brownish pigmentation sur- right side a decided ptosis, small pupil, rounding pupil, which measures 4 to light blue iris, and a dryness of the 5 mm. Fundus normal. Vision 20/20. . As well as I could detect with- The grandmother states when the out a dilated pupil (the parents refus- child is unwell, the drooping of the ing eye drops) the fundus was normal upper lid and the narrowing of the pu- and there were no corneal deposits. In pil of the right eye are perceptibly in- July, 1915, nearly seven years later I creased. Perspires on left side of face again examined the child. He had been only. (Fig. 2.) well and healthy. The upper right lid Case III. J. L. M., male, age 57. still drooped, but not greatly, there was States that all of his life the left eye some suggestion of a facial atrophy on has been smaller than the right and of the same side, the pupil was still quite a lighter color. Family history nega- small compared to the left eye, yet it tive, all children have dark eyes. The reacted well to light; the iris was blue, patient was brought to me as a refrac- vision 20/20 and fundus was normal tive case on account of headaches and dizziness. Patient is a brunette. Two m years ago he had a stroke of apoplexy I causing left hemiplegia, which now partially exists. He gives a positive luetic history, and has taken appropri- m M ate treatment including salvarsan. Examination: Right 20/15 correct- I I I I i I M m M M o o ed. Palpebral aperture 12 mm. Iris brown ; active to light and meas- Fig. 2. Author's case. M, affected male; F, affected female; m, normal male; f, normal female; o, sex ure 2.5 mm. Fundus shows many undetermined. small vitreous opacities, but no cor- neal deposits. Typical retinal arterio- with no corneal deposits (without my- sclerosis, i. e., beaded and corkscrew driasis). The left eye was normal and arteries. Pupil does not dilate to epi- the iris brown. (Fig. 2.) nephrin, and sluggishly to cocain, as compared to left. Tonometer 20 mm. Case II. Master D, age 5. The fam- Left 20/20 corrected. Palpebral aper- ily history is the same as case I, the ture 10 mm. Iris light grey and- active patient being his first cousin. The ma- to light., Pupil measures 3 mm., does ternal grandmother gave me the his- not dilate to epinephrin, but actively tory of the family and patient, and she and widely to cocain. Fundus no cor- stated that the condition to be de- neal deposits, but similar vitreous opa- scribed existed from birth. The patient's cities and retinal changes as in right. father (uncle to case I) has blue eyes Decided left facial hemiatrophy and ap- and the mother's eyes are hazel and parent . No anhidrosis. 1 am told she is blind in one eye "from Tonometer 20 mm., Hg. Visual fields the rupture of a blood vessel." At contracted peripherally. Systolic blood birth there was some abnormality (a pressure 172 mm. Hg. breech presentation) although no in- struments were used. There are two Case IV. J. E. M., male, age 38. younger children with normal eyes of Family and hereditary history nega- the same color. tive. Father's eyes brown, mother's Examination : Right, drooping upper blue. Patient is only member in fam- lid, facial hemiatrophy, palpebral fissure ily with differently colored irides and measured 5 mm., pupil active to light, he states that he has had this differ- 2 mm. in diameter. Color of iris was ence all of his life. He consulted me blue. Two drops of 1-1000 solution for pain in eyes after reading. epinephrin did not dilate pupil. Cocain Examination. Right eye comp. H. HETEROCHROMIA IRIDIS 259

astig. Vision 20/20. Pupil same size as cal cupping with atrophic changes of left and reacted to light. Color of iris glaucoma simplex. Tension 52 mm. gray. Slight drooping of upper lid. Pal- Hg. Corneal anesthesia. Left, vision pebral aperture 6 mm. Fundus normal. 20/30. Small . Pupil 2.5 No corneal deposits. mm., wide, active, iris gray, slightly Left eye. H. astig. Vision 20/20, shallow A. C, no drooping of upper pupil active to light. Color of iris lid. Fundus normal, sensitive, brown. Palpebral aperture 8 mm. De- no deposits. Field contracted peri- cided bluish discoloration of ar- pherally with an encroachment on na- ranged in patches above and out, and sal side. No enlargement of blind spot down and out. After using the same nor . There was no anhidrosis; number of drops of homatropin in but there existed a decided asymmetry each eye for an hour to dilate the pu- to the face; the left side much sunken, pils for retinoscopy, it was observed with a deepening of facial furrows. We that the right (light iris) was dilated assumed that the facial atrophy was to maximum with loss of accommoda- due to the general hemiplegia and not tion, whereas the left pupil still re- to a seventh nerve involvement. It is acted to light, with little loss of accom- difficult at this late day to explain in this modation. Prolonged use of the drops case any direct connection between the did produce . Seen one light iris and facial hemiatrophy or month later. Slight ptosis on the right hemiplegia on the left side, unless we side and right pupil 2.5 mm. whereas can imagine that in infancy certain tro- left 2 mm. No response to epinephrin phic disturbances developed as a re- and right pupil dilated to 4 mm. after sult of the hemiplegia, but even this twenty minutes use of one drop of gives nothing very definite. cocain. Left did not dilate. The only additional evidence of a sympathetic In closely reviewing the thirty-three paralysis was a slight ptosis on the cases reported it is very noticeable that lighter side. in a good percentage the only evidence of a sympathetic alteration was a nar- Case V. P. R. R., male, age 43, con- rowing of the pupil in the lighter eye. sulted me on account of defective sight While this is evidence of a sympathetic of long duration in the right eye. Sev- paralysis, it is not altogether positive. In eral members of his family have bad case III which I believe to be of sympa- eyes, evidently refractive errors and thetic paralysis (having ptosis and facial perhaps from ocular injuries. Blue or hemiatrophy), the pupil was larger and gray colored eyes predominate in the dilated under cocain more readily than family. The patient is a decided bru- its fellow. I take for granted that the nette with black and states that authors have eliminated the many when several months of age he was par- other influences which would cause a alyzed on the entire left side of body small pupil, before positively declaring and face. He states that the left eye the case as one of sympathetic disturb- ance. In this connection it is inter- has always been of lighter color than 3 the right. The patient is a farmer of esting to note Pollock's- well known moderate intellect. A general physical experiment in which he caused a dila- and neurologic examination was made tion of the pupil from a mydriatic and by Dr. H. Crenshaw, who reported a contraction by direct light in cases nothing abnormal except a general left where he had completely excised the superior cervical sympathetic and the hemiplegia and there were no positive ciliary ganglia. evidences of a sympathetic paralysis. The is as follows: Pollock concluded after his experi- Right, vision, light perception, extra- ments that "evidence is given that a ocular muscles normal, pupil dilated motor plexus with nerve cells exist in and inactive, measures 5 mm. Iris light the sphincter and in the dilatator pupil- brown, with one area of intense brown lae of the rabbit's iris. This plexus lies pigment above and a sector shaped between the individual cells of the area of gray below. Media clear. Typi- muscles and contains fibers of extreme 260 F. P. CALHOUN tenuity. The plexus persists after sepa- cataract in an advanced age. For two ration of the iris from the central nerv- years the patient's sight had failed and ous system. It may, therefore, be re- the color of the right iris has changed. garded in the same nature as the plex- There was pain around the right eye, us of Auerbach and Meissner in the in- facial hemiatrophy with anhidrosis of testines." same side that appeared at same time It should also be borne in mind that as heterochromia. Author had seen in rabbit experiments where the su- patient much before onset of trouble perior cervical sympathetic ganglion has and the condition described did not been completely removed there is often then exist. The eye showed ptosis, a paradoxic dilation of the pupil. enophthalmus, descemetitis, blue iris, The phenomenon has been observed pupil does not dilate as well to cocain by LangendorfP4, where several days as opposite side, no effect by epine- after the ganglion has been removed phrin. Aqueous slightly turbid, tension the pupil markedly dilates, and he ex- subnormal and changes. plains it by vasomotor changes, i. e., Metzner20 reports Mendel's case in dilatation of the iris vessels causes the which there were certain suggestive pupil to contract, while a narrowing peripheral depigmented changes in the produces a dilatation of the pupil. This iris. vasomotor change also takes place in A traumatic paralysis of the superior the ear; at first an increased warmth, cervical ganglion or nerve in adult life and then later a coldness. is by no means an uncommon accident, Another fact to be noted from the and as yet no reports have been made reported cases of heterochromia iridis of a subsequent iris decoloration. I associated with undoubted sympathetic personally have followed two such paralysis is that the paralysis was cases. I have also inquired of the older usually congenital or first noticed in ophthalmic surgeons of large experi- early infancy; and the difference in the ence, who at one time advocated and color of the irides developed at the practiced sympathectomy for glau- natural time when changes take place coma, and in no instance has there been in the color of the iris. In several cases noted any subsequent change in the (Mayou19) there was a history of for- color of the iris. ceps delivery, which was naturally sup- posed to be the cause of the paralysis. SUGGESTED ALLIED CAUSES. However it is not difficult to find It is noted that in case III there ex- equally as many reports of a sympa- isted slight deafness, which from the thetic paralysis from forceps delivery history and examination suggests without iris decoloration (Reese2" and nerve impairment. I can offer no opin- Burrows20) altho in many of these ion from this limited experience as to reports no reference is made to the whether there is any association be- color of the iris. This lack of depig- tween the auditory, ocular and sympa- mentation in light colored irides of thetic disturbances. Mendel30 men- blondes with an associated sympa- tioned a similar change in one of his thetic paralysis can easily be explained. cases. It is well known that deafness Mayou27 has also mentioned cases of is often present in albino cats (Beau- sympathetic paralysis without iris de- mont31) and in two cats which had coloration associated with cervical rib. and deafness, Of all the reported cases of sympa- Alexander and Lander32 studied the thetic paralysis developing in adult life anatomy of the eyes and ears. They Bistis28 reports the only positive case found an absence of pigment in the where a change in the color of the iris perilymphatic cells of the auditory or- subsequently developed; and the case gan, and on the other hand the meso- is well worth reviewing. dermal pigment was absent in the Bistis' case. Female age 38. The lighter iris. mother showed differences in the color These same authors called attention to of the irides and the lighter eye showed the influence which certain gland like HETEROCHROMIA IRIDIS 261 structures at the posterier part of the ing membrane and hypotonia. This first described by Collins33, latter observation was to a certain ex- might have in producing a depigmen- tent agreed with in our experiments. tation of the iris. According to Grif- By more recent experiments on rab- fin3*' these glands control the amount bits these same authors concluded that of pigment in, the eye, as shown by the superior sympathetic ganglion their absence in albino eyes and their must have an independent tonus as re- imperfect development in feebly pig- gards the dilatation of the pupil, for if mented blue eyes. . As plausible as this on one side division of the nerve was theory seems, the presence of these made ,below the ganglion, and on the glands are nevertheless doubted by opposite side the ganglion was extir- other able men, Alt35 and Rutteman30, pated, the pupil was smaller on the ex- who were not even able to find their tirpated side. Their experiments also lumen. FinnorP7 finds these so called showed that the extirpation of the gan- pigmented glands, but thinks that they glion was never accompanied by a de- are pigmented plugs; and while he ad- pigmentation of the iris, but that a mits that gland like bodies may be de- resection of the nerve below the gan- monstrated, he considers the lumen an glion was followed by a decoloration artefact produced by the process of of the iris. These last mentioned ex- hardening; and a section of such tissue periments present new phases to the would resemble a tubular-like gland subject with which we have had no ex- cut cross-wise. Therefore with this ap- perience, and which are quite contrary parent uncertainty, we could hardly ac- to the generally accepted physiology of cept at the present time the sugges- the sympathetic system. tion that the so called ciliary glands of Collins have any influence in causing In this connection it is of interest to hctcrochromia iridis. know that Galczowski reported a case of heterochomia where in the lighter eye, the pupil and the palpcbral fissure EXPERIMENTAL WORK were wider and the eye was more prom- Iii regard to the experimental work, inent than its fellow. Obviously there which lias been done on animals by were symptoms of a sympathetic stim- dividing the sympathetic nerve, or ex- ulation or irritation. cising the superior cervical ganglion, Angelucci''8 found that section of the THE AUTHOR'S EXPERIMENTS ganglion produced trophic alterations An excision of the cervical sympa- of the eye; among them being a disap- thetic ganglion was made in the rabbit. pearance of the pigment of the iris, Guinea pigs were first employed in with an atrophy and of our experiments, mainly to perfect the the choroid, besides certain well de- operative technic of the removal of fined alterations of the blood vessels 10 the superior cervical ganglion, and of the iris. Bistis' produced similar later Belgian hares were used. After changes in the iris, and in one case the operation the ganglion was pre- he was able to demonstrate a cloudi- served in normal saline solution, later ness of the aqueous, and find in sec- stained with methylene blue (vital tions deposits on the posterior surface stain) and examined microscopically. of the. cornea, which to his mind was highly suggestive of an inflammatory Light ether anesthesia was adminis- process. Later Metzner and Wolfflin20 tered, the fur on the under surface of added evidence that a sympathetic pa- the was shaved, the part washed ralysis caused a distinct loss of pig- with soap and water, sponged with al- ment in the iris, and also recorded cohol and then painted with tincture other changes which had previously of iodine. The ganglion was rapidly been observed, such as , flat- exposed and grasped with a pair of tening of "the cornea (Angelucci), tissue forceps and excised with scis- changes in the motility of the nictitat- sors. The skin incision was closed with continuous silk sutures and a sterile 262 F. P. CAmOTJN

gauze dressing applied with adhesive American Ophthalmological Society v. tape. Apparently the animals did not 16, p. 291-298. suffer in any way from the operation TABLE 1. and were quite alert shortly after- wards. There were no . Tonometric readings of the right eye before and after operation: As the rabbit's pupil is often oval (the Rabbit No. 1—Average tension be- vertical diameter being the greatest) pu- fore operation, 22 mm. hg.; total aver- pillary measurements were made with age after, 24 mm. hg. a millimeter rule along the horizontal Rabbit No. 3—Average tension be- meridian of the cornea, that is from canthus to canthus. The eyes-were ex- fore operation, 27 mm. hg.; total aver- posed to daylight from a northerly di- age after, 22 mm. hg. rection. Tonometric readings were Rabbit No. 4 — Average tension be- made with the Schiotz instrument and fore operation, 26 mm. hg.; total aver- it was applied the moment after an in- age after, 21 mm. hg. stillation of one drop of a 4 per cent Rabbit No. 5—Average tension be- aqueous solution of cocain. The lids fore operation, 25 mm. hg.; total aver- were gently retracted with the fingers, age after, 14.8 mm. hg. and usually the readings were easily Rabbit No. 6—Average tension be- and presumably accurately made; al- fore operation, 27.3 mm. hg.; total av- though at times the animals were ex- erage after, 22 mm. hg. ceedingly nervous and frightened Rabbit No. 7—Average tension be- which apparently accounted for the fore operation, 21 mm. hg.; total aver- wide variations in the intraocular ten- age after, 12.1 mm. hg. sion. Rabbit No. 8—Average tension be- fore operation, 7 mm. hg.; total aver- The 7.5 milligram weight was em- age after, 17.8 mm. hg. ployed, but when there was doubt of Rabbit No. 9—Average tension be- the accuracy, other weights were used fore operation, 16 mm. hg.; total aver- as controls and the readings usually age after, 14.3 mm. hg. corresponded. General average tension before opera- It was exceedingly difficult to dis- tion, 21.5 mm. hg.; after operation, 18.5 tinguish early decoloration of the iri- mm. hg. des, and it is possible that one's imag- A summary of the above experi- ination had its influence in causing cer- ments on the nine rabbits, after a com- tain discrepancies made in our early plete excision of the right superior cer- observations, but when a decided vical sympathetic ganglion shows: change was noted, this opinion was 1. No marked influence on lacri- concurred in by three or four other ob- mation. There was an increase in one servers. Eyes which showed no great case immediately after operation. change in the color during life pre- 2. The nictitating membrane was sented a marked difference after enu- not affected by the operation. cleations and when held side by side 3. A paresis of Miiller's muscle, for a closer comparison. which caused drooping of the upper lid Five guinea pigs were used, and the in all cases on the operated side. four that survived, all showed a nar- 4. The average horizontal diameter rowing of the palpebral aperture and of the pupil before operation was 7.6 myosis, but no microscopic change in mm. It contracted immediately after the color of the iris on the operative the operation, and usually so remained, side even seven months after the opera- the average diameter then being 6 mm. tion. Weeping of the eye on the opera- In those cases where epinephrin was tive side was noticed as a symptom in instilled into the conjunctival sac, it three cases after recovery from ether caused a dilatation of the pupil on the anesthesia and later disappeared. The operated side. detailed account of these experiments 5. There was no appreciable oph- is published in the Transactions of the thalmoscope change in the and HETEROCHROMIA IRIDIS 263 choroid. In rabbit No. 4, as seen from CASES COMPLICATED BY CATARACT OR the notes, there were certain interest- UVEITIS. ing developments in the iris which I There is another classification of pri- was not able to explain. The tags of mary lieterochromia iridis to be consid- pigment undoubtedly developed from ered, namely those cases in which there the epithelial layer, but what influence is an uveal affection, evidenced by de- the operation had in causing them is a posits on the posterior surface of the matter of conjecture. While I could cornea, which may and usually does not detect deposits on the posterior terminate in cataract. These compli- surface of the cornea a cloudiness of cated cases may or may not be asso- the aqueous was surely present at one ciated with the apparent disturbances time; also there were opacities in the of the sympathetic. Of the thirty-three media, which I placed in the posterior cases of iris decoloration associated part of the lens, as the rabbit's lens is with sympathetic paralysis, ten cases very thick. These opacities later dis- were complicated with uveitis or cata- appeared. ract. 6. There was an appreciable gross Lawrence and Hutchiuson were change in the color of the iris on the among the first to describe the associa- operated side in all cases except one; tion of cataract with lieterochromia rabbit No. 3 died 24 days after opera- iridis, and Fuchs41 claims priority for tion. The longer the animal lived usu- first calling attention to the fact that ally the more distinct was this dis- chronic cyclitis with deposits occurred coloration ; and where the eyes were in the lighter eye. He also called at- enucleated and placed side by side for tention to the fact that in his series of closer comparison the change was more thirty-eight cases, twenty occurred decided. About five weeks after op- within the first three decades, nine in eration, changes in the color of the iris the fourth decade, and the remaining were first detected, altho in one case number scattered. It was his opinion (rabbit No. 8) a suspected change took that heterochromia was usually due to place in fifteen clays, which was more some anatomic difference in the positive during the fifth week. Un- stroma of the iris, and when the reti- questionable variations in the color of nal layer was affected, [which condi- the iris were noted in rabbit No. 4. tion he had observed], it was then due That is to say. at one time the change to a chronic , lie often was barely perceptible, and at other noted that the pupil was larger on the times the decoloration was decided. lighter side. 7. The intraocular tension (see Butler8 regards the cause as un- chart and table), shows varying esti- known, but when associated with a mates, without any uniformity. Tak- sympathetic paralysis, the chronic cy- ing an average first reading before op- clitis may be comparable to the iritis eration, the right eye was 21.5 mm. and iridocyclitis which are occasion- Hg., and left 22 mm. Hg. A combined ally seen in herpes ophthalmia, and are usually regarded as trophic disturb- average of all readings after operation ances. The same author also describes (omitting the first reading), on the a train of symptoms which in part are right was 18.5 mm. Hg., and the aver- as follows: age of all readings on the left was 21.2 mm. Hg. This observation would The change in the color of the iris lead us to believe that the removal of may last several years before other complications set in, but sooner or the superior cervical sympathetic gan- later the patient complains of bad sight glion lowers the intraocular tension in in the blue eye. There is never pain or the eye on the operated side. redness, possibly a ciliary blush. There 8. The age or weight of the 'animal is no associated dyscrasia, altho pa- apparently had no influence in these tients look "out of sorts." Occasion- experiments. ally there is a transient albuminuria. 264 F. P. CALHOUN

The eye shows fine punctata, Scalinci regards the cataract as due which soon covers the whole posterior to changed physiochemic relations surface of the cornea, altho in other with the circulating nutritive fluids or cases it is arranged sector shape. An to biologic alterations in the content of exudation may develop in the vitreous, the nutritive fluid itself, due to vaso- followed by opacities of the lens, which motor paralysis. are often punctate, and glaucoma is not Knapp, discussing Ellett's46 paper on an infrequent . Choroidi- "Heterochromia Iridis, Heterochromic tis and have been ob- Cyclitis, etc.," was of the opinion that served. The prognosis is bad. The disturbances of the sympathetic system usually begins in youth, and is had very little to do in producing these slow and may extend over a period of changes (cyclitis). In practically all years or even decades. of his cases, the patients have reacted Contrary to the views of Butler, and to the tuberculin test, and in a large other observers, Galezowski is of the number they have done well with tu- opinion that the depigmentation is pre- berculin . ceded by a chronic inflammatory con- But few writers have attempted to dition. On the other hand, Malgat re- explain the alterations .in the iris asso- gards the heterochromia as due to a ciated with a sympathetic paralysis; or difference in the blood circulating in in other words how a sympathetic par- the iris or ciliary body and from a lack alysis caused an iris decoloration. The of nourishment to the lens, a cataract investigation of Angelucci on rabbits being the natural consequence. Hirsch- and offers us a reasonable explan- berg is of this same opinion, but thinks ation. He concluded that the eye re- that the defective circulation starts sents trophic disturbances on account en embryo or before the development of of the influence which the cervical the iris pigment. This condition may sympathetic exerts on the movements remain stationary for years, to again of the walls of the blood vessels (vaso- become active and cause a uveitis and motor effect). It is well known that cataract. Gunn refers to the iris which for a time after the superior sympa- contains sectors of different colors, and thetic has been excised, that there is which subsequently regains its color, a dilatation of the blood vessels, which and he thinks that it is suggestive of 48 in the case of the rabbit can easily be an abnormal innervation. Finally Dor demonstrated in the ears. Later it is thinks that besides the congenital followed by a thickening of the vessel heterochromia (he does not mention wall which tends to contract the lu- sympathetic paralysis), there exists a men. With the weakening of the nu- disease of the eye yet unknown, which tritive changes thus brought about, begins in heterochromia and ends in there is an arrest of development of cataract. the eye, and in the case of the iris, It is natural to ascribe the formation there is a more or less pronounced de- of cataract in these cases directly to the gree of simple atrophy, with its accom- absence of iris pigment, and also to the panying decoloration. influence of the action of ordinary day- light. But Sym has drawn our atten- I cannot find recorded a report of a tion to the fact that albinos are no more microscopic examination of a human liable to in proportion to their decolorated iris associated with sym- number than are the normally pig- pathetic paralysis. Bistis, in his exam- mented. ination of rabbit eyes, found a great Others attribute the cataracts to the reduction in the pigment and a thick- chronic cycliticwhich frequentlyaccom- ening of the vessel wall. The pig- panies heterochromia; and as certain ment in the anterior layer is much re- other intraocular changes are fre- duced and appeared in small aggrega- quently noted, and as occasionally seri- tions. The iris stroma possessed no ous complications follow extractions, it pigment cells, but contained a large is a commonly accepted cause. number of nuclei which occupy the HETEROCHROMIA IR1DIS 265 place of the stroma cells. These nu- was noted an appreciable difference in clei are round or oval and are situated the general pigmentation in the ex- in a basement substance composed of treme anterior border layer. fibrillary connective tissue. He was Rabbit No. 5. Interval of five weeks also able to detect deposits in the pos- and four days between operation and terior surface of the cornea. These find- death. After operation the right iris ings, together with a cloudiness of the appeared lighter than the left, but no aqueous' and the vessel wall changes, difference was detected microscopically. he thinks, are suggestive of an inflam- matory condition. Rabbit No. 8. Interval of approxi- mately twenty-eight weeks between Fuchs was the first to examine a operation and death. There was noted heterochromic iris, occurring in cata- before and after enucleation a decided racts. In one case he could demon- difference in the pigmentation of the strate cells on the back of the cornea. irides. Our findings did not differ ma- There was some depigmentation in terially from those of Bistis, Fuchs and the anterior layer, principally of Lagleyze. The greatest changes were small pigment granules. In the deeper noted in the anterior border layer, layer there were only isolated remains where there was a general atrophy of of the branching pigment stroma cells the branching pigment cells; this atro- and these had lost their shape and had phy was likewise present to a large ex- become round. These should not be tent in the chromophores of the ves- confounded with clump cells 'found sel layer. In certain areas along the near the sphincter and Bruch's mem- margin of the anterior border layer, brane. The retinal pigment layer was there appeared to be a disorganization normal. The texture of the stroma had or absorption of the pigment cells, entirely changed and the network of which probably corresponded to the the branching stroma cells had been lighter areas seen on the iris during replaced by nucleated cells of a differ- life. The pigment epithelium was un- ent character. There was no accumu- affected, and there was no sign of in- lation of nuclei around the blood ves- flammation. There was a difference in sels as is seen in an inflammatory in- the thickening of the vessel walls, due filtration of the iris. Protoplasm is to a hyaline degeneration, altho all of scanty and occurs around the nucleus the iris vessels are characterized by a like a seal ring. Lymphocytes were thickening of adventitia. We could not only occasionally found and no polynu- detect other marked vessel changes clear leucocytes were seen. The blood mentioned by other observers, which vessels showed a hyaline degeneration; was probably due to the short interval the nuclei were scarce, as were the endo- between the operation and enucleation thelial nuclei. Complete closure of the in this particular animal, as compared lumen was observed. to Fuchs' examination of the human Lagleyze15 confirmed Fuchs' observa- heterochromic eye. tions except there was greater atrophy and more depigmentation in the ante- Rabbit No. 4. Interval of thirteen rior layers. months and twelve days between the operation and death. Before operation AUTHOR'S FINDINGS. there was a noticeable difference in the Rabbit No. 1. Interval of eleven color of the irides. With the low mag- weeks and two days between opera- nification the general comparison of tion and death. The notes show that the sections showed a marked differ- after enucleation the right iris was ence. In the section of the right eye "distinctly lighter" than the left, altho there was a "washed out" appearance a suggestion of decoloration was noted in the anterior border and vessel layer some time before death. Microscopic with a noticeable depigmentation of study of each eye did not show any de- the cells surrounding the larger vessels. cided variation from the normal, except These changes were especially noted in a few of the thinnest sections there in the middle and upper thirds of the 266 P. P. CALHOUN iris, and to some extent in the ciliary re- only a mixed hue, but of many nation- gion. alities, a proportion of our fairly nu- The sections did not reveal any merous cases of heterochromia are not cause for the changes detected during pathologic specimens, but simply life (i. e., the iris tags and lens opaci- "freaks" of nature. ties (?) described in the notes). Regarding the inheritance of sympa- With the higher magnification, the thetic paralysis, I believe that its cause changes were similar to those de- may be transmitted, and its manner of scribed in rabbit No. 8, except for an producing heterochromia is similar to increase in adventitia thickening. any other form of congenital sympa- thetic paralysis, including those of ACQUIRED SECONDARY HETEROCHROMIA traumatic origin (forceps deliveries). IRIDUM. Assuming then this sympathetic dis- turbance in fetal life, it would not be Cases of heterochromia iridum oc- difficult to explain the arrested devel- curring secondary to some acquired in- opment of the iris pigment on the in- traocular state are common to all oph- volved side; and we could suppose the thalmologists of any experience. A se- changes in those cases occurring in vere iridocyclitis, foreign bodies early life, where the iris pigment has (metal) in the , degenerative developed. These changes can only be changes of myopia and chronic glau- explained by nutritional disturbances coma are the common causes. of trophic origin—first a vasodilation, then a hyaline degeneration of the ad- COMMENT. ventitia, and finally a contraction of Those who have studied the litera- the vessel lumen. ture of heterochromia iridis, or even casually glance over the many reports The great number of clinical reports and discussions which I have very show that the difference in the color briefly collected, must have been im- of the irides to have taken place within the first few months or years of life pressed with the vastness of the sub- when the pigment cells were young and ject and the lack of unity of opinion of apparently easily absorbed; on the the many authors. I, therefore, with other hand I have not found a record trepidation, hesitate to express an opin- where a sympathetic paralysis in the ion, unless substantiated by facts, and adult produced by trauma or operation, unfortunately in this character of in- ever caused iris depigmentation. vestigation, "cold," positive facts are very few. I shall then confine myself A chronic uveitis (deposits on the to a systematic arrangement of the posterior corneal surface), is often rec- cases and causes of heterochromia, and ognized in association with hetero- express my personal opinion only chromia with or without an accom- where experience warrants it. I do not panying sympathetic paralysis. Many feel, however, that the last word on such cases may have escaped close ob- heterochromia iridis has been written, servation. It is claimed that the yet we do know a great deal concern- lighter iris renders the eye liable to a ing it. chronic , while others are equally sure that the cyclitis precedes I firmly believe in the influence of the decoloration, in fact, produces it. heredity and with the subject under In support of either opinion, we have consideration, I am convinced that in no real proof. a proportionate number of these cases certain tendencies are inherited which From our clinical observation and cause a difference in the color of the experimental study the corneal depos- irides. This statement especially ap- its which often accompany the hetero- plies to the cases in which there is not chromia should be regarded as a symp- even the suggestion of any alteration tom of disease, and where a sympa- of the cervical sympathetic system. In thetic paralysis is associated, it may this country, where our people are not properly be reckoned as the cause, pro- HETEROCHROMIA IR1DIS 267 ducing the passive hyperemia of the gin in youth and have the train of iris and ciliary body which Sym and symptoms described by Butler, but Scalinci describe. Precipitates have hardly as severe and usually without been found on the posterior surface of the severe complications. From the the rabbit's cornea, and I have ob- investigations of Fuchs and others it served a turbid aqueous after an exci- is not a true inflammatory type of dis- ease, such as iritis or cyclitis, and its sion of the sympathetic ganglion, and precipitates may be produced from the if we could at will observe our clinical same type of passive congestion which cases, I believe we would rind similar takes place in sympathetic disturb- changes at some time. ances. The origin appears to be in To m}' mind there is much to be said the vessels themselves,'a type of scle- in favor of Scalinci's theoretic con- rosis with obliteration. Whether or not sideration of the cause for these pre- this vasomotor disturbance is of tro- cipitates and the formation of cata- phic origin due to a sympathetic alter- racts. lie maintains that there arc ation without external evidence, is only abnormal substances which percolate a suggestion which other investigators thru an abnormally pigmented iris and of more original thought might con- ciliary body, due to vasomutor paraly- sider. sis. The normal aqueous does not con- In regard to the formation of cata- tain albumin, but when the anterior ract, it also appears that its origin is chamber is emptied, that which is then especially due to a lack of nutrition or formed contains it, and fibrin may be to changes in the aqueous. demonstrated. This rapidly formed Finally our investigations have led fluid is regarded as a transudate from us to make the following conclusions: the superficially placed vessels in the ciliary body, rather than a secretion of ( 1 ) That the difference in the color the body itself, and it is produced by of the hides should be called Hetero- a lowering of the intraocular tension. chromia Iridis. This change may account for the (2) That in a small number of cloudy aqueous and precipitates noted cases it is inherited. in rabbits and for the precipitates seen (3) That in all other cases it is a in man. symptom of some abnormal ocular The following ocular changes have state. been produced experimentally: First (4) That in a large percentage of a decoloration of the iris (Bistis, Metz- the cases, a paralysis of the cervical ner, et al.) ; secondly, a cloudiness ot sympathetic is the responsible cause the aqueous (author) ; thirdly, the for- for this heterochromia through its tro- mation of conical deposits (Bistis), phic disturbances. This paralysis may and lastly, uncertain lens opacities. be inherited. The experiments have not been con- (5) That besides a congenital het- tinued long enough to note more de- erochromia there is an of cided lens changes, in fact it might unknown origin which begins in heter- take years for them to develop, far be- ochromia and ends in cataract. yond the natural life of the rabbit. In closing I wish to acknowledge my This, however, does not explain the debt of gratitude to Dr. G. Rachman, other type, in which there is no evi- professor of physiology in the medical dence of a sympathetic alteration, and school of Rmory University, in whose yet clinically we have the same pic- department our experiments were con- ture, namely heterochromia, precipi- ducted. His advice was valuable, and tates, and finally cataract. the abstracts which he made of the for- It is as Dor expressed an unknown eign journals greatly facilitated, the disease. It may and usually does be- preparation of this paper. 268 F. P. CALHOTJN

REFERENCES. 1. Hirschberg. Wortebuch der Augenheilkunde. 2. Hutchinson, J. "Notes of Miscellaneous Cases." Royal London Oph. Hospital Reports. 1869. Vol. VI., p. 44. 3. Lawrence, W. "Treatise of of the Eye," by W. Lawrence 1843, 3rd Amer. Edi- tion, by Isaac Hays, Philadelphia. 4. Wilde. Dublin Quart. Journal. Nov., 1848. 5. Weill. ' "Uber Heterophthalmus." Zeitsch. f. Augenhlk. Vol. XI, 1904. 6. Scalinci. "Eterocromia e paralisi del Simpatico." Arch, di Ottalmalogia. Feb., 1915. 7. Malgat. "La Chromheteropie." Recueil d'ophtalmologie. Vol. XVII. 3, 1895, p. 449. 8. Butler, T. Harrison. "Heterochromic Cyclitis." Ophthalmoscope, Vol. IX, No. 7, 1911, p. 501. 9. Fuchs, E. Klin. Monatsb. fur Augenhlk, 1906. 10. Sym, Wm. Geo. Review of Scalinci's Article, Ophthalmic Review, Vol. XXXIV, 1915, p. 167. 11. Galezowski, J. "Heterochromie de l'iris, cataracte et troubles sympathiques." Recueil d' Opht. XXXIII, p. 76. 12. Bistis, J. "Heterochromie und Kataraktbildung." Centralbl. f. prakt. Augenhlk., Vol. XXII, p. 138, 1898. 13. Smith, Priestley. "Notes on the origin of familial and hereditary disorders." Oph. Review, Vol. XXXV, p. 70, 1916. 14. Osborne. Dublin Quart. Journal, Vol. VII, p. 33. , 15. Gunn, Marcus. "Congenital malformation of the eyeball and its appendages." Ophthalmic Review, Vol. VlII, p. 239, 1889. 16. Gossage, A. M. "The inheritance of certain abnormalities." Quart. Med. Jour. Oxford. I, p. 341, 1907. 17. Przibrams. Arch, fur Entwicklungsmechanik. Vol. XXV, p. 260. 18. Mayou, M. S. "Heterochromia iridis associated with paralysis of the sympathetic in early life." Ophthalmic Review, Vol. XXIX, p. 190, 1910. 19. Mayou, M. S. "Paralysis of the Sympathetic (birth injury), with slight heterochromia iri- dis." Ophthalmoscope, Vol. XIV, No. 8. p. 421, 1916. 20. Samelsohn. Arch, fur Ophthalmol., 1875. 21. Dethleffsen, A. "77 Falle von Heterochromia iridum." Kiel Dissert, 1911. 22. Lutz, A. "Uber einige weiteren Falle von Heterochromia iridum." Deutche med. Woch- ensch, XXIV, p. 1125, 1910. 23. Pollock, W. B. I. "The presence of the nerve plexus of the iris after excision of the cili- ary and superior cervical ganglion." Arch. f. vergleichende Ophthal, Vol. IV, pt. 1, 1914. 24. Langendorf, O. "Uber die Beziehungen des oberen sympathischen Halsganglion zum Auge und zu den Blutgefassen des Kopfes." Klin. Monatsbl. f. Augenhlk., Vol. XXXVIII, p. 129, 1900. 25. Reese, Robt. G. "A case of traumatic paralysis of the Cervical Sympathetic with occulo- pupillary symptoms, following forceps delivery." N. Y. E. & E. Inf. Reports, Jan., 1896. 26. Burrows, Harrold. "Two cases of paralysis of the cervical sympathetic following forceps delivery." Ophthalmoscope, Jany., 1915. 27. Mayou, M. S. "Two cases of paralysis of the sympathetic associated with cervical rib." Ophthalmoscope, Vol. XIV, No. 6, p. 313, 1916. 28. Bistis, J. "La paralysis du sympathetique dans l'etiologie de l'heterochromie." Archives d'Ophtal., Vol. XXXII. p. 578, 1912. 29. Metzner and Wolfflin, "Klinische und experimentalle Untersuchungen iiber Halssym. "Arch. f. Oph., Vol. LXXXIX, p. 308, p. 1915. 30. Mendel. Recorded by Metzner and Wolfflin. 31. Beaumont, W. M. "Heterochromia iridum in cats." Ophthalmoscope, Vol. IX, p. 630, 1911. 32. Alexander and Lander. Quoted by Lutz. See reference No. 22. 33. Collins, Treacher. Trans. Oph. Society United Kingdom, Vol. XI, 1890. 34. Griffin, John. "Criticism concerning recent views as to the secretory function of the ciliary ■body." Oph. Review, Vol. XIII, p. 247. 35. Alt. A. "On Treacher Collins' so-called glands of the ciliary body." The Amer. Journal of Oph., Vol. XIII, p. 3. 36. Rutteman, C. "Die sogenannten Drusen von Treacher Collins in achen Abschnitt des Zili- arkorpers." Dissertation, Amsterdam, 1914. 37. Finnoff, W. C. "The Ciliary Glands." Arch, of Oph., Vol. XLIV, No. 6, p. 626. 38. Angelucci. "Studi sulle influenze fisiologiche'del ganglion cervicale superiore del simpatio, &c, &c." Arch, di Ottolmol. I, p. 71, 1893. 39. Bistis, J. "Clinical and experimental investigations on the etiology of heterochromia." Arch, of Oph., Vol. XLIV, No. 4, 433, translation Arch. f. Augenhk., 1913. HETBROCHROMIA IRIDIS 269

40. Metzner and Wolfflin. Clinical and experimental studies of paralysis of the cervical sym- pathetic. Graefe's Arch, fur Oph., Vol. 91, p. 167. 41. Fuchs, E. "Uber Komplikationen der Heterochromie." Zeitsch. f. Augenhk., Vol. XV, p. 105, 1906. . ' 42. Galezowski, J. "Heterochromie de l'iris, etc." Recueil d'Oph., Vol. XXXII, 169, 1919. 43. Dor. Encyclopedie Francaise, Vol. VII, p. 189. 44. Brown, E. V. L. Trans, of German text of "The Anatomy and Histology of - ball, etc.," by M. Salzman, Chicago, 1912. 45. Lagleyze. "L'oeil des albinos." Arch. d'Ophlal., Vol. XXVII, p. 280, 1907. 46. Ellett, E. C. Heterochromia Iridis, Heterochromie Cyclitis and Allied Conditions." Tr. Am. Oph. Soc, 53 Meeting, May 29, 1917.

SYMPATHETIC IRIDOCYCLITIS AND POSSIBLY RELATED PRO- CESSES IN OTHER PARTS OF THE BODY.

D. F. HARDRIDGE, M. D.

PHOENIX, ARIZONA. This argument supports the idea that the essential causative agent of sympathetic oph- thalmia may exist in the body outside of an injured eye, and be transmitted through the blood currents. Microorganisms entering the exciting eye through injury might become established elsewhere in the body. Submitted as a Candidate's Thesis to the American Ophthalmological Society.

It is a fact accepted by most observ- results. Those of known origin, due, ers that sympathetic iridocyclitis is de- as for example, to focal infections, sy- pendent upon a chronic plastic uvei- philitic, or tubercular invasion, are par- tis of the first eye. Preceding the fi- ticularly difficult of discrimination. brinous inflammatory process, the cap- Histologically, there may be specific sule of the eyeball must have been differences. opened; usually by trauma, occasion- This contribution was suggested by ally by an ulcer, or by operation, a recent experience which recalled to such as for cataract or iridectomy. Cer- my mind the only case of sympathetic tain cases, however, have been report- iridocyclitis which has occurred in my ed in which the so called typical find- own practice. I have, of course, ob- ings were present, the capsule not hav- served several cases of so called sym- ing been opened, following certain in- pathetic irritation. That is, certain traocular growths. evidences of irritation were present in In my opinion, these dogmatic state- the fellow eye, but prompt removal of ments should be regarded circumspect- the injured eye was immediately fol- ly, for the reason that, while the, estab- lowed by a cessation of these signs. lishment of a sympathetic iridocyclitis In view of what is about to be stated, may require the occurrence of these it is extremely doubtful whether they events, it must not be overlooked that would have actually developed into they are only events in the process, for cases of true sympathetic iridocyclitis. underlying there is an agent inaugurat- One frequently encounters instances ing these changes. The agent may be where trivial injuries to one eye, such a toxin or bacteria, specific in nature, as a small particle of foreign material or of special affinity for uveal tissue. on the cornea, will entail considerable Clinically, sympathetic iridocyclitis irritability in its fellow. May not the shows no characteristic features to dif- irritability in the fellow eye, following ferentiate it from so called idiopathetic more serious injury, frequently partake or nontraumatic iridocyclitis; that is, largely of this character? Clinically as regards involvement, cause, and end we have no means of determining, def-