The purpose of this article is to report a case of a nineyear-old girl who presented with right periorbital swelling, ecchymosis, and proptosis. After therapy for presumed orbital cellulitis was unsuccessful, an orbital biopsy was performed and was interpreted as idiopathic inflammatory pseudotumor of the orbit. Twenty-two months later the patient was re-admitted for investigation of a severe anemia. During this second hospitalization, a renal biopsy, laboratory studies, and physical examination findings established the diagnosis of Wegener's granulomatosis.
To our knowledge, this is the fourth report of Wegener's granulomatosis in children presenting as an orbital inflammatory pseudotumor. This is the first case, however, in which nearly two years elapsed between the initial orbital involvement and the development of generalized features which led to the diagnosis of Wegener's granulomatosis.
The clinician should consider the possibility of Wegener's granulomatosis in children with orbital inflammatory pseudotumor. Such patients should be followed over a long period of time.
A 9 %-year-old white female was admitted to a community hospital on January 3, 1979, with a one-month history of right periorbital swelling, erythema, and proptosis. She had been treated for one month with oral erythromycin and Keflex, without resolution.
The family history revealed a paternal aunt with systemic lupus erythematosus and auto-immune hemolytic anemia. Both a maternal aunt and cousin have rheumatoid arthritis.
The past history revealed an illness one year prior to admission that was thought to have been infectious mononucleosis. The patient also had a five-year history of recurrent "sinusitis" accompanied by frontal headache and nasal discomfort. The patient claimed to be allergic to penicillin.
On admission to the community hospital, the patient stated that she "felt well" and denied eye pain, decreased vision, diplopia, or headache. A review of systems was negative for fever, weight loss, malaise, respiratory or constitutional symptoms.
Physical examination revealed normal vital signs. The patient was afebrile. Swelling and ecchymosis of the right periorbital tissues were noted. Visual acuities were normal, as were the pupils and fundi. The physical examination was otherwise unremarkable.
Sinus films were obtained and revealed a chronic right maxillary sinusitis. The CBC, differential count, routine urinalysis, and serum electrolytes were normal.
The patient was begun on decongestants and intravenous Keflin for presumptive right orbital cellulitis secondary to right maxillary sinusitis. The periorbital swelling increased over the first 36 hours after admission, and the question of a resistant organism was therefore raised.
FIGURE 1: Examination of patient on admission revealing swelling, erythema, and inflammation of right upper and lower lids. Left eye and lids are normal.
FIGURE 2: Examination of patient on day 2 after admission revealed limited ability of the right eye to elevate. Early injection of the temporal bulbar conjunctiva is evident.
Intravenous gentamycin and clindamycin were added to her regimen. When no improvement in the periorbital swelling was noted on the third hospital day, the patient was transferred to the Children's Hospital National Medical Center.
On admission, the patient was afebrile and had normal vital signs. Swelling, erythema, and induration of both the right upper and lower lid were evident (Figure 1).
An ophthalmology consultation revealed visual acuities of % in both eyes. Exophthalmometry revealed 2 mm of proptosis of the right eye. There was no limitation of extraocular movements, which were painless, diplopia was not present. The pupils and fundi were normal.
Laboratory studies included a normal CBC, WBC, and differential count. The erythrocyte sedimentation rate was 44 mm per hours. The creatinine was 0.6 mg/dl. Routine urinalysis was normal. A PPD was unreactive. Cultures of the blood and of a percutaneous aspirate from the right eyelid were negative. A CT scan revealed anterior right orbital swelling without abscess formation; the sinuses were clear. Sinus x-rays showed questionable right maxillary mucosal thickening.
FIGURE 3: Orbital histopathology revealing predominately lym * phocyte infiltrated fibro-fatty tissue. Plasma cells, eosinophiles (few), and macrophages are present together with focal nodular infiltration.
The initial impression was partially treated orbital cellulitis. Intravenous chloramphenicol therapy was begun.
On day two, the patient was noted to have limited elevation of the right eye (Figure 2). The lid swelling improved over the next two days, but worsened on day four. Gentamycin was added to the intravenous regimen and surgical exploration was considered. On day six, the patient was noted to have five mm of proptosis and a firm non-tender mass was palpated in the superior nasal orbital quadrant. Visual acuity remained % in both eyes and limited elevation of the right eye continued. On day seven, the child was evaluated by an ENT consultant. Fiberoptic examination of the nasopharynx failed to demonstrate inflammation or mass.
On day eight, the patient's orbital swelling worsened and temporal bulbar conjunctival injection was noted. The question of an orbital tumor or pseudotumor was raised, and a repeat CT scan was obtained. This revealed only soft tissue swelling in the anterior right orbit. The sinuses appeared normal.
On day 11, a biopsy of the mass was obtained. Pathological examination revealed fibro-fatty tissue diffusely infiltrated by inflammatory cells, predominately lymphocytes, plasma cells, and a few eosinophils. Focal nodular inflammation and macrophages with foamy cytoplasm were also noted. The picture was thought to be consistent with the diagnosis of idiopathic inflammatory pseudotumor (Figure 3 ). On day 12, after a normal chest x-ray was obtained, the patient was started on prednisone (60 mg/day). A dramatic decrease in lid swelling ensued. Elevation of the right eye had significantly improved at the time of discharge, two weeks after admission.
Prednisone was gradually tapered over the next two months without recurrence of lid swelling. The child remained well for approximately 22 months until October, 1980, when she developed a "flu-like" illness with weakness, malaise, fever, dizziness, and anorexia. She experienced two syncopal episodes and one episode of gross hematuria one day prior to hospitalization.
FIGURE 4: Renal biopsy consistent with necrotizing glomerulonephritis demonstrating loss of normal glomerular architecture with evidence of sclerosis.
FIGURE 5: Nasal biopsy illustrating loss of normal nasal mucosal architecture with necrotizing inflammation.
The patient was readmitted to the community hospital on November 11, 1980. Physical examination revealed a pale, lethargic white female. Vital signs revealed a mild fever, tachypnea, and tachycardia. Conjunctival pallor was noted. Laboratory studies demonstrated a hematocrit of 14.2% with a hemoglobin of 4.6 mg/dl. Red blood cell indices were mildly hypochromic and microcytic. The WBC and differential count were within normal limits; the platelet count was 115K. A urine specimen was clear and amber in color. It revealed too numerous to count RBCs and 3+ proteinuria. The BUN was 60 mg/dl and the creatinine was 3.8 mg/dl. The electrolytes were normal; the erythrocyte sedimentation rate was 81 mm per hour. An LE cell prep was negative. A chest x-ray revealed bilateral diffuse infiltrates. An IVP revealed poor renal function without obstruction or ditatation. An abdominal sonogram was normal. The child was transferred to Children's Hospital National Medical Center for further evaluation.
Physical examination on admission on November 8, 1980, revealed a thin, lethargic, pale white female. Vital signs were: Temp. 37.5 C, pulse 112, respirations 20, and blood pressure l2?i&. There was a mild proptosis of the right eye, with a question of early papilledema. A grade ??/VI systolic ejection murmur was noted. Laboratory results included: BUN 55 mg/dl and creatinine 3.2 mg/dl; the urine was dark with too numerous to count RBCs and 2+ protein. The hematocrit was 12%, the hemoglobin was 4.2 mg/dl, and the WBC was 7800 with a normal differential count. A platelet count was also normal. Antinuclear antibodies were present at 1:80, a VDRL was positive at 1:16, and an LE cell prep was positive, as was a direct Coomb's test. Cryoglobulins were present in the serum. Serum levels of C3 and C4 were normal. An anergy panel was unreactive. Serum immunoglobulins IgG, IgA, and IgE were slightly elevated.
Chest x-ray demonstrated multiple peripheral nodules under three cm (ill-defined) without cavitation. A renal scan demonstrated normal size kidneys with bilaterally poor function. A bone marrow aspirate was hypocellular except for erythroid hyperplasia.
A renal biopsy performed on November 10, 1980, revealed segmental sclerosing and necrotizing glomerulonephritis with crescent formation (Figure 4). Immunofluorescent staining for IgG, IgA, IgM, and C3 was positive. A nasal biopsy performed several days later demonstrated necrotizing inflammation (Figure 5). Pulmonary function tests revealed mild interstitial restrictive disease. The diagnosis of Wegener's granulomatosis was made in view of the constellation of pulmonary, sinus, and renal disease. The orbital biopsy slides from January 15, 1979, were reviewed and, in view of the entire clinical history and biopsy material, were thought to be consistent with the diagnosis of Wegener's granulomatosis.
After multiple blood transfusions, the patient was begun on Cytoxan and pulse high-dose intravenous steroids. She was discharged on Cytoxan and prednisone on November 25, 1980.
The patient was readdmitted to Children's Hospital National Medical Center one week later with a history of severe headaches, vomiting, and seizures. A diagnosis of hypertensive encephalopathy with cerebral vasculitis was made, and another course of intravenous steroids was given. After emergency blood pressure lowering was accomplished, stabilization was achieved with dilantin, Apresoline, Lasix, and propranolol. Cytoxan and steroids were continued.
Intravenous pulse steroids were again administered in February 1981. Renal functions continued to deteriorate, necessitating the institution of hemodialysis in May 1981. Blood pressure medications, dilantin, Cytoxan, and steroids were continued until a kidney transplantation was performed on January 25, 1982. After transplantation, immurali was started and Cytoxan was discontinued. The patient was maintained on steroids. A rejection episode one week after transplantation was treated with radiation and high dose intravenous steroids. A second rejection episode in May 1982, was treated with pulse steroid therapy.
Aside from several problems related to chrome steroid therapy, the patient remains well at this writing, with improved renal function and normal blood pressure. All antihypertensive drugs and dilantin have been discontinued.
Ophthalmic examination in April 1983 revealed % visual acuity in both eyes. No proptosis, restrictions of ocular motility, inflammatory lesions, or fundus abnormalities were present.
The disease entity which we refer to now as Wegener's granulomatosis was first described in 1931 by Klinger1 in his report of a patient with sepsis, sinusitis, nephritis, and disseminated vasculitis. Wegener2-3 more clearly defined the disease both clinically and pathologically.
In 1954, Godman and Churg established the criteria for the diagnosis of Wegener's granulomatosis.4 These included necrotizing granulomatosis lesions of the respiratory tract, generalized focal necrotizing vasculitis - involving both arteries and veins - almost universally involving the lungs and less frequently other sites, and focal glomerulitis.
Pseudotumor of the orbit coexistent with Wegener's granulomatosis has been well documented in adults.5 This combination of entities may coexist in either a generalized form6 or in the limited form of Wegener's granulomatosis.7 There are only three cases810 reported of orbital pseudotumor as the presenting sign of Wegener's granulomatosis in children under the age of 16. In the first of these, the diagnosis was established by orbital and renal biopsy at the time of admission,8 in the second case,9 there was a three-month delay between the initial presentation and histopathologic confirmation, and in the third case,10 there was a six-month delay in diagnosis. All of these cases showed bilateral ocular signs. Interestingly, Biodi and Gass5 suggested that bilateral pseudotumor, either simultaneously or consecutively, should alert the clinician to the presence of a systemic disease. Controversy persists, however, over the significance of bilaterality. Although there is some debate as to the proper classification of Wegener's granulomatosis, most authorities acknowledge that the disease may be viewed as either generalized, in which there is renal involvement, or limited11·12 in which there is no renal involvement and the prognosis is better.
The most frequent signs and symptoms are referrable to the upper and lower respiratory tract. Chronic nasal discharge, obstruction, epistaxis, sinusitis, hemoptysis, and persistent cough are the most frequent initial complaints.13 Fever, constitutional symptoms, arthralgia, skin lesions, and neurological symptoms are also frequent, though not universal findings. Laboratory evidence of elevated erythrocyte sedimentation rate, anemia, leukocytosis, thrombocytosis, hyperglobulinemia, especially of the IgG and IgA is characteristic in Wegener's granulomatosis. Renal function tests and urinalysis are abnormal during the active phase of the disease when there is renal involvement. Radiologic evidence of the disease includes sinusitis, pulmonary infiltrates (often of a fleeting nature), cavitation, and pleural effusions.14
Biopsy specimens of the nasopharynx, sinuses, lung, and kidneys often provide confirmatory tissue diagnosis. The respiratory systems demonstrate necrotizing granulomata, with or without vasculitis, while kidney biopsy specimens classically demonstrate a focal necrotizing glomerulitis with fibroid destruction of the glomerular capillary loop. The diagnosis is made only when the constellation of clinical signs, laboratory data, radiologic studies and biopsy material is reviewed as a whole.
In a review of the literature in 1958, Walton15 reported that the disease was invariably fatal with a mean survival time of five months. With the introduction of immunosuppressive agents in the 1960s, the prognosis for survival increased. Novak and Pearson16 reported dramatic clinical response to cyclophosphamide. Long-term follow-up of patients treated with this drug has also been quite encouraging.17 Most authors advocate using systemic steroids to some extent during the initial remission induction.18. Cyclophosphamide has also been reported by some authors to reinduce remission after recurrence of the disease,19 and in one patient with recurrence after successful renal transplantation.
Ocular involvement has been reported in 39%>-50% of patients with Wegener's granulomatosis.13·14·20·21 Straatsma21 divided the ocular involvement into contiguous and focal forms. Contiguous involvement implies direct extension into the orbit from involved paranasal sinuses. This causes proptosis, optic neuritis, nasolacrimal duct and extraocular muscle dysfunction, and orbital inflammation. Focal vasculitic lesions, unrelated to adjacent sinus disease, are manifested by conjunctivitis, scleritis, episcleritis, uveitis, and granulomatous vasculitis of the retina, choroid and optic nerve.20·21
Both orbital pseudotumor and Wegener's granulomatosis are uncommon in childhood. Idiopathic inflammatory pseudotumor accounts for between 3% and 8.5% of cases of orbital tumors in childhood.2225 Wegener's granulomatosis accounts for less than 1% of childhood tumors. In fact, to date, there are 21 well-documented cases of this entity occurring in children under the age of sixteen.810·12·18·20·26-30 Of these, eight patients (38%) had ocular or orbital involvement during the course of the disease. Four of these eight patients (50%) presented initially with idiopathic inflammatory pseudotumor (Table). The remaining four cases had papillitis,10 uveitis,10 optic atrophy,20 and periphlebitis30 (one each). Of the 21 reported cases, two (10%)12·30 had the limited form of the disease, in which the kidneys were spared, while nineteen (90%) had the generalized form.
Although there have been three reports of pseudotumor as the presenting sign in Wegener's granulomatosis, the interval of 22 months between the initial presentation with proptosis, sinusitis, orbital mass, and the final tissue diagnosis of Wegener's granulomatosis is unique. In fact, a period of 19 months elapsed after steroids were discontinued before the second hospitalization was required (during which the diagnosis of Wegener's granulomatosis was confirmed). Although no definite etiology had been established for Wegener's granulomatosis, most current theories hold that it is an allergic or hypersensitivity reaction. DeRemee et al.31 have proposed a unifying concept based on sites of involvement to encompass the various findings. It is their observation that patients may progress from primarily sinus and respiratory involvement to renal involvement.
Wegener's granulomatosis should always be considered as a diagnosis in children with pseudotumor of the orbit, especially those with sinusitis, chronic cough, epistaxis, anemia, or fever. As the present case clearly demonstrates, long-term follow-up may be necessary to exclude this possibility.
CLINICAL CHARACTERISTICS OF THE FOUR PATIENTS WHO PRESENTED INITIALLY WITH IDIOPATHIC INFLAMMATORY ORBITAL PSEUDOTUMOR
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8. Weiter J and Farkas TG: Pseudotumor of the orbit as a presenting sign in Wegener's granulomatosis. Suri; Ophthalmol 1972; 17:106-119.
9. Allen JC, France TD: Pseudotumor as the presenting sign of Wegener's granulomatosis in a child. J Pediatr Ophthalmol Strabismus 1977; 14:158-159.
10. Moorthy AV, Chesney RW, Segar WE, et al: Wegener granulomatosis in childhood: Prolonged survival following cytotoxic therapy. J Pediatr Ophthalmol Strabismus 1977; 91:616-618.
11. Carrington CB and Liebow AA: Limited forms of angeitis and granulomatosis of Wegener's type. Arn J Med 1966; 41:497-527.
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17. Reza MJ, Dornfield L, Goldberg LS, et al: Wegener's granulomatosis: Long-term follow-up of patients treated with cyclophosphamide. Arthritis Rheum 1975; 18:501-506.
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19. Steinman TI, Jaffee BF, Monaco AP, et al: Recurrence of Wegener's granulomatosis after kidney transplantation. Am J Med 1980; 68:458-460.
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26. Baliga R, Chang, CH, Bidani AK, et al: A case of generalized Wegener's granulomatosis in childhood: Successful therapy with cyclophosphamide. Pediatrics 1978; 61:286-290.
27. Cohen SR, King KK, Landing BH, et al: Wegener's granulomatosis causing laryngeal and tracheobronchial obstruction in an adolescent girl. Ann Otol Rhinol Laryngol 1978; 87(suppl): 15-19.
28. Dabbage S, Chevalier RL, Sturgill BC: Prolonged anuria and aortic insufficiency in a child with Wegener's granulomatosis. Clin Nephrol 1982; 17:155-159.
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31. DeRemee RA, McDonald TJ, Harrison EG, et al: Wegener's granulomatosis: Anatomic correlates, a proposed classification. Mayo Clin Proc 1976; 51:777-781.
CLINICAL CHARACTERISTICS OF THE FOUR PATIENTS WHO PRESENTED INITIALLY WITH IDIOPATHIC INFLAMMATORY ORBITAL PSEUDOTUMOR