THE OCULAR FEATrURES OF A CASE OF ACUTERETICULOENDOTHELIOSIS(LETTERER-SIWE TYPE)

BY Parker leath, M.D.

THE HISTORY of the patient whose case is reported here, as given by thereferrer was as follows:A male child, white, of Basque extractioni, was well until he developed"cradle-cap" at age one year, nine months. Treatment with violet ray clearedthe lesions for a short time, but they returned. At age one year, 11 months,he began to limp and had pain in the right leg. Physical examination dis-closed deep tenderness in the middle of the right femur and a small palpablemass. X-ray films showed a tumor of the right femur with destruction of thecortex and periosteal thickeniing. A biopsy gave a diagnosis of benigneosinophilic granuloma. Radiation therapy was given over the tumor site.During this time the patient developed a generalized maculopapular rashwith petechias. Two months later a bone survey revealed a similar lesion inthe left rib wvhich upoin removal showed the same lesion as that in thefemur. During the niext year the patient developed lesions of the skull, bothfemurs, ilia, lumbosacral spine, right humerus, both forearms, the seventhleft rib, the right scapula, and both clavicles. X-ray therapy was used withvarying response. The patient developed bilateral exophthalmos which wasgreater on the right side. Also during this period he had six attacks ofgeneralized pruritic rash, each lasting three to four weeks. Weight had beenstable the previous year and appetite had diminished. His blood count hadbeen normal until age one year, 10 months. At that time his hemoglobin was10.2 and the red counlt, 3.37 million. During the next five months hereceived six blood transfusions to maintain adequate hemoglobin and redcount.

The patient was first examined at the Childrens Hospital, Boston, atthe age of three years, two months. He was a well-developed andwell-nourished white boy with a diffuse reddish brown macularpapular rash. There were petechias in the mouth and a creamy dis-charge from the right ear canal. Small lymph nodes were palpable inthe anterior cervical and axillary regions. A grade II systolic murmurwas heard along the left sternal border, but the chest and heart other-Tl. A?,t. OpirH. Soc., vol. 57, 1959

Ocular Features in Reticuloendotheliosiswise were not remarkable. The liver and spleen were not palpable. Alarge perianal area of red denuded tissue was noted.Ophthalmoscopic examination showed scattered vitreous strands,

more edema of the right nerve head than of the left, and diffuse grayishcoloration of the fundi with obscuration of the vessels for the mostpart and loss of transparency. Patches of soft exudates were seen inboth fundi.During the first week of admission adrenocorticotrophic hormone

base-line studies were made. A skin and bone biopsy established a]diagnosis of Letterer-Siwe disease. The marked pruritis and skin rashover the body became secondarily infected despite treatment withpyribenzamine, sedatives, and aureomvcin, and the use of plastic bedclothing. Serum constantly oozed from the skin lesions. The patientwas started upon adrenocorticotrophic hormone therapy, and received50 mg. intramuscularly daily for four days. His condition progressivelybecame worse and he died one hour after his temperature droppedto 94°F.

Laboratory data were as follows. Hemoglobin ranged from 5.1 to9.1; red count was 2.1 million, whites 800 to 2,750. Urine was negative.Blood chemistry showed non-protein nitrogen, 21.3 mg. per hundred,protein, 3.5 gm. per hundred; sodium, 138.2 mEq. L.; calcium, 6.9 mg.per hundred; phosphorus, 4.2 mg. per hundred; phosphatase, Bodanskyunits 3; potassium, 5.5; uric acid, 2.2. Ear culture indicated manyStaphylococcus aureus.

AUTOPSY

The patient was a well-developed, well-nourished child with exten-sive secondarily infected skin lesions over the trunk and scaling,elevated, bright red, circular lesions of the face and extremities. Theheart, lungs, spleen, liver, and kidneys all weighed above normal fora child of his age. Gross lipogranulomata were demonstrable in theright femur, the cystic seventh left rib, the vertebral bodies, thecalverium, the dura, the petrous bones, the orbits, the sella turcica, thepituitary, the axillary lymph nodes, and the subpelvic regions of bothkidneys. Papilledema was demonstrable in the right eye.On microscopic examination, the lipogranulomatosis was found to

involve the lungs, skin, choroid coat of one eye, and other parts of theother eye, spleen, and the apparently uninvolved bone marrow as wellas the organs in which it was noted grossly. The granulomata weremade up of histiocytes, fibroblasts, and a few giant cells. The histio-cytes varied in size, shape, and contents. In some regions sudanophilic

291

Parker Heath

FIGURE 1Whole eye, O.S.; 4X; the ciliary body partly differentiated, C.B.; arti-factual opening at limbus, 0; scleral thickening and swelling, S.;swollen macula, M.; edema of optic nerve; retinal separation is an

ac.

material was included, while in others the histiocytes containedhemosiderin pigment or, occasionally, leucocytes. Slight hemosiderosisof the liver was noted as well as chronic cholecystitis.

OCULAR FINDINGS

Macroscopic examination of the left eye revealed these dimensions:horizontal 20.5 mm.; anterioposterior, 20 mm. The lens was in position;the anterior chamber appeared normal. The attached optic nerve pro-

292

Ocular Features in Reticuiloendotheliosis

FIGURE 2

Sclera, 70 X; areas of swelling, and softening, S.; histiocytes andgrantilomatous reaction, H.G.; lamellar or zonal reaction; new-formied

capillaries.

truded 6 mm. The retina appeared uneven in thickness, especially thickposteriorly and in the macula, and was artifactually separated. Thecornea had had an incision near the mesial limbus.

Microscopic findings showed that the angle was that of a child with afew strands of mesenchymal tissue crossing over the trabecula.Schlemm's canal was open. The iris was a brunette type and showedcystic posterior epithelium due to material processed out or postmortemchange. Some iris sections showed markedly swollen ganglion cellscontaining granular substances and in this way resembled ganglioncells in the retina. The iris cells lay just anterior to the pigment layer.In some meridians the iris base was applied lightly across the trabeculawith only a weak union. Other meridians incorporated a ciliary process.The lens lay in position in the bulb and was relatively healthy withintact epithelium and capsule. The ciliary body was infantile indifferentiation. The episclera was lightly congested with inflammatory

9:3'-

Parker Heath

'.,~~~~~~~~~~~~~~~~~~A ....................... ..*. ...

FIGURE 3

Sclera at insertion of external rectus, 115X; softening zone, S.; externalrectus, R.; scattered histiocytes and lympliocytes, H.L.

cells wlhich increased over zones of deeper scleral involvement. At thelimbus a moderate degree of chemosis was seen and a few cells ofinflammation were scattered around vessels in the conjunctiva. Theattaclhed internal rectus muscle showed a few perivascular lympho-cytes. The sclera contained a body of oval-shaped edema on thetemporal side and was more than doubled in thickness. The outerborders of the zone of edema showed more cells, lymphocytes, andhistiocytes. Some of the latter contained necrotic nuclei. Necrosis inthe edematous area was moderate, and lymphocytes were collectedabout vessels. Capillaries were increased with new formations in theepisclera containing swollen endothelial cells. The inflammatory pro-cess in the sclera showed lamination, alternation of viable strands oftissue with necrosis, and cell collections. The oblique muscle attachedto the posterior sclera showed a few lymphocytes about vessels. Theretina and choroid over the involved sclera escaped even though thescleral thickness was increased five times and the outlying episciera

294C)

......

Ocular Features in Reticuloendotheliosis 295

X~~~~~~

FIGURE 4

Peripheral retina, 100X; swollen galnglion cells, C.

showed substantial increase of new-formed vessels. The necrotic andwavy swollen collagen contained groups of inflammatory cells in-cluding epitheloids and beginning granulomatous arrangement. Theretina showed striking changes in the inner layers, consisting ofmarkedly swollen ganglion cells with shrunken nuclei, granular cyto-plasm and staining eosinophilic and basophilic, and containing a dis-associating granular staining substance. The latter was gatheredsomewhat into pockets with rounded borders fringed with histiocytes.Swollen granular cysts were seen in the nerve-fiber layer applied to itsouter surface, and within the inner reticular layer. Conspicuous largemultinucleated giant cells had formed and were in the process of form-ing from histiocytes; some were reminiscent of "teuton" giant cells.Nuclei wvere both peripheral and indiscriminately arranged. The cyto-plasm stained unevenly and contained double refractive granules. Theaccumulation of histiocytes, some weakly lipophylic, was especiallyheavy in the macular area whlere edema had pushed the outer layersinwards. Considerable poly-staining substances were notedl in the

Parker Heath

4,, ,#*;.. .. ..:...... ;

*.. +.... .--- ; *: 9 : ,.:~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~....M

9", t*9 ."i4

FIGURE 5

Posterior retina, 115X; marked histiocytes, H.; forming giant cells,G.C.; edematous inner retictilar layer, R.

outer and inner reticular layers. Histiocytes were distributed to a lesserdegree in other parts of the retina, and least in the outer layers. Therod and cone layer showed a moderate degree of postmortem change.Strands of histiocytes and unformed conglomerate giant cells had beencast off into the vitreous from the inner retinal surface. From the innerlayer large ovoid and rounded pockets of granular substances extendedinto the inner reticular layer. These apparently represented extra-cellular collections of alien substances which were related to thegranulomatous reaction and the formation of epitheloid and giant cells.The retina was well differentiated and its separations were artifactual.All retinal changes increased in the posterior segment. The choroidwas thinned by fixation and contained few scattered lymphocytes. Thenerve head was swollen by edema, and the lamina cribosa took a

straight course. Supplying vessels appeared somewhat dilated, both inthe nerve head and in the pia. Different sections showed the ciliary

296

Ocular Features in Reticuloendotheliosis

..

FIGURE 6. MIACULAR AREA HEAV'ILY LA1)EN WITH HISTIOCYTES AND GIANT CELLS

vessels vitlh collectioins of histiocvtes, some with foamy cytoplasm, inthe walls. In other sections the cell collections represented a moderateperivasculitis. In no areas were eosinophiles conspicuous.

Diagnosis. The patient's condition was diagnosed as acute reticulo-enidotheliosis with intraocular involvement (Letterer-Siwe disease).

CONIMIENT

Thlree qutite different clinical picttures (5)), eosinophilic gratnulomat ofbone, Schiiller-Clhristian disease, and Letterer-Siwe disease, have beenvariously classified by pathologists. Eosinophilic granuloma of bonetypically appears as a circumscribed painful bone abscess localized inone or more bones without systemic signs and is self-healing. Atypicalcases show lutng involvement. Microscopically the lesion is a mixtureof inflammatory cells with eosinophiles and many histiocytes andaccompanied by some necrosis. Lipophilia is not outstatnding andoccurs secondarily to necrosis.

297

Parker Heath

FIGURE 7

Histiocytosis, H; new-formed giant cells, C.C.; vitreouis strands cast off fromretina, V.S.; edematouis reticular layer, R.L.

Letterer-Siwe disease is an acute toxic systemic process resemblingan acute infectious reticuloendotheliosis. Infants are affected fatally bya combination of cutaneous hemorrhages, lymphadenopathy, fever,hepatosplenomegaly, and subsequent anemia. Microscopically the he-matopoietic organs-lymph nodes, bone, spleen, and liver-are diffuselyinvolved with a histiocytic cell proliferation and areas of necrosis.

Schbiller-Christian disease is a slowly progressive systemic lipo-granulomatosis usually involving viscera and bones without hepato-splenomegaly. The clinical manifestations vary with the localizationof the xanthomatous lesions. One triad which may be present is that ofbone involvement, exophthalmos, and diabetes insipidus. Microscopic-ally the granulomata of Schiiller-Christian disease are composed oftumorous collections of granulation tissue containing numerous histio-cytes as foam cells, fibroblasts, and giant cells. Cell inclusions aresudanophilic. In advanced states the histiocytes disappear and theprocess becomes fibrotic.

2d98

Ocular Features in Reticuloendotheliosis 299

FIGURE 8. FAIY HISTOCYTES IN WALL OF CILIARY ..E.SE H

The patterns of the three diseases enumerated above would seem toindicate that each is a separate entity. This position is taken by somepathologists (1, 2). Others believe that transitional and intermediateforms exist between the three diseases indicating an identity of nature(3, 4). Since the cause or causes remain unknown uncertainty cloudsclassification.The case presented here apparently began as benign eosinophilic

granuloma of bone zas indicated by biopsy. Diffuse skin and bonelesions with anemia developed later and biopsy at this stage indicatedLetterer-Siwe disease. Autopsy and microscopic study showed exten-sive skin, skeletal, lung, visceral, and bone marrow involvements,including enlargements of spleen, liver, and kidney. These changeswere accompanied by granulomatous mobilization of histioeytes, fibroblasts, and giant cell formations. Lipogranulomatosis was irregularlypresent. The evolution of this case brought out features suggesting thethree diseases listed above. Beginning with a relatively isolated boneabscess with eosinophilia, the case went downhill with acute diffuse

involvements including severe anemia, all suggesting Letterer-Siwedisease. Finally, numerous granulomata with inclusions of sudanophilicmaterial appeared in a distribution in part suggesting Schuller-Christian disease. The enigmatic pattern and course are furthercomplicated by a most unusual ocular manifestation. Intraocularinvolvement with any one of the three diseases is most exceptional. Thedistribution of the major inflammation in the least vascular sclera andthe richly supplied retina indicates nonspecific processes operatingunder laws of chance, dual agents, or successive closely timed specificattacks. Although the inner layers of the retina are separated by agranular material and the swollen ganglion cells indicate crippledfunction, the over-all impression is that the process is at the stagewhen reversal could occur. Scleral involvement is more conventionalas a granulomatous inflammation. While the retinal and scleralemphasis is striking, other ocular tissues show increased histiocytes andswollen ganglion cells, for example, the iris and choroid. The new-formed capillaries are chiefly in the sclera and do not appear, as dothose seen with nevoxanthoendotheliosis, in the iris and ciliary body.Nor is hemorrhage conspicuous. The histiocytes contain to moderatedegree sudanophilic material and necrosis is limited, and it is possiblethat the necrosis is a factor in fat staining. An interesting feature of thiscase is the seeding of the vitreous from the retina with histiocytes andlinked nuclei. Ophthalmoscopic findings are consistent with the histo-pathologic features. Mobilizations of histiocytes are encountered withinvessel walls to a marked degree only in isolated situations.Exophthalmos resulted from orbital involvement with granular

bodies, some of which were applied to the optic nerve in the right orbit.

CONCLUSION

The case reported shows an unusual form of scleritis with softening,swelling, and lamellar granulomatous inflammation; a unique retino-pathy selecting the inner layers with granulomatous reaction in aninfant afflicted with Letterer-Siwe disease bearing some resemblancesto eosinophilic granuloma of bone and also to Schuller-Christiandisease.

REFERENCES1. Siwe, S. A., The reticuloendotheliosis in children, Advances in Pediatrics,

4:117, 1949.2. Otani, S., A discussion of eosinophilic granuloma of bone, Letterer-Siwe disease

and Schuller-Christian disease, J. Mt. Sinai Hosp., N.Y., 24 (6), 1079, Nov.-Dec., 1957.

300 Parker Heath ''

Ocular Features in Reticuloendotheliosis 3013. Farber, S., The nature of some diseases ascribed to disorders of lipid meta-

bolism, Am. J. Dis. Child., 68:350, 1944.4. Lichtenstein, L., Histiocytosis X, Arch. Path., 56:84, 1953.5. Letterer, E., Aleukemische Reticulose (ein Beitrag z. d. proliferativen

Erkrankungend. Retikuloendothelial-apparates), Frankfurt Ztschr. Path., 30:377, 1924.

6. Siwe, S. A., Die Retikuloendotheliose: Ein neues Krankheitsbild unter denHepatosplenomegalien, Ztschr. Kinderh., 55:212, 1933.

DISCUSSIONDR. FRANK B. WALSH. Our experience with Letterer-Siwe disease in theJohns Hopkins Hospital is limited and I have had only three case histories tostudy. In those three patients initial evidence of the disease was swelling ofthe glands in the neck. Differential diagnosis included the following: woodythyroiditis in one case; tuberculosis; Hodgkin's disease; lymphoma; atypicalleukemia; eosinophilic granuloma Hand-Schuller-Christian disease; Letterer-Siwe disease. Two of the three children recovered. The treatment includednitrogen-mustard, X-ray, and steroid therapy.

It is of interest that nevoxanthoendothelioma has been suggested to havea relation to the Letterer-Siwe, eosinophilic granuloma, Hand-Schuller-Christian disease group. Dr. Lorenz Zimmerman has remarked that nevo-xanthoendothelioma is characteristically a benign lesion which clearsspontaneously except when it produces hyphema and secondary glaucoma.He does not think it is truly related to the Letterer-Siwe syndrome.

Dr. Heath has just reported what seems to be a unique finding: changesin the superficial retina compatible with Letterer-Siwe disease. An ophthal-moscopic examination might have been interesting.Through the courtesy of Dr. Zimmerman I am enabled to show a slide

exemplifying changes in' the choroid compatible with Letterer-Siwe disease.The patient qualified for a diagnosis of Letterer-Siwe disease merging intoHandcSchuller-Christian disease. Dr. Edith Parkhill studied this patient andestablished the diagnosis. The bony changes illustrating involvement of theorbit are of interest.A recent comprehensive review article by Topouzian and his associates is

very worthwhile (Topouzian, L. K., S. Sarrafian, and E. L. Compere, Clinicalaspects of histiocytosis: Report of six cases, Quart. J. Northwestern Univ.Med. School, 32 (2):106-126, 1958).

DR. HAROLD F. FALLS. Approximately eight years ago, while visiting Vander-bilt University, I saw a case of Letterer-Siwe disease. I postulated at thattime that the disease was probably gene determined and was most likely arecessive trait. It was interesting to learn at that time that a sibling of thechild had also died of Letterer-Siwe disease. A perusal of the literature sincethat time suggests that Letterer-Siwe disease may be a consequence of geneaction. Careful family histories should be included in the study of all thesecases.

302 Parker HeathDr. Parker Heath is an authority on these disease entities and since he has

had such an intimate experience I should like to ask this question. Does hepersonally favor the unitarian or duality concept of these diseases?We have seen a case of Letterer-Siwe disease in which the choroid alonie

was involved.

DR. HEATH. I should like to thank Dr. Walsh aind Dr. Falls for their kindremarks. The implications of Letterer-Siwe disease are extraordinarily wide-ranging. Letterer-Siwe's granuloma is related to other granulomatous reac-tions. Characteristic microscopic appearances and progressive natures do notmake different diseases the same. Some say that eosinophilic granuloma ofbone, Letterer-Siwe disease, and Schiiller-Christian disease are definitelydistinct and this seems true for the pure clinical types. The proponents ofone disease with multiphases say that although the granulomas of the threesyndromes are different, obvious intermediate forms exist. The progressionof this case from the original biopsy material, which is that of eosinophilicgranuloma, to the Letterer-Siwe picture over a period of time is veryconvincing.To answer Dr. Falls's (Iuestion, I believe there are intermediate phases

and I believe that Farber and others are right when they say that one phaseof the disease may progress into another. Different manifestations have beensuggested as due to variation in penetrance of the gene.

It is very interesting that my case displays a new kind of retinal processand adds one more to our collection of retinopathies. I do not think onewould miss the picture, having seen it once: the over-all gravness, muchincreased in the posterior segment, the soft, fluffv exudates, the slightlvswollen nerve head, the obscuration of the vessels.The appearance of the lesion, both microscopic and clinical, suggests

reversible traits.The intracellular collections of chlolesterol of Schiuller-Christian disease

are not usually seen in Letterer-Siwe disease. However, in the presence ofnecrosis, lipid collections do accumulate in the histiocytes of Letterer-Siwedisease.The nevoxanthoendothelioma group carries histiocytes of benign nature

with "teuton" cells which we see in some of the Letterer-Siwe specimens,and I am inclined to include the nevoxanthoendothelioma, so-called, as arelated histiocytosis. I think, for the most part, the difference is one ofendotheliosis-more endothelial structures and hemorrhages in the nevogroup.

Edith Parkhill's case was reported to the Ophthalmic Pathology Clul.The retina wvas not similarly involved.