Chacko, Joseph MD; Brock, Wade MD; Brown, Harry MD; Luetmer, Patrick MD; Giannini, Caterina MD, PhD
Jones Eye Institute (JC, HB), University of Arkansas for Medical Sciences, Little Rock, Arkansas; Arkansas Oculoplastic Surgery (WB), PLLC, Little Rock; and Departments of Neuroradiology (PL) and Neuropathology (CG), Mayo Clinic, Rochester, Minnesota.
Supported in part by an unrestricted grant from Research to Prevent Blindness (New York, NY) and the Pat & Willard Walker Eye Research Center, Jones Eye Institute, University of Arkansas for Medical Sciences (Little Rock, AR).
Presented in part at the North American Neuro-Ophthalmology Society Annual Meeting Frank B. Walsh Session, March 2010, Tucson, AZ.
Address correspondence to Joseph Chacko, Jones Eye Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205; E-mail: firstname.lastname@example.org
A 48-year-old white woman complained of worsening blurry vision in both eyes lasting 1 year and pain in both eyes for the previous month, which worsened with eye movements. She had experienced frequent headaches and transient visual obscurations during the preceding month, but she denied nausea, vomiting, and diplopia. Her medical history was significant for hypertension, acid reflux, anemia, and retroperitoneal fibrosis requiring ureteral stenting in the past year. She had undergone hysterectomy 13 years earlier. Her family history was significant for leukemia in her father. Social history revealed that she was an 18 pack-year smoker, but had quit 16 years earlier. Her only medication was valsartan. She denied any use of methysergide.
On examination, the patient's blood pressure was 160/88 and her weight was 216 pounds. Visual acuity with correction was 20/20 in each eye. Color vision was normal, and pupils were brisk in each eye without a relative afferent pupillary defect. Intraocular pressure measured 18 mm Hg in each eye. Visual fields were full to confrontation, and slit-lamp examination was unremarkable.
There was slight ptosis of the left upper lid, and xanthelasmae were present (Fig. 1). There was no proptosis. Ocular motility revealed mild bilateral limitation of upgaze. The optic discs were mildly swollen (Fig. 2), and the fundi otherwise were normal. Neuroimaging was obtained (Fig. 3A-E).
MRI of the brain and orbits (Fig. 3) demonstrates sharply marginated, bilaterally symmetric, uniformly enhancing masses filling and mildly expanding the intraconal spaces. The masses are isointense to the optic nerves on T1 images (Fig. 3A, 3C, 3D) and demonstrate markedly low signal on T2 images (Fig. 3B). Despite the size of the masses and mild displacement of the extraocular muscles, there is no deformity of the globes and no obvious proptosis. The optic nerves are encased without displacement or evidence of infiltration. The fat planes at the orbital apex are preserved, and there is no evidence of intracranial extension. No additional masses are seen, and the imaging including the intracranial contents is otherwise negative.
At this point, the differential diagnosis of bilateral, symmetric, and enhancing intraconal orbital masses was broad. The diagnostic categories of inflammatory, neoplastic, and infectious were entertained. Inflammatory conditions in the differential included sarcoidosis, Wegener granulomatosis, thyroid eye disease, and idiopathic orbital inflammation (i.e., orbital pseudotumor). Neoplastic processes include lymphoma, sarcoma, meningiomas, and neurofibromas. Infectious entities such as syphilis and tuberculosis needed to be ruled out. Less common entities considered were eosinophilic granuloma, Waldenstrom macroglobulinemia, polyarteritis nodosa, and Erdheim-Chester disease.
A battery of laboratory tests were performed. Triiodothyronine, thyroid stimulating hormone, thyroxine, angiotensin-converting enzyme, antinuclear antibodies, perinuclear antineutrophil cytoplasmic antibodies, cytoplasmic antineutrophil cytoplasmic antibodies, SS-A, SS-B, rapid plasma reagin, and purified protein derivative (tuberculin) were all normal. Abnormal values were erythrocyte sedimentation rate: 44 mm/h; C-reactive protein: 59.2 mg/L (normal: 0-10 mg/L); lysozyme: 25 μmg/mL (normal: 9-17 μmg/mL); and rheumatoid factor: 33 IU/mL (normal 0-14 IU/mL). These abnormal values suggested an inflammatory process. A lumbar puncture was also performed. The opening pressure was 14 cm of water. Cerebrospinal fluid composition was normal, with no cells being present. A left anterior orbitotomy was performed with biopsy.
The orbital biopsy specimen showed dense fibrosis with a sparse polymorphous inflammatory cell infiltrate, mostly, lymphocytes (Fig. 4). These findings are nonspecific.
In reviewing the patient's history, she had undergone a needle biopsy in the past year to make a diagnosis of retroperitoneal fibrosis. The orbital and retroperitoneal biopsy findings (Fig. 5) were very similar.
The retroperitoneal needle biopsy specimen also shows fibrosis with a marked polymorphous inflammatory cell infiltrate, composed of lymphocytes as well as histiocytes and eosinophils (Fig. 5A). Staining with CD-68, an immunohistochemical stain that highlights macrophages, revealed marked positivity (Fig. 5B) as did staining with CD-45, an immunohistochemical stain for lymphocytes (Fig. 5C). The findings are consistent with “idiopathic retroperitoneal fibrosis.”
Multifocal fibrosclerosis consisting of bilateral sclerosing orbital pseudotumor and retroperitoneal fibrosis.
Multifocal fibrosclerosis is a rare idiopathic autoimmune disorder characterized by fibrous lesions at multiple sites. The link between retroperitoneal fibrosis, Riedel thyroiditis, and idiopathic orbital inflammation was first suggested by Barrett in 1958 (1). The literature since has greatly expanded the number of locations in the body where the fibrous lesions may occur (Table 1) (2-6). A few cases have been familial, suggesting a genetic factor (2).
When involving the orbit, multifocal fibrosclerosis is indistinguishable from a solitary sclerosing orbital pseudotumor. It can affect intraconal and/or extraconal compartments, extraocular muscles, and the lacrimal gland. Symptoms and signs include pain, proptosis, ptosis, diplopia, and visual loss. Orbital infiltration can lead to visual loss from optic nerve compression or, rarely, from serous detachment of the retina or retinal pigment epithelium (7).
Pathology specimens show a predominance of fibrous connective tissue, active fibroblasts, and a leukocytic infiltrate consisting of lymphocytes, plasma cells, and eosinophils. The hyalinized fibrous tissue and chronic inflammatory cell infiltrate are sometimes arranged in concentric whorls around attenuated blood vessels (5). The lack of Touton giant cells and foamy lipid-laden macrophages distinguishes this disorder from Erdheim-Chester disease.
Our patient was treated initially with 80 mg prednisone daily with a slow taper. She reported some subjective improvement in vision. Her neuro-ophthalmic examination has shown resolution of the disc swelling with resultant mild pallor of both optic discs. Rheumatology started her on mycophenolate mofetil as a steroid-sparing agent, but she discontinued it after 2 months due to expense. Unfortunately, she has developed congestive heart failure, pedal edema, and renal insufficiency due to the multifocal fibrosclerosis. Radiographs of the knee have shown bony sclerosis, which was noted by Richards et al (3) in their case as well. We also suspect that the “xanthelasmae” of her eyelids are actually subcutaneous fibrosis, as she has no history of hyperlipidemia. Her vision of 20/20 in both eyes with full visual fields has been preserved for more than 9 months using varying doses of prednisone.
Patients with bilateral orbital pseudotumor should be evaluated systemically for multifocal fibrosclerosis. Renal function should be checked. Patients found to have renal insufficiency should be investigated for a treatable urinary obstruction due to retroperitoneal fibrosis. The prognosis for multifocal fibrosclerosis is quite variable (6). Treatment options include observation, steroids, steroid-sparing (antineoplastic) agents, radiation, and surgery.
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2. Comings DE, Skubi KB, Van Eyes J, Motulsky AG. Familial multifocal fibrosclerosis. Ann Intern Med 1967;66:884-892.
3. Richards AB, Skalka HW, Roberts FJ, Flint A. Pseudotumor of the orbit and retroperitoneal fibrosis. A form of multifocal fibrosclerosis. Arch Ophthalmol 1980;98:1617-1620.
4. Levine MR, Kaye L, Mair S, Bates J. Multifocal fibrosclerosis. Report of a case of bilateral idiopathic sclerosing pseudotumor and retroperitoneal fibrosis. Arch Ophthalmol 1993;111:841-843.
5. Aylward GW, Sullivan TJ, Garner A, Moseley I, Wright JE. Orbital involvement in multifocal fibrosclerosis. Br J Ophthalmol 1995;79:246-249.
6. Berger JR, Snodgrass S, Glaser J, Post MJ, Norenberg M, Benedetto P. Multifocal fibrosclerosis with hypertrophic intracranial pachymeningitis. Neurology 1989;39:1345-1349.
7. Friberg TR, Stewart T. Ocular involvement in systemic idiopathic fibrosis. Retina 1983;3:34-39.
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