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JAMA Ophthalmology Clinical Challenge
December 22, 2016

Recalcitrant Orbital Pain in a 50-Year-Old Woman

Author Affiliations
  • 1Department of Ophthalmology, University of California–San Francisco, San Francisco
JAMA Ophthalmol. Published online December 22, 2016. doi:10.1001/jamaophthalmol.2016.3783

A 50-year-old woman presented to the emergency department for 3 months of right orbital pain. Her medical history was noncontributory. Examination revealed a right afferent pupillary defect, visual acuity of hand motion OD and 20/30 OS, full extraocular movements, and bilateral retinal dot blot hemorrhages. Magnetic resonance imaging (MRI) showed enhancement along the right intracanalicular optic nerve and adjacent sinuses (Figure). Glycosylated hemoglobin level was elevated at 10.3% (to convert to proportion of total hemoglobin, multiply by 0.01). Workup results for sarcoidosis, IgG4-related disease, seropositive and seronegative arthropathies, human immunodeficiency virus, tuberculosis, syphilis, Epstein-Barr virus, and herpes simplex virus types 1 and 2 were negative.

T1 fat-suppressed postgadolinium magnetic resonance imaging. A, Contrast enhancement centered on the right intracanalicular optic nerve (blue arrowhead), involving right orbital apex and posterior ethmoidal sinus (white arrowhead). B, Enhancement encircling right optic nerve (arrowhead).

T1 fat-suppressed postgadolinium magnetic resonance imaging. A, Contrast enhancement centered on the right intracanalicular optic nerve (blue arrowhead), involving right orbital apex and posterior ethmoidal sinus (white arrowhead). B, Enhancement encircling right optic nerve (arrowhead).

Orbital apex and sinus biopsy revealed acute and chronic inflammation without neoplasm or microorganisms. Specimen cultures grew methicillin-sensitive Staphylococcus aureus (MSSA). The patient was diagnosed as having type 2 diabetes and MSSA sino-orbital infection. She was discharged 10 days later with intravenous (IV) antibacterials, sitagliptin, insulin, and oral opiates.

The patient returned to the emergency department 2 weeks later with recurrent orbital pain. Although examination was stable, MRI showed increased apical enhancement. The diagnosis was revised to nonspecific orbital inflammation and the neurology department initiated a 3-day course of IV methylprednisolone. Pain rapidly resolved, repeated MRI showed reduced enhancement, and she was discharged with a prednisone taper.

Ten days later, the patient returned once again to the emergency department with pain. Although imaging was stable, examination revealed visual acuity of no light perception OD and new-onset right-sided third, fourth, and sixth cranial neuropathies.

Box Section Ref ID

What Would You Do Next?

  1. Repeat IV methyprednisolone with slower taper

  2. Initiate steroid-sparing immunomodulator

  3. Initiate broad-spectrum IV antibacterials

  4. Repeat biopsy of orbital apex and sinuses


Invasive sino-orbital aspergillosis

What to Do Next

D. Repeat biopsy of orbital apex and sinuses

Infectious, neoplastic, and inflammatory processes can cause painful infiltrative sino-orbital disease. This patient was first thought to have MSSA sino-orbital infection. Lack of improvement with antibiotics, combined with a 25% to 75% rate of S aureus nasal carriage in insulin-dependent patients,1 led to a revised diagnosis of nonspecific orbital inflammation. Although early clinical and radiologic improvements were noted after initiating corticosteroids, worsening pain and ophthalmoplegia eventually developed.

Failure of both antibiotic and corticosteroid therapies was inconsistent with initial biopsy yielding only nonspecific inflammatory cells and growth of MSSA nasal flora. Consequently, highly morbid pathologies, such as invasive fungal infection and malignancy, could no longer be eliminated with confidence. Repeating IV methylprednisolone or initiating a steroid-sparing immunomodulator could be lethal if fungal infection were present. Initiating broad-spectrum IV antibacterials would not address fungal or neoplastic processes in a patient with alarming symptoms. Therefore, the next appropriate step was a repeated biopsy of the orbital apex and sinuses.

Repeated biopsy revealed necrosis and invasive septate fungal hyphae, which was consistent with invasive sino-orbital aspergillosis (ISOA). Cultured specimens confirmed Aspergillus. Corticosteroids were immediately stopped and the patient was prescribed long-term systemic antifungal therapy. The final diagnosis was obtained 5 months after symptoms began.

Diagnosing invasive aspergillosis can be fraught with difficulty. One deceiving aspect is that immune strength does not necessarily correlate with infection. Given elevated glycosylated hemoglobin at presentation, this patient was immunocompromised and susceptible to fungal disease. However, infection worsened despite normalization of blood glucose, highlighting that ISOA can progress despite improving immune status. In fact, ISOA can occur in individuals with well-controlled diabetes and even entirely immunocompetent patients.24 Among 17 immunocompetent patients with ISOA reviewed by Sivak-Callcott et al,2 76% presented with severe headache, 41% received systemic steroids for presumed inflammatory conditions, and 71% eventually died of the infection. Lack of frank immunosuppression, especially when combined with a false-negative biopsy result, can lead to premature dismissal of ISOA. Clancy and Nguyen3 documented that, among 29 immunocompetent adults with ISOA, 21% had nondiagnostic cultures with pathology yielding only nonspecific inflammation. Reassuring histopathology and low clinical suspicion due to lack of immunosuppression resulted in a median 6-month duration from symptom onset to final diagnosis.3

Last, this case reinforces the notion that glucocorticoids can ameliorate neoplastic and infectious processes associated with inflammation.5 Although the immunosuppressive effects of steroids render them ultimately deleterious in sino-orbital fungal disease, even ISOA can transiently improve with steroids. Spoor et al6 documented a healthy woman presumed to have nonspecific orbital inflammation who showed rapid improvement in pain and visual acuity after initiating oral prednisone. Two weeks later, her clinical status regressed, inciting biopsy that revealed ISOA, which eventually proved to be fatal.

Patient Outcome

Although visual acuity remained no light perception OD, painful ophthlamoplegia resolved within 1 month of initiating antifungal therapy. After 6 months of treatment, despite supratherapeutic antifungal levels and normalized glycosylated hemoglobin, MRI revealed new enhancement along the right olfactory sulcus. This intracranial involvement is considered inoperable owing to proximity of the internal carotid artery.

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Article Information

Corresponding Author: Evan Kalin-Hajdu, MD, Department of Ophthalmology, University of California–San Francisco, 400 Parnassus Ave, San Francisco, CA 94143 (evan.kalin-hajdu@ucsf.edu).

Published Online: December 22, 2016. doi:10.1001/jamaophthalmol.2016.3783

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Additional Contributions: We thank the patient for granting permission to publish this information.

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Sivak-Callcott  JA, Livesley  N, Nugent  RA, Rasmussen  SL, Saeed  P, Rootman  J.  Localised invasive sino-orbital aspergillosis: characteristic features. Br J Ophthalmol. 2004;88(5):681-687.
Clancy  CJ, Nguyen  MH.  Invasive sinus aspergillosis in apparently immunocompetent hosts. J Infect. 1998;37(3):229-240.
Levin  LA, Avery  R, Shore  JW, Woog  JJ, Baker  AS.  The spectrum of orbital aspergillosis: a clinicopathological review. Surv Ophthalmol. 1996;41(2):142-154.
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