morphological variation of dalen-fuchs nodules insympatheticophthalmia · br j ophthalmol: first...

British Journal ofOphthalmology, 1985, 69, 197-201

Morphological variation of Dalen-Fuchs nodulesin sympathetic ophthalmiaMICHAEL REYNARD, RALPH S RIFFENBURGH, AND DON S MINCKLERFrom the Department of Ophthalmology, University ofSouthern California, and theEstelle Doheny Eye Foundation, Los Angeles, California, USA

SUMMARY Fifty cases of sympathetic ophthalmia were examined histologically to determine theincidence and morphology of Dalen-Fuchs nodules. At least one well-defined Dalen-Fuchs nodulewas identified in 18 (36%) of the eyes examined. Three types of lesions at the level of the retinalpigment epithelium were recognised. One type was found to consist of focal hyperplasia andaggregation of retinal pigment epithelial cells. A second type, classically referred to asDalen-Fuchs nodules, consisted of epithelioid cells and lymphocytes covered by an intact dome ofretinal pigment epithelium. The third type of lesion was characterised by degeneration of theoverlying retinal pigment epithelium leading to disorganisation of the Dalen-Fuchs nodule andpossible release of their contents into the subretinal space. Our study demonstrated thatDalen-Fuchs nodules in sympathetic ophthalmia vary in their morphological appearance asdetermined by light microscopy.

Isolated nodular collections of cells lying betweenBruch's membrane and the retinal pigment epi-thelium, in association with sympathetic ophthalmia,are classically referred to as Dal6n-Fuchs nodules.'The morphologic appearance of the nodular lesionswas originally described in 1881 by Brailey2 as 'smallglobular aggregations of unpigmented cells, in orupon the pigment epithelial layer . . . by means ofwhich small tracts of the ciliary retina may be raisedin an arch-like manner.' The classic studies by Dalen3in 1904 and Fuchs4 in 1905 showed that these hemi-spherical nodular lesions consisted primarily of epi-thelioid cells, lymphocytes, and metaplastic cellsfrom the retinal pigment epithelium.Although the Dalen-Fuchs nodule is a character-

istic pathological feature of sympathetic dphthalmia,found in both sympathising and exciting eyes, it is notpathognomonic for this entity. Dalen-Fuchs noduleshave also been reported in sarcoidosis, tuberculosis,and the Vogt-Koyanagi-Harada syndrome.5 6The purpose of this study is to describe the mor-

phological variation of Dalen-Fuchs nodules insympathetic ophthalmia.

Corrcspondencc to Dr Michael Reynard, 22(X) Santa MonicaBoulevard, Suitc 209, Santat Monica, California 90404, USA.

Materials and methods

Fifty histologically verified cases of sympathetic oph-thalmia obtained from the pathology files of theEstelle Doheny Eye Foundation, Los Angeles,California, USA, and from cases referred to theDoheny Sympathetic Ophthalmia Study wereevaluated by light microscopy to determine the in-cidence and morphological features of Dalen-Fuchsnodules. In 48 cases the exciting eye was examinedhistologically. In two unrelated cases the sympath-ising eye was examined histologically.

Results

INCIDENCEThe presence of at least one well-defined Dalen-Fuchs nodule was confirmed in 18 (36%) cases. Thisfigure represents a conservative estimate, becauseserial sections were not available in all cases.

MORPHOLOGICAL VARIATION OF DALtN-FUCHSNODULESThe Dalen-Fuchs nodule is recognised typically as ahemispherical mound primarily consisting of epi-thelioid cells and occasional lymphocytes beneath the

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Michael Reynard, Ralph S Riffenburgh, and Don S Minckler

Fig. 1 Focal hypertrophy andaggregation ofthe retinalpigmentepithelium suggestive ofearlyDalen-Fuchs noduleformation.(Haematoxylin and eosin, x 135).

......................... ..

Fig. 2 Diffusegranulomatousuveitis with obliteration ofthechoriocapillaris andfocal moundsofretinalpigment epithelial cells.(Haematoxylin and eosin, x50).

retinal pigment epithelium. Careful evaluation of ourmaterial revealed a morphological spectrum oflesions occurring along the retinal pigmentepithelium.The first type of lesion providing the earliest

indication of Dalen-Fuchs nodule formation consistsof focal hyperplasia and aggregation of retinal pig-ment epithelial cells (Fig. 1). The retinal pigmentepithelial cells form small mounds or localised areasof stratification (Fig. 2).The second type of lesion is characterised by the

presence of well defined and closely packed collec-tions of epithelioid cells underlying a dome of retinalpigment epithelium. These lesions are classicallyinterpreted as Dalen-Fuchs nodules (Fig. 3).Metaplastic cells from the retinal pigment epi-thelium, lymphocytes, and giant cells may occasion-ally be found within this nodular structure (Fig. 4).

Fig. 3 Well-defined Dalen-Fuchs nodule consisting oflymphocytes and epithelioid cells beneath a dome ofretinalpigment epithelial cells. (Haematoxylin and eosin, x 108).

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Morphological variation ofDalen-Fuchs nodules in sympathetic ophthalmia

i 41 c

Fig. 4 Dalen-Fuchs nodule containing epithelioid cells and a giant cell. The dome ofretinalpigment epithelium appears tohave undergone degeneration. (Haematoxylin and eosin, x 40; inset x 108).

In the third type of lesion the retinal pigment epi-thelial dome of the Dalen-Fuchs nodule degenerates.The retinal pigment epithelium disappears first at theapex of the nodule and then completely. Degenera-tion of the retinal pigment epithelial dome may allowcells of the Dalen-Fuchs nodule to separate fromeach other and be released into the subretinal space(Fig. 5). All three types of lesions described mayoccur in the same case.A clear relationship between duration of disease

and morphological type of Dalen-Fuchs nodule couldnot be established; the three types of lesions

Table 1 Location of Dalen-Fuchs nodules

Locationi of Daklea-Fucls hiterval of timne ini weeks frownnodules symptoins to enuc'leatiotn

(18 cases)

0-3 4-11 12+

Anterior to cquator 5 2 ()Postcrior to cquator 0 3Gcncralized involvcment 1 2 4*

*Including two symp.ithising cycs.

described were found in eyes enucleated early andlate in the course of sympathetic ophthalmia. Eyeswith Dalen-Fuchs nodules that were enucleatedrelatively early in the course of sympathetic oph-thalmia tended to have nodules limited to an areaanterior to the equator (Table 1). Generalised in-volvement of Dalen-Fuchs nodules along the entirelength of retinal pigment epithelium was foundprimarily in eyes enucleated late in the course ofsympathetic ophthalmia.

Discussion

Our present study showed that Dalen-Fuchs nodulesin sympathetic ophthalmia vary in their morpho-logical appearance as determined by light microscopy.The earliest histological finding suggestive of Dalen-Fuchs nodule formation was focal disturbance of theretinal pigment epithelium with cellular hyperplasiaand aggregation. The Dalen-Fuchs nodule appears toenlarge as a result of epithelioid cells and lympho-cytes accumulating beneath a dome of retinal pigmentepithelium.' Ultrastructural studies indicate the pig-ment epithelial cells forming the dome of the Dalen-

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Michael Reynard, Ralph S Riffenburgh, and Don S Minckler

Fig. 5 Dissolution ofDalen-Fuchs nodules with apparentrelease oftheir contents into thesubretinal space. Well definedDalen-Fuchs nodules were presentin thesame section. (Haematoxylinandeosin, x50).

Fuchs nodule elongate in a vertical direction to reachBruch's membrane.7 As a result, a complex cage-likeframework is formed within the nodule.' "Metaplasticcells from the retinal pigment epithelium, lympho-cytes, and giant cells may occasionally be found with-in the Dalen-Fuchs nodule. Ultimately, the retinalpigment epithelial dome degenerates and disappears.Terms such as 'autolysis" and 'bursting'4 have beenused by other investigators to describe the histo-logical appearance of Dalen-Fuchs nodules in thisform. The spectrum of morphological changesoccurring at the level of the retinal pigment epi-thelium is consistent with Ernst Fuchs's originalhypothesis that Dalen-Fuchs nodules undergo anevolutionary sequence of development.4 However,further evidence is necessary to confirm thishypothesis.The source of cells that collect within the Dalen-

Fuchs nodule is controversial. By means of detailedelectron microscopic study Font and associates8found that the vast majority of cells within Dalen-Fuchs nodules represented transformed retinal pig-ment epithelium. They concluded that -epithelioidcells in Dalen-Fuchs nodules were derived fromretinal pigment epithelial cells. However, usingimmunological and ultrastructural analysis Jakobiecand associates9 found that Dalen-Fuchs nodules werecomposed of a mixture of histiocytes, lymphocytes,and depigmented epithelial cells. These authorsconcluded that many of the cells comprising Dalen-Fuchs nodules are of bone marrow origin. Ourobservations suggested that the cellular compositionof Dalen-Fuchs nodules may vary according to themorphological form sampled for analysis: Dalen-Fuchs nodules sampled early in their development

may show a predominance of metaplastic epithelialcells whereas, mature Dalen-Fuchs nodules mayshow a mixture of cellular components.

Similarly, the correlation between fundus angio-graphic findings and Dalen-Fuchs nodules has beencontroversial."' Lewis and colleagues" presentedfluorescein angiographic findings in a sympathisingeye that showed early blockage of backgroundfluorescence by multiple discrete lesions at the levelof the retinal pigment epithelium; these lesionsgradually stained during the later phases of theangiogram. Histopathological examination of theexciting eye showed multiple areas of choriocapillarisobliteration by inflammatory cells and overlyingDalen-Fuchs nodules. Sharp and coworkers'2reported a case with comparable histopathologicaland angiographic findings. In contrast Segawa andMatsuoka'' showed fine, hyperfluorescent dots in theposterior pole of a sympathising eye during thearterial phase; these dots corresponded in dimensionwith Dalen-Fuchs nodules in the exciting eye.Spitznas'4 and other investigators'5 " describedsimilar angiographic findings.The morphological spectrum of Dalen-Fuchs

nodules suggests that it may present a variable angio-graphic appearance. Blockage of choroidal fluor-escence may occur when an intact dome of retinalpigment epithelium contains the cellular elements ofthe Dalen-Fuchs nodule; the collection of denselypacked epithelioid cells covered by tight intercellularjunctions of the retinal pigment epithelium providesan effective block of underlying choroidal fluor-escence." Gradual accumulation of fluorescein intoDalen-Fuchs nodules may produce focal hyper-fluorescence. '2 However, degeneration of the retinal

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Morphological variation ofDalen-Fuchs nodules in sympathetic ophthalmia

pigment epithelium overlying the Dalen-Fuchsnodule may allow fluorescein dye to permeate a focusin the retinal pigment epithelium and graduallyaccumulate in the subretinal space.'5 Variation inthe angiographic appearance of Dalen-Fuchs nodulesmay therefore be related to its fluoresceinpermeability and morphologic form.We concluded that the morphological spectrum of

Dalen-Fuchs nodules may explain its variable histo-logical and fluorescein angiographic presentation.The observations of our study provides a backgroundfor additional clinicopathological correlation ofDalen-Fuchs nodules in sympathetic ophthalmia.

We thank Milton Reynard and Nancy J Cramer for technicalassistance.

References

I Duke-Elder S, Perkins ES. Diseases of the uveal tract. In: Duke-Elder S, ed. System of ophthalmology. London: Kimpton, 1966;9: 581-3.

2 Brailey WA. On the pathology of sympathetic ophthalmitis.Trans Int Med Congs, seventh session, 1881; 3: 35-9.

3 Dalen A. Zur kenntnis der sogenannten Choroiditis sympath-etica. Mitt A ugenklinik des Carolin Med Chirurg Instit zStockholm 1904; 6:1-22.

4 Fuchs E. Uber sympathisierende Entziindung (nebst

Bemerkungen uber serose traumatische Iritis). Albrecht vonGraefes Arch Klin Ophthalmol 1905; 61: 365-456.

5 Campinchi R, Faure JP, Bloch-Michel E, Haut J. Uveitis:Immunologic and allergic phenomenon. Springfield: Thomas,1963; 5: 160.

6 Greer CH. Ocular pathology. Oxford: Blackwell, 1979; 3: 40.7 Ishikawa T, Ikui H. The fine structure of the Dal6n-Fuchs nodule

in sympathetic ophthalmia. Jpn J Ophthalmol 1972; 16: 254-65.8 Font RL, Fine BS, Messmer E, Rowsey JF. Light and electron

microscopic study of Dal6n-Fuchs nodules in sympathetic oph-thalmia. Ophthalmology 1982; 89: 66-75.

9 Jakobiec FA, Marboe CC, Knowles DM, et al. Human sympath-etic ophthalmia. An analysis of the inflammatory infiltrate byhybridoma-monoclonal antibodies, immunochemistry, and cor-relative electron microscopy. Ophthalmology 1983; 90: 76-95.

10 Puliafito CA, Smith TR, Packer AJ, Albert DM. Sympatheticuveitis. Ophthalmology 1980; 87: 355-8.

11 Lewis ML, Gass JDM, Spencer WH. Sympathetic uveitis aftertrauma and vitrectomy. Arch Ophthalmol 1978; 96: 263-7.

12 Sharp DC, Bell RA, Patterson E, Pinkerton RMH. Sympatheticophthalmia. Histopathologic and fluorescein angiographic cor-relation. Arch Ophthalmol 1984; 102: 232-5.

13 Segawa K, Matsuoka N. 'Sympathetic ophthalmia. A compara-tive fluorographic and electron microscopic study. Jpn J Oph-thalmol 1971; 15: 81-7.

14 Spitznas M. Fluoreszenzangiographie der sympathischen Oph-thalmia. Klin MonatsblAugenheilkd 1976; 169: 195-2(X).

15 Dreyer WB, Zegarra H, Zakov ZN, Gutman FA. Sympatheticophthalmia. Am J Ophthalmol 1981; 92: 816-23.

16 Kayazawa F. A case of sympathetic uveitis. Ann Ophthalmol1980;12:1106-8.

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morphological variation of dalen-fuchs nodules insympatheticophthalmia · br j ophthalmol: first...

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