A 55-Year-Old Woman With Orbital Inflammation
PASCALE SCHWAB,1DAVID HARMON,2RICHARD BRUNO,2FREDERICK W. FRAUNFELDER,2AND
DONNA HYUNCHUNG KIM2
History of the present illness
A 55-year-old woman presented to the emergency depart-
ment for a 2-day history of progressive right eye pain,
redness, and swelling. She denied antecedent trauma, si-
nus congestion, rhinorrhea, diplopia, diminished vision,
headache, fevers, or chills. Extraocular movements wors-
ened her pain. She had recently been diagnosed with
postmenopausal osteoporosis and received her first infu-
sion of zoledronic acid by her rheumatologist 4 days prior
to symptom onset. A review of systems was otherwise
Her medical history included well-controlled type 1 dia-
betes mellitus with proliferative diabetic retinopathy re-
quiring panretinal photocoagulation laser treatment, pri-
mary hypothyroidism, osteoarthritis, gastroesophageal
reflux disease, gastroparesis, and postmenopausal osteo-
porosis of the hip and lumbar spine. Due to her gastroin-
testinal comorbidities, her rheumatologist had treated her
with an intravenous (IV) bisphosphonate rather than an
oral bisphosphonate. Medications additionally included
insulin, cetirizine, levothyroxine, probiotic, calcium, and
vitamin D, as well as metoclopramide and antiemetics as
Social and family history
She denied tobacco, alcohol, or illicit drug use and worked
as a telephone dispatcher. Her mother and sister had os-
Vital signs showed a temperature of 36.8°C, a blood pres-
sure of 149/77 mm Hg, and a pulse of 75 beats/minute. She
appeared alert, oriented, and in no distress. A head and
neck examination revealed markedly swollen, tender, and
erythematous right periorbital soft tissue, diffuse clear
conjunctival chemosis, and restricted ocular motility (Fig-
ure 1). Eyelid fluctuance and crepitus were absent. Visual
acuity was 20/20 bilaterally. Pupils were 3–4 mm and
without afferent defect. The remainder of the ophthalmo-
logic examination was normal, aside from bilateral pan-
retinal photocoagulation scars. No lymphadenopathy was
found. The remainder of her examination was normal.
Laboratory and radiologic evaluations
Admission laboratory values are listed in Table 1. A com-
plete blood count and differential cell count were normal.
Renal function was normal at baseline. Blood glucose was
mildly elevated. Ionized calcium was expectedly low fol-
lowing an IV bisphosphonate infusion. Blood cultures
were drawn. An orbital computed tomography (CT) scan
with IV contrast (Figure 2) revealed diffuse inflammatory
stranding within the right retrobulbar fat and thickening of
the right posterior sclera and preseptal soft tissue inferi-
orly. The paranasal sinuses contained no fluid collection
or evidence of subperiosteal abscess.
The patient is a 55-year-old woman with well-controlled
type 1 diabetes mellitus, diabetic retinopathy, gastro-
esophageal reflux, gastroparesis, and postmenopausal os-
teoporosis who presented with a 2-day history of nontrau-
matic unilateral eye pain associated with periorbital
edema, chemosis, and restricted extraocular movements.
She had no associated fevers, leukocytosis, or clinical or
radiographic evidence of sinusitis.
The clinical presentation of acute-onset, progressive uni-
lateral periocular edema, chemosis, and ocular motility
restriction raises concern for an orbital inflammatory pro-
1Pascale Schwab, MD: Oregon Health and Science Uni-
versity and Portland VAMC, Portland;2David Harmon, MD,
MPH, Richard Bruno, BA, Frederick W. Fraunfelder, MD,
Donna Hyunchung Kim, MD: Oregon Health and Science
Address correspondence to Pascale Schwab, MD, Division
of Arthritis and Rheumatic Diseases, Oregon Health and
Science University, Portland Veterans Affairs Medical Cen-
ter, 3181 SW Sam Jackson Park Road OP09, Portland, OR
97239. E-mail: firstname.lastname@example.org.
Submitted for publication March 14, 2012; accepted in
revised form August 1, 2012.
Arthritis Care & Research
Vol. 64, No. 11, November 2012, pp 1776–1782
© 2012, American College of Rheumatology
cess. CT or magnetic resonance imaging (MRI) is helpful
for discerning whether orbital inflammation is diffuse or
localized to a specific tissue type within the orbit, as in the
case of dacryoadenitis (lacrimal gland) or myositis (extra-
ocular muscle). Our patient exhibited radiographic find-
ings of diffuse orbital inflammation, which in adults can
arise from a number of conditions, including infectious,
inflammatory, thyroid, neoplastic, traumatic, or idiopathic
etiologies (1,2) (Table 2).
Orbital cellulitis should first be excluded because it can
Figure 1. The patient’s initial appearance shows eyelid swelling,
erythema, ptosis, and chemosis.
Table 1. Laboratory results*
Ionized calcium, mmoles/liter
* WBCs ? white blood cells; BUN ? blood urea nitrogen.
Figure 2. Computed tomography scan of the head on day 1 shows
diffuse inflammatory stranding within the right retrobulbar fat,
mild posterior scleritis, and mild preseptal soft tissue thickening
Table 2. Differential diagnosis of orbital
Granulomatosis with polyangiitis (Wegener’s)
Giant cell arteritis
Bacterial (Staphylococcus, Streptococcus)
Fungal (Mucormycosis, Aspergillus)
Viral (herpes zoster)
* Adapted, with permission, from ref. 1.
cause irreversible visual compromise and life-threatening
complications. It often presents acutely in the setting of
antecedent periocular skin trauma or underlying sinus
disease and is accompanied by fever and leukocytosis.
Bacteria such as Staphylococcus or Streptococcus are the
most common causes, although fungi such as Mucormy-
cosis or Aspergillus should be considered, particularly
in hosts with poorly controlled diabetes mellitus, renal
transplantation, or chronic immunosuppression (3). Viral
causes such as herpes zoster have been reported, but are
rare (4). Although this patient lacked typical infectious
features such as fever, leukocytosis, or sinus disease, the
possibility of a bacterial orbital cellulitis could not be
excluded entirely and initially prompted empirical broad-
spectrum antibiotics. Fungal infection was less likely in
the absence of underlying sinus disease or poor glycemic
Systemic inflammatory conditions such as sarcoidosis
may present with acute diffuse orbital inflammation. Clin-
ical features of sarcoidosis are variable and include pul-
monary, hematologic, skin, musculoskeletal, neurologic,
endocrine, and ophthalmic manifestations. Ophthalmic
disease occurs in up to 50% of cases and is the presenting
symptom in a subset of patients (5). Orbital involvement is
characterized by insidious bilateral lacrimal gland enlarge-
ment and rarely by unilateral diffuse orbital inflammation.
Hilar adenopathy supports the diagnosis, which is usually
confirmed by lymph node or conjunctival biopsies (6).
Diffuse orbital inflammation can be a manifestation of a
small- to medium-vessel vasculitis, particularly granulo-
matosis with polyangiitis (Wegener’s) (GPA) (2). GPA is a
pulmonary disease and pauciimmune glomerulonephritis.
Ocular involvement occurs in 25–50% of patients and
manifests as scleritis, episcleritis, or uveitis. Diffuse or-
bital involvement is less common and often spreads from
contiguous sinus granulomatous inflammation, although it
may also originate in the orbits. Diagnosis is based on
systemic clinical features and demonstration of vasculitis
bodies to proteinase 3 are highly specific for GPA, but a
negative test should not exclude this diagnosis, especially
in patients with limited disease that spares the lungs or
kidneys (8). Systemic causes of orbital inflammation typi-
cally present with additional extraorbital findings that
help elicit the diagnosis. Our patient presented with iso-
lated orbital inflammation, a normal examination, and an
unremarkable review of systems.
Thyroid orbitopathy, which is characteristically bilat-
eral, is nonetheless the most common cause of unilateral
proptosis in adults. Lid retraction is the most common
early clinical finding, whereas more advanced disease can
lead to proptosis, ocular motility restriction, exposure
keratopathy, and compressive optic neuropathy (9,10). CT
or MRI typically shows orbital adipose changes and fusi-
form enlargement of the inferior, medial, and superior
rectus muscles that spares the tendon insertions (11). Al-
though acute exacerbations are possible, thyroid orbitopa-
thy typically follows a chronic course (9,10). Our patient’s
presentation was rapidly progressive and lacked the char-
acteristic radiographic features.
Malignancy is an infrequent cause of orbital inflamma-
tion. Orbital lymphoma, uveal melanoma, and metastases
have been reported and follow an insidious clinical course
(12–14). CT or MRI and tissue biopsy are required for the
diagnosis. Treatment is largely directed at the underlying
Traumatic orbital fractures and subsequent edema and
retrobulbar hemorrhage can cause significant proptosis,
hemorrhagic chemosis, ocular motility restriction, and op-
tic neuropathy, which mimic orbital inflammation. A his-
tory of trauma is essential and was not reported by our
Finally, idiopathic orbital inflammation (also known as
orbital pseudotumor) is a nonmalignant process that
should be considered in the absence of the aforementioned
etiologies. It is a diagnosis of exclusion based on clinical,
radiographic and, if necessary, histopathologic data. The
process can involve any orbital structure and usually pres-
ents with abrupt-onset eye pain, swelling, proptosis, oph-
thalmoplegia, and redness (2).
The patient was admitted to the hospital. Intravenous
ampicillin/sulbactam and vancomycin were started due to
Figure 3. A photograph taken within 24 hours of the second dose
of intravenous methylprednisolone shows resolved right eye or-
1778 Schwab et al
concern for orbital cellulitis. Her temperature and leuko-
cyte count remained normal. Serum blood glucose aver-
aged at 183 mg/dl during the admission. Bacterial and
fungal blood cultures revealed no growth.
Over the next 48 hours, her condition worsened. Her
extraocular movements became restricted. Repeat orbital
CT showed increased orbital fat stranding and inflamma-
tory changes of the right extraocular muscles, posterior
sclera, and optic nerve sheath.
In the absence of sinusitis or systemic symptoms, the
diagnosis of idiopathic orbital inflammation or “orbital
pseudotumor” was considered. A literature review re-
vealed several cases of bisphosphonate-associated acute
orbital inflammation whose features resembled those of
our patient. IV methylprednisolone 1 gm was adminis-
tered based on reported benefits in published similar
cases. The patient’s eye pain and swelling improved dra-
matically over the subsequent hours. A second dose was
given the following day with further improvement (Figure
3). Antibiotics were discontinued 4 days after their initia-
tion, and the patient was discharged on a 3-week predni-
sone taper (initial dosage 60 mg/day). Followup ophthal-
mologic examinations 1 and 5 weeks later (the latter after
completion of the steroid taper) demonstrated no residual
Ophthalmic complications of oral and IV bisphosphonates
have been well described in clinical trials and postmarket-
ing surveillance. They range from eye pain (in 2% of
patients) to ocular inflammation, including conjunctivitis,
scleritis, episcleritis, and uveitis (in 0.1–0.2% of patients)
(15–17). Acute, diffuse orbital inflammation that mimics
orbital cellulitis via proptosis, conjunctival chemosis, pos-
terior scleritis, and ophthalmoplegia, however, has been
We performed a PubMed search using the terms “orbital
inflammation” and “bisphosphonate” together, reviewed
all references of pertinent articles, and identified 17 cases
of acute bisphosphonate-induced orbital inflammation
published in the English literature (18–32) (Table 3). We
also garnered additional cases from the National Registry
Table 3. Summary of cases of bisphosphonate-induced diffuse orbital inflammation (including
the current study)
Case characteristics (n ? 17)
Age, range years
Skeletal metastases or multiple myeloma (7)
Paget’s disease of bone (2)
Charcot joint (1)
Knee osteonecrosis (1)
?1 to 6*
Bisphosphonates given (no.)
Time from exposure to onset of eye
manifestations, range days
Systemic symptoms, no. (%)
Bilateral involvement, no. (%)
Systemic antibiotics given, no. (%)
Systemic steroids given, no. (%)
Rechallenge with bisphosphonates, no. (%)
Ocular symptoms, no. (%)
Ocular signs, no. (%)
Afferent pupillary defect
* Two cases with onset 10 days and 3 weeks post–alendronate initiation.
† Three of 4 patients experienced recurrent orbital inflammation upon rechallenge.
of Drug-Induced Ocular Side Effects (www.eyedrug
registry.com) located at the Casey Eye Institute in Port-
land, Oregon. There were no other reports of bisphospho-
nate-induced diffuse orbital inflammation. Patients were
ages 55–89 years and received a bisphosphonate for ap-
proved indications such as bony metastases, multiple my-
eloma, osteoporosis, and Paget’s disease of bone, as well as
for off-label uses, including osteonecrosis and Charcot
joint. The majority of the patients received an IV amino-
bisphosphonate (either pamidronate or zoledronic acid)
(19–32). Two patients received oral alendronate (18). In
cases of IV bisphosphonate exposure, symptoms began
within hours up to 6 days following drug administration
(19–32); cases involving oral alendronate presented 10
days and 3 weeks after drug initiation (18). Systemic
symptoms were present in one-third of patients (18–
20,23,27,29,32). Ophthalmic symptoms primarily in-
cluded unilateral eye pain (89%) (18–30,32), diplopia
(50%) (18–21,23,27,31), and
(19,24,25,27,29,32). Ophthalmic signs included lid edema
(94%) (18,20–32), conjunctival hyperemia (83%) (18,20–
32), conjunctival chemosis (78%) (19–29,31,32), motility
defect (61%) (18–21,23,24,27,29,31,32), proptosis (50%)
(19,22–24,26,28,31,32), anterior uveitis (22%) (18,23,
25,32), fundus abnormalities (17%) (18,22,25), and an af-
ferent pupillary defect (17%) (19,24,25). Orbital imaging,
when available, revealed pre- and/or postseptal fat strand-
ing, extraocular muscle inflammation, and scleral thicken-
ing. Antibiotics were administered to 6 of 18 patients
without symptomatic improvement (19,22,24,29,30). All
but 2 patients required treatment with systemic steroids
(21,29), which improved symptoms. In most cases, the
bisphosphonate was discontinued. One patient who was
continued on alendronate experienced recurrent symp-
toms upon discontinuation of systemic steroids (18). A
second patient who had received zoledronic acid was
switched to pamidronate and experienced mild conjunc-
tivitis and hyperemia (22), but experienced no further
symptoms after repeated dosing and steroid pretreatment.
A third patient experienced recurrent eye symptoms on
repeated pamidronate infusion; these resolved spontane-
ously (21). A fourth patient continued on monthly zole-
dronic acid without symptom recurrence (23).
The Naranjo algorithm is a validated tool designed to
assess the likelihood of an adverse drug reaction and cat-
egorizes associations as doubtful, possible, probable, or
definite (33). Bisphosphonate-induced orbital inflamma-
tion in our patient’s case is possible or probable based on
the temporal relationship to drug administration, lack of a
clear alternate explanation, and similar case reports in the
literature. Although a rechallenge with zoledronic acid
and subsequent reoccurrence of orbital symptoms would
have strengthened the association and would have sup-
ported causality, the severity of the patient’s presentation
precluded this test.
A recent case–control study of 69 patients presenting
with their first episode of idiopathic orbital inflammation
between 2000 and 2006 and compared to 296 adult con-
trols with retinal detachment found an increased risk of
orbital inflammation in users of an oral bisphosphonate
(odds ratio 8.68, 95% confidence interval 1.16–65) (34), a
finding that further adds support to this association.
Bisphosphonates, specifically IV aminobisphosphonates,
have been associated with an acute-phase reaction (APR)
characterized by fever, musculoskeletal pain, gastrointes-
tinal symptoms, eye inflammation, and fatigue. A recent
detailed analysis of the adverse events recorded in the
Health Outcomes and Reduced Incidence with Zoledronic
Acid Once Yearly pivotal fracture trial, which compared
IV zoledronic acid to placebo for the treatment of post-
menopausal osteoporosis, reported a 42% rate of APRs in
the treatment arm compared to 11% in the placebo group.
Ninety percent of the APRs were rated as mild to moder-
ate, and 0.6% in the treatment arm had eye pain or inflam-
mation compared to 0.1% in the placebo group (35). Fever
following bisphosphonate infusion has been associated
with a release of cytokines, specifically interleukin-6
and tumor necrosis factor ?, that results from activation of
?/? T cells via inhibition of farnesyl diphosphate synthase
Aminobisphosphonates such as pamidronate and zole-
dronic acid inhibit the osteoclast cholesterol synthesis
pathway and induce osteoclast apoptosis, thereby de-
creasing bone resorption. Specifically, these drugs inhibit
farnesyl diphosphate synthase and the subsequent forma-
tion of lipid side chains required for GTP binding protein
localization to the osteoclast cell membrane. This causes
accumulation of the lipid side chain precursors, isopentyl
pyrophosphate (IPP) and
which are potent activators of ?/? T cells. In vitro treat-
ment of peripheral blood cells with zoledronic acid results
in the accumulation of these precursors in monocytes,
which in turn have been shown to activate ?/? T cells via
direct cell contact (39).
Interestingly, in vitro studies have shown that hy-
droxymethylglutaryl-coenzyme A reductase inhibitors co-
administered with bisphosphonates attenuate ?/? T cell
activation by blocking IPP formation (40). Subsequent
clinical trials failed to demonstrate benefits of statins over
placebo in the prevention of bisphosphonate-induced
APR, however, and may be a consequence of the strong
first pass hepatic metabolism of statins (41,42). Fortu-
nately, the incidence of APRs decreases with subsequent
bisphosphonate infusions, an effect not due to patient
dropout (41). The severity of APRs may also be reduced in
patients pretreated with acetaminophen (35,41).
We speculate that this and other similar cases of dra-
matic post–bisphosphonate orbital inflammation repre-
sent an extreme APR phenomenon. It is unclear why the
orbital tissue is uniquely susceptible. While most APRs
resolve after a few days, only 2 of 18 orbital inflammation
cases were self-limited (21,29). Systemic glucocorticoids
were rapidly effective in all reported cases. A placebo-
controlled study to determine the efficacy of glucocorti-
coids is not feasible, however, due to the extremely low
incidence of this complication. Consequently, treatment
will likely remain anecdotal. Route and dose of glucocor-
ticoids should be individualized based on severity of or-
bital findings and concerns of optic nerve compromise.
Finally, it is unknown if patients already taking glucocor-
1780Schwab et al
ticoids have a reduced risk of ophthalmic adverse events
after bisphosphonate exposure.
Rheumatologists should be aware of the bisphospho-
nates’ potential ophthalmic adverse effects and should
educate their patients accordingly. Patients who develop
otherwise unexplained recurrent or recalcitrant uveitis,
episcleritis, or scleritis during oral bisphosphonate ther-
apy should discontinue the drug. Early recognition of or-
bital inflammation after IV bisphosphonate exposure may
prevent unnecessary invasive procedures or antibiotic ex-
posure and may expedite treatment with glucocorticoids.
Although several patients in the literature were rechal-
lenged with an IV bisphosphonate and experienced no
recurrence (23), mild recurrence with steroid pretreatment
(22), or even self-limited recurrence (21), most cases were
severe and a few were vision threatening (19,24,25). We
therefore suggest avoidance of bisphosphonate rechallenge
unless absolutely necessary, such as in the treatment of
painful bony metastases. With osteoporosis treatment, cli-
nicians should consider alternative therapies.
The authors would like to thank Dr. Jim Rosenbaum for his
helpful review of the manuscript.
All authors were involved in drafting the article or revising it
critically for important intellectual content, and all authors ap-
proved the final version to be published. Dr. Schwab had full
access to all of the data in the study and takes responsibility for
the integrity of the data and the accuracy of the data analysis.
Study conception and design. Schwab, Harmon, Bruno.
Acquisition of data. Schwab, Harmon, Bruno, Kim.
Analysis and interpretation of data. Schwab, Harmon, Fraun-
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1782 Schwab et al