Presumed Histoplasmic Choroiditis

A M E R I C A N J O U R N A L OF OPHTHALMOLOGY MAY, 1967

VOLUME 63

NUMBER 5, PART I

P R E S U M E D H I S T O P L A S M I C CHOROIDITIS T. F. SCHLAEGEL, JR., M.D.,

JANET C. WEBER, P H . D . , EUGENE HELVESTON, AND DAVID KENNEY,

M.D.,

M.D.

Indianapolis, Indiana

Histoplasmic choroiditis has been fairly well recognized since its description ,by.. Woods and Wahlen in 1959.1 By November, 1966, we had made the clinical diagnosis in ;. 190 patients. Our purpose is to report addi­ tional clinical characteristics in order to clarify features of this rather clear-cut enti­ ty of unknown etiology. METHOD

We focussed attention on the the clinical course of our first 100 patients. Unfortu­ nately we were not able to garner data about every aspect of each of these patients. The diagnosis was based on the typical clinical picture combined with a test positive for histoplasmosis. In making this presumptive diagnosis, other measures were not consid­ ered warranted; for example, X-ray exam­ ination of the chest did not seem necessary, since in our experience the roentgenologist was unable to differentiate histoplasmic in­ volvement from other granulomatous dis­ ease. All that is needed is the typical ocular picture combined with some evidence that the patient has contracted histoplasmosis in the past. For this purpose the histoplasmin skin test is both simple and superior.2 From the Department of Ophthalmology, Indi­ ana University School of Medicine. This study was supported in part by Research to Prevent Blindness, Inc., New York, by the Better Vision Fund, Indiana University, and by United States Public Health Service research grant FR00162-02. Computer time was made available by the Medical Research Computation Center under United States Public Health Service research grant FR-00162.

Fig. 1 (Schlaegel, Weber, Helveston and Kenney). Disseminated areas of choroiditis may involve any portion. RESULTS AND COMMENT A. OCULAR CHARACTERISTICS

Clear media. It is important to emphasize that in presumed ocular histoplasmosis the media are clear. Cells are rarely seen in ei­ ther the anterior chamber or vitreous.3 Disseminated choroiditis. These lesions were similar to those described previously,1·3-7·9·13'20·22·23'25.26'31-33 that is, small, yellow moderately soft, randomly scattered, usually nonpigmented and atrophie areas, 0.1 to 0.5 disc diameter in size, involving the pigment epithelium and choroid. These yel­ low spots were found in any region of the fundus (fig. 1). When seen in the acute stage, there was a slight yellowish swelling of the choroid (fig. 2) and occasionally a

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AMERICAN JOURNAL OF OPHTHALMOLOGY

MAY, 1967

Fig. 2 (Schlaegel, Weber, Helveston and Kenney). Active nod­ ular choroiditis—yellowish spheri­ cal swelling of choroid. Atrophie choroiditis—yellowish slightly de­ pressed plaquelike remnant.

slight haze or ground-glass appearance in the overlying retina. In the atrophie stage there was a slight depression in the region of the pigment epithelium and choroid, but the lesion was never completely punched out. It was rare to see choroidal vessels because they were usually covered by a yellow plaque. We consider these yellow spots to be the most characteristic feature of presumed histoplasmic choroiditis, so we refuse to make the diagnosis unless at least one of them is seen in at least one eye or the patient has some of the characteristic changes around the optic nervehead.5 Circumpapillary choroiditis. Seventy per­ cent of our patients had areas of choroiditis TABLE 1 CLASSIFICATION OF MACULAR LESIONS

IN

HISTOPLASMIC CHOROIDITIS

(After Makley and associates) Grade

Features

1 Yellow-white spot of the disseminated type IH Yellow-white spot with associated hemorrhage 2 Greenish-gray, slightly elevated nodule. 3 Nodule with hemorrhage 4 Nodule with hemorrhage and edema residues 5 Atroph ic scar (usually elevated but may be flat)

around both discs and an additional 15%, lesions around one disc. Neither disc was involved in the remaining 15%. These le­ sions were arbitrarily grouped into four rec­ ognizable patterns: diffuse, nodular, mixed and hemorrhagic. The first three types were of value in the making of a clinical diag­ nosis. The fourth or hemorrhagic type was the only one giving rise to symptoms and it resulted in 20/200 vision or worse in half the cases.5 Macular choroiditis. The natural history of macular choroiditis is for it to progress through the stages described by Makley and associates8 (table 1), from a mild area of choroiditis to a legally blinding scar. It typi­ cally begins outside the fovea, causing leak­ age which may result in a disci form detach­ ment, apparently by seepage of serum and/or blood through Bruch's membrane and then either under the pigment epitheli­ um or the sensory retina. Macular involve­ ment is a dreaded complication which often (56%) leads to legal blindness. The only place we have observed disciform detach­ ment has been in the disc-macula region;

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TABLE 2 RELATION BETWEEN FINAL VISUAL ACUITY AND LOCATION AND SEVERITY OF HISTOPLASMIC CHOROIDITIS I N 5 0 PATIENTS

Final Visual Acuity 20/20 or better 20/25 through 20/40 20/50 through 20/70 28/80 through 20/100 20/200 or worse

TOTAL

Central Lesions Mild 1 1 4 6

Moderate

Eccentric LesioiIIS Severe

Mild

Moderate

Severe

3 4

2 8

1 3 2 1 7 14

2

1

4 1 1

1 1 2 8 12

this may be due to the fact that in other areas disciform detachments give rise to few or no symptoms. It seems more likely, however, that they occur at the posterior pole because of some physiologic character­ istics of this region, such as the blood pres­ sure gradient and nerve control of the short posterior ciliary arteries, as postulated by Potts. 8 The macular lesions of histoplasmosis are not diagnostic. Since such lesions may be due to other causes, the diagnosis of histo­ plasmosis should never be made on the basis of the appearance of the macula alone. We attempted to divide the macular involvement into mild, moderate and severe and into cen­ tral and eccentric (table 2 ) . This was not satisfactory since the severity and position of the choroiditis varies. Eccentric lesions often progress to a central location. If such a lesion does not progress too far or if it is not too severe, central vision may be spared or may recover ( 1 6 % ) . A study of these eight patients (table 2) revealed that in half of them the choroiditis was small and inac­ tive and produced no real damage to vision. In the other half, the vision dropped to as low as counting fingers due to a macular in­ volvement as severe as Makley Grade 3, but then improved to 20/20. Exacerbations. An exacerbation is defined as a temporary worsening of a chronic vi­ sion-damaging macular or circumpapillary choroiditis, one that usually lasts one to two years before healing. Recurrences. There are two types : ( 1 ) a

4 6

Total 8 6 5 3 28 50

scarred area may become active (fig. 3) ; (2) fresh areas of choroiditis may appear in uninvolved choroid. Recurrences are most serious when the second macula becomes in­ volved. When this happened our histories indicated that it did so in from one month to 28 years. The average time elapsing was six and two-thirds years (median four and one-sixteenth). This compares with an aver­ age interval of four years found in the Ohio study.6 Of 100 cases, both maculas were in­ volved in 33. Since we see the more severe cases, these figures do not mean that the pa­ tient who has had one macula damaged has a 3 3 % chance of having the second one in­ volved. One of the most common questions asked by patients is their chances of having their second macula damaged. We do not know, but our experience would suggest that their chances are about 1:10. We think this estimate is of considerable value to them. Our most instructive patient (J. C ) , who was the source of Figure 2, gave a history of lethargy and a fever of about 1°F. These attacks of fever, lasting three or four weeks, recurred several times over a period of sev­ eral years and were associated with the ap­ pearance of new areas of choroiditis. After the fever and lethargy had been present one to two weeks, the patient would notice a point of flashing light. We would then focus the ophthalmoscope and slitlamp on this spot and see an active area of choroiditis (fig. 2 ) . As the fever and lethargy receded the photopia would diminish and the cho-

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MAY, 1967

Fig. 3 (Schlaegel, Weber, Helveston and Kenney). (A) Appearance of scars in March, 1961, and (B) in April, 1964. In the interim, an acute hemorrhagic flare-up had occurred at the site of the upper scar.

roiditis gradually subside. Blood cultures for H. capsulatum and chest X-ray films have all been negative. Another patient with a similar history developed a palpable liver and spleen but refused a thorough work-up. Reactivation did not follow any other known factor, except, of course, the subcu­ taneous injection of histoplasmin. At the time of the diagnostic histoplasmin skin test, four of 57 (7%) developed a hemorrhage adjacent to their choroiditis. Of importance to the epidemiology is the fact that recur­ rences have been observed as long as 15 years after the patient has moved out of the endemic area.12 B. GENERAL CHARACTERISTICS

Incidence. Frequency varies with locality and type of practice. On our service, histoplasmic choroiditis accounts for 22% of our uveitis cases and at Johns Hopkins for 20%.° It is uncommon in New York,10 Seattle11 and San Francisco12 but common in the Midwest, where the disease is endem­ ic. Sex. Males (63%) were more frequently affected than females (37%). Although pos­ itive skin tests appear to be equally com­ mon, the active disease (whether systemic

or ocular) occurs more frequently in males.2'3 Age. The present study confirms13 that the peak age of involvement is during the fourth decade. Compared with other types of uveitis cases, there were significantly fewer patients with histoplasmosis under 20 and over 50 years of age and significantly more from 30 to 39 (table 3). Race. We have not seen a single Negro among the 190 patients diagnosed as having presumed histoplasmic choroiditis. Although there is no difference in the sensitivity to histoplasmin among Negro and white resi­ dents of the same community,14 Furcolow found only seven of 145 pulmonary cases in Negroes.22 The rarity of ocular histoplas­ mosis in the Negro is confirmed by Van Metre, who had seen only one with ocular involvement,15 but is opposed by Asbury16 who, in a population survey of presumably normal people, found "histo" spots twice (2.5%) as commonly in Negroes as in whites (1.3%). It is possible that peripheral histoplasmic choroiditis is more common in the Negro and the macular type more com­ mon in white individuals. Diagnostic tests. We confirmed the find­ ings of Van Metre and Maumenee4 that

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TABLE 3 RELATION BETWEEN AGE OF ONSET AND DIAGNOSIS OF HISTOPLASMIC OR NONHISTOPLASMIC UVEITIS

Age (yr)

Histoplasmic Choroiditis

All other Uveitis

Age of Onset (yr)

Age Seen (yr)

0-19 20-20 30-39 40-49 50-79

3 36 40 22 11

3* 27 43t 23 16*

TOTAL

112

Age Seen (yr) 15 18 19 16 25

112

93

Column 2 VS 3: - χ 2 = 20.7266, p <0.001 * Age brackets which make a contribution to difference t Age bracket which makes largest contribution to difference

there is a reduced reactivity to toxoplasmin (p < 0.001). Because presumed toxoplasmosis cases are removed from our series a significant decrease in the number of pa­ tients with positive toxoplasmin skin tests would be expected. It is, however, not nec­ essary for the toxoplasmin and tuberculin skin tests to be negative in order to make a diagnosis of histoplasmosis. Woods and Wahlen required this for their pioneering study but now that the clinical picture has been established, such a requirement is no longer warranted. A diagnosis was not made without a posi­ tive test, so all histoplasmin skin tests were positive with one exception. This patient had the typical clinical picture plus a posi­ tive complement fixation test for histoplas­ mosis. Furcolow2 found that only 8 3 % of patients with chronic subclinical histoplas­ mosis had a positive skin test. It can change from positive to negative in older people, especially women.16 Since histoplasmic cho­ roiditis seems to occur in the chronic or rel­ atively quiescent stage of systemic histoplas­ mosis when the skin test may become nega­ tive, one may fail to diagnose ocular cases if a positive skin test is required. To try to determine what percentages of cases might be undiagnosed, we examined a series with the typical clinical picture and a negative histoplasmin skin test (6) and compared them with those with the typical ocular picture and a positive skin test (50). Since this figure of 1 1 % with a negative

histoplasmin skin test approaches the 17% figure of Furcolow in chronic subclinical systemic histoplasmosis, we may postulate that about 1 1 % of cases may be undiag­ nosed by use of the criteria of a positive skin test. Season. Involvement of the first macula occurred more frequently (p < 0.02) in the months of September, October and Novem­ ber (table 4 ) . This higher incidence might be correlated with the increased outdoor dust or outdoor activity in the preceding summer months, but the cause is unknown. COMMENT

New areas of . histoplasmic choroiditis usually arise in uninvolved choroid and not as a budding inflammation, as in recurrent toxoplasmosis. Another difference is that the Toxoplasma parasite has a predilection for the retina whereas "histoplasmosis" has a predilection for the choroid. When the yeast phase of H. capsulatum in great dilu­ tion was injected into the vitreous of pri­ mates, no infection was produced in the vit­ reous or retina but areas of choroiditis resembling those seen in humans were produced.18 Because these areas of choroidi­ tis are discrete, it is likely they arise from dissemination. They may appear 1019 to 2020 years before the macula becomes involved (if it becomes involved at all). The percentage of the population de­ veloping macular choroiditis is not known but is smaller than the percentage who de-

924

AMERICAN JOURNAL OF OPHTHALMOLOGY

MAY, 1967

TABLE 4 RELATION BETWEEN SEASON OF THE YEAR AND ONSET OF HISTOPLASMIC CHOROIDITIS

Onset

Spring (M . A. M.) Summer (J.J.A.)

First eye (57) Second eye (37) TOTAL

(95)

Fall (S. 0. N.)

Winter (D. J. F.)

P

No.

%

No.

%

No.

%

No.

%

14

24.56

10

17.54

24

42.10

9

15.79

0.02*

8

21.62

12

32.43

11

29.22

6

16.22

N.S.

22

23.40

22

23.40

35

37.23

15

15.96

0.05f

* x22=9.8772 t x =8.8936 velop disseminated choroiditis. W h e t h e r or not peripheral lesions play a role in the sub­ sequent involvement of the macula by some method such as sensitization of the tissues is not known. It is likely that they are of no significance and that it is only when a n area of choroiditis involves the disc-macula area that a symptomatic disciform detachment of the retina results. Since no organisms have been recovered from the eye, the dissemi­ nated areas of choroiditis could be allergic reactions: either "ocular histoplasmids" comparable to cutaneous coccidioidids, tuberculids, and trichophytids or areas of vas­ cular inflammations comparable to erythema nodosum 3 4 in the subcutaneous tissues. If this is true, choroidosis may be a better term than choroiditis. SUMMARY

Presumed histoplasmic choroiditis was diagnosed in 190 patients on the basis of a characteristic clinical picture and a positive skin test.* It was found more frequently in males in the fourth decade, the white race and during the fall months. Fifty-six per­ cent of those with macular lesions developed 20/200 vision or less and only 1 6 % retained or recovered 2 0 / 2 0 vision. Other than the reaction from the injection of histoplasmin in skin testing or desensitization, no reason for recurrences of inflammation was uncov­ ered but recurrences were occasionally seen * One case was diagnosed with a positive com­ plement-fixation test.

during a period of fever and lethargy. T w o types have been observed: ( 1 ) a scarred area may reactivate and ( 2 ) fresh choroidi­ tis may appear in uninvolved areas. Involve­ ment of the second macula, when it oc­ curred, happened in from one month to 28 years and was estimated to occur in about one case in 10. 1100 West Michigan Street .(46207) REFERENCES

1. Woods, A. C. and Wahlen, H. E. : The probable role of benign histoplasmosis in the etiology of granulomatous uveitis. Tr. Am. Ophth. Soc. 57:318, 1959. 2. Furcolow, M. L. : Tests of immunity in his­ toplasmosis. New Eng. J. Med. 268:357, 1963. 3. Maumenee, A. E. : Audio Digest, Vol. 4, No. 2, Side B. 4. Van Metre, T. E. and Maumenee, A. E. : Specific ocular uveal lesions in patients with evi­ dence of histoplasmosis. Arch. Ophth. 71:314, 1964. 5. Schlaegel, T. F., Jr. and Kenney, D. : Changes around the optic nerve head in presumed ocular histoplasmosis. Am. J. Ophth. 62:454, 1966. 6. Makley, T. A., Long, J. W., Suie, T. and Ste­ phan, J. D. : Presumed histoplasmic chorioretinitis with special emphasis on the present modes of therapy. Tr. Am. Acad. Ophth. Otolaryng. 69 :443, 1965. 7. Schlaegel, T. F., Jr.: Discussion of Makley et al." 8. Potts, A. M. : An hypothesis on macular dis­ ease. Tr. Am. Acad. Ophth. Otolaryng. in press. 9. Van Metre, T. E.: Role of the allergist in diagnosis and management of patients with uvei­ tis. JAMA, 195:167, 1966. 10. Coles, R. S. : Personal communication. 11. Hungerford, L. N. : Personal communica­ tion.

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12. Hogan, M. J. : Personal communication. 13. Walrna, D., Jr. and Schlaegel, T. F., Jr.: Presumed histoplasmic choroiditis. Am. J. Ophth. 57:107,1964. 14. Edwards, P. Q. and Palmer, C. E. : Sensi­ tivity to histoplasmin among Negro and white residents of different communities in the U.S.A. Bull. WHO 30:57S, 1964. 15. Van Metre, T. E. : Personal communication. 16. Asbury, T. : The status of presumed ocular histoplasmosis; including a report of a survey. Tr. Am. Ophth. Soc. in press. 17. Baker, R. D. : Histoplasmosis in routine au­ topsies. Am. J. Clin. Path. 41:457,1964. 18. Smith, J. L. and Singer, J. A. : Experimen­ tal ocular histoplasmosis VI. Fluorescein fundus photographs of choroiditis in the primate. Am. J. Opthth. 58:1021, 1964. 19. Harley, R. D. : Personal communication. 20. Maumenee, A. E. : A symposium on differential diagnostic problems of posterior uvei­ tis. Dec. 2-5, 1964, Univ. Calif. M. Center, San Francisco. 21. Krause, A. C. and Hopkins, W. G. : Ocular manifestations of histoplasmosis Am. J. Ophth. 34:564,1951. 22. Maumenee, A. E. : In Kimura, S. J. and Caygil, W. M. (ed.) : Retinal Diseases: Symposium on Differential Diagnostic Problems of Posterior Uveitis. Philadelphia, Lea and Febiger, 1966, pp. 255-256. 23. Maumenee, A. E. : Twenty-First Annual

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925

Gifford Memorial Lecture. Chicago Ophth. Soc. May 21, 1966. 24. Newell, F. W., Krill, A. E. and Thomson, A. : The treatment of uveitis with six-mercaptopurine. Am. J. Ophth. 61:1250, 1966. 25. Klien, B. A. : Personal communication. 26. Falls, H. F. and Giles, C. L. : The use of amphotericin-B in cases of chorioretinitis. Am. J. Ophth. 49:1288,1960. 27. Holeman, C. W., Jr. and Einstein, H. : The toxic effects of amphotericin-B in man. Calif. Med. 99:90, 1963. 28. Coles, R. S.: Audio Digest, Vol. 4, No. 2, Side A. 29. Gass, J. D. M. : Personal communication. 30. Edwards, P. Q. and Klaer, J. H. : Worldwide geographic distribution of histoplasmosis and his­ toplasmin sensitivity. Am. J. Trop. Med. Hyg. 5:235, 1956. 31. Jarvis, G. J. and McCulloch, C. : Ocular histoplasmosis. Canad. M. A. J. 89:1270, 1963. 32. McCulloch, C. : Histoplasmosis. Tr. Canad. Ophth. Soc. 26:107, 1963. 33. Giles, C. L. and Falls, H. F.: Further evaluation of amphotericin-B therapy in presump­ tive histoplasmosis chorioretinitis. Am. J. Ophth. 51:588, 1961. 34. Medeiros, A. A., Marty, S. D., Tosh, F. E. and Chin, T. D. Y. : Erythema nodosum and er­ ythema multiforme as clinical manifestations of histoplasmosis in a community outbreak. New Eng. J. Med. 274:415, 1966.

MINIATURE

Robert I I of Scotland was not a great king, but everybody spoke well of him, and a writer who lived at the time says no man could have had a tenderer heart than he had. Another says that he was a tall good-natured looking man and that his eyes were so bloodshot that they looked as if they were "lined with scarlet." S o his subjects who gave nicknames to most of their kings, called him " K i n g Blearie." P . H u m e Brown, Short History of Scotland, p. 105