Middle-aged man seen for 3 days of aching eye pain and blurred vision

The left optic nerve head showed circumferential edema and hyperemia with dilated and tortuous peripapillary retinal vessels.

Issue: October 25, 2015

ByBradley A. Hansen, MD

ByLaurel N. Vuong, MD

A 53-year-old HIV-positive man was admitted to Tufts Medical Center for 3 days of worsening periocular pain and blurred vision in his left eye.

Initially, he noticed mild swelling of the left upper eyelid associated with an ipsilateral aching pain when he looked in left lateral gaze. As the pain worsened, he also noticed blurred vision in the left eye. He denied sinusitis or symptoms of an upper respiratory infection, nasal or ocular discharge, diplopia or headaches. He also noted that for the last “few days” he had “not felt well,” including feeling “unsteady” on his feet. He denied any fevers or chills. His CD4 count was within normal limits, and his viral load was undetectable.

Examination

The patient’s initial exam in the middle of the night showed a best corrected visual acuity of 20/25-2 in the right eye and 20/30-3 in the left eye. Pupils were equal and brisk with no evidence of an afferent defect. Confrontation visual fields and Ishihara color plates were full bilaterally. Lid exam showed mild boggy edema and erythema of the upper lid with tenderness to palpation. He had full versions and ductions with associated pain of the left eye on abduction. IOP was within normal limits. Slit lamp biomicroscopy was unremarkable. Posterior segment examination showed mild arteriovenous nicking in both eyes. The left optic nerve head showed circumferential edema and hyperemia with dilated and tortuous peripapillary retinal vessels. The right optic nerve and fundus exam was normal.

What is your diagnosis?

Eye pain, blurred vision

Given the patient’s compromised immune status, initial work-up included an MRI, lumbar puncture and broad serologic testing for infectious and inflammatory etiologies, including CMV, EBV, HSV, tuberculosis, syphilis, toxoplasmosis, Bartonella, Lyme, Cryptococcus, histoplasmosis, lupus and sarcoidosis. Although initial labs showed a normal white blood cell count, intravenous antibiotics and acyclovir were started empirically for possible early meningitis or encephalitis.

Figure 1. Color fundus photo of the left eye showing optic disc edema, hemorrhages, vessel tortuosity and vascular sheathing.

Figure 2. Cirrus OCT of the macula in the left eye showing optic nerve and peripapillary elevation with associated subretinal fluid and inner retinal hyper-reflective deposits.

Images: Hansen B, Vuong L

Several hours later, his ophthalmic examination had worsened. There was 2 mm of proptosis, limited extraocular movements in all gazes and an early left relative afferent pupillary defect in the left eye. The vision in the left eye had declined to finger counting at 2 feet. The left optic nerve edema had also worsened with peripapillary vascular sheathing (Figure 1). OCT confirmed severe optic nerve and peripapillary elevation with associated subretinal fluid and inner retinal hyper-reflective deposits in the macula (Figures 2 to 3. Fluorescein angiography showed late leakage of the left optic disc and from the peripapillary vasculature with no other posterior or peripheral lesions or leakage (Figure 4). MRI of the orbits with and without gadolinium revealed enlargement of the intraorbital left optic nerve. The T2-weighted images showed hyperintensity of the optic nerve, retrobulbar fat, lacrimal gland, and pre- and post-septal soft tissues on the left side, consistent with infection or inflammation (Figure 5).

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Over the next 24 hours as the results of his infectious work-up were pending, the patient’s exam continued to worsen and his vision declined to light perception in the left eye. When the test results returned normal, he was started on 1 g of intravenous Solu-Medrol (methylprednisolone sodium succinate), and a left lacrimal gland biopsy was performed. The biopsy showed prominent lymphoplasmacytic infiltrates with focal germinal center formation and a mixed population of B and T cells, consistent with a diagnosis of idiopathic orbital inflammation.

Idiopathic orbital inflammation

Idiopathic orbital inflammation is a diagnosis of exclusion. The differential diagnosis should initially remain broad and include the categories of infection, inflammation and malignancy, including lymphoproliferative and metastatic disease. Classically, these patients describe an abrupt onset of symptoms with no history of sinusitis or systemic illness. The most common signs and symptoms include periocular pain (58% to 69%), edema (75% to 79%), extraocular muscle restriction (54%), proptosis (32% to 63%), eye redness (48%), diplopia (31% to 38%), conjunctival chemosis (29%), ptosis (17%) and decreased vision (21%). Findings are typically unilateral but more commonly bilateral in pediatric patients.

Figure 3. Cirrus OCT retinal nerve fiber layer analysis showing severe optic nerve and peripapillary thickening in the left eye.

Figure 4. Fluorescein angiography showing late peripapillary leakage in the left eye.

Imaging studies are not diagnostic but may be helpful, both to rule out other etiologies and for localization of the areas of inflammation. High-resolution CT is considered the modality of choice because of the important contrasts of orbital fat, muscle, bone and adjacent paranasal sinus cavities. However, MRI is superior when focusing on the soft tissue details of the optic nerve and cavernous sinus. Radiologic changes in idiopathic orbital inflammation may be characterized by normal-appearing sinuses with a diffuse orbital mass, uveoscleral thickening, contrast enhancement of Tenon’s potential space, proptosis, thickened extraocular muscles and optic nerve enlargement. The localization of these findings on imaging allows for classification into subtypes. More common findings of inflammation include dacryoadenitis (32% to 54%), myositis (10% to 50%) and scleritis (4%). Optic neuritis, perineuritis and cavernous sinus (Tolosa-Hunt syndrome) involvement are less common.

Figure 5. MRI of the orbits, axial view, showing enlarged intraorbital left optic nerve with hyperintensity of the optic nerve, orbital fat and soft tissues on the left side.

Figure 6. Color fundus photo of the left eye showing resolution of optic nerve edema with residual macular exudates after steroid therapy.

Biopsy and histopathologic analysis may aid in the diagnosis of idiopathic orbital inflammation. Pathologic findings are divided into three principal types: lymphoid, granulomatous and sclerosing. These classifications may be helpful with disease staging and prediction of treatment response.

Discussion

Idiopathic orbital inflammation, also known as nonspecific orbital inflammation, orbital inflammatory syndrome or orbital pseudotumor, was first described in 1905 by Birch-Hirschfeld. The term “inflammatory pseudotumor” was later applied by Umiker and colleagues in the 1950s because of its propensity to mimic malignant processes. The pathophysiology of idiopathic orbital inflammation is still not fully understood. Different hypothesis include infectious, post-infectious (possible association with recent streptococcal pharyngitis) and aberrant wound healing. An immune-mediated process has also been implicated, with one patient series reported by Mombaerts and colleagues describing 10% of patients having a concurrent autoimmune disease. Associations have been documented with Crohn’s disease, systemic lupus erythematosus, rheumatoid arthritis, myasthenia gravis, sarcoidosis, granulomatosis with polyangiitis and ankylosing spondylitis. Given these potential associations and varied clinical presentations, the recommended initial work-up for idiopathic orbital inflammation may include a complete blood count, metabolic panel, thyroid function tests, anti-nuclear antibodies, anti-neutrophil cytoplasmic antibodies, angiotensin-converting enzyme, rheumatoid factor and appropriate infectious testing.

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Appropriate management of these patients varies depending on severity and inflammation location. Swamy and colleagues suggest that observation may be appropriate in mild cases with a reported 20% of patients achieving remission at 6 months. In this series, it was suggested that patients who fail to improve or have worsening symptoms should be promptly started on systemic therapy. Systemic corticosteroids are considered the mainstay of therapy at a suggested dose of 1 mg/kg to 1.5 mg/kg for 1 to 2 weeks followed by a slow taper over 6 to 12 weeks. Patients often have a rapid and complete response with intravenous or oral steroids. Some clinicians have suggested that this rapid response may even help to confirm the diagnosis. It is important to recognize, however, that malignant etiologies may also improve in the short term with steroids. NSAIDs have not been formally evaluated for the treatment of idiopathic orbital inflammation but may be appropriate in patients with mild disease. Additional therapeutic options that are typically reserved for refractory cases include radiation, steroid-sparing chemotherapy (cyclosporine, tacrolimus, azathioprine, cyclophosphamide, methotrexate), IVIG, plasmapheresis and surgical resection.

Although there is limited support in the literature, locally administered steroid therapy may be a reasonable option if systemic therapy is not tolerated. Leibovitch and colleagues described 10 patients with biopsy-proven anterior idiopathic orbital inflammation who received intraorbital triamcinolone acetonide. In this small series, all patients had complete resolution at 9 months with four requiring repeat injections.

Despite the rapid response and resolution with steroids, recurrence is a significant challenge with an average rate of 30% to 52%. Yan and colleagues suggested that male gender and severe proptosis may be associated with a higher rate of recurrence. There does not seem to be any recurrence correlation with anatomic or pathologic classification status.

Biopsy can aid in the diagnosis of idiopathic orbital inflammation and allow for classification. The American Society of Ophthalmic Plastic and Reconstructive Surgery has suggested starting intravenous or oral corticosteroids first in highly suspected cases. If there is an inadequate response by 1 to 2 weeks or a recurrence during the steroid taper, biopsy should then be considered and the etiology reassessed.

Follow-up

The patient experienced symptomatic and visual improvement within 1 day of starting intravenous Solu-Medrol therapy. At his 2-month follow-up visit, optic nerve edema had resolved (Figure 6) and vision returned to 20/30 in the left eye.

References:
Yuen SJA, et al. Arch Ophthalmol. 2003;doi:10.1001/archopht.121.4.491.
Berger JW, et al. Int Ophthalmol Clin. 1996;doi:10.1097/00004397-199603610-00017.
Char DH, et al. Ophthalmology. 1993;doi:10.1097/00041327-199406000-00030.
Chaudhry IA, et al. Middle East Afr J Ophthalmol. 2008;doi:10.4103/0974-9233.53370.
Chavis RM, et al. Arch Ophthalmol. 1978;doi:10.1001/archopht.1978.03910060329006.
Ding ZX, et al. Clin Radiol. 2011;doi:10.1016/j.crad.2011.03.018.
Francis IX, et al. Ophthalmology. 2001;doi:10.1016/S0161-6420(01)00655-8.
Fujii H, et al. Ophthalmologica. 1985;doi:10.1159/000309523.
Garner A. Br J Ophthalmol. 1992;doi:10.1136/bjo.76.1.47.
Harris GJ. Ophthal Plast Reconstr Surg. 2006;doi:10.1097/01.iop.0000203734.52333.93.
Jacobs D, et al. Curr Opin Ophthalmol. 2002;doi:10.1097/00055735-200212000-00001.
Leibovitch I, et al. Arch Ophthalmol. 2007;doi:10.1001/archopht.125.12.1647.
Leone CR, et al. Ophthalmology. 1985;doi:10.1016/S0161-6420(85)33854-x.
Mombaerts I, et al. Ophthalmology. 1996;doi:10.1016/S0161-6420(96)30663-5.
Narla LD, et al. Radiographics. 2003;doi:10.1148/rg.233025073.
Serop S, et al. Acta Ophthalmol. 1994;doi:10.1111/j.1755-3768.1994.tb02807.x.
Smith JW. Am J Gastroenterol. 1992;87(3):405-406.
Swamy BN, et al. Br J Ophthalmol. 2007;doi:10.1097/IEB.0b013e31816c41de.
Umiker WO, et al. J Thorac Surg. 1954;28(1):55-63.
Van de Mosselaer G, et al. Arch Ophthalmol. 1980;doi:10.1001/archopht.1980.01020040473016.
Yan J, et al. Yan Ke Xue Bao. 2007;23(1):58-64.

For more information:
Bradley Hansen, MD, and Laurel Vuong, MD, can be reached at New England Eye Center, Tufts University School of Medicine, 750 Washington St., Box 450, Boston, MA 02111; website: www.neec.com.
Edited by Kristen E. Dunbar, MD, and Kendra Klein, MD. They can be reached at the New England Eye Center, Tufts University School of Medicine, 750 Washington St., Box 450, Boston, MA 02111; website: www.neec.com.