Woman presents with worsening pain, redness in right eye
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A 68-year-old woman presented to the Lahey Clinic emergency room with worsening pain, swelling and redness in her right eye.
The patient was in a normal state of health until 3 days before presentation when she noticed increased tearing of the right eye. The following morning, she had right upper and lower eyelid swelling in addition to right eye conjunctival injection. She presented to an urgent care at this time where she was diagnosed with conjunctivitis and started on erythromycin ointment. However, by that evening, her symptoms worsened to the point at which she was having difficulty opening her eyelids. She had also developed blurry vision, binocular double vision and pain worse with eye movements. She also reported new-onset right-sided sinus pressure at this time.
The patient’s ocular history was notable only for presbyopia. She was not on any ophthalmic medications. Her medical history included hypertension, hyperlipidemia, osteoporosis, stage 1 breast cancer status post excisional biopsy and partial mastectomy 5 years prior, anxiety and depression. Her medications included losartan, zoledronate, vitamin D3 and acetaminophen as needed. Her family history was significant for congestive heart failure in her father and hypertension in her brother. There was no known family history of ocular disease. She was a retired high school teacher, never smoked and drank alcohol only occasionally. Her allergies included atenolol (fatigue), lisinopril (fatigue) and codeine (hallucinations). Her review of systems was unremarkable, except for right-sided sinus pressure.
Examination
Best corrected visual acuity was 20/60 in the right eye and 20/20 in the left eye. Pupils were equal in size and briskly reactive to light with no afferent pupillary defect. IOP was 17 mm Hg in both eyes, with full confrontation visual fields. Color vision using Ishihara color plates was full in both eyes. Extraocular motility was restricted in the right eye (–0.5 on abduction, –1 on adduction and –1 on supraduction) and was full and painless in the left eye. When assessing for proptosis with the Hertel exophthalmometer, the right eye was noted to have 2 mm of proptosis compared with the left eye. External exam noted 1+ right upper lid edema and erythema, upper lid ptosis with 0.5 mm lagophthalmos and mild proptosis (Figure 1).
Source: Kate V. Dennett, MD, Geetha Athappilly, MD, and Sarkis Soukiasian, MD
Slit lamp examination noted 2+ diffuse conjunctival chemosis with trace injection in the right eye, trace inferior punctate epithelial erosions of the right cornea, deep and quiet anterior chambers bilaterally, flat iridis and 1+ nuclear sclerotic cataracts. Posterior segment examination demonstrated bilateral posterior vitreous detachments, pink and healthy optic nerves with a cup-to-disc ratio of 0.6, flat maculae, vessels of normal course and caliber, and a flat and attached retinal periphery bilaterally.
CT of the orbits was obtained, which demonstrated prominent right-sided conjunctival edema and abnormal fat stranding along the inferior aspect of the right superior muscle complex and along the posterosuperior margin of the globe, interpreted by radiology to be consistent with orbital cellulitis (Figure 2). There were no signs of sinusitis, with only minimal mucosal thickening. MRA/MRV of the head did not show ophthalmic vein or cavernous sinus thrombosis, and there was no evidence of a carotid-cavernous fistula. MRI of the brain and orbits showed right-sided periorbital soft tissue swelling, conjunctival edema and postseptal inflammatory changes, including edema and enhancement along the posterior scleral margin, along the optic nerve sheath, throughout the intraconal fat and involving the anterior aspect of the right superior muscle complex (Figure 3). There was no enlargement of the extraocular muscles and no evidence of an orbital abscess or orbital mass.
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Motility restriction, proptosis
The patient’s presentation was notable for unilateral decreased vision, extraocular motility restriction, proptosis with eyelid edema and erythema, and significant conjunctival chemosis. The differential diagnosis for this presentation fell into three main categories: infectious, noninfectious inflammation and vascular.
From an infectious etiology, orbital cellulitis, less common than preseptal cellulitis, is a true ophthalmic emergency with the potential to cause orbital compartment syndrome and irreversible vision loss. Clinical manifestations are like our patient’s presentation and may include eye pain, eye pain with movement and/or ophthalmoplegia if there is involvement of extraocular muscles or cranial nerves, proptosis, eyelid erythema and edema. Visual acuity may also be decreased. Orbital cellulitis often develops from contiguous spread of sinus infection, which was concerning as our patient reported right-sided sinus pressure; however, there was no sinusitis present on imaging. In addition, the patient denied any infectious risk factors including recent infections or immunosuppression.
Noninfectious orbital inflammation is the most common cause of painful orbital mass in adults and the third most common orbital disease after thyroid eye disease and orbital lymphoma. Clinically, it can present almost identically to orbital cellulitis if diffuse, as seen in our patient. If more localized, it can affect the extraocular muscles, lacrimal gland, sclera, uvea, superior orbital fissure and cavernous sinus (Tolosa-Hunt syndrome). Orbital inflammation may be caused by a specific etiology such as IgG4-related disease or granulomatous disease, such as sarcoidosis or granulomatosis with polyangiitis, or it may be idiopathic, which is a diagnosis of exclusion.
The patient’s presentation may also be of a vascular etiology, such as a fistula or venous sinus thrombosis; however, the patient denied any symptoms of headaches, tinnitus or head trauma, and MRA/MRV of the head was unremarkable.
Workup and management
The patient was diagnosed with orbital cellulitis vs. orbital inflammation and was started on intravenous ampicillin/sulbactam, to which she reported significant subjective improvement in symptoms after receiving the first dose in the emergency department. However, on reevaluation the next day, she reported worsening overnight of blurred vision and eyelid swelling. Clinically, exam noted decreased visual acuity in the right eye to 20/400 (20/100 with pinhole), continued extraocular motility restrictions, worsening diffuse conjunctival chemosis, new central Descemet’s folds with mild stromal edema and new rare anterior chamber cell in the right eye. Complete blood count was within normal limits, including the white blood cell count, and she remained afebrile.
Given that the patient worsened while on broad-spectrum antibiotics, her presentation was then presumed to be secondary to an orbital inflammatory process rather than cellulitis. Further lab workup was obtained, including angiotensin converting enzyme, lysozyme, IgG-4, QuantiFERON Gold, treponemal antibody, anti-neutrophilic cytoplasmic antibody, antinuclear antibody and Lyme antibody, all of which were negative and within normal limits. Upon further questioning, the patient reported having her first intravenous infusion of Reclast (zoledronate, Novartis) for osteoporosis 1 day before symptom onset. Thus, it was determined that perhaps her orbital inflammatory process was secondary to zoledronate.
Discussion
Bisphosphonates are a class of medications used in the management of bone disorders, including osteoporosis, Paget’s disease, bone metastasis and bone disease in multiple myeloma. Bisphosphonates inhibit osteoclast-induced bone resorption. With the current aging population, there has been an increase in the indication and usage of this class of medications. Of the two classes of bisphosphonates, the newer aminobisphosphonates that have a nitrogen side chain (zoledronate, risedronate and alendronate) are linked with inducing orbital inflammation. At a molecular level, they are associated with gamma-delta T-cell activation, releasing cytokines (IL-1, IL-6) and inflammatory mediators, resulting in a potential transient acute phase reaction in patients who receive intravenous bisphosphonate therapy. This reaction typically lasts 24 to 72 hours and is characterized by fever, myalgia and arthralgia. Clinical trials of intravenous zoledronate suggest that approximately one in three patients experiences such a reaction with the first infusion. However, this incidence was found to decline progressively with subsequent infusions. Although less common, this reaction may occur with oral bisphosphonates as well. The non-aminobisphosphonates do not exhibit this activation.
Overall, this acute phase reaction is thought to contribute to the development of orbital and ocular inflammation. The most common signs are conjunctivitis and anterior uveitis, but they can also include periorbital edema, ptosis, scleritis, isolated cranial nerve palsy, superior rectus-levator complex inflammation and retrobulbar optic neuritis. The incidence ranges from 0.046% to 1%. The majority of bisphosphonate-associated orbital inflammation cases were found to have zoledronate as the causative bisphosphonate, as it has the highest potency and is more widely used, shown to be effective in once-yearly dosing for osteoporosis. The mean age of presentation in bisphosphonate-associated orbital inflammation is 67 years old with a female predominance, and mean symptom onset is 2.9 days after infusion. Concomitant anterior uveitis was reported in 30% of cases, as was bilateral involvement. This is an important point and potential distinguishing factor, as anterior uveitis and/or bilateral involvement can be, but are not typically, seen in idiopathic orbital inflammation. In oral bisphosphonate use, the mean time to symptom onset was found to be longer, approximately 19.7 days after use, reflecting the slower onset of drug action.
In a 2017 case report with associated literature review, Umunakwe and colleagues described a patient seen at Vanderbilt Eye Institute who presented with unilateral orbital and ocular inflammation, including ptosis, scleritis, Descemet’s folds, posterior synechiae and anterior uveitis with a layered hypopyon and hyphema, which began 12 hours after receiving an initial zoledronate infusion. This appears to be the only reported case describing corneal inflammation, which was also present in our patient.
Cases in the literature report varying management strategies for future bisphosphonate use after an episode of orbital inflammation. These strategies include discontinuation of the medication, switching to a different class of bisphosphonate, prophylactic steroids before infusion and re-challenging without prophylactic steroids. Overall, it appears that the development of orbital inflammation does not necessarily preclude patients from receiving subsequent bisphosphonate treatments, as there are reported cases in which patients have not developed reaction with re-challenge (with and without steroid prophylaxis). However, the importance of further investigation in this area should be emphasized, as treatment despite an episode of orbital inflammation may be clinically significant, such as in cases of multiple myeloma and bone metastasis.
Clinical course continued
Intravenous ampicillin/sulbactam was discontinued, and the patient was started on oral prednisone 80 mg daily with prednisolone eye drops four times per day in the right eye. Due to right optic nerve sheath inflammation present on imaging, she was monitored closely to ensure there was no optic nerve decompensation clinically. Subjectively, the patient reported remarkable improvement in symptoms after 1 day of oral prednisone. Exam was overall improved as well, with a best corrected visual acuity of 20/60 noted with pinhole, as well as decreased eyelid edema and chemosis and improving Descemet’s folds and stromal edema. She was ultimately discharged on oral prednisone. The patient’s endocrinologist, who prescribed her zoledronate, was also contacted and informed of our findings.
The patient was evaluated in the clinic 1 week after discharge, with significant subjective and clinical improvement. Visual acuity in the right eye was 20/20, with minimal periorbital swelling and conjunctival injection (Figure 4). The cornea was clear, and there was no anterior chamber reaction. At the 1-month follow-up visit, vision remained 20/20, the exam was unremarkable, and the patient continued an oral prednisone taper.
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- For more information:
- Kate V. Dennett, MD, Geetha Athappilly, MD, and Sarkis Soukiasian, MD, can be reached at New England Eye Center, Tufts University School of Medicine, 800 Washington St., Box 450, Boston, MA 02111; website: www.neec.com.
- Edited by Allison V. Coombs, DO, MS, and Nisha S. Dhawlikar, MD, MPH. They can be reached at New England Eye Center, Tufts University School of Medicine, 800 Washington St., Box 450, Boston, MA 02111; website: www.neec.com.