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Idiopathic Inflammatory Orbital Pseudotumor in Childhood
Idiopathic Inflammatory Orbital Pseudotumor in Childhood II. Results of Diagnostic Tests and Biopsies LINDA MOTTOW-LIPPA, MD, FREDERICK A. JAKOBIEC, MD, MARY SMITH, BA
Abstract: Twenty-nine patients with pediatric orbital pseudotumor underwent a wide variety of diagnostic tests including biopsies. The following abnormalities were discovered: peripheral blood eosinophilia (9/29 patients); elevated ESR (17/17); elevated antinuclear antibody titres in the Tolosa-Hunt variant (2/2); hypercomplementemia (2/3); and mild CSF pleocytosis (2/6). Thyroid function tests were normal in nine patients so studied. B-mode ultrasonography performed on 12 patients displayed abnormalities in all cases (some combination of Tenonitis, myositis, perioptic inflammation, or mass effect). Computed tomography in seven patients provided higher resolution confirmation of these findings. Orbital bone changes and serious sinus disease were absent on routine radiographic studies. Biopsies performed on 16 patients disclosed mild lymphocytic inflammation in all cases, fibrosis and tissue eosinophilia in 9 biopsies (6 correlating with peripheral blood eosinophilia). Nine biopsies demonstrated a lipogranulomatous response to damaged fat cells. A true vasculitis or extensive lymphoid hyperplasia was not identified in any biopsy specimen. [Key words: pseudotumor, pediatric, orbit, inflammation, eosinophilia, CT scanning, ultrasonography, idiopathic orbital inflammation, lymphocytes, plasma cells.] Ophthalmology 88:565574, 1981
In an earlier paper, the clinical features of idiopathic inflammatory orbital pseudotumor in 29 children were found to be sufficiently distinctive to permit clinical suspicion or confident diagnosis of the entity in most cases.' A clinical trial of corticosteroids, which usually produces a striking resolution of symptoms of short duration within 48 hours, solidifies the diagnosis.'·2 Before systemic corticosteroids are employed, howFrom the Departments of Ophthalmology and Pathology, Manhattan Eye, Ear and Throat Hospital, The New York Hospital-Cornell Medical Center, New York City, and the Eye Bank for Sight Restoration, New York City. Dr. Jakobiec is the recipient of the Research to Prevent Blindness Robert E. McCormick Scholar Award. Reprint requests to Frederick A. Jakobiec, MD, Manhattan Eye, Ear and Throat Hospital, 210 East 64th Street, New York, New York 10021. 0161-6420/81/0600/0565/$1.00
© American Academy of Ophthalmology
ever, it is worthwhile to study the orbits of pediatric patients believed to have pseudotumor with A- and B-scan ultrasonography, routine radiography, hypocycloidal tomography, and computerized tomography. One should also obtain a complete blood count with an absolute eosinophil count. If the patient presents with a complete painful external ophthalmoplegia resembling the Tolosa-Hunt syndrome, the serum level of antinuclear antibodies may help to confirm the diagnosis. 3 The constellation of clinical findings outlined in the first paper, and the results of diagnostic and laboratory tests to be presented in this one, exclude the need for a diagnostic orbital biopsy in the vast majority of cases. In this paper, we are nonetheless able to report the results of orbital biopsies obtained on 16 patients before the clinical and diagnostic picture of pediatric orbital pseudotumor had clearly emerged. 565
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RESULTS Materials and methods have already been delineated in the earlier paper. 1 DIAGNOSTIC TESTS
Peripheral blood studies. Complete blood counts, performed on all 29 patients, demonstrated peripheral eosinophilia in nine patients. Relative counts varied between 6 and 20%, with absolute counts ranging from 70 to 150. Seventeen patients had a determination of the erythrocyte sedimentation rate, 11 of whom had repeated studies; all were elevated, ranging from 20 to 116. In six out of eight patients on whom serum protein electrophoresis was performed, there was mild elevation of alpha-2 globulin in two patients, beta globulin in five patients, and gamma globulin in three patients. Antinuclear antibody titres were studied in eight patients. The two patients with the Tolosa-Hunt variant had positive results; titres remained elevated in one patient with persistent disease, and in the other the titre reverted to normal upon clinical remission. Two out of three patients studied for serum complement titres had hypercomplementemia during the attack; one patient evaluated for fibrinogen levels displayed an increased amount of the protein. With respect to thyroid function tests, all nine patients studied showed normal results, with four having normal T3-T4' one a normal T 3, one a normal proteinbound iodide, and one a normal Werner suppression test. Heterophile counts performed on three patients were negative, and four VMA and pheochromocytoma screens were likewise nonrevealing. Stool analysis. Two Latin-American patients were found incidentally to have positive stool cultures for trichuriasis or Entamoeba histoiytica, but had normal peripheral blood eosinophil counts. Skin testing. Of 11 patients tested for tuberculin sensitivity, two patients showed mild local induration and erythema, but had negative chest x-rays, consistent with exposure to tuberculosis but not overt infection. These patients had been covered adequately with antitubercular therapy at the time of hospitalization before steroid therapy was introduced; they were not thought to be actively infected. No clinical improvement occurred until after the steroid therapy was begun. Lumbar puncture. Of SIX patIents III whom lumbar puncture was performed, two demonstrated a mild lymphocytic pleocytosis suggestive of parameningeal irritation, while four others had repeated taps that were entirely normal. Ultrasonographic studies. Thirteen orbital evaluations were performed in 12 patients using high resolution B-scan ultrasonography adapted to a water bath technique. Resolution was sometimes suboptimal due to agitation, pain, and photophobia. All 12 patients studied demonstrated orbital inflammatory changes of some kind. Three distinct changes were characteris566
tically seen: (1) sonolucency in the region immediately posterior to the globe, indicative of edema in Tenon's potential space (seen in seven patients) (Fig 1); (2) mottling of the optic nerve outline, occasional enlargement of the nerve with blunting of the anterior angle at the point of its insertion into the globe, and accentuation of the sheath by internal echoes (seen in four patients) (Fig 2); and (3) thickening of the extraocular muscles, secondary to inflammatory involvement (seen in six patients) (Fig 3). In four of these six patients with myositis, an inflammatory involvement of the orbital soft tissues was also suggested. Clearly localized masses were detected in two patients, one being superonasal, the other in the lacrimal region. One additional patient demonstrated multifocal "solid" masses. Seven patients showed acoustic variation in at least two orbital structures. One had both muscle and nerve changes, and three had nerve changes continuous with inflammation in Tenon's space. Only three patients showed the classical triad of inflammatory changes affecting muscle, optic nerve, and Tenon's capsule. Radiographic studies. Skull x-rays were performed on 18 patients, in some cases repeatedly. Abnormalities were initially detected in six of these patients,
Fig 1. Edema fluid (arrows) has accentuated Tenon's space adjacent to the optic nerve.
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Fig 2. B-scan ultrasonogram displaying characteristic squaring off of the optic nerve shadow (ON), which normally appears triangular at the insertion near the globe.
the most common finding being an increased soft tissue density over the affected orbit, seen in four patients. Retrospective film review increased the prevalence of this finding to 10 patients. Only one patient studied demonstrated any orbital enlargement. Possible clinoid erosion was also initially thought to be present in one patient with the Tolosa-Hunt syndrome but was reinterpreted as normal. Coned-down orbital views were performed in 13 patients who did not have preliminary skull x-rays; soft tissue densities were appreciated in 12 cases. Tomographic studies were performed in seven patients, revealing normal orbits in four and an increased frontal-temporal bone density in the patient with myositis and mandibular exostosis by history. One series of tomograms initially reported as normal was reinterpreted as displaying an increased soft tissue density over the affected orbit. This density could be further resolved to the discretely enlarged rectus muscles (Fig 4). Sinus involvement was radiographically demonstrated in only four of the 13 sinus films performed, with mild ethmoid clouding seen. Computed axial tomography (CT scan) was performed in seven patients, supplementing information available through ultrasonic and other radiographic studies. The CT scans demonstrated in one patient isolated enlargement of the right medial rectus muscle, a finding enhanced by the injection of contrast mate-
Fig 3. B-scan ultrasonogram showing massive thickening of an extraocular muscle (M).
rial. Proptosis in another patient was due to a diffuse soft tissue density in the medial orbit. Striking contrast enhancement of Tenon's potential space complemented the findings of tenonitis by ultrasonographic scanning in two cases (Fig 5). Carotid angiography performed in three patients was reported as normal, corroborated on review of two of these three cases, including the patient with possible clinoid erosion on skull films. Orbital venograms were normal in the three patients who were so studied, one of whom also had a normal angiogram. A thermogram, performed in one Tolosa-Hunt patient with normal carotid angiography, was also normal. PATHOLOGIC FINDINGS
Twenty orbital biopsy specimens were obtained from 16 of the 29 patients in the series (two biopsies were performed on two patients and three on a third). Most of these biopsies were obtained in the era preceding the use of ultrasonography and computed tomography, before it became possible to distinguish orbital inflammatory disease from various neoplastic stimulants. The data obtained from the biopsy speci-
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Fig 4. Non-computed tomogram of the orbit behind the globe showing resolution of a soft tissue mass into three discernible extraocular muscles (arrows).
mens reflected the tendency of surgeons to sample tissues in an inflamed orbit that would be the least apt to produce postoperative functional impairment. Consequently, many specimens were from the orbital fat, lacrimal gland, and portions of the extraocular muscles. Another variable was the stage of the disease at the time that tissues were obtained: biopsy specimens obtained in the acute phase would be expected to have a different set of histopathologic features from those obtained late in the disease or after recurrences. The most common finding was that of fibrosis and edema of the involved orbital structures. The lacrimal gland (Fig 6), extraocular muscles (Fig 7), orbital fat (Fig 8), and postcapillary venules (Fig 9) all displayed increased deposition of collagen fibers with a light dispersal of inflammatory cells. In the lacrimal gland, the lobules of lacrimal tissue were separated more widely by thickenings of the interlobular septa. Inflammatory cells made incursions into the periphery ofthe lobules,
eventually leading to obliteration of the lobular architecture. Acinar structures were particularly vulnerable; as involution of the parenchyma progressed, the remaining tubular units failed to stain for zymogen granules with PAS stain, indicating survival only of the ductal epithelium. Both the extraocular muscles and the orbital fat displayed a similar tendency of accentuation and thickening of their normally occurring connective tissue and fibroblastic components. The combination of inflammatory cells and fibrosis in the extraocular muscles led to degeneration of the myofibers. In the orbital fat the usually delicate septa became thickened and frequently confluent, and the venules and capillaries acquired a more pronounced adventitial cuff of collagen. Biopsies obtained in late or recurrent disease demonstrated much more hyalinized connective tissue within the affected sites. In some of the biopsy specimens, particularly those obtained early in the clinical course, the proliferating fibroblastic tissue had an immature, loose myxomatous character (Fig 10), in which stellate and bipolar fibroblasts with rather plump nuclei displaying prominent nucleoli were suspended in a delicate collagenous matrix. This tissue was most prominent in the fat and natural fibrous planes of the orbit, rather than within the muscles or the lacrimal gland. The orbital fat frequently exhibited a spillover of the septal inflammation into the lobules (Fig 11). Nine biopsies from 16 patients displayed a lipogranulomatous response (Fig 12). In these regions necrosis of the lobules of the fat created by intruding inflammation led to the release of intracellular lipid into the extracellular space, provoking a foreign-body, multinucleated, giant-cell histiocytic response. Locules of dissolved fat were found in the midst of this inflammatory reaction pattern. There was a definite tendency for the inflammatory cells to orient themselves prominently around capillaries and postcapillary venules (Figs 8, 9, and 13). The
Fig 5. Left, computed tomographic study of the orbits of a patient with a right pseudotumor (arrow) fails to disclose any orbital mass. Right. with contrast enhancement, the right sclera and Tenon's space are thickened (arrow), accounting for the inflammatory signs.
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Fig 6. Top left , lymphocytic and plasmacytic infiltration within the lobules of the lacrimal gland has resulted in disappearance of the ac ini with survival of only ductular elements, which are being overcome by fibrous replacement (hematoxylin and eosin , original magnification x 25). ~ig 7. Top right , a light mononuclear infl ammation of the extraoc ular mu scles with increased depo sition of collagen between the myofibers (hematoxylin and eosin, original magnification x 280). Fig 8. Center left , increased fibro sis of the interlobular septa of the orbital fat. Note the lymphocytic perivascular cuffing around the venule within the orbital fat (hematoxylin and eosin , original magnification x 60). Fig 9. Center right, perivenular infiltration oflymphocytes, pkisma cells, and bilobed eosinophils, with increase in the adventitial collagen. Fig 10. Bottom left , fibrous tissue replacing the orbital fat exhibiting delicate collagen fibers and loosely di spersed fibroblasts (hematoxylin and eosin , original magnification x 250). Fig II. Bottom right , myriad bilobed eosinophils infiltrating the orbital fat (hematoxylin and eosin , original magnification x 120).
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Fig 12. Top lefi. chronic inflammation of the orbital fat has resulted in damage to the lipocytes, with release of intracellular lipid and a lipogranulomatous. multinucleated foreign body reaction (hematoxylin and eosin. original magnification x 80). Fig 13. Top right. dense lymphocytic cuffing of orbital veins, without any damage to the vessel walls (hematoxylin and eosin. original magnification x60). Fig 14. Center lefi. densely hylanized orbital connective tissue forming concentric lamellae suggestive of granulomas. Connective tissues only minimally and focally inflamed (hematoxylin and eosin, original magnification x 60). Fig 15. Center right. each of the concentric lamellae of collagen is actually shown to have developed around a nearly obliterated blood vessel, which. however, shows no eVidence of fibrinoid necrosis (hematoxylin and eosin, original magnification x 220). Fig 16. Left. a rare focus of follicular lymphoid hyperplasia from a late specimen of hyalinized orbital connective tissue replacing the orbital fat (hematoxylin and eosin. original magnification x 70).
intensity of this response was sometimes suggestive of a vasculitis, but the vessels were devoid of a muscularis. Furthermore, there was neither fibrin, mural necrosis, nuclear dust (Ieukocytoclastic vasculitis), nor interstitial infarcts (stellate necrosis) in these regions. In late specimens, concentric lamellae of collagen deposition suggested burned-out granulomata (Fig 14), but a nearly obliterated vessel could almost always be discovered at the center of such structures (Fig 15). Sheets of lymphocytic hyperplasia were not encountered in the biopsy specimens, but occasionally sur570
viving follicles of lymphoid tissue were separated by bands of hyalinized connective tissue (Fig 16). The inflammatory infiltrates were composed of various admixtures of eosinophils, lymphocytes, and plasma cells. Polymorphonuclear leukocytes were not prominent and were generally encountered only in areas of lipogranulomatous response. Tissue eosinophilia was prominent in nine specimens out of 16 biopsied cases (Figs 9 and 11). In these cases, the eosinophils were scattered throughout the proliferating fibroblastic tissue, localized in cuffs around small
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blood vessels, and involved the lobules of fat. Six of the nine patients with impressive tissue eosinophilia had peripheral blood eosinophilia also. Lymphocytes and plasma cells were most sparse in biopsy specimens from acute cases, but tended to constitute the majority of the cells from late biopsies; they were commonly present around venules and in the hyalinized interstitium (Fig 13). One patient had a scalene node biopsy that revealed benign reactive lymphoid hyperplasia concomitant with active orbital disease.
DISCUSSION Inflammatory causes of proptosis far outnumber neoplastic ones, so when a younger patient presents with rapidly evolving orbital signs and symptoms, the clinician ought to seek evidence for an inflammatory causation first. When this exercise fails, the available data should be reassembled with an emphasis on a possible neoplastic etiology. In our earlier paper, we collated the clinical data on 29 patients 20 years of age or less who had idiopathic orbital inflammatory pseudotumor. 1 In analyzing the results of diagnostic tests, we have discovered that invariably these investigations fortify the clinical impression without the need for biopsy. The clinical picture includes orbital pain of abrupt onset, variable lid swelling and erythema, chemosis, conjunctival and epimysial vessel engorgement, proptosis, motility dysfunction, a palpable mass in 45% of patients, and visual decrease. Nearly half of our patients were bilaterally affected, with recurrences alternating from one side to another. The ocular symptoms were accompanied in 53% ofthe patients by such systemic complaints as headache, fever, vomiting, pharyngitis, anorexia, abdominal pain , and lethargy. Periorbital inflammation was sometimes accompanied by intraocular involvement, with iritis in eight and papilledema in ten patients. After a careful clinical examination, the most important diagnostic adjuncts are radiographic and ultrasonographic evaluations of the orbit. X-ray studies should include views of the skull, orbits, and sinuses. Routine radiographic and tomographic studies of the orbits characteristically reveal intact orbital walls without bone destruction, widening of sutures and fissures, or hyperostosis. This contrasts with the radiographic findings in rhabdomyosarcoma, wherein 50% of cases may display various degrees of erosion of the medial orbital wall with careful tomography. 4 Eosinophilic granuloma produces large osseous defects because this lesion originates within the bone. s Since inflammatory pseudotumor evolves so rapidly, insufficient time elapses in most cases to produce significant bony abnormalities. One patient with hyperostosis in the vicinity of an orbital pseudotumor was exceptional because he had previously had an
exostosis of the mandible, and it is our interpretation that his bone reactivity exceeded that expected in the overall population of pseudotumor patients. While patients with pseudo tumor may on occasion display some clouding of the ethmoid tissues, this is not the fulminant sinusitis encountered in conjunction with an orbital cellulitis. A soft tissue density in the involved orbit frequently can be identified in non-computed tomographic studies, and it may even be possible (rarely) to distinguish individual extraocular muscle thickenings. However, computed tomography and ultrasonography resolve such soft tissue involvements to much greater advantage. Ultrasonography is now available in most ophthalmology departments and can be repeated safely. The latter consideration is relevant in young individuals with developing tissues and longer life expectancies, and who therefore might experience increased risk for late side effects from multiple radiographic exposures . The inflammatory or congestive changes in pseudotumor are reflected ultrasonographically as subtle variations in the normal orbital visceral pattern, rather than as the gross distortions observed in mass lesions. In cases of acute orbital pseudotumor, ultrasonography will reveal some combination of widening of Tenon's potential space, squaring off of the optic nerve shadow, and thickening of the extraocular muscles. These findings are particularly compelling when they are found together, constituting a diagnostic triad. Recourse to computed tomography is indicated if the results of ultrasonographic testing are ambiguous. Most of the patients in this series were studied prior to the introduction of high resolution computed tomography. The three-dimensional depiction of orbital involvement in inflammatory pseudotumor afforded by modern computed tomography is superior to that obtained from Ultrasonography. Contrast enhancement during computed tomography can highlight very subtle alterations caused by inflammatory involvement, particularly a sclerotenonitis that could be missed without this expedient. Computed tomography is also useful in the differential diagnosis of pseudotumor. Both ruptured dermoids and hemorrhagic lymphangiomas can produce an inflammatory response closely mimicking orbital pseudotumor. Dermoids often produce a contiguous bone defect as well as a lipid density cyst in the midst of the inflammatory process,6 whereas in lymphangioma, high resolution can display a honeycomb appearance created by the cystic lymphangiomatous channels. The absence of a tumor blush on anteriography in four children was reassuring, ruling out an anterior cavernous sinus mass, but the amount of information obtained from this potentially dangerous method of investigation is minimal compared to that from other less invasive techniques. The caveat of Fowler et al. is well taken 7 : a cavernous sinus aneurysm or parasellar syndrome produced by meningiomas or pituitary tumors must be excluded. However, each of these diagnoses 571
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is exceedingly rare in children, and the absence of widening of the superior orbital fissure or anterior clinoid erosion further reduces these possibilities. As reported by Sondheimer and Knapp in 1973, orbital venography performed in patients with the Tolosa-Hunt syndrome can demonstrate compression of the superior ophthalmic vein. 8 In the two patients in our group with a picture of the Tolosa-Hunt syndrome, orbital venography was normal. We believe that the diagnostic value of orbital venography has been supplanted by ultrasonography and computed tomography. Other regularly performed laboratory tests supplement the data derived from the more sophisticated technological evaluations reviewed above . An elevated peripheral eosinophil count is of particular importance when discovered (in nine of our 29 patients), suggesting a systemic allergic response . With exclusion of parasitic infestation by history, lack of symptoms, negative serial stools for ova and parasites, and negative serology (particularly trichinella benzoate flocculation and counter electrophoresis), peripheral blood eosinophilia might implicate participation of eosinophils locally producing inflammation in the orbit. Of nine patients biopsied showing eosinophilic infiltration of orbital tissues, six patients demonstrated peripheral blood eosinophilia. Although rarely present in pediatric pseudotumor patients, antinuclear antibodies are helpful in supporting the diagnosis of the Tolosa-Hunt variant. 3 Other corroborative evidence includes the absence of seropositive factors for collagen vascular disease (latex fixation , LE prep) and the lack of any clinical evidence for hepatitis, thyroiditis, ulcerative colitis or pulmonary fibrosis, or drug intake (DPH), any of which may stimulate the production of antinuclear antibodies. 3 An elevated ESR (found in all 16 patients in this series who were studied) , indicative of an inflammatory systemic response, is less likely to be seen as a localized orbital tumor, such as rhabdomyosarcoma. Serologic studies for the evaluation of thyroid function were within normal limits in the nine patients so studied. The painful, explosive onset of inflammation in pediatric orbital pseudotumor and its rapid and complete suppression with systemically administered corticosteroids are clinical features at ·variance with the typical picture of Graves' disease, which is a mild disease in childhood. The results from the biopsy specimens are especially worth emphasizing because in the future, tissue documentation of idiopathic orbital inflammation will be obviated by the increased accuracy of clinical and diagnostic evaluations. Due to the variable but significant contribution of fibrous tissue to the inflammatory reactions, the differentiation of these lesions microscopically from a lymphoma was never a serious consideration. Early on, the fibrous tissue has a loose texture, with widely spaced fibroblasts set in a finely fibrillar collagenous stroma, and contains only a light dispersal of inflammatory cells. As the disease progresses , an intense hyalinization of the connective tis-
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sue develops. We were struck by the prominence of an eosinophilic infiltrate in the majority of specimens, and this often correlated with a peripheral blood eosinophilia. Lymphocytes and plasma cells were ubiquitous, but were generally widely separated without forming sheet-like patterns or intense hyperplasias. In fact, none of our patients displayed reactive lymphoid hyperplasia. lo The late sequelae of pseudotumor are the consequences of increased deposition of collagen within the extraocular muscles, around the optic nerve and globe, and within the lacrimal gland and fat, particularly in those severe cases where the inflammatory disease recurs or is not arrested successfully by therapy. We found no evidence in our specimens of true immunogenic granulomatous inflammation, in that the granulomata occurred only in the vicinity of inflamed fat, a response more consistent with a foreign-body type of reaction to the lipid released from damaged fat cells. Our specimens also failed to incriminate a vasculitis as the central pathogenetic event in orbital pseudotumor. The vascular changes that we noted were pericapillary and perivenular collections of lymphocytes or eosinophils, and secondary perivascular fibrosis. No areas of fibrinoid necrosis , stellate necrosis, or "nuclear dust " were observed. Moreover, the absence in our patients' clinical histories of any apoplectic vascular events (central retinal artery occlusion, nerve fiber layer infarcts, choroidal infarcts) leads us to the conclusion that vasculitis per se is not a common underlying feature of orbital pseudotumor. Henderson II has described leukocytoclastic vasculitis in the biopsies from some of his younger patients. Heersink and Rodrigue_s in their series of orbital pseudotumors from all ages felt that they had identified vasculitis,12 but our review of their published photomicrographs suggests that their findings are more consistent with the perivascular leukocytic or lymphocytic cuffing that we have documented. Several clinical simulators of pseudotumor are readily differentiable pathologically. We believe that Iymphoproliferative disorders, categorized in the past along with pseudotumor,9 are both clinically and pathologically distinctive, in that they primarily affect adults, and have a more insidious symptomatology and a more prominent mass effect. 13 Furthermore, heterogeneity of the inflammatory cell population in pseudotumor should effectively exclude a lymphoma. 13 - IS The inflammatory component of Graves' disease may be only subtly different from that of pseudotumor, but tissue eosinophilia, if present, militates strongly for the latter. In eosinophilic granuloma, the mass of the lesion is not contributed to by fibroblastic proliferation, but rather by polygonal histiocytes. S In granulocytic sarcoma, the mass of the lesion is composed of atypical mononuclear cells. 16 In fungal and parasitic diseases, there is far more prominent granulomatous inflammation; special stains will delineate the nature ofthe organism. A hemorrhage into a lymphangioma may be ruled out by deeper
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sections to find the lymphangiomatous tissue , and a ruptured dermoid by finding portions of the cyst wall. Eosinophils will not be prominent in either disease. Some striking parallels may be drawn between pediatric orbital pseudotumor and eosinophilic fasciitis, a newly described scleroderma variant. In the latter, the acute onset of painful swelling of the distal extremities progressing to sclerosis, accompanied by peripheral eosinophilia and hypergammoglobulinemia, correspond to the clinical features of pseudotumor. Histopathologically, the patterns in the orbit and subcutaneous fascia of the limbs 19 are virtually identical. Although we know of no patients with concurrent orbital and limb inflammation (Dr. Rodman, personal communication, July 1980), the clinical and pathologic similarities between the two syndromes invite speculation upon a similar pathogenesis finding different topographic expression. No orbital involvement has been described in eosinophilic fasciitis, nor have any of our young patients developed inflammatory change in their limbs. However, it is tempting to speculate upon a similar pathogenesis, with topographically different "end-organs." In idiopathic orbital inflammatory pseudotumor, the commonly associated findings of headache, malaise , and vomiting, along with the abnormal blood counts sedimentation rates, serum globulins, CSF, pleocytosis, and positive ANA, all point toward a generalized ailment, the brunt of which is borne by the connective tissues of the orbit. The abrupt onset of orbital pseudotumor and the prominence of eosinophils, both in the orbit and in the blood, suggest that some immunologic reaction may well be responsible. The field of this reaction includes the intraocular tissues , in view of the frequent coexistent finding of uveitis among patients with pediatric orbital pseudotumor. The nature of the inciting antigenic stimulus remains elusive and may be the product of an organic or inorganic agent. Particulate isolates or elevations of viral titres have not been demonstrated. The relative paucity of mast cells reduces the role of a histamine-mediated response, unless chemotaxis of sensitized lymphocytes by degenerated mast cells is operant. The prominence of eosinophils might invoke an antigen-antibody mechanism. However, no immune complexes have been demonstrated, and the expected depletion of serum complement is not found (four patients in our series actually demonstrated elevations in serum complement levels). The accumulations of C3 and IgG and/or IgM in the fascia and muscle interstitium in eosinophilic fasciitis should prompt a search for analogous depositions in pseudotumor. These analyses were impossible in our retrospective study, and prospective investigations may be thwarted by the reduced need for a tissue diagnosis and the deleterious effects of biopsy in pediatric pseudotumor.3 Unfortunately, no satisfactory animal model has been developed yet. Retrobulbar injections of bovine serum albumin into the orbits of sensitized rabbits approximate the clinical picture, but his-
topathologically the response is exclusively polymorphonuclear in nature. 21 The concept of orbital pseudotumor as a forme fruste of Toxocara canis infestation is intriguing, but the absence of a prominent granulomatous inflammation argues against deposition of the parasite itself in the orbit. In four patients with pseudotumor who were evaluated for testing for ELISA titres, an elevation was discovered in only one, a finding of little present value in the view of the fact that 10% of the normal population manifests such elevated titres (personal communication, Dr. David Abramson, 7/29/80). The simultaneous occurrence of painful ophthalmoplegia (Tolosa-Hunt variant) in one of our patients , and of orbital myositis in a cousin and a sibling, further raises the possibility of either a common environmental antigenic stimulus, or a hereditary propensity for an orbital inflammatory response. The elevation of antinuclear antibody titres might further suggest an autoimmune response, be it to an extrinsic antigeninduced cross reaction, or an intrinsic inborn misdirection of antibody production . Just why the orbits should be the sole target for inflammation in pseudotumor, or the distal extremities in eosinophilic fasciitis, is still a mystery. The role of muscle exertion exacerbating in eosinophilic fasciitis and the frequent association of trauma preceding the onset of symptoms in pseudotumor suggests the induction of locally increased vascular permeability that may result in the release of a circulating antigen into the traumatized tissue planes. The elaborate connective tissue system and associated capillaries of the orbit might serve as the orbital shock-organ, mediating delivery of the "agent provocateur" to the lacrimal gland, extraocular muscles, fat and connective tissue planes of the sclera, and perioptic connective tissues. Koorneef's elegant anatomical work has established that the connective tissues of the muscles, fat, Tenon's layer, perioptic region, ahd the periorbita are not anatomically isolated, but rather constitute a continuous network. 22 .23 This at least helps to explain the multifocality of involvement in pediatric orbital pseudotumor, which we believe is fundamentally a disease of the orbital connective tissue septa, analogous to a diffuse fasciitis.
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15. Knowles OM II, Jakobiec FA. Orbital lymphoid neoplasms: Clinical , pathologic and immunologic characteristics. In : Jakobiec FA, ed. Ocular and Adnexal Tumors. Birmingham : Aesculapius, 1978; 806-38. 16. Jakobiec FA, Jones IS. Lymphomatous, plasmacytic, histiocytic and hematopoietic tumors. In: Duane, TO, ed. Clinical Ophthalmology, New York: Harper & Row, 1979; 39:38-40. 17. Shulman LE. Diffuse fasciitis with eosinophilia: A new syndrome? Trans Assoc Am Physicians 1975; 88:70-86. 18. Shulman LE. Diffuse fasciitis with eosinophilia: A new syndrome. Arthritis Rheum 1977; 20 :5205-15. 19. Barnes L, Rodnan GP, Medsger TA , Jr, Short 0: Eosinophilic fasciitis: Apathologic study of twenty cases. Am J Patho11979 ; 96:493 - 517. 20. Rodnan GP, DiBartolomeo AG, Medsger TA, Jr. Eosinophilic fasciitis : Report of six cases of a newly recognized scleroderma-like syndrome. (Abstract) Arthritis Rheum 1975; 18:525. 21 . Goodner EK, Aronson SB. Experimental immunogenic orbital inflammation. Arch Ophthalmol1974; 91:303-7. 22 . Koornneef L. Orbital septa: anatomy and function. Ophthalmology 1979; 86:876 - 80. 23. Koornneef L. Spacial aspects of orbital musculo-fibrous ti ssues in man. Lisse, The Netherlands : Swets Publishing Co ., 1977.
Abstract: Twenty-nine patients with pediatric orbital pseudotumor underwent a wide variety of diagnostic tests including biopsies. The following abnormalities were discovered: peripheral blood eosinophilia (9/29 patients); elevated ESR (17/17); elevated antinuclear antibody titres in the Tolosa-Hunt variant (2/2); hypercomplementemia (2/3); and mild CSF pleocytosis (2/6). Thyroid function tests were normal in nine patients so studied. B-mode ultrasonography performed on 12 patients displayed abnormalities in all cases (some combination of Tenonitis, myositis, perioptic inflammation, or mass effect). Computed tomography in seven patients provided higher resolution confirmation of these findings. Orbital bone changes and serious sinus disease were absent on routine radiographic studies. Biopsies performed on 16 patients disclosed mild lymphocytic inflammation in all cases, fibrosis and tissue eosinophilia in 9 biopsies (6 correlating with peripheral blood eosinophilia). Nine biopsies demonstrated a lipogranulomatous response to damaged fat cells. A true vasculitis or extensive lymphoid hyperplasia was not identified in any biopsy specimen. [Key words: pseudotumor, pediatric, orbit, inflammation, eosinophilia, CT scanning, ultrasonography, idiopathic orbital inflammation, lymphocytes, plasma cells.] Ophthalmology 88:565574, 1981
In an earlier paper, the clinical features of idiopathic inflammatory orbital pseudotumor in 29 children were found to be sufficiently distinctive to permit clinical suspicion or confident diagnosis of the entity in most cases.' A clinical trial of corticosteroids, which usually produces a striking resolution of symptoms of short duration within 48 hours, solidifies the diagnosis.'·2 Before systemic corticosteroids are employed, howFrom the Departments of Ophthalmology and Pathology, Manhattan Eye, Ear and Throat Hospital, The New York Hospital-Cornell Medical Center, New York City, and the Eye Bank for Sight Restoration, New York City. Dr. Jakobiec is the recipient of the Research to Prevent Blindness Robert E. McCormick Scholar Award. Reprint requests to Frederick A. Jakobiec, MD, Manhattan Eye, Ear and Throat Hospital, 210 East 64th Street, New York, New York 10021. 0161-6420/81/0600/0565/$1.00
© American Academy of Ophthalmology
ever, it is worthwhile to study the orbits of pediatric patients believed to have pseudotumor with A- and B-scan ultrasonography, routine radiography, hypocycloidal tomography, and computerized tomography. One should also obtain a complete blood count with an absolute eosinophil count. If the patient presents with a complete painful external ophthalmoplegia resembling the Tolosa-Hunt syndrome, the serum level of antinuclear antibodies may help to confirm the diagnosis. 3 The constellation of clinical findings outlined in the first paper, and the results of diagnostic and laboratory tests to be presented in this one, exclude the need for a diagnostic orbital biopsy in the vast majority of cases. In this paper, we are nonetheless able to report the results of orbital biopsies obtained on 16 patients before the clinical and diagnostic picture of pediatric orbital pseudotumor had clearly emerged. 565
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RESULTS Materials and methods have already been delineated in the earlier paper. 1 DIAGNOSTIC TESTS
Peripheral blood studies. Complete blood counts, performed on all 29 patients, demonstrated peripheral eosinophilia in nine patients. Relative counts varied between 6 and 20%, with absolute counts ranging from 70 to 150. Seventeen patients had a determination of the erythrocyte sedimentation rate, 11 of whom had repeated studies; all were elevated, ranging from 20 to 116. In six out of eight patients on whom serum protein electrophoresis was performed, there was mild elevation of alpha-2 globulin in two patients, beta globulin in five patients, and gamma globulin in three patients. Antinuclear antibody titres were studied in eight patients. The two patients with the Tolosa-Hunt variant had positive results; titres remained elevated in one patient with persistent disease, and in the other the titre reverted to normal upon clinical remission. Two out of three patients studied for serum complement titres had hypercomplementemia during the attack; one patient evaluated for fibrinogen levels displayed an increased amount of the protein. With respect to thyroid function tests, all nine patients studied showed normal results, with four having normal T3-T4' one a normal T 3, one a normal proteinbound iodide, and one a normal Werner suppression test. Heterophile counts performed on three patients were negative, and four VMA and pheochromocytoma screens were likewise nonrevealing. Stool analysis. Two Latin-American patients were found incidentally to have positive stool cultures for trichuriasis or Entamoeba histoiytica, but had normal peripheral blood eosinophil counts. Skin testing. Of 11 patients tested for tuberculin sensitivity, two patients showed mild local induration and erythema, but had negative chest x-rays, consistent with exposure to tuberculosis but not overt infection. These patients had been covered adequately with antitubercular therapy at the time of hospitalization before steroid therapy was introduced; they were not thought to be actively infected. No clinical improvement occurred until after the steroid therapy was begun. Lumbar puncture. Of SIX patIents III whom lumbar puncture was performed, two demonstrated a mild lymphocytic pleocytosis suggestive of parameningeal irritation, while four others had repeated taps that were entirely normal. Ultrasonographic studies. Thirteen orbital evaluations were performed in 12 patients using high resolution B-scan ultrasonography adapted to a water bath technique. Resolution was sometimes suboptimal due to agitation, pain, and photophobia. All 12 patients studied demonstrated orbital inflammatory changes of some kind. Three distinct changes were characteris566
tically seen: (1) sonolucency in the region immediately posterior to the globe, indicative of edema in Tenon's potential space (seen in seven patients) (Fig 1); (2) mottling of the optic nerve outline, occasional enlargement of the nerve with blunting of the anterior angle at the point of its insertion into the globe, and accentuation of the sheath by internal echoes (seen in four patients) (Fig 2); and (3) thickening of the extraocular muscles, secondary to inflammatory involvement (seen in six patients) (Fig 3). In four of these six patients with myositis, an inflammatory involvement of the orbital soft tissues was also suggested. Clearly localized masses were detected in two patients, one being superonasal, the other in the lacrimal region. One additional patient demonstrated multifocal "solid" masses. Seven patients showed acoustic variation in at least two orbital structures. One had both muscle and nerve changes, and three had nerve changes continuous with inflammation in Tenon's space. Only three patients showed the classical triad of inflammatory changes affecting muscle, optic nerve, and Tenon's capsule. Radiographic studies. Skull x-rays were performed on 18 patients, in some cases repeatedly. Abnormalities were initially detected in six of these patients,
Fig 1. Edema fluid (arrows) has accentuated Tenon's space adjacent to the optic nerve.
MonOW-LlPpA, et al • ORBITAL PSEUDOTUMOR
Fig 2. B-scan ultrasonogram displaying characteristic squaring off of the optic nerve shadow (ON), which normally appears triangular at the insertion near the globe.
the most common finding being an increased soft tissue density over the affected orbit, seen in four patients. Retrospective film review increased the prevalence of this finding to 10 patients. Only one patient studied demonstrated any orbital enlargement. Possible clinoid erosion was also initially thought to be present in one patient with the Tolosa-Hunt syndrome but was reinterpreted as normal. Coned-down orbital views were performed in 13 patients who did not have preliminary skull x-rays; soft tissue densities were appreciated in 12 cases. Tomographic studies were performed in seven patients, revealing normal orbits in four and an increased frontal-temporal bone density in the patient with myositis and mandibular exostosis by history. One series of tomograms initially reported as normal was reinterpreted as displaying an increased soft tissue density over the affected orbit. This density could be further resolved to the discretely enlarged rectus muscles (Fig 4). Sinus involvement was radiographically demonstrated in only four of the 13 sinus films performed, with mild ethmoid clouding seen. Computed axial tomography (CT scan) was performed in seven patients, supplementing information available through ultrasonic and other radiographic studies. The CT scans demonstrated in one patient isolated enlargement of the right medial rectus muscle, a finding enhanced by the injection of contrast mate-
Fig 3. B-scan ultrasonogram showing massive thickening of an extraocular muscle (M).
rial. Proptosis in another patient was due to a diffuse soft tissue density in the medial orbit. Striking contrast enhancement of Tenon's potential space complemented the findings of tenonitis by ultrasonographic scanning in two cases (Fig 5). Carotid angiography performed in three patients was reported as normal, corroborated on review of two of these three cases, including the patient with possible clinoid erosion on skull films. Orbital venograms were normal in the three patients who were so studied, one of whom also had a normal angiogram. A thermogram, performed in one Tolosa-Hunt patient with normal carotid angiography, was also normal. PATHOLOGIC FINDINGS
Twenty orbital biopsy specimens were obtained from 16 of the 29 patients in the series (two biopsies were performed on two patients and three on a third). Most of these biopsies were obtained in the era preceding the use of ultrasonography and computed tomography, before it became possible to distinguish orbital inflammatory disease from various neoplastic stimulants. The data obtained from the biopsy speci-
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Fig 4. Non-computed tomogram of the orbit behind the globe showing resolution of a soft tissue mass into three discernible extraocular muscles (arrows).
mens reflected the tendency of surgeons to sample tissues in an inflamed orbit that would be the least apt to produce postoperative functional impairment. Consequently, many specimens were from the orbital fat, lacrimal gland, and portions of the extraocular muscles. Another variable was the stage of the disease at the time that tissues were obtained: biopsy specimens obtained in the acute phase would be expected to have a different set of histopathologic features from those obtained late in the disease or after recurrences. The most common finding was that of fibrosis and edema of the involved orbital structures. The lacrimal gland (Fig 6), extraocular muscles (Fig 7), orbital fat (Fig 8), and postcapillary venules (Fig 9) all displayed increased deposition of collagen fibers with a light dispersal of inflammatory cells. In the lacrimal gland, the lobules of lacrimal tissue were separated more widely by thickenings of the interlobular septa. Inflammatory cells made incursions into the periphery ofthe lobules,
eventually leading to obliteration of the lobular architecture. Acinar structures were particularly vulnerable; as involution of the parenchyma progressed, the remaining tubular units failed to stain for zymogen granules with PAS stain, indicating survival only of the ductal epithelium. Both the extraocular muscles and the orbital fat displayed a similar tendency of accentuation and thickening of their normally occurring connective tissue and fibroblastic components. The combination of inflammatory cells and fibrosis in the extraocular muscles led to degeneration of the myofibers. In the orbital fat the usually delicate septa became thickened and frequently confluent, and the venules and capillaries acquired a more pronounced adventitial cuff of collagen. Biopsies obtained in late or recurrent disease demonstrated much more hyalinized connective tissue within the affected sites. In some of the biopsy specimens, particularly those obtained early in the clinical course, the proliferating fibroblastic tissue had an immature, loose myxomatous character (Fig 10), in which stellate and bipolar fibroblasts with rather plump nuclei displaying prominent nucleoli were suspended in a delicate collagenous matrix. This tissue was most prominent in the fat and natural fibrous planes of the orbit, rather than within the muscles or the lacrimal gland. The orbital fat frequently exhibited a spillover of the septal inflammation into the lobules (Fig 11). Nine biopsies from 16 patients displayed a lipogranulomatous response (Fig 12). In these regions necrosis of the lobules of the fat created by intruding inflammation led to the release of intracellular lipid into the extracellular space, provoking a foreign-body, multinucleated, giant-cell histiocytic response. Locules of dissolved fat were found in the midst of this inflammatory reaction pattern. There was a definite tendency for the inflammatory cells to orient themselves prominently around capillaries and postcapillary venules (Figs 8, 9, and 13). The
Fig 5. Left, computed tomographic study of the orbits of a patient with a right pseudotumor (arrow) fails to disclose any orbital mass. Right. with contrast enhancement, the right sclera and Tenon's space are thickened (arrow), accounting for the inflammatory signs.
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Fig 6. Top left , lymphocytic and plasmacytic infiltration within the lobules of the lacrimal gland has resulted in disappearance of the ac ini with survival of only ductular elements, which are being overcome by fibrous replacement (hematoxylin and eosin , original magnification x 25). ~ig 7. Top right , a light mononuclear infl ammation of the extraoc ular mu scles with increased depo sition of collagen between the myofibers (hematoxylin and eosin, original magnification x 280). Fig 8. Center left , increased fibro sis of the interlobular septa of the orbital fat. Note the lymphocytic perivascular cuffing around the venule within the orbital fat (hematoxylin and eosin , original magnification x 60). Fig 9. Center right, perivenular infiltration oflymphocytes, pkisma cells, and bilobed eosinophils, with increase in the adventitial collagen. Fig 10. Bottom left , fibrous tissue replacing the orbital fat exhibiting delicate collagen fibers and loosely di spersed fibroblasts (hematoxylin and eosin , original magnification x 250). Fig II. Bottom right , myriad bilobed eosinophils infiltrating the orbital fat (hematoxylin and eosin , original magnification x 120).
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Fig 12. Top lefi. chronic inflammation of the orbital fat has resulted in damage to the lipocytes, with release of intracellular lipid and a lipogranulomatous. multinucleated foreign body reaction (hematoxylin and eosin. original magnification x 80). Fig 13. Top right. dense lymphocytic cuffing of orbital veins, without any damage to the vessel walls (hematoxylin and eosin. original magnification x60). Fig 14. Center lefi. densely hylanized orbital connective tissue forming concentric lamellae suggestive of granulomas. Connective tissues only minimally and focally inflamed (hematoxylin and eosin, original magnification x 60). Fig 15. Center right. each of the concentric lamellae of collagen is actually shown to have developed around a nearly obliterated blood vessel, which. however, shows no eVidence of fibrinoid necrosis (hematoxylin and eosin, original magnification x 220). Fig 16. Left. a rare focus of follicular lymphoid hyperplasia from a late specimen of hyalinized orbital connective tissue replacing the orbital fat (hematoxylin and eosin. original magnification x 70).
intensity of this response was sometimes suggestive of a vasculitis, but the vessels were devoid of a muscularis. Furthermore, there was neither fibrin, mural necrosis, nuclear dust (Ieukocytoclastic vasculitis), nor interstitial infarcts (stellate necrosis) in these regions. In late specimens, concentric lamellae of collagen deposition suggested burned-out granulomata (Fig 14), but a nearly obliterated vessel could almost always be discovered at the center of such structures (Fig 15). Sheets of lymphocytic hyperplasia were not encountered in the biopsy specimens, but occasionally sur570
viving follicles of lymphoid tissue were separated by bands of hyalinized connective tissue (Fig 16). The inflammatory infiltrates were composed of various admixtures of eosinophils, lymphocytes, and plasma cells. Polymorphonuclear leukocytes were not prominent and were generally encountered only in areas of lipogranulomatous response. Tissue eosinophilia was prominent in nine specimens out of 16 biopsied cases (Figs 9 and 11). In these cases, the eosinophils were scattered throughout the proliferating fibroblastic tissue, localized in cuffs around small
MOTTOW-LlPPA, et al • ORBITAL PSEUDOTUMOR
blood vessels, and involved the lobules of fat. Six of the nine patients with impressive tissue eosinophilia had peripheral blood eosinophilia also. Lymphocytes and plasma cells were most sparse in biopsy specimens from acute cases, but tended to constitute the majority of the cells from late biopsies; they were commonly present around venules and in the hyalinized interstitium (Fig 13). One patient had a scalene node biopsy that revealed benign reactive lymphoid hyperplasia concomitant with active orbital disease.
DISCUSSION Inflammatory causes of proptosis far outnumber neoplastic ones, so when a younger patient presents with rapidly evolving orbital signs and symptoms, the clinician ought to seek evidence for an inflammatory causation first. When this exercise fails, the available data should be reassembled with an emphasis on a possible neoplastic etiology. In our earlier paper, we collated the clinical data on 29 patients 20 years of age or less who had idiopathic orbital inflammatory pseudotumor. 1 In analyzing the results of diagnostic tests, we have discovered that invariably these investigations fortify the clinical impression without the need for biopsy. The clinical picture includes orbital pain of abrupt onset, variable lid swelling and erythema, chemosis, conjunctival and epimysial vessel engorgement, proptosis, motility dysfunction, a palpable mass in 45% of patients, and visual decrease. Nearly half of our patients were bilaterally affected, with recurrences alternating from one side to another. The ocular symptoms were accompanied in 53% ofthe patients by such systemic complaints as headache, fever, vomiting, pharyngitis, anorexia, abdominal pain , and lethargy. Periorbital inflammation was sometimes accompanied by intraocular involvement, with iritis in eight and papilledema in ten patients. After a careful clinical examination, the most important diagnostic adjuncts are radiographic and ultrasonographic evaluations of the orbit. X-ray studies should include views of the skull, orbits, and sinuses. Routine radiographic and tomographic studies of the orbits characteristically reveal intact orbital walls without bone destruction, widening of sutures and fissures, or hyperostosis. This contrasts with the radiographic findings in rhabdomyosarcoma, wherein 50% of cases may display various degrees of erosion of the medial orbital wall with careful tomography. 4 Eosinophilic granuloma produces large osseous defects because this lesion originates within the bone. s Since inflammatory pseudotumor evolves so rapidly, insufficient time elapses in most cases to produce significant bony abnormalities. One patient with hyperostosis in the vicinity of an orbital pseudotumor was exceptional because he had previously had an
exostosis of the mandible, and it is our interpretation that his bone reactivity exceeded that expected in the overall population of pseudotumor patients. While patients with pseudo tumor may on occasion display some clouding of the ethmoid tissues, this is not the fulminant sinusitis encountered in conjunction with an orbital cellulitis. A soft tissue density in the involved orbit frequently can be identified in non-computed tomographic studies, and it may even be possible (rarely) to distinguish individual extraocular muscle thickenings. However, computed tomography and ultrasonography resolve such soft tissue involvements to much greater advantage. Ultrasonography is now available in most ophthalmology departments and can be repeated safely. The latter consideration is relevant in young individuals with developing tissues and longer life expectancies, and who therefore might experience increased risk for late side effects from multiple radiographic exposures . The inflammatory or congestive changes in pseudotumor are reflected ultrasonographically as subtle variations in the normal orbital visceral pattern, rather than as the gross distortions observed in mass lesions. In cases of acute orbital pseudotumor, ultrasonography will reveal some combination of widening of Tenon's potential space, squaring off of the optic nerve shadow, and thickening of the extraocular muscles. These findings are particularly compelling when they are found together, constituting a diagnostic triad. Recourse to computed tomography is indicated if the results of ultrasonographic testing are ambiguous. Most of the patients in this series were studied prior to the introduction of high resolution computed tomography. The three-dimensional depiction of orbital involvement in inflammatory pseudotumor afforded by modern computed tomography is superior to that obtained from Ultrasonography. Contrast enhancement during computed tomography can highlight very subtle alterations caused by inflammatory involvement, particularly a sclerotenonitis that could be missed without this expedient. Computed tomography is also useful in the differential diagnosis of pseudotumor. Both ruptured dermoids and hemorrhagic lymphangiomas can produce an inflammatory response closely mimicking orbital pseudotumor. Dermoids often produce a contiguous bone defect as well as a lipid density cyst in the midst of the inflammatory process,6 whereas in lymphangioma, high resolution can display a honeycomb appearance created by the cystic lymphangiomatous channels. The absence of a tumor blush on anteriography in four children was reassuring, ruling out an anterior cavernous sinus mass, but the amount of information obtained from this potentially dangerous method of investigation is minimal compared to that from other less invasive techniques. The caveat of Fowler et al. is well taken 7 : a cavernous sinus aneurysm or parasellar syndrome produced by meningiomas or pituitary tumors must be excluded. However, each of these diagnoses 571
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is exceedingly rare in children, and the absence of widening of the superior orbital fissure or anterior clinoid erosion further reduces these possibilities. As reported by Sondheimer and Knapp in 1973, orbital venography performed in patients with the Tolosa-Hunt syndrome can demonstrate compression of the superior ophthalmic vein. 8 In the two patients in our group with a picture of the Tolosa-Hunt syndrome, orbital venography was normal. We believe that the diagnostic value of orbital venography has been supplanted by ultrasonography and computed tomography. Other regularly performed laboratory tests supplement the data derived from the more sophisticated technological evaluations reviewed above . An elevated peripheral eosinophil count is of particular importance when discovered (in nine of our 29 patients), suggesting a systemic allergic response . With exclusion of parasitic infestation by history, lack of symptoms, negative serial stools for ova and parasites, and negative serology (particularly trichinella benzoate flocculation and counter electrophoresis), peripheral blood eosinophilia might implicate participation of eosinophils locally producing inflammation in the orbit. Of nine patients biopsied showing eosinophilic infiltration of orbital tissues, six patients demonstrated peripheral blood eosinophilia. Although rarely present in pediatric pseudotumor patients, antinuclear antibodies are helpful in supporting the diagnosis of the Tolosa-Hunt variant. 3 Other corroborative evidence includes the absence of seropositive factors for collagen vascular disease (latex fixation , LE prep) and the lack of any clinical evidence for hepatitis, thyroiditis, ulcerative colitis or pulmonary fibrosis, or drug intake (DPH), any of which may stimulate the production of antinuclear antibodies. 3 An elevated ESR (found in all 16 patients in this series who were studied) , indicative of an inflammatory systemic response, is less likely to be seen as a localized orbital tumor, such as rhabdomyosarcoma. Serologic studies for the evaluation of thyroid function were within normal limits in the nine patients so studied. The painful, explosive onset of inflammation in pediatric orbital pseudotumor and its rapid and complete suppression with systemically administered corticosteroids are clinical features at ·variance with the typical picture of Graves' disease, which is a mild disease in childhood. The results from the biopsy specimens are especially worth emphasizing because in the future, tissue documentation of idiopathic orbital inflammation will be obviated by the increased accuracy of clinical and diagnostic evaluations. Due to the variable but significant contribution of fibrous tissue to the inflammatory reactions, the differentiation of these lesions microscopically from a lymphoma was never a serious consideration. Early on, the fibrous tissue has a loose texture, with widely spaced fibroblasts set in a finely fibrillar collagenous stroma, and contains only a light dispersal of inflammatory cells. As the disease progresses , an intense hyalinization of the connective tis-
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sue develops. We were struck by the prominence of an eosinophilic infiltrate in the majority of specimens, and this often correlated with a peripheral blood eosinophilia. Lymphocytes and plasma cells were ubiquitous, but were generally widely separated without forming sheet-like patterns or intense hyperplasias. In fact, none of our patients displayed reactive lymphoid hyperplasia. lo The late sequelae of pseudotumor are the consequences of increased deposition of collagen within the extraocular muscles, around the optic nerve and globe, and within the lacrimal gland and fat, particularly in those severe cases where the inflammatory disease recurs or is not arrested successfully by therapy. We found no evidence in our specimens of true immunogenic granulomatous inflammation, in that the granulomata occurred only in the vicinity of inflamed fat, a response more consistent with a foreign-body type of reaction to the lipid released from damaged fat cells. Our specimens also failed to incriminate a vasculitis as the central pathogenetic event in orbital pseudotumor. The vascular changes that we noted were pericapillary and perivenular collections of lymphocytes or eosinophils, and secondary perivascular fibrosis. No areas of fibrinoid necrosis , stellate necrosis, or "nuclear dust " were observed. Moreover, the absence in our patients' clinical histories of any apoplectic vascular events (central retinal artery occlusion, nerve fiber layer infarcts, choroidal infarcts) leads us to the conclusion that vasculitis per se is not a common underlying feature of orbital pseudotumor. Henderson II has described leukocytoclastic vasculitis in the biopsies from some of his younger patients. Heersink and Rodrigue_s in their series of orbital pseudotumors from all ages felt that they had identified vasculitis,12 but our review of their published photomicrographs suggests that their findings are more consistent with the perivascular leukocytic or lymphocytic cuffing that we have documented. Several clinical simulators of pseudotumor are readily differentiable pathologically. We believe that Iymphoproliferative disorders, categorized in the past along with pseudotumor,9 are both clinically and pathologically distinctive, in that they primarily affect adults, and have a more insidious symptomatology and a more prominent mass effect. 13 Furthermore, heterogeneity of the inflammatory cell population in pseudotumor should effectively exclude a lymphoma. 13 - IS The inflammatory component of Graves' disease may be only subtly different from that of pseudotumor, but tissue eosinophilia, if present, militates strongly for the latter. In eosinophilic granuloma, the mass of the lesion is not contributed to by fibroblastic proliferation, but rather by polygonal histiocytes. S In granulocytic sarcoma, the mass of the lesion is composed of atypical mononuclear cells. 16 In fungal and parasitic diseases, there is far more prominent granulomatous inflammation; special stains will delineate the nature ofthe organism. A hemorrhage into a lymphangioma may be ruled out by deeper
MOTTOW-LlPPA, et al • ORBITAL PSEUDOTUMOR
sections to find the lymphangiomatous tissue , and a ruptured dermoid by finding portions of the cyst wall. Eosinophils will not be prominent in either disease. Some striking parallels may be drawn between pediatric orbital pseudotumor and eosinophilic fasciitis, a newly described scleroderma variant. In the latter, the acute onset of painful swelling of the distal extremities progressing to sclerosis, accompanied by peripheral eosinophilia and hypergammoglobulinemia, correspond to the clinical features of pseudotumor. Histopathologically, the patterns in the orbit and subcutaneous fascia of the limbs 19 are virtually identical. Although we know of no patients with concurrent orbital and limb inflammation (Dr. Rodman, personal communication, July 1980), the clinical and pathologic similarities between the two syndromes invite speculation upon a similar pathogenesis finding different topographic expression. No orbital involvement has been described in eosinophilic fasciitis, nor have any of our young patients developed inflammatory change in their limbs. However, it is tempting to speculate upon a similar pathogenesis, with topographically different "end-organs." In idiopathic orbital inflammatory pseudotumor, the commonly associated findings of headache, malaise , and vomiting, along with the abnormal blood counts sedimentation rates, serum globulins, CSF, pleocytosis, and positive ANA, all point toward a generalized ailment, the brunt of which is borne by the connective tissues of the orbit. The abrupt onset of orbital pseudotumor and the prominence of eosinophils, both in the orbit and in the blood, suggest that some immunologic reaction may well be responsible. The field of this reaction includes the intraocular tissues , in view of the frequent coexistent finding of uveitis among patients with pediatric orbital pseudotumor. The nature of the inciting antigenic stimulus remains elusive and may be the product of an organic or inorganic agent. Particulate isolates or elevations of viral titres have not been demonstrated. The relative paucity of mast cells reduces the role of a histamine-mediated response, unless chemotaxis of sensitized lymphocytes by degenerated mast cells is operant. The prominence of eosinophils might invoke an antigen-antibody mechanism. However, no immune complexes have been demonstrated, and the expected depletion of serum complement is not found (four patients in our series actually demonstrated elevations in serum complement levels). The accumulations of C3 and IgG and/or IgM in the fascia and muscle interstitium in eosinophilic fasciitis should prompt a search for analogous depositions in pseudotumor. These analyses were impossible in our retrospective study, and prospective investigations may be thwarted by the reduced need for a tissue diagnosis and the deleterious effects of biopsy in pediatric pseudotumor.3 Unfortunately, no satisfactory animal model has been developed yet. Retrobulbar injections of bovine serum albumin into the orbits of sensitized rabbits approximate the clinical picture, but his-
topathologically the response is exclusively polymorphonuclear in nature. 21 The concept of orbital pseudotumor as a forme fruste of Toxocara canis infestation is intriguing, but the absence of a prominent granulomatous inflammation argues against deposition of the parasite itself in the orbit. In four patients with pseudotumor who were evaluated for testing for ELISA titres, an elevation was discovered in only one, a finding of little present value in the view of the fact that 10% of the normal population manifests such elevated titres (personal communication, Dr. David Abramson, 7/29/80). The simultaneous occurrence of painful ophthalmoplegia (Tolosa-Hunt variant) in one of our patients , and of orbital myositis in a cousin and a sibling, further raises the possibility of either a common environmental antigenic stimulus, or a hereditary propensity for an orbital inflammatory response. The elevation of antinuclear antibody titres might further suggest an autoimmune response, be it to an extrinsic antigeninduced cross reaction, or an intrinsic inborn misdirection of antibody production . Just why the orbits should be the sole target for inflammation in pseudotumor, or the distal extremities in eosinophilic fasciitis, is still a mystery. The role of muscle exertion exacerbating in eosinophilic fasciitis and the frequent association of trauma preceding the onset of symptoms in pseudotumor suggests the induction of locally increased vascular permeability that may result in the release of a circulating antigen into the traumatized tissue planes. The elaborate connective tissue system and associated capillaries of the orbit might serve as the orbital shock-organ, mediating delivery of the "agent provocateur" to the lacrimal gland, extraocular muscles, fat and connective tissue planes of the sclera, and perioptic connective tissues. Koorneef's elegant anatomical work has established that the connective tissues of the muscles, fat, Tenon's layer, perioptic region, ahd the periorbita are not anatomically isolated, but rather constitute a continuous network. 22 .23 This at least helps to explain the multifocality of involvement in pediatric orbital pseudotumor, which we believe is fundamentally a disease of the orbital connective tissue septa, analogous to a diffuse fasciitis.
REFERENCES 1. Mottow LS, Jakobiec FA. Idiopathic inflammatory orbital pseudotumor in childhood I. Clinical characteristics. Arch Ophthalmol 1978; 96: 141 0 - 7 2 . Jakobiec FA, Mottow, L. Pediatric orbital inflammatory pseudotumor. In: Jakobiec FA, ed . Ocular and Adnexal Tumors. Birmingham: Aesculapius, 1978; 644 - 58 3. Lesser R. Jampol LM . Tolosa-Hunt syndrome and antinuclear factor. Am J Ophthalmol 1974; 77:732-4. 4. Abramson DH. Ellsworth RM, Tretter p. e\ al. The treatment of orbital rhabdomyosarcoma with radiation and chemotherapy. Ophthalmology 1979; 86:1330 - 5. 5. Jakobiec FA, Trokel SL, Aron-Rosa D, et al. Localized
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