Heterochromic Cyclitis

HETEROCHROMIC CYCLITIS ( F U C H S ' SYNDROME) A.

FRANCESCHETTI,

M.D.

Professor of Ophthalmology, University of Geneva Geneva, Switzerland

You may be somewhat surprised that I have chosen for my lecture the complicated heterochromia or heterochromic syndrome of Fuchs. Indeed the classical symptoms al­ ready described in the second half of the last century by Lawrence,1 Hutchinson, 2 Gunn,3 and others are particularly well known since the standard publication of Fuchs 4 in 1906. In general the marked heterochromia ac­ companied by keratic precipitates in the lighter eye, atrophy of the iris, especially in the pupillary region, and, possibly, compli­ cating cataract makes the diagnosis very easy. Furthermore, as Duke-Elder 5 states in his textbook, the ordinary objective signs of inflammation and subjective pains are absent. In spite of this, I have always been sur­ prised to see in a certain number of cases that the nature of the affection is not recog­ nized and that erroneous diagnosis may lead to serious consequences for the patient. The difficulties arise in general from : 1. The heterochromia may be very slight or absent for a long time. Exceptionally the diseased eye may even appear darker. 2. Subjective disturbing alterations of the vitreous associated with the keratic deposits may suggest an uveitis of another origin. 3. Bilateral Fuchs' syndrome is not so rare as it is generally believed. My personal experience is based on 62 cases of Fuchs' syndrome, of which 32 were in males and 30 in females, confirming that the sex ratio is 1 to 1. Concerning the heterochromia, it is espe­ cially in blue eyes that the difference of coloration can easily be overlooked but this can also sometimes happen in the case of brown eyes.

Certain authors affirm (Lloyd 6 ) that the heterochromic cyclitis may develop in the darker eye, the lighter being normal. I agree with Berliner7 that, owing to the marked atrophy of the stroma, the posterior pigment layer will shine through and for that reason the diseased eye may appear darker, espe­ cially if the eyes are gray or blue. In one of my three cases with heterochromia inversa, the difference of coloration was not only due to the alterations of the cyclitic right eye but also to an atrophy of the peripheral part of the iris in the fellow eye. It is naturally difficult to say if the decoloration of the left eye must be con­ sidered as an abortive form of Fuchs' syn­ drome. It is interesting to note that in this case there is a consanguinity of the parents ; this is rather exceptional in Fuchs' hetero­ chromic cyclitis, as I found it only twice in 62 cases (3.2 percent).

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As heterochromia is not a constant symp­ tom, the question arises if the diagnosis can be made when it is based only on the other symptoms of the affection. This is especially important in the bilateral form of Fuchs' syndrome. As far as my cases are concerned I can assert that it is practically always possible to recognize Fuchs' syndrome setting aside heterochromia, if a careful examination is made of the cornea, the iris, and, if possible, the vitreous body. 1. If a patient is examined with the slitlamp, the aspect of the precipitates on the posterior surface of the cornea must lead one to think of the possibility of an hetero­ chromic cyclitis. These keratic deposits may be round or star-shaped. Their number is quite variable. They are usually situated in the lower part of the cornea but may cover

HETEROCHROMIC CYCLITIS

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O.S.

Fig. 1 (Franceschetti). Keratic deposits in a case of bilateral Fuchs' syndrome. In the right eye, situated in the lower part of the cornea; in the left, covering the whole posterior surface (pers. obs. Nr 77/S2).

the whole posterior surface (fig. 1). It must be emphasized that between the precipitates very fine filaments are generally found. These may also be more or less starshaped, and must not be confused with bedewing in ordinary iritis (fig. 2).* What is usually not mentioned in the text­ books is the fact that the interpretation of the precipitates is much easier in retrolight. At a rule the deposits in Fuchs' syndrome are more or less translucid and show a gran­ ular structure (fig. 3). In general they are not pigmented. After operation of the cataract they usually reappear after some days or weeks, which speaks against the theory of Pau 10 that the lens is responsible for the corneal precipitates. Sometimes they seem to be smaller than before the operation. In one of my cases they reappeared six years after the cataract extraction, and there are cases men­ tioned in the literature in which they did not * Absence of precipitates has been observed (see Duke-Elder,8 François*) but must be extremely rare as I did not find such absence in any of my 62 cases.

reappear at all. Concerning the aqueous humor, I agree with Vogt, 11 Paufique,12 and others that generally the anterior chamber is optically empty, that is no Tyndall phenomenon is visi­ ble. On the other hand, circulating bodies in

Fig. 2 (Franceschetti). Fine filaments between the corneal precipitates in a case of Fuchs' syn­ drome (pers. obs. Nr 4244/54).

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A. FRANCESCHETTI

Fig. 3 (Franceschetti). Granular structure of the precipitates seen in retrolight. Numerous filaments (pers. obs. Nr 8427/53).

the anterior chamber are extremely frequent. Only in one case, did I find on the anterior surface of the lens white deposits which had, more or less, the same character as those of the posterior surface of the cornea (fig. 4). In the literature a similar finding (Biozzi13) was mentioned only once. 2. The atrophie alterations of the iris are naturally very important for the diagnosis. In advanced cases transpupillary retroillumination will reveal the defective retinal pig­ ment layer, especially in the pupillary region (moth-eaten appearance). What is generally most striking is the atrophy of the pigmented edge of the iris, which can be transformed into a more or less complete hyaline border, and the visible radial vessels. Most characteristic is the small glassy type of ephemeral nodules at the pupillary margin described in detail by Vogt.14 Although they can be found in more than one third of the cases, they are very often overlooked. Sometimes they have a more fluffy character and they can be larger in size. It is very important to know that larger nodules can be found on the anterior surface of the iris, especially in the sphincter area. When they are multiple, they can form a

kind of chain. Exceptionally they may be found spread over the iris surface. Instruc­ tive cases have been published by J. Streiff15 and Vogt.14 These formations can easily be taken for real tubercle nodules. As Fran­ çois16 and Georgiades17 have reported, and I have been able to confirm, the histologie alterations of the iris are always degenative in character and are characterized by a hyalinosis of the vessels with an important narrowing of the lumen (fig. 5). In spite of the assertion of certain au­ thors, I agree with Vogt18 and Duke-Elder 19 that posterior synechias are lacking in heterochromic cyclitis, except after operation for glaucoma. This is an essential point in the diagnosis of Fuchs' syndrome and especially in bilateral cases or when one eye is lost. 3. The diagnosic value of the vitreous alterations is generally underestimated. As emphasized by Vogt,20 biomicroscopic ex­ amination with high magnification, except in cases with cataract, reveals the presence of white dots. Generally they are adherent to the framework of.the vitreous, but may also be found in the open spaces. In contrast to

Fig. 4 (Franceschetti). Deposits on the anterior surface of the lens in a case of Fuchs' syndrome (pers. obs. Nr 4244/54).

HETEROCHROMIC CYCLITIS

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Fig. S (Franceschetti). Pro­ nounced hyalinosis of the iris ves­ sels in a case of Fuchs' heterochromia. The eye was enucleated for secondary glaucoma (pers. obs. Nr 8716/53).

uveitis of any other etiology, the vitreous dots are nearly exclusively white and not brownish (fig. 6 ) . Not infrequently the patient first com­ plains of moving veils before the eye. This is particularly true in young people. In one of my cases these troubles had already begun when the patient was eight years of age. These 'mouches volantes" are due to a con­ densation of the curtainlike membranes of the vitreous which may form more or less compact veils. This fact is not well known and often leads to the erroneous diagnosis

of infectious, and especially, tuberculous, choroiditis even in the absence of fundus alterations. Chorioretinal alterations in Fuchs' heterochromia are exceptional and more often of the degenerative than inflammatory type. A frequent consequence of heterochromic cyclitis is a cataract which has all the char­ acteristics of the complicating or endocrine type (posterior subcapsular at the start, iridescence of the posterior mirror zone, anterior subcapsular vacuoles, rapid pro­ gression—sometimes many years after the first symptoms). A cataract on the diseased eye only is naturally a help in the diagnosis but one must not forget that opacities of the lens may not occur even up to the age of 60 years. It is well known since Fuchs' original paper that the prognosis for the cataract extrac­ tion in complicated heterochromia is excel­ lent—I would like to say even better than in normal eyes ; the reason for this is that the atrophie iris (in the same way as blue eyes) produces less reaction. Amsler 21 and his collaborators showed that the penetration rate of fluorescein into the anterior chamber is significantly increased in Fuchs' syndrome. It is even higher than in tuberculous uveitis of chronic evolution (Georgiades 22 ). It is especially in the first 10 to IS minutes that the rate of penetration clearly exceeds the extreme limit of normal variation (figs. 7 and 8 ) . Fig. 6 (Franceschetti). A case of heterochromic Taking into consideration this curious al­ cyclitis with typical white dots of the vitreous (pers. teration of the permeability of the bloodobs. Nr 3625/52).

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A. FRANCESCHETTI

| -..,„ h limill 9* ftοrmsl vorijl.r

Fig. 8 (Franceschetti). Penetration rate of fluorescein into the anterior chamber in bilateral Fuchs' syndrome, (pers. obs. Nr 38SS/S2.)

Fig.. 7 (Franceschetti). Penetration rate of fluorescein into the anterior chamber in unilateral Fuchs' syndrome, (pers. obs. Nr 4121/53.) H =: heterochromic eye, N = normal eye.

aqueous barrier, I was interested to see whether there were also repercussions on the behavior of amino acids tested by paper chromatography. Until now I have only ex­ amined a few cases. It seems that leucine and valine are some­ what increased. Furthermore, in addition to serine, glycine, alpha-alanine, and glutamine appear more distinctly. So the paper chromatogram of the aqueous humor in heterochromia is very similar to that found in nor­ mal rabbits when the aqueous humor shows a higher protein content. Naturally those ex­ periments have to be repeated in a larger number of cases. The credit goes to Amsler and Verrey 23 for having shown that, in heterochromic cyclitis exclusively a puncture of the anterior chamber produces a filiform hemorrhage in the angle, in general on the side opposite the puncture. Verrey 24 and François 25 found by gonioscopic examination that the hemor­ rhage arises from the region of Schlemm's

canal. I can confirm the findings of Georgiades26 that exceptionally the filiform hem­ orrhage is lacking. François, 25 Vannini,27 and others have made gonioscopic examinations in Fuchs' disease. My personal observations corre­ spond to those published recently by Van­ nini.27 Of 15 cases, six showed a normal angle, five showed more or less numerous radial and concentric vessels in the region of the trabecular system (table 1). In one case these vessels appeared only some time after the beginning of the examination with the contact glass. In four cases undifferentiated tissue par­ tially occupied the region of the angle. In two there was a marked vascularization ; in two others the alteration looked like a veil on the base of the iris. In only four cases with secondary glau­ coma (three in: aphakic eyes), did I find goniosynechias, with a large angle, even on the opposite side of the incision. Secondary glaucoma is a well-known com-

TABLE 1 FREQUENCY

OF PATHOLOGIC FINDINGS

BY GONIOSÇOPY IN F U C H S '

Number of Cases

Normal

Increased Vascularization

Presence of Nondifferentiated Tissue often with Increased Vascularization

Vannini (1954)

15

8

3

4

Personal observation

15

6

5

4

Author

HETEROCHROMIA

HETEROCHROMIC

CYCLITIS

1-55

TABLE 2 F R E Q U E N C Y OF GLAUCOMA I N U N I L A T E R A L A N D BILATERAL F U C H S ' SYNDROME

Number of Eyes with Unilateral Fuchs' Syndrome

Secondary Glaucoma

Number of Eyes with Bilateral Fuchs' Syndrome

Secondary Glaucoma

Males

27

4

14.8%

10

1

10%

Females

27

3

11.1%

6

3

60%

Total

54

7

13.0%

16

4

25%

showed heterochromia. In the future, special attention should be paid to the relationship between Posner-Schlossman syndrome, and glaucoma in Fuchs' heterochromia. Up to 1946, François 30 found about 400 cases of Fuchs' syndrome in the literature; only 14 (3.5 percent) were bilateral. That incidence is certainly too low for among my 62 cases, eight (12.9 percent) are bilateral (table 3 ) . In the recent statistics of Georgiades,31 four out of 52 (7.7 percent) patients were affected in both eyes. I am convinced that a great number of bilateral cases are not recognized because they show a heterochromic cyclitis with almost no heterochromia; for that reason I prefer the name of Fuchs' syndrome. The question about the congenital or ac­ quired nature of the complicated hetero­ chromia is still open. Certain authors do not accept the diagnosis of Fuchs' syndrome if the heterochromia is not congenital (Kalt 3 2 ). Only in 14.5 percent of my cases, the con­ genial origin of the heterochromia was cer­ tain (table 3 ) . Concerning the etiology of Fuchs' hetero-

plication in Fuchs' syndrome and is prac­ tically the only one that has to be feared. It seems to be more frequent in bilateral cases than in unilateral (Franceschetti and Hermann 28 ). Taking into account that in bilateral cases the probability of glaucoma for each eye must be calculated separately, of 16 eyes of eight patients with bilateral Fuchs' syndrome, four developed secondary glaucoma, but the difference between 25 percent in bilateral and 13 percent in uni­ lateral cases is not statistically* significant (table 2 ) . In discussing the differential diagnosis of heterochromic glaucoma, the syndrome of Posner and Schlossman29 must be mentioned before all else. These authors described, in 1948, and again in 1953, that curious syn­ drome of glaucomatocyclitic crises which always seems to be unilateral. As in hetero­ chromia, there are no posterior synechias; the episodes of cyclitic precipitates are us­ ually accompanied by open-angle glaucoma. In their first series, three of the nine cases * ÷2 = 1 . 3 5 .

TABLE 3 STATISTICAL DATA IN 62 CASES OF FUCHS' SYNDROME

Right Eye

Left Eye

32

14

13

Female

30

13

Total

62

Sex Male

%

Number

Bilateral

Without Congenital Hetero­ Hetero­ chromia chromia

Status Dysraphi- Secondary Glaucoma cus

5

2

6

19

5

14

3

2

3

9

5

27

27

8

4

9

28

10

43.5

43.5

45.2

16.1

12.9

6.4

14.5

A. F R A N C E S C H E T T I

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TABLE 4 F R E Q U E N C Y OF CERVICAL ARTHROSIS IN 33 CASES OF F U C H S ' SYNDROME AND 6 6 " N O R M A L " CONTROLS

Age (yr.)

" N o r m a l " Controls

Fuchs' Syndrome Number of Cases

With Arthrosis

Percent

Number of Cases

With Arthrosis

Percent

15-29

6

0

0

12

1

30-39

5

0 .

0

10

2

40-49

12

8

66.7

24

11

45.8

50-59

9

8

88.9

18

16

88.9

60-69

1

1

2

2

Total

33

17

66

32

100 51.5

chromia, a great number of authors affirm the tuberculous nature of the affection. I must point out that neither my late friend Dr. Semadeni of Davos, who examined thoroughly 35 cases of heterochromia (see Ruppli 33 ) nor I myself was able to find a higher incidence of tuberculous symptoms in these patients than in any other section of the population. This question is not only of theoretic in­ terest but has an enormous practical im­ portance. We have seen a great number of patients treated for years and years for their "tuberculous" heterochromic cyclitis; many have been advised to change or to give up their profession. It is not my purpose to discuss here the theory of the sympathetic origin of this syndrome (see François 34 ). I would like to mention only some constitutional and hereditary features in connection with the problem of the etiology of heterochromia. According to Passow,35 who found in 80 percent of his cases of heterochromia, symp­ toms of a status dysraphicus (Bremer), this hereditary constitutional type should be considered as the primary cause of Fuchs' syndrome. Like many other authors, I found in nearly 50 percent of my cases certain signs of Bremer's status dysraphicus but, with one exception, all the cases were very slight.

8.3 20

100 48.5

Since 1946, Paufique and his school36 have insisted on the frequency of cervical arthro­ sis and discopathy in Fuchs' syndrome, which may cause disturbances in the sympa­ thetic innervation and finally Fuchs' syn­ drome. Recently Georgiades,37 who examined 68 cases of complicated heterochromia, found in 55 percent alterations of the cervical column. X-ray examination of the cervical region has been made in 33 of my cases but, before drawing any conclusion, it seemed to me necessary to obtain analogous information about normal persons of the same age groups. Dr. J. E. W. Brocher,* Dr. Kammermann, and I have made a systematic X-ray examination of the cervical column in 33 cases of Fuchs' syndrome and in 66 "nor­ mal" controls. Those investigations con­ firmed the fact that cervical arthrosis is more or less a physiologic manifestation after the age of 40 years, increasing much with age. Furthermore we were surprised to see that in the normal persons examined, the fre­ quency of cervical arthrosis was practically the same as in Fuchs' syndrome (table 4). * I would like to thank Dr. J. E. W . Brocher, lecturer in general pathology at the University of Geneva, whose large experience in the interpretation of X-ray findings of the cerebral column was a great help to me.

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TABLE S D E G R E E OF ARTHROSIS IN 17 CASES OF F U C H S ' SYNDROME AND IN 32 CASES OF " N O R M A L " CONTROLS

Fuchs' Syndrome Age (yr.)

Number of Cases with Arthrosis

"Normal" Controls

Degree of Arthrosis

+

++

++ +

Number of Cases with Arthrosis

Degree of Arthrosis

+

++

+++

15-29

0

1

1

30-39

0

2

4

40-49

8

7

1

11

8

2

1

50-59

8

2

3

16

9

7

3

60-69

1

1

Total

17

1.0

3

58.8

%

4

17.7

23.5

TABLE 6 N U M B E R OF ASSOCIATED ANOMALIES IN 62 SYNDROME

Anomaly

Males (32)

Homer's syndrome Syringomyelia Homolateral congenital deafness Disseminated sclerosis Nevi Vitiligo (familial) Incontinentia pigmenti Retinitis pigmentosa Dental anomalies Polydactylia Consanguinity

— 1 1 1 1 1

—· 1 1 1 2

32

3

In addition the degree of arthrosis was not very different in the two groups, although the frequency of pronounced arthrosis seems to be somewhat higher in those with Fuchs' syndrome than in "normal" controls (table 5)· In conclusion our statistics show that the role of cervical arthrosis in Fuchs' syndrome must not be overestimated, although it may be responsible in certain cases. Finally, I would examine briefly the he-

CASES OF FUCHS'

2

2

Females (30) 3 1

— — — — 1

— — — 1

22

11

59.5

29.7

4 10.8

reditary factor in Fuchs' syndrome. Until now only a few cases of direct inheritance have been described, which allows no defini­ tive conclusions. If we have to deal with affections where the hereditary factor is diffi­ cult to establish, we can sometimes get more information if we look for associated anom­ alies. They are of very different types and no one occurs frequently (table 6). Never­ theless, different anomalies of pigmentation, such as nevi, vitiligo, incontinentia pig­ menti, and retinitis pigmentosa, have been found, and this does not seem to be due to chance alone. At the moment we know, in spite of the few cases I have mentioned, very little about the role of inheritance in Fuchs' heterochromia. If one day we have the good for­ tune to find identical twins with Fuchs' syndrome, we hope it will then be easier to answer the difficult question of the role of a genetic factor in complicated heterochromia. Clinique Ophtalmologique.

REFERENCES

1. Lawrence, W. : Treatise on Diseases of the Eye. Philadelphia, Isaac Hays, 1853, ed. 3. 2. Hutchinson, J. : Roy. Ophth. Hosp. Rep., 6:277, 1869. 3. Gunn, M. : Ophth. Rev., 8:232, 1889.

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4. Fuchs, E.: Ztschr. f. Augenh., 15:191-212, 1906. 5. Duke-Elder, W. S. : Textbook of Ophthalmology. London, Kimpton, 194S, v. 3, pp. 2360-2362. 6. Lloyd, R. I. : Am. J. Ophth., 14:287-299, 1931. 7. Berliner, M. L. : Biomicroscopy of the Eye. New York, Hoeber, 1949, v. 2, pp. 903-905. 8. Duke-Elder, W. S. : Ref. 5, p. 2362. 9. François, J. : Ann. ocul., 187:2S5-272,1954. 10. Pau, H. : Arch. f. Ophth., 150:340-357, 1950. 11. Vogt, A.: Lehrbuch und Atlas der Spaltlampenmikroskopie des lebenden Auges. Berlin, Springer, 1930, v. 1, p. 215. 12. Paufique, L., and Etienne, R. : Semaine hop. Paris, 28 :2294-2310, 1952. 13. Biozzi, G. : Boll, ocul., 15:67-144, 1936. 14. Vogt, A. : Ref. 11, Zurich, Schweizer Druck- und Verlagshaus, 1942, v. 3, pp. 885-889. 15. Straff, J. : Klin. Monatsbl. f. Augenh., 76 :321-339, 1926. 16. François, J. Ann. ocul., 179:559-557, 1946. 17. Georgiades, G.': Contribution to the Study of Heterochromia. Salonica, 1953, p. 142. 18. Vogt, A.: Ref. 11. 19. Duke-Elder, W. S. : Ref. 5. 20. Vogt, A. : Ref. 14, p. 1000. 21. Amsler, M. : Bull, et mém. Soc. franc, d'ophtal., 59:304-313, 1946. Asmler, M., and Huber, A. : Ophthalmologica, 111:155-176, 1946. Amaler, M., and Verrey, F.: Ophthalmologica, 111:177-181, 1946. 22. Georgiades, G. : Ref. 17. 23. Amsler, M., and Verrey, F. : Ophthalmologica, 111:177-181, 1946. 24. Verrey, F. : Clinique de l'humeur aqueuse pathologique. Neuchatel-Paris, Delachaux et Niestle, 1954, pp. 214-217. 25. François, J. : Ref. 9. 26. Georgiades, G. : Ref. 17. 27. Vannini, A. : Rass. ital. ottal., 23 :l-23, 1954. 28. Franceschetti, A., and Hermann, P. : Bull. Soc. ophtal. de France, 1952, pp. 426-436. 29. Posner, A., and Schlossman, A.: Arch. Ophth., 29:517-535, 1948; Tr. Am. Acad. Ophth., 57:531536, 1953. 30. François, J. : Ref. 16. 31. Georgiades, G. : Ref. 17. 32. Kalt, M. : Les uvéites hypertensives. Rapport Soc. franc, ophtal., Paris, Masson, 1949, pp. 176-177. 33. Ruppli, H. : Beitrag zur klinischen Bild und zur Aetiologie der Fuchs' sehen Heterochromie. Geneva, Thesis, 1952. 34. François, J. : Ann. ocul., 182:585-596,1949. 35. Passow, A. : Arch. f. Augenh., 107:1-51,1923. 36. Paufique, L., and Chavanne, H. : Bull, et mém. Soc. franc, ophtal., 59.209-219, 1946. Paufique, L., and Etienne, R. : Bull. Soc. ophtal. de France, 1949, pp. 839-844. Chevassus, J. : L'hétérochromie compliquée de Fuchs, avec précipités et cataracte, signe de lésion sym­ pathique dans les altérations du rachis cervical. Lyon, Thesis, 1950. 37. Georgiades, G. : Ref. 17.